Accepted Manuscript Randomized Controlled Trials in Adult Traumatic Brain Injury: A Review of Compliance to CONSORT Statement Juan Lu , Kelli W. Gary , Al Copolillo , John Ward , Janet P. Niemeier , Kate L. Lapane PII:
S0003-9993(14)01280-5
DOI:
10.1016/j.apmr.2014.10.026
Reference:
YAPMR 56049
To appear in:
ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION
Received Date: 8 July 2014 Revised Date:
3 October 2014
Accepted Date: 31 October 2014
Please cite this article as: Lu J, Gary KW, Copolillo A, Ward J, Niemeier JP, Lapane KL, Randomized Controlled Trials in Adult Traumatic Brain Injury: A Review of Compliance to CONSORT Statement, ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION (2015), doi: 10.1016/ j.apmr.2014.10.026. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Running Title: Quality of RCT reports in TBI research
RI PT
Randomized Controlled Trials in Adult Traumatic Brain Injury: A Review of Compliance to CONSORT Statement
Juan Lu1, Kelli W. Gary2, Al Copolillo3, John Ward4, Janet P. Niemeier5, Kate L. Lapane6
3. 4. 5.
SC
EP
6.
M AN U
2.
Department of Family Medicine and Population Health, Division of Epidemiology, Virginia Commonwealth University, Richmond, VA, U.S.A. Email: [email protected]; Phone number: 8048289786 Department of Occupational Therapy, Virginia Commonwealth University, Richmond, VA, U.S.A. Email: [email protected]; Phone number: 8048283412 Department of Occupational Therapy, Virginia Commonwealth University, Richmond, VA, U.S.A. Email: [email protected]; Phone number: 8048282220 Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, U.S.A. Email: [email protected]; Phone number: 8048278400 Department of Physical Medicine and Rehabilitation, Carolinas Rehabilitation, 1100 Blythe Boulevard, Charlotte, NC, U.S.A. Email: [email protected]; Phone number:7043552046 Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA, U.S.A. Email: [email protected]; Phone number: 5088568999
TE D
1.
Juan Lu M.D., M.P.H., Ph.D.
AC C
Corresponding author: Address:
Email address: Phone number: Fax number:
Department of Family Medicine and Population Health, Division of Epidemiology, Virginia Commonwealth University, Richmond, VA, U.S.A. [email protected] 804 8289786 804 8289773
The authors report no declarations of interest. The work is supported by CTSA award No. UL1TR000058 from the National Center for Advancing Translational Sciences
1
ACCEPTED MANUSCRIPT
Abstract Objective: To describe extent to which adherence to Consolidated Standards of Reporting Trials (CONSORT) Statement in randomized controlled trials (RCTs) in adult traumatic brain injury
RI PT
(TBI) has improved over time. Data Sources: MedLine, PsycINFO and CINAHL databases were searched from inception to September, 2013.
SC
Study Selection: Primary report of randomized controlled trials in adult traumatic brain injury. The quality of reporting on CONSORT checklist items was examined and compared over time.
M AN U
Study selection was conducted by 2 researchers independently. Any disagreements were solved by discussion.
Data Extraction: Two reviewers independently conducted data extraction based on a set of structured data extraction forms. Data regarding the publication years, size, locations,
TE D
participation centers, intervention types, intervention groups and CONSORT checklist items were extracted from the including trials.
Data Synthesis: Of 105 trials reviewed, 38.1%, 5.7% and 32.4% investigated drugs, surgical
EP
procedures and rehabilitations as the intervention of interest, respectively. Among reports published between 2002-2010 (n=51) and 2011-September, 2013 (n=16), median sample size
AC C
was 99 and 118; 39.2% and 37.5% detailed implementation of randomization process; 60.8% and 43.8% of all reports provided information on method of allocation concealment; 56.9% and 31.3% stated how blinding was achieved; 15.7% and 43.8% reported information regarding trial registration and only 2.0% and 6.3% stated where full trial protocol could be accessed, respectively. Conclusions: Reporting of several important methodological aspects of RCTs conducted in adult TBI population improved over years; however, quality of reporting remains below an acceptable 1
ACCEPTED MANUSCRIPT
level. The small sample sizes suggest that many RCTs are likely underpowered. Further improvement is recommended in designing and reporting RCTS.
Randomized controlled trials – RCTs Traumatic brain injury - TBI
AC C
EP
TE D
M AN U
Consolidated Standards of Reporting Trials - CONSORT
SC
Abbreviations
RI PT
Key words: Randomized controlled trials, traumatic brain injury, CONSORT Statement
2
ACCEPTED MANUSCRIPT
1 2
Well-designed and properly conducted RCTs provide the most reliable evidence in health interventions. This, in turn, leads to improvement in the prevention or treatment of disease (1).
4
Many RCTs have been conducted with adequate methodological rigor to advance scientific
5
knowledge. The ability to evaluate and disseminate this knowledge directly rest on the
6
transparent and thorough reporting of trial methodology and findings. The lack of adequate
7
reporting influences readers’ interpretation of the evidence and makes it more difficult to
8
replicate the results for future research and follow recommended treatment options (2, 3). In
9
order to alleviate this problem, guidelines have been created to assist researcher, peer-reviewers
SC
M AN U
10
RI PT
3
and journal editors in complete reporting of RCTs.
The Consolidated Standards of Reporting Trials (CONSORT) Statement is a minimum
12
set of evidence-based recommendations designed to improve the quality of reporting RCTs. It
13
was initially published in 1996 (4), then revised twice subsequently in 2001 and 2010 (5, 6). The
14
revisions were each accompanied by a detailed explanation and elaboration document for the
15
purpose of enhancing the use, understanding, and dissemination of the Statement (7, 8). The
16
COSNORT provides structured guidance to help researchers prepare reports of trial findings,
17
facilitate complete and transparent reporting, and aid in critical appraisal and interpretation. The
18
most current version of the statement includes a 25 item checklist and a flow diagram. The
19
checklist provides standardized approaches to report the trial design, analysis and interpretation
20
and the diagram gives instructions to display the progress of all participants throughout the trial.
EP
AC C
21
TE D
11
Since the initial publication, the quality of clinical trial reporting has improved over the
22
years in general (9, 10) and in many medical specialties (11-13). However, far from satisfactory,
23
incompleteness and inaccurate reporting of trial results compounded with poor methodological
24
rigor remain a serious concern (10, 14-16). 3
ACCEPTED MANUSCRIPT
Thus far, there are limited assessments of CONSORT compliance and improved
26
reporting in randomized controlled trials (RCTs) in traumatic brain injury (TBI) literature. We
27
previously reported on 100 RCTs in adult TBI with the aims of synthesizing evidenced based
28
interventions and facilitating the effectiveness of interdisciplinary care (17). The current review
29
extends previous work by (1) examining the extent that these reports of RCTs adhere to the
30
CONSORT Statement and (2) assess whether the quality of reports has improved over time.
31
Methods
32
Study sample
SC
From our previous review (17), we searched databases of MedLine, PsycINFO and
M AN U
33
RI PT
25
CINAHL to identify all primary reports of RCTs in adult TBI populations through June 29th,
35
2011, using the search terms of ‘Traumatic Brain Injury or Brain Injury’ plus ‘Randomized
36
Controlled Trials or Randomised Controlled Trials’. Hand searches against published reviews
37
were also performed. Two authors independently assessed titles, abstract and full-texted articles
38
according the eligibility criteria. We excluded trials with (1) exclusive pediatric samples, (2)
39
acquired brain injury samples, unless the sample was predominantly TBI or the results were
40
reported separately for the TBI sample and met the search criteria, (3) a sample size less than 20,
41
(4) a focus on specific symptoms following TBI (e.g. elbow contractures, seizures, etc.), (5) a
42
focus on safety and pharmacokinetics solely, or (6) non-English languages. As a result, the
43
review selected 100 eligible studies, including 93 published RCT reports and seven studies with
44
unpublished results (18).
EP
AC C
45
TE D
34
For this review, we updated the initial research and further included 12 published RCT
46
reports up to September, 2013. After excluding seven studies with unpublished results from the
47
previous review, this review included a total of 105 RCT reports in adult TBI populations.
48
Data extraction 4
ACCEPTED MANUSCRIPT
49 50
Data extraction was carried out by three authors (J.L., A.E.C. and K.W.G.). For each article, at least two authors independently extracted data. To ensure the quality and consistency
52
of the data extraction, the process started with practice on the first ten reports reviewed, from
53
which authors extracted data based on a set of structured data extraction forms and discussed all
54
discrepancies. Most differences were due to differing interpretation of the data extraction form;
55
thus the form was modified and the exercise repeated using another ten articles until agreement
56
was reached for all data items listed on the form. Following the agreement on the data extraction
57
form, the same authors continued the process of data extraction and resolving discrepancies for
58
the remaining reports. The overall rater agreement on the assessment of checklist items is 96%.
59 60 61
CONSORT compliance
62
original 25 items, this study evaluated the items that can be assessed and compared objectively
63
across trials. The methodological items include: the use of the term ‘randomized trial’ in the title,
64
location of data collection, predefined primary outcome, sample size estimation, method of
65
randomization sequence generation, allocation concealment and implementation, who was blind
66
and how blinding was achieved, publication of a participant flow diagram, period of recruitment,
67
period of follow up, as well as the attrition due to loss to follow-up and intention to treat
68
analysis. Since more than half the trial reports in this review were published before CONSORT
69
revision in 2001 (5, 7), Table 1 provides methodological items and definitions used to assess
70
reporting of RCTs, and comparisons of these items in CONSORT versions 2001 and 2010. The
71
definitions were mainly adopted from Hopewell and colleagues (10) with some revision. In
72
addition, the information regarding the status of trial registration, accessibility of the full
M AN U
SC
RI PT
51
AC C
EP
TE D
We used the 2010 CONSORT reporting guideline (6, 8) to evaluate the studies. From the
5
ACCEPTED MANUSCRIPT
73
protocol and funding resources (i.e., reported as solely industry, part industry or non-industry, or
74
not reported) were also assessed. Table 1 here
75
Other data extraction
79
trials), participation centers (i.e., single or multicenter), intervention types (i.e., drug
80
intervention, rehabilitation or others) and intervention groups (i.e., two, or three or more groups).
SC
We also extracted data on the trial publication years, size, locations (i.e., U.S. or non-U.S.
Statistical analysis
M AN U
81 82 83 84
RI PT
76 77 78
We summarize the data descriptively. The numbers and proportions of the methodological items were reported by the publication years. The years were grouped into three periods: trial reports
86
published (1) before the CONSORT 2001 revision, (2) after the 2001 revision but before the
87
2010 revision and (3) after the 2010 revision. The descriptive summary statistics were used to
88
compare the quality of RCT reports published between the periods. Risk ratios and associated
89
95% confidence intervals were calculated and used to quantify changes in reporting between the
90
publication periods. Forest plots were used to illustrate the methodological compliance between
91
the publication years. SAS (Version 9.4, SAS Institute Inc., Cary, NC, US) was used for all
92
analyses.
93 94
Results
95
Study selections
EP
AC C
96
TE D
85
A total of 105 RCT reports were included in the current review. Figure 1 shows the
97
article identification process.
98 99 100
General trial characteristics
Figure 1 here 6
ACCEPTED MANUSCRIPT
101 102
Table 2 provides information on general trial characteristics, according to the publication periods of (1) 1976-2001 (before and up to the revision in 2001), (2) 2002-2010 (before and up
104
to the revision in 2010) and (3) 2011-September, 2013 (after the revision in 2010). Of 105
105
eligible trial reports reviewed, 38 (19-57) , 51 (58-108) and 16 (109-124) were published up to
106
the first, second and after the second waves of the revisions respectively. A vast majority
107
(94.3%) of trials used parallel group design (99/105), and the remaining 3.8% (4/105) and 1.9%
108
(2/105) used crossover and other types of designs respectively. Overall, 38.1% (40/105) of the
109
trials investigated drugs as the primary intervention of interest, 5.7% (6/105) assessed surgical
110
procedures, 32.4% (34/105) assessed rehabilitation related interventions and 23.8% (25/105)
111
studied other types of treatment, such as hypothermia treatment, nutritional treatments, etc.
112
Noticeably, the percentages of trials investigating drug treatments have decreased over the years,
113
with 47.4% (18/38), 35.3% (18/51) and 25.0% (4/16) reported during the periods of 1976-2001,
114
2002-2010 and 2011-September, 2013, respectively. The percentages of rehabilitation related
115
interventions were 31.6% (12/38), 37.3% (19/51) and 18.8% (3/16) during the accordance
116
periods, respectively.
SC
M AN U
TE D
EP
117
RI PT
103
Of all trial reports reviewed, 45.7% (48/105) of trials were conducted in the United Sates while 54.3% (57/105) were conducted abroad or internationally. The proportion of trials
119
conducted in the States decreased relatively from the period of 1976-2001 to the periods of 2002-
120
2010, and 2011-September, 2013 [from 50.0% (19/38) to 41.2% (21/51) and 50% (8/16)]. Close
121
to 50% (52/105) of all reports clearly stated that the trial was conducted at a single center and
122
41.9% (44/105) stated that the trial took place at multiple centers; the number of study centers
123
was not explicitly defined in 8.6% of the reports (9/105). Close to 89% (93/105) of all trials
124
consisted of two study groups, while 11.4% (12/105) consisted of three or more groups. The
AC C
118
7
ACCEPTED MANUSCRIPT
125
median number of participants recruited per trial was 102.0 (10th to 90th percentile: 39.0 to
126
463.0).
128
CONSORT compliances of the methodological items
RI PT
Table 2 here
127
Table 3 shows information on the CONSORT compliances of the methodological items,
129
according to the publication periods of (1) 1976-2001, (2) 2002-2010 and (3) 2011-September,
131
2013.
Table 3 here
M AN U
132 133 134 135 136 137
SC
130
Statement of ‘Randomization’ in the title and location of data collection About 50% (52/105) of all trial reports stated that the study was randomized in the title of the report. Compared with the reports published during the period of 1976-2001, an
139
improvement is observed in reports published during the periods of 2002-2010 and 2011-
140
September, 2013, from 34.2% (13/38) to 60.8% (31/51) and 50% (8/16). 81% (85/105) of all
141
reports provided location of the trial data collection, with 84.2% (32/38), 72.6% (37/51) and
142
100% (16/16) for the three periods respectively.
143 144 145
Predefined primary outcomes and sample size calculations
146
(43/105) stated that a sample size calculation had been undertaken. The proportions of pre-
147
specified primary outcomes among reports reviewed were relatively high and further improved
148
after the CONSORT revision in 2001. 84% (43/51) and 93.8% (15/16) of the trials reported the
149
primary outcomes during the periods of 2002-2010 and 2011-September, 2013 whereas 63.2%
150
(24/38) of the trials during the periods of 1976-2001. An improvement in reporting the study
151
sample size is also observed after 2001. 41.8% (21/51) and 75.0% (12/16) of the reports stated
EP
TE D
138
AC C
Of all reports, 78.1% (82/105) defined the primary outcome; whereas only 41.0%
8
ACCEPTED MANUSCRIPT
152
that sample size calculation had been undertaken during the periods of 2002-2010 and 2011-
153
September 2013, whereas only 26.3% (10/38) during the period of 1976-2001.
154 155 156
Methods of randomization sequence generation, allocation concealment and implementation
157
randomization sequence, 45.7% (48/105) reported the allocation concealment method and 28.6%
158
(30/105) provided information on who generated the sequence, administered the intervention
159
and/or assigned the intervention groups.
SC
RI PT
Overall, 46.7% (49/105) of the trials reported the methods used to generate the
A steady improvement is observed in reporting the methods that were used to generate
161
the randomization sequence after the revisions in 2001 and 2010. During the periods of 2002-
162
2010 and 2011-September 2013, 58.8% (30/51) and 68.8% (11/16) of trials reported the
163
methods, while only 21.1% (8/38) during the periods of 1976-2001. An improvement in
164
reporting the methods of allocation concealment and implementation of the randomization
165
process is also observed during the two later periods. For the periods of 1976-2001, 2002-201 0
166
and 2011-September 2013, 26.3% (10/38), 60.8% (31/51) and 43.8% (7/16) of trials reported the
167
allocation concealment methods; and 10.5% (4/38), 39.2% (20/51) and 37.5% (6/16) of trials
168
provided any information on who implemented the randomization process.
TE D
EP
169
M AN U
160
Moreover, among 30 trials that reported personnel who implemented the randomization process, only 16.7% (5/30) clearly stated all personnel who generated sequence, assigned
171
intervention groups and/or administered intervention; while 43.3% (13/30) and 40.0% (12/30)
172
reported personnel who implemented either one or two of the three randomization tasks stated
173
above. The reporting of individual personnel who implemented the randomization process was
174
poor across all observed publication periods.
175 176
Who was blinded and how blinding was achieved
AC C
170
9
ACCEPTED MANUSCRIPT
177
Among all reports, 58.1% (61/105) reported whether there was any blinding, 12.4% (13/105) stated that the trial was not blinded, and 29.5% (31/105) did not report who was blinded
179
at all. Of 61 trials reporting any blinding, 82.0% (50/61) provided specific details on who was
180
blinded after assignment to interventions (for example, study participants, care providers,
181
outcome assessors), whereas the remaining 18.0% (11/61) simply used the terms “blinded”,
182
“single blind”, or “double blind” without providing further details. The performance of the
183
reporting on any blinding was relatively consistent over time. However, among the trials
184
reporting any blinding, 87.5% (28/32) and 100.0% (8/8 ) of the reports published during 2002-
185
2010 and 2011-September, 2013 provided specific details on who was blinded, while only 61.9%
186
(13/21) during 1976-2001 provided such details.
SC
M AN U
187
RI PT
178
In addition to reporting who was blinded, 52.4% (55/105) of the trial reports provided information on how blinding was achieved. Of these, 63.6% (35/55) specifically described any
189
similarities between the interventions or procedures (e.g., identical in size, color, taste, or method
190
of administration), whereas the remaining 36.4% (20/55) simply used the term “placebo” without
191
providing further details. For the periods of 1976-2001, 2002-2010 and 2011-September 2013,
192
55.3% (21/38), 56.9% (29/51) and 31.3% (5/16) of the trial reports provided information on how
193
blinding was achieved. Among trials reporting any blinding, 61.9% (13/21), 65.5% (19/29) and
194
60.0% (3/5) of the trial reports provided specific details on how blinding was achieved.
195 196 197 198
Participation diagram, periods of recruitment and follow up and attritions of loss to follow ups and intention to treat analysis
199
inclusion of a participation diagram in trial reports has been improving since its revision in 2010,
200
from 65.8 (25/38) and 60.8% (31/51) for the reports published during 1976-2001 and 2002-2010
201
to 81.3% (13/16) during 2011-September, 2013.
AC C
EP
TE D
188
A participant flow diagram was given in 46.7% (49/105) of the trial reports. The
10
ACCEPTED MANUSCRIPT
202
Overall, more than two-thirds of the trial reports [67.6% (71/105)] supported information on the time of the recruitment period and most of the reports [82.9% (87/105)] provided
204
information on the follow up period. The reporting of trial recruitment period was relatively
205
consistent over the study periods [76.3% (29/38), 66.7% (34/51), and 75.0% (12/16)
206
respectively], but reporting on follow-up periods was improving [76.3% (29/38), 84.3% (43/51)
207
and 93.8% (15/16), respectively].
Of all trials, 88.6% (93/105) of the trial reports provided information on any loss to
SC
208
RI PT
203
follow-up for each study group or reported no loss to follow up; among 93 trials reporting such
210
information, 88.2% (82/93) provided the reasons for attrition or reported that there was no loss to
211
follow-up. Of the periods within which the reports were reviewed, the period of 1976-2001 did
212
the worst relative to the others, with 76.3% (29/38) of the trials reporting any loss of follow up or
213
reporting no loss to follow up; and of those 29 reports, 79.3% (23/29) providing the reasons for
214
attrition or reporting that there was no loss to follow up. Of the periods of 2002-2010 and 2011-
215
September, 2013, 94.1% (48/51) and 100% (16/16) provided such information, and 91.7%
216
(44/48) and 93.8% (15/16) provided the reasons for attrition or reported that there was no loss to
217
follow up, respectively.
TE D
EP
218
M AN U
209
Similar to performance of reporting of the attrition to loss to follow up, 84.8% (89/105) of all trial reports stated that intention to treat analysis was applied. Among 89 trials, 42.7%
220
(38/89) of the trials included all randomized participants in the analysis, 57.3% (51/89) included
221
randomized subjects with available outcomes only. Again, of the three periods, the period of
222
1976-2001 did worse relative to the others, with 78.9% (30/38) of the trials stating that intention
223
to treat analysis was applied. Further, of the 30 trials, 43.3% (13/30) included all randomized
224
participants in the analysis. Of the two later periods, 84.3% (43/51) and 100.0% (16/16) stated
AC C
219
11
ACCEPTED MANUSCRIPT
225
that the intention to treat analysis was applied, and 41.9% (18/43) and 43.8% (7/16) reported the
226
inclusion of all randomized participants in the analysis.
227 228 229
Trial registrations, protocols and funding resources
230
registration and where the full trial protocol could be accessed (1.9%, 2/105). Since the first
231
U.S. Federal law of requiring trial registration was established in 1997 and the registry of
232
ClinicalTrials.gov was released by National Institution of Health (NIH) in 2000, the trial report
233
regarding the information of the trial registration still well below the optimal level. For the two
234
later periods of 2002-2010 and 2011-September, 2013, only 15.7% (8/51) and 43.8% (7/16)
235
reported such information accordingly, although recognizing some trials conducted abroad may
236
not necessary having the same requirement.
RI PT
SC
M AN U
237
Of all reports reviewed, only 16.2% (17/105) of the trial reports provided details of trial
Overall, the details of the funding sources were provided in 64.8% (68/105) of all trial reports. Of these 68 trials, 26.5% (18/68) of the trials were funded solely [17.7% (12/68)] or
239
partially [8.8% (6/68)] by industry and the remaining 73.5% (50/68) were funded by non-
240
industry resources. Among all that reported the funding sources, 38.1% (8/21), 17.1% (6/35) and
241
33.4% (4/12) of the trials were fully or partially funded by industry during the periods of 1976-
242
2001, 2002-2010 and 2011-September, 2013, respectively.
243 244 245
RCTs published during 1976-2001 vs. those published during 2002-2010
246
first revision in 2001) with those (n=51) published during 2002-2010 (following the first revision
247
and up to the second revision in 2010). There was a statistically significant improvement
248
between the two periods in the proportion of trial reports that reported pre-specified
249
primary/secondary outcomes [Relative Risk (RR):1.33, 95% confidence interval (CI):1.15-1.75)]
AC C
EP
TE D
238
Figure 2 shows the comparison of RCTs (n=38) published during 1976-2001 (up to the
12
ACCEPTED MANUSCRIPT
and the method of randomization sequence generation (RR: 2.79, 95% CI: 1.45-5.39), details of
251
the allocation concealment (RR: 2.31, 95% CI: 1.30-4.11) and attrition due to loss to follow up
252
(RR 1.23, 95% CI 1.02-1.49). Various improvements between the two periods in the proportion
253
of the reports were also observed, although they did not reach statistical significance. The
254
improvements included providing sample size calculation (RR 1.41, 95% CI 0.84-2.92), blinding
255
after assignment of interventions (RR 1.27, 95% CI 0.96-1.68), and intent to treat analysis (RR
256
1.07, 95% CI 0.87-1.31). Figure 2 here
257
SC
RI PT
250
RCTs published during 2002-2010 vs. those published during 2011-September, 2013
261
(following the first revision and up to the second revision in 2010) with those (n=16) published
262
during 2011-September, 2013 (following the second revision). There was a statistically
263
significant improvement between the two periods in the proportion of trial reports including
264
details in sample size calculation (RR 1.82, 95% CI 1.18-2.81) and intent to treat analysis (RR
265
1.18, 95% CI 1.05-1.34). The improvements between the two periods were also observed in the
266
proportion of the reports including details of the primary outcome (RR 1.11, 95% CI 0.93-1.32)
267
and the methods of random sequence generation (RR 1.17, 95% CI 0.78-1.75) and loss to follow
268
up (RR: 1.06: 95% CI: 0.99-1.14), but did not reach statistical significance. There was no
269
difference in the proportion of trials that provided specific details on the method of allocation
270
concealment (RR 0.72, 95% CI 0.40-1.31) and on who was blinded after assignment to
271
interventions (RR 0.70, 95% CI 0.44-1.10).
M AN U
258 259 260
AC C
EP
TE D
Figure 3 shows a further comparison of RCTs (n=51) published during 2002-2010
Figure 3 here
272 273
Discussion
13
ACCEPTED MANUSCRIPT
274 275
Study findings We performed comprehensive assessment of the quality of reports from105 RCTs in adult TBI research published in databases of MedLine, PsycINFO and CINAHL between 1976
277
and September, 2013. The quality of reports was examined against the CONSORT reporting
278
guidelines and compared over time. We specifically compared (1) RCT reports (n=38) published
279
during 1976-2001 (up to the first CONSORT revision in 2001) with those (n=51) published
280
during 2002-2010 (following the first revision and up to the second revision in 2010), and (2)
281
reports published during 2002-2010 with those (n=16) published during 2011-September, 2013
282
(following the second revision in 2010). Over the past 3 decades, the quality of RCT reports has
283
improved over time in the field of TBI research. From the period of 1976-2001 to the period of
284
2002-2010, a significant improvement was observed in reporting the pre-specified primary and
285
secondary outcomes, methods of randomization sequence generation and allocation concealment,
286
and trial attritions due to loss to follow-up. From the period of 2002-2010 to the period of 2011-
287
September, 2013, significant improvements continued in reporting the details of sample size
288
calculation and intent to treat analysis. Various improvements were also noticed in other
289
CONSORT checklist items, although the improvements were not statistically significant.
SC
M AN U
TE D
EP
290
RI PT
276
Of 105 eligible trials reviewed in adult TBI research, 38.1% of the trials investigated drugs as the primary intervention of interest, 5.7% assessed surgical procedures, 32.4% assessed
292
rehabilitation related interventions and 23.8% studied other types of treatment. A vast majority
293
of trials in adult TBI used parallel group design (94.3%, 99/105), mostly with two study groups
294
(88.6%, 93/105). In this cohort, the median size per trial is 102 subjects with the 10th and 90th
295
percentile ranging between 39 and 463. Little improvement in reporting has been seen over time.
296
The small size observed in this review is of concern. In general, for a trial with two comparison
AC C
291
14
ACCEPTED MANUSCRIPT
groups, a sample size of 102 (or 51 per group) has only 56% power to detect a difference
298
between an event rate of 40% and 60% (e.g., an improvement of 20% from an unfavorable
299
outcome to a favorable outcome in the treatment group) at a 0.05 significance level. In practice,
300
the effect size could be even smaller than the absolute differences as given in our example; and
301
the power determined a priori could be further compromised by study attrition. As pointed out by
302
other studies, trials with inadequate power could result in a high false-negative error rate and are
303
likely associated with publication bias (9, 125, 126).
SC
304
RI PT
297
Among all CONSORT checklist items examined, the improvement in reporting the methods of randomization sequence generation and allocation concealment noticed in this study
306
are of great importance, as studies have shown that it is strongly associated with effect estimates
307
(127-130). For any RCTs, the method of randomization is a key component to minimize any
308
measured and unmeasured differences between the comparison groups. A successful
309
randomization process relies on three different steps: sequence generation, allocation
310
concealment and implementation. After generation of unpredictable allocation sequence, it is
311
important to conceal this sequence from the investigators enrolling participants. Proper designed
312
allocation concealment mechanism prevents selection bias and can always be successfully
313
implemented (8).
TE D
EP
After participants received treatment assignment, blinding is another important safeguard
AC C
314
M AN U
305
315
against bias in RCTs although may not feasible in some situation (131). Blinding refers to
316
withholding information about the assigned intervention from people involved in the trial who
317
may potentially be influenced by this knowledge. Blinding usually reduces differential
318
assessment of outcomes, therefore the information bias, but can also improve compliance and
319
retention of trial participants while reducing biased supplemental care or treatment (132). A
15
ACCEPTED MANUSCRIPT
320
recent review by Wood and colleagues (133) found that, for subjective outcomes, trials that used
321
inadequate or unclear allocation concealment yield 31% larger estimates of effect than those that
322
used adequate concealment and trials that were not blinded yield 25% larger estimates. A portion of trials reviewed by this study are non-pharmacological trials (32.4% of all
RI PT
323
trials are rehabilitation-related interventions, 5.7% are surgical trials), for these trials, blinding of
325
intervention allocation status from the participants and caregivers may not be feasible depending
326
on the study design and nature of intervention studied. However, it is recommended that the
327
outcome assessors be blinded whenever possible, particularly for those subjective outcome
328
measurements. Further, if blinded, the trials should explicitly report method of blinding (i.e.,
329
who and how), description of the similarity of the interventions, and whether or not those
330
administering co-interventions were blinded (134).
M AN U
331
SC
324
Although the data suggest that there has been significant improvement in reporting the quality parameters of allocation concealment, we should also point out that the current quality of
333
reporting RCTs is still below an acceptable level. Among the most recent reports published in the
334
period between 2011-September, 2013, less than half of all reports provided information on the
335
method of allocation concealment; detailed the implementation of the randomization process;
336
stated how blinding was achieved; and provided information regarding the trial registration. As
337
these quality parameters are associated with potential biased estimation of intervention effect, we
338
further highlighted some recommendations in Text Box 1 to facilitate the future awareness and
339
improvement in these areas.
341
EP
AC C
340
TE D
332
Text Box 1 here
Comparison to clinical trial reports in other areas of medicine
16
ACCEPTED MANUSCRIPT
342
The observation from our review on the quality of RCT reports trials is, in general, consistent with the current literature in other specialties. Many studies review the quality in
344
reporting RCTs through use of the CONSORT statement. They represent a wide range of areas
345
of medicine and span over the past couple of decades (135). More recent reviews demonstrate
346
greater adherence to CONSORT criteria (10, 15, 136-138). Like our study, most of the published
347
reviews relied on use of CONSORT 2000, but some used 1996 CONSORT guidelines to judge
348
the quality of RCTs. Comparable with our study, findings from these reviews point to overall
349
improvement in the quality of RCT reports over time as indicated by adherence to CONSORT
350
guidelines. However, most conclude that the quality of reports on RCTs has yet to reach
351
acceptable levels.
M AN U
SC
RI PT
343
A variety of methods have been used to judge the quality of RCTs and explore whether
353
improvements had occurred over time. Similar to our procedures, most studies engaged two or
354
more reviewers in a process of identifying the presence or absence of CONSORT criteria in
355
systematically identified research publications. Researchers typically searched for articles
356
identified as RCTs or clinical trials within a medical specialty area, e.g., endoscopy, psychiatry,
357
obstetrics/gynecology (12, 139, 140). Other reviews focused on a particular diagnosis or
358
intervention procedure, e.g., fractures, acupuncture, stroke (141-143). PubMed/Medline was the
359
most commonly used source; the second most popular source was the Cochrane Database of
360
Systematic Reviews. Most studies calculated the percentage of CONSORT criteria met per
361
study, a median or mean percent score, and the number of studies that reached a certain level of
362
CONSORT compliance.
363 364
AC C
EP
TE D
352
To our knowledge, our study is the only study that provided a comprehensive methodological assessment of randomized trials in adult TBI that covers more than three decades
17
ACCEPTED MANUSCRIPT
of publications. Comparing the quality of reports among the publication periods allows us to
366
examine the extent to which the quality of RCT reports in TBI research has improved over time.
367
Our sample is acquired from three large online databases and with no restriction to any specific
368
journals. Therefore, we are confident that it contains the majority of the RCT publications in
369
adult TBI. Relatively unique to our study is that we calculated risk ratios with 95% confidence
370
intervals for several key methodological items which allow quantifying changes in reporting
371
between the publication periods.
SC
372
RI PT
365
It is difficult to ascertain specific improvements or areas of neglect in use of the CONSORT across a wide range of studies. Some studies noted improvement in allocation
374
concealment (139) while others reported limited adherence in this area (142). Some saw ongoing
375
deficiency in describing the randomization process and blinding following assignment to
376
intervention group (138, 139) while others noted improvement or strength in these areas (144).
377
These differences in findings may be related to the search procedures, topic of interest and time
378
period from which the trial reports were published. Relatively consistent across all studies and in
379
agreement with our study is the recognition of improvements over time but ongoing need for
380
better adherence to CONSORT guidelines as an indicator of high quality research. The
381
endorsement by professional journals of the CONSORT Statement may influence the
382
completeness of reporting RCTs (137, 145, 146). Currently, Archives of Physical Medicine and
383
Rehabilitation, Journal of Neurosurgery, and Neurosurgery are among the TBI specialty journals
384
that endorse the CONSORT guidelines. To extend the effort, 28 rehabilitation journals recently
385
published editorial acknowledgements (147) calling for further elevation of the quality of
386
disability and rehabilitation research and mandatory use the reporting guidelines, not only for
AC C
EP
TE D
M AN U
373
18
ACCEPTED MANUSCRIPT
387
reporting RCTs, but also for other study designs. Future studies should follow up with the
388
impact of such mandatory effort on the quality of reporting RCTs in these journals.
389 390 391
Limitations
392
inclusion/exclusion criteria from our previous report (17), and these procedures could have
393
limited inclusion of all published RCT reports in TBI during the search period. However, such
394
exclusion would be minimal. Studies included in the review allowed us to fulfill our primary aim
395
to describe methodological compliance with the CONSORT recommendation and compare
396
improvement in trial reporting over time among a representative sample. Some CONSORT
397
checklist items were not assessed in this review since they could not be objectively compared
398
across trials even though they are all of equal importance in evaluating the quality of the report.
399
We agree with Hopewell and colleagues (10) on the point that poor reporting does not
400
necessarily mirror the actual methods that were carried out in a trial. In practice, there might be
401
studies that had better quality of design in the study protocol than that in the final publication.
402
Conversely, there might be studies that have shown more information about the trial design and
403
conduct in the published reports than that in the actual protocols.
404
Conclusions
405
Reporting of several important methodological aspects of RCTs conducted in adult TBI
406
population improved over the years, however, quality of reporting remains below an acceptable
407
level. The small sample sizes suggest that many RCTs are likely underpowered. Further
408
methodological improvement is recommended in both designing and reporting RCTs. Currently,
409
only limited TBI specialty journals endorsed CONSORT guidelines. More journals are
410
encouraged to join the effort to promote transparent and high quality reporting of RCTs.
AC C
EP
TE D
M AN U
SC
RI PT
Our search technique relied on MeSH key words and terms and certain
19
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
References
1. Altman DG, Moher D, Schulz KF. Improving the reporting of randomised trials: The CONSORT statement and beyond. Stat Med. 2012 Nov 10;31(25):2985-97. 2. Chalmers I, Glasziou P. Avoidable waste in the production and reporting of research evidence. Obstet Gynecol. 2009 Dec;114(6):1341-5. 20
ACCEPTED MANUSCRIPT
3. Laine C, Goodman SN, Griswold ME, Sox HC. Reproducible research: Moving toward research the public can really trust. Ann Intern Med. 2007 Mar 20;146(6):450-3.
RI PT
4. Begg C, Cho M, Eastwood S, Horton R, Moher D, Olkin I, et al. Improving the quality of reporting of randomized controlled trials. the CONSORT statement. JAMA. 1996 Aug 28;276(8):637-9. 5. Moher D, Schulz KF, Altman DG. The CONSORT statement: Revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet. 2001 Apr 14;357(9263):1191-4.
SC
6. Schulz KF, Altman DG, Moher D, CONSORT Group. CONSORT 2010 statement: Updated guidelines for reporting parallel group randomised trials. BMC Med. 2010 Mar 24;8:18,7015-8-18.
M AN U
7. Altman DG, Schulz KF, Moher D, Egger M, Davidoff F, Elbourne D, et al. The revised CONSORT statement for reporting randomized trials: Explanation and elaboration. Ann Intern Med. 2001 Apr 17;134(8):663-94. 8. Moher D, Hopewell S, Schulz KF, Montori V, Gotzsche PC, Devereaux PJ, et al. CONSORT 2010 explanation and elaboration: Updated guidelines for reporting parallel group randomised trials. BMJ. 2010 Mar 23;340:c869.
TE D
9. Chan AW, Altman DG. Epidemiology and reporting of randomised trials published in PubMed journals. Lancet. 2005 Mar 26-Apr 1;365(9465):1159-62. 10. Hopewell S, Dutton S, Yu LM, Chan AW, Altman DG. The quality of reports of randomised trials in 2000 and 2006: Comparative study of articles indexed in PubMed. BMJ. 2010 Mar 23;340:c723.
EP
11. Ladd BO, McCrady BS, Manuel JK, Campbell W. Improving the quality of reporting alcohol outcome studies: Effects of the CONSORT statement. Addict Behav. 2010 Jul;35(7):660-6.
AC C
12. Areia M, Soares M, Dinis-Ribeiro M. Quality reporting of endoscopic diagnostic studies in gastrointestinal journals: Where do we stand on the use of the STARD and CONSORT statements? Endoscopy. 2010 Feb;42(2):138-47. 13. Ziogas DC, Zintzaras E. Analysis of the quality of reporting of randomized controlled trials in acute and chronic myeloid leukemia, and myelodysplastic syndromes as governed by the CONSORT statement. Ann Epidemiol. 2009 Jul;19(7):494-500. 14. Smith BA, Lee HJ, Lee JH, Choi M, Jones DE, Bausell RB, et al. Quality of reporting randomized controlled trials (RCTs) in the nursing literature: Application of the consolidated standards of reporting trials (CONSORT). Nurs Outlook. 2008 JanFeb;56(1):31-7. 21
ACCEPTED MANUSCRIPT
15. Kane RL, Wang J, Garrard J. Reporting in randomized clinical trials improved after adoption of the CONSORT statement. J Clin Epidemiol. 2007 Mar;60(3):241-9.
RI PT
16. Sut N, Senocak M, Uysal O, Koksalan H. Assessing the quality of randomized controlled trials from two leading cancer journals using the CONSORT statement. Hematol Oncol Stem Cell Ther. 2008 Jan-Mar;1(1):38-43. 17. Lu J, Gary KW, Neimeier JP, Ward J, Lapane KL. Randomized controlled trials in adult traumatic brain injury. Brain Inj. 2012;26(13-14):1523-48.
SC
18. Maas AI, Roozenbeek B, Manley GT. Clinical trials in traumatic brain injury: Past experience and current developments. Neurotherapeutics. 2010 Jan;7(1):115-26. 19. Kitamura K. Therapeutic effect of pyritinol on sequelae of head injuries. J Int Med Res. 1981;9(3):215-21.
M AN U
20. Saul TG, Ducker TB, Salcman M, Carro E. Steroids in severe head injury: A prospective randomized clinical trial. J Neurosurg. 1981 May;54(5):596-600. 21. Braakman R, Schouten HJ, Blaauw-van Dishoeck M, Minderhoud JM. Megadose steroids in severe head injury. results of a prospective double-blind clinical trial. J Neurosurg. 1983 Mar;58(3):326-30.
TE D
22. Ward JD, Becker DP, Miller JD, Choi SC, Marmarou A, Wood C, et al. Failure of prophylactic barbiturate coma in the treatment of severe head injury. J Neurosurg. 1985 Mar;62(3):383-8.
EP
23. Dearden NM, Gibson JS, McDowall DG, Gibson RM, Cameron MM. Effect of highdose dexamethasone on outcome from severe head injury. J Neurosurg. 1986 Jan;64(1):818.
AC C
24. Smith HP, Kelly DL,Jr, McWhorter JM, Armstrong D, Johnson R, Transou C, et al. Comparison of mannitol regimens in patients with severe head injury undergoing intracranial monitoring. J Neurosurg. 1986 Dec;65(6):820-4. 25. Artru F, Chacornac R, Deleuze R. Hyperbaric oxygenation for severe head injuries. preliminary results of a controlled study. Eur Neurol. 1976;14(4):310-8. 26. Young B, Ott L, Twyman D, Norton J, Rapp R, Tibbs P, et al. The effect of nutritional support on outcome from severe head injury. J Neurosurg. 1987 Nov;67(5):668-76. 27. Eisenberg HM, Frankowski RF, Contant CF, Marshall LF, Walker MD. High-dose barbiturate control of elevated intracranial pressure in patients with severe head injury. J Neurosurg. 1988 Jul;69(1):15-23.
22
ACCEPTED MANUSCRIPT
28. Niemann H, Ruff RM, Baser CA. Computer-assisted attention retraining in headinjured individuals: A controlled efficacy study of an outpatient program. J Consult Clin Psychol. 1990 Dec;58(6):811-7.
RI PT
29. Ruff RM, Niemann H. Cognitive rehabilitation versus day treatment in head-injured adults: Is there an impact on emotional and psychosocial adjustment? Brain Inj. 1990 OctDec;4(4):339-47. 30. Bailey I, Bell A, Gray J, Gullan R, Heiskanan O, Marks PV, et al. A trial of the effect of nimodipine on outcome after head injury. Acta Neurochir (Wien). 1991;110(3-4):97-105.
SC
31. Calatayud Maldonado V, Calatayud Perez JB, Aso Escario J. Effects of CDP-choline on the recovery of patients with head injury. J Neurol Sci. 1991 Jul;103 Suppl:S15-8.
M AN U
32. Muizelaar JP, Marmarou A, Ward JD, Kontos HA, Choi SC, Becker DP, et al. Adverse effects of prolonged hyperventilation in patients with severe head injury: A randomized clinical trial. J Neurosurg. 1991 Nov;75(5):731-9. 33. Rockswold GL, Ford SE, Anderson DC, Bergman TA, Sherman RE. Results of a prospective randomized trial for treatment of severely brain-injured patients with hyperbaric oxygen. J Neurosurg. 1992 Jun;76(6):929-34.
TE D
34. Gaab MR, Trost HA, Alcantara A, Karimi-Nejad A, Moskopp D, Schultheiss R, et al. "Ultrahigh" dexamethasone in acute brain injury. results from a prospective randomized double-blind multicenter trial (GUDHIS). german ultrahigh dexamethasone head injury study group. Zentralbl Neurochir. 1994;55(3):135-43.
EP
35. A multicenter trial of the efficacy of nimodipine on outcome after severe head injury. the european study group on nimodipine in severe head injury. J Neurosurg. 1994 May;80(5):797-804. 36. Neistadt ME. The effects of different treatment activities on functional fine motor coordination in adults with brain injury. Am J Occup Ther. 1994 Oct;48(10):877-82.
AC C
37. Smith KR,Jr, Goulding PM, Wilderman D, Goldfader PR, Holterman-Hommes P, Wei F. Neurobehavioral effects of phenytoin and carbamazepine in patients recovering from brain trauma: A comparative study. Arch Neurol. 1994 Jul;51(7):653-60. 38. Grumme T, Baethmann A, Kolodziejczyk D, Krimmer J, Fischer M, von Eisenhart Rothe B, et al. Treatment of patients with severe head injury by triamcinolone: A prospective, controlled multicenter clinical trial of 396 cases. Res Exp Med (Berl). 1995;195(4):217-29. 39. Harders A, Kakarieka A, Braakman R. Traumatic subarachnoid hemorrhage and its treatment with nimodipine. german tSAH study group. J Neurosurg. 1996 Jul;85(1):82-9.
23
ACCEPTED MANUSCRIPT
40. Young B, Runge JW, Waxman KS, Harrington T, Wilberger J, Muizelaar JP, et al. Effects of pegorgotein on neurologic outcome of patients with severe head injury. A multicenter, randomized controlled trial. JAMA. 1996 Aug 21;276(7):538-43.
RI PT
41. Young B, Ott L, Kasarskis E, Rapp R, Moles K, Dempsey RJ, et al. Zinc supplementation is associated with improved neurologic recovery rate and visceral protein levels of patients with severe closed head injury. J Neurotrauma. 1996 Jan;13(1):25-34. 42. Couser RJ, Hoekstra RE, Ferrara TB, Wright GB, Cabalka AK, Connett JE. Neurodevelopmental follow-up at 36 months' corrected age of preterm infants treated with prophylactic indomethacin. Arch Pediatr Adolesc Med. 2000 Jun;154(6):598-602.
SC
43. Marion DW, Penrod LE, Kelsey SF, Obrist WD, Kochanek PM, Palmer AM, et al. Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med. 1997 Feb 20;336(8):540-6.
M AN U
44. Wade DT, King NS, Wenden FJ, Crawford S, Caldwell FE. Routine follow up after head injury: A second randomised controlled trial. J Neurol Neurosurg Psychiatry. 1998 Aug;65(2):177-83. 45. Marshall LF, Maas AI, Marshall SB, Bricolo A, Fearnside M, Iannotti F, et al. A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury. J Neurosurg. 1998 Oct;89(4):519-25.
TE D
46. Paniak C, Toller-Lobe G, Durand A, Nagy J. A randomized trial of two treatments for mild traumatic brain injury. Brain Inj. 1998 Dec;12(12):1011-23.
EP
47. Marmarou A, Nichols J, Burgess J, Newell D, Troha J, Burnham D, et al. Effects of the bradykinin antagonist bradycor (deltibant, CP-1027) in severe traumatic brain injury: Results of a multi-center, randomized, placebo-controlled trial. american brain injury consortium study group. J Neurotrauma. 1999 Jun;16(6):431-44.
AC C
48. Morris GF, Bullock R, Marshall SB, Marmarou A, Maas A, Marshall LF. Failure of the competitive N-methyl-D-aspartate antagonist selfotel (CGS 19755) in the treatment of severe head injury: Results of two phase III clinical trials. the selfotel investigators. J Neurosurg. 1999 Nov;91(5):737-43. 49. Levine B, Robertson IH, Clare L, Carter G, Hong J, Wilson BA, et al. Rehabilitation of executive functioning: An experimental-clinical validation of goal management training. J Int Neuropsychol Soc. 2000 Mar;6(3):299-312. 50. Paniak C, Toller-Lobe G, Reynolds S, Melnyk A, Nagy J. A randomized trial of two treatments for mild traumatic brain injury: 1 year follow-up. Brain Inj. 2000 Mar;14(3):219-26.
24
ACCEPTED MANUSCRIPT
51. Salazar AM, Warden DL, Schwab K, Spector J, Braverman S, Walter J, et al. Cognitive rehabilitation for traumatic brain injury: A randomized trial. defense and veterans head injury program (DVHIP) study group. JAMA. 2000 Jun 21;283(23):3075-81.
RI PT
52. Bateman A, Culpan FJ, Pickering AD, Powell JH, Scott OM, Greenwood RJ. The effect of aerobic training on rehabilitation outcomes after recent severe brain injury: A randomized controlled evaluation. Arch Phys Med Rehabil. 2001 Feb;82(2):174-82. 53. Cruz J, Minoja G, Okuchi K. Improving clinical outcomes from acute subdural hematomas with the emergency preoperative administration of high doses of mannitol: A randomized trial. Neurosurgery. 2001 Oct;49(4):864-71.
SC
54. Shiel A, Burn JP, Henry D, Clark J, Wilson BA, Burnett ME, et al. The effects of increased rehabilitation therapy after brain injury: Results of a prospective controlled trial. Clin Rehabil. 2001 Oct;15(5):501-14.
M AN U
55. Shiozaki T, Hayakata T, Taneda M, Nakajima Y, Hashiguchi N, Fujimi S, et al. A multicenter prospective randomized controlled trial of the efficacy of mild hypothermia for severely head injured patients with low intracranial pressure. mild hypothermia study group in japan. J Neurosurg. 2001 Jan;94(1):50-4. 56. Chen B, Liu YS. Randomized double-blind clinical trial of moderate dosage naloxone in acute moderate and severe traumatic brain injury]. Hunan Yi Ke Da Xue Xue Bao. 2002 Feb 28;27(1):58-60.
TE D
57. Dirette DK, Hinojosa J, Carnevale GJ. Comparison of remedial and compensatory interventions for adults with acquired brain injuries. J Head Trauma Rehabil. 1999 Dec;14(6):595-601.
EP
58. Chen L, Zeng F, Yang L, Chai J, Li K, Lu M, et al. Curative effect of wilsonii injecta on severe head injury. Chin J Traumatol. 2002 Apr;5(2):82-5.
AC C
59. Clifton GL, Miller ER, Choi SC, Levin HS, McCauley S, Smith KR,Jr, et al. Hypothermia on admission in patients with severe brain injury. J Neurotrauma. 2002 Mar;19(3):293-301. 60. Cruz J, Minoja G, Okuchi K. Major clinical and physiological benefits of early high doses of mannitol for intraparenchymal temporal lobe hemorrhages with abnormal pupillary widening: A randomized trial. Neurosurgery. 2002 Sep;51(3):628,37; discussion 637-8. 61. de Kruijk JR, Leffers P, Meerhoff S, Rutten J, Twijnstra A. Effectiveness of bed rest after mild traumatic brain injury: A randomised trial of no versus six days of bed rest. J Neurol Neurosurg Psychiatry. 2002 Aug;73(2):167-72.
25
ACCEPTED MANUSCRIPT
62. Lee H, Kim SW, Kim JM, Shin IS, Yang SJ, Yoon JS. Comparing effects of methylphenidate, sertraline and placebo on neuropsychiatric sequelae in patients with traumatic brain injury. Hum Psychopharmacol. 2005 Mar;20(2):97-104.
RI PT
63. Powell J, Heslin J, Greenwood R. Community based rehabilitation after severe traumatic brain injury: A randomised controlled trial. J Neurol Neurosurg Psychiatry. 2002 Feb;72(2):193-202. 64. Lu LQ, Jiang JY, Yu MK, Hou LJ, Chen ZG, Zhang GJ, et al. Standard large trauma craniotomy for severe traumatic brain injury. Chin J Traumatol. 2003 Oct;6(5):302-4.
SC
65. Zhi D, Zhang S, Lin X. Study on therapeutic mechanism and clinical effect of mild hypothermia in patients with severe head injury. Surg Neurol. 2003 May;59(5):381-5.
M AN U
66. Cooper DJ, Myles PS, McDermott FT, Murray LJ, Laidlaw J, Cooper G, et al. Prehospital hypertonic saline resuscitation of patients with hypotension and severe traumatic brain injury: A randomized controlled trial. JAMA. 2004 Mar 17;291(11):13507. 67. Whyte J, Hart T, Vaccaro M, Grieb-Neff P, Risser A, Polansky M, et al. Effects of methylphenidate on attention deficits after traumatic brain injury: A multidimensional, randomized, controlled trial. Am J Phys Med Rehabil. 2004 Jun;83(6):401-20.
TE D
68. Aquilani R, Iadarola P, Contardi A, Boselli M, Verri M, Pastoris O, et al. Branchedchain amino acids enhance the cognitive recovery of patients with severe traumatic brain injury. Arch Phys Med Rehabil. 2005 Sep;86(9):1729-35.
EP
69. Bell KR, Temkin NR, Esselman PC, Doctor JN, Bombardier CH, Fraser RT, et al. The effect of a scheduled telephone intervention on outcome after moderate to severe traumatic brain injury: A randomized trial. Arch Phys Med Rehabil. 2005 May;86(5):851-6.
AC C
70. Brown TH, Mount J, Rouland BL, Kautz KA, Barnes RM, Kim J. Body weightsupported treadmill training versus conventional gait training for people with chronic traumatic brain injury. J Head Trauma Rehabil. 2005 Sep-Oct;20(5):402-15. 71. Edwards P, Arango M, Balica L, Cottingham R, El-Sayed H, Farrell B, et al. Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months. Lancet. 2005 Jun 410;365(9475):1957-9. 72. Jha A, Weintraub A, Allshouse A, Morey C, Cusick C, Kittelson J, et al. A randomized trial of modafinil for the treatment of fatigue and excessive daytime sleepiness in individuals with chronic traumatic brain injury. J Head Trauma Rehabil. 2008 JanFeb;23(1):52-63.
26
ACCEPTED MANUSCRIPT
73. Jiang JY, Xu W, Li WP, Gao GY, Bao YH, Liang YM, et al. Effect of long-term mild hypothermia or short-term mild hypothermia on outcome of patients with severe traumatic brain injury. J Cereb Blood Flow Metab. 2006 Jun;26(6):771-6.
RI PT
74. Maas AI, Murray G, Henney H,3rd, Kassem N, Legrand V, Mangelus M, et al. Efficacy and safety of dexanabinol in severe traumatic brain injury: Results of a phase III randomised, placebo-controlled, clinical trial. Lancet Neurol. 2006 Jan;5(1):38-45. 75. McDonald S, Tate R, Togher L, Bornhofen C, Long E, Gertler P, et al. Social skills treatment for people with severe, chronic acquired brain injuries: A multicenter trial. Arch Phys Med Rehabil. 2008 Sep;89(9):1648-59.
SC
76. Wilson DJ, Powell M, Gorham JL, Childers MK. Ambulation training with and without partial weightbearing after traumatic brain injury: Results of a randomized, controlled trial. Am J Phys Med Rehabil. 2006 Jan;85(1):68-74.
M AN U
77. Elgmark Andersson E, Emanuelson I, Bjorklund R, Stalhammar DA. Mild traumatic brain injuries: The impact of early intervention on late sequelae. A randomized controlled trial. Acta Neurochir (Wien). 2007 Feb;149(2):151,9; discussion 160. 78. Dahlberg CA, Cusick CP, Hawley LA, Newman JK, Morey CE, Harrison-Felix CL, et al. Treatment efficacy of social communication skills training after traumatic brain injury: A randomized treatment and deferred treatment controlled trial. Arch Phys Med Rehabil. 2007 Dec;88(12):1561-73.
TE D
79. Qiu W, Zhang Y, Sheng H, Zhang J, Wang W, Liu W, et al. Effects of therapeutic mild hypothermia on patients with severe traumatic brain injury after craniotomy. J Crit Care. 2007 Sep;22(3):229-35.
EP
80. Tiersky LA, Anselmi V, Johnston MV, Kurtyka J, Roosen E, Schwartz T, et al. A trial of neuropsychologic rehabilitation in mild-spectrum traumatic brain injury. Arch Phys Med Rehabil. 2005 Aug;86(8):1565-74.
AC C
81. Wilson BA, Emslie H, Quirk K, Evans J, Watson P. A randomized control trial to evaluate a paging system for people with traumatic brain injury. Brain Inj. 2005 Oct;19(11):891-4. 82. Jiang JY, Xu W, Li WP, Xu WH, Zhang J, Bao YH, et al. Efficacy of standard trauma craniectomy for refractory intracranial hypertension with severe traumatic brain injury: A multicenter, prospective, randomized controlled study. J Neurotrauma. 2005 Jun;22(6):623-8. 83. Moein H, Khalili HA, Keramatian K. Effect of methylphenidate on ICU and hospital length of stay in patients with severe and moderate traumatic brain injury. Clin Neurol Neurosurg. 2006 Sep;108(6):539-42.
27
ACCEPTED MANUSCRIPT
84. Qiu WS, Liu WG, Shen H, Wang WM, Hang ZL, Zhang Y, et al. Therapeutic effect of mild hypothermia on severe traumatic head injury. Chin J Traumatol. 2005 Feb;8(1):2732.
RI PT
85. Temkin NR, Anderson GD, Winn HR, Ellenbogen RG, Britz GW, Schuster J, et al. Magnesium sulfate for neuroprotection after traumatic brain injury: A randomised controlled trial. Lancet Neurol. 2007 Jan;6(1):29-38. 86. Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, et al. ProTECT: A randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med. 2007 Apr;49(4):391,402, 402.e1-2.
SC
87. Zhu XL, Poon WS, Chan CC, Chan SS. Does intensive rehabilitation improve the functional outcome of patients with traumatic brain injury (TBI)? A randomized controlled trial. Brain Inj. 2007 Jun;21(7):681-90.
M AN U
88. Bell KR, Hoffman JM, Temkin NR, Powell JM, Fraser RT, Esselman PC, et al. The effect of telephone counselling on reducing post-traumatic symptoms after mild traumatic brain injury: A randomised trial. J Neurol Neurosurg Psychiatry. 2008 Nov;79(11):127581. 89. Bilotta F, Caramia R, Cernak I, Paoloni FP, Doronzio A, Cuzzone V, et al. Intensive insulin therapy after severe traumatic brain injury: A randomized clinical trial. Neurocrit Care. 2008;9(2):159-66.
TE D
90. Cicerone KD, Mott T, Azulay J, Sharlow-Galella MA, Ellmo WJ, Paradise S, et al. A randomized controlled trial of holistic neuropsychologic rehabilitation after traumatic brain injury. Arch Phys Med Rehabil. 2008 Dec;89(12):2239-49.
EP
91. Constantinidou F, Thomas RD, Robinson L. Benefits of categorization training in patients with traumatic brain injury during post-acute rehabilitation: Additional evidence from a randomized controlled trial. J Head Trauma Rehabil. 2008 Sep-Oct;23(5):312-28.
AC C
92. Vanderploeg RD, Schwab K, Walker WC, Fraser JA, Sigford BJ, Date ES, et al. Rehabilitation of traumatic brain injury in active duty military personnel and veterans: Defense and veterans brain injury center randomized controlled trial of two rehabilitation approaches. Arch Phys Med Rehabil. 2008 Dec;89(12):2227-38. 93. Xiao G, Wei J, Yan W, Wang W, Lu Z. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: A randomized controlled trial. Crit Care. 2008;12(2):R61. 94. Bombardier CH, Bell KR, Temkin NR, Fann JR, Hoffman J, Dikmen S. The efficacy of a scheduled telephone intervention for ameliorating depressive symptoms during the first year after traumatic brain injury. J Head Trauma Rehabil. 2009 Jul-Aug;24(4):230-8.
28
ACCEPTED MANUSCRIPT
95. Novack TA, Banos JH, Brunner R, Renfroe S, Meythaler JM. Impact of early administration of sertraline on depressive symptoms in the first year after traumatic brain injury. J Neurotrauma. 2009 Nov;26(11):1921-8.
RI PT
96. Harris OA, Muh CR, Surles MC, Pan Y, Rozycki G, Macleod J, et al. Discrete cerebral hypothermia in the management of traumatic brain injury: A randomized controlled trial. J Neurosurg. 2009 Jun;110(6):1256-64. 97. Tenovuo O, Alin J, Helenius H. A randomized controlled trial of rivastigmine for chronic sequels of traumatic brain injury-what it showed and taught? Brain Inj. 2009 Jun;23(6):548-58.
SC
98. Willmott C, Ponsford J. Efficacy of methylphenidate in the rehabilitation of attention following traumatic brain injury: A randomised, crossover, double blind, placebo controlled inpatient trial. J Neurol Neurosurg Psychiatry. 2009 May;80(5):552-7.
M AN U
99. Yang M, Guo Q, Zhang X, Sun S, Wang Y, Zhao L, et al. Intensive insulin therapy on infection rate, days in NICU, in-hospital mortality and neurological outcome in severe traumatic brain injury patients: A randomized controlled trial. Int J Nurs Stud. 2009 Jun;46(6):753-8.
TE D
100. Banos JH, Novack TA, Brunner R, Renfroe S, Lin HY, Meythaler J. Impact of early administration of sertraline on cognitive and behavioral recovery in the first year after moderate to severe traumatic brain injury. J Head Trauma Rehabil. 2010 SepOct;25(5):357-61.
EP
101. Bernard SA, Nguyen V, Cameron P, Masci K, Fitzgerald M, Cooper DJ, et al. Prehospital rapid sequence intubation improves functional outcome for patients with severe traumatic brain injury: A randomized controlled trial. Ann Surg. 2010 Dec;252(6):959-65.
AC C
102. Bulger EM, May S, Brasel KJ, Schreiber M, Kerby JD, Tisherman SA, et al. Out-ofhospital hypertonic resuscitation following severe traumatic brain injury: A randomized controlled trial. JAMA. 2010 Oct 6;304(13):1455-64. 103. Coester A, Neumann CR, Schmidt MI. Intensive insulin therapy in severe traumatic brain injury: A randomized trial. J Trauma. 2010 Apr;68(4):904-11. 104. Hoffman JM, Bell KR, Powell JM, Behr J, Dunn EC, Dikmen S, et al. A randomized controlled trial of exercise to improve mood after traumatic brain injury. PM R. 2010 Oct;2(10):911-9. 105. Rapoport MJ, Mitchell RA, McCullagh S, Herrmann N, Chan F, Kiss A, et al. A randomized controlled trial of antidepressant continuation for major depression following traumatic brain injury. J Clin Psychiatry. 2010 Sep;71(9):1125-30.
29
ACCEPTED MANUSCRIPT
106. Yurkewicz L, Weaver J, Bullock MR, Marshall LF. The effect of the selective NMDA receptor antagonist traxoprodil in the treatment of traumatic brain injury. J Neurotrauma. 2005 Dec;22(12):1428-43.
RI PT
107. Carnevale GJ, Anselmi V, Johnston MV, Busichio K, Walsh V. A natural setting behavior management program for persons with acquired brain injury: A randomized controlled trial. Arch Phys Med Rehabil. 2006 Oct;87(10):1289-97.
SC
108. Hassett LM, Moseley AM, Tate RL, Harmer AR, Fairbairn TJ, Leung J. Efficacy of a fitness centre-based exercise programme compared with a home-based exercise programme in traumatic brain injury: A randomized controlled trial. J Rehabil Med. 2009 Mar;41(4):247-55.
M AN U
109. Bell KR, Brockway JA, Hart T, Whyte J, Sherer M, Fraser RT, et al. Scheduled telephone intervention for traumatic brain injury: A multicenter randomized controlled trial. Arch Phys Med Rehabil. 2011 Oct;92(10):1552-60. 110. Clifton GL, Valadka A, Zygun D, Coffey CS, Drever P, Fourwinds S, et al. Very early hypothermia induction in patients with severe brain injury (the national acute brain injury study: Hypothermia II): A randomised trial. Lancet Neurol. 2011 Feb;10(2):131-9. 111. Cooper DJ, Rosenfeld JV. Does decompressive craniectomy improve outcomes in patients with diffuse traumatic brain injury? Med J Aust. 2011 May 2;194(9):437-8.
TE D
112. Cottenceau V, Masson F, Mahamid E, Petit L, Shik V, Sztark F, et al. Comparison of effects of equiosmolar doses of mannitol and hypertonic saline on cerebral blood flow and metabolism in traumatic brain injury. J Neurotrauma. 2011 Oct;28(10):2003-12.
EP
113. McFadden KL, Healy KM, Dettmann ML, Kaye JT, Ito TA, Hernandez TD. Acupressure as a non-pharmacological intervention for traumatic brain injury (TBI). J Neurotrauma. 2011 Jan;28(1):21-34.
AC C
114. CRASH-2 Collaborators, Intracranial Bleeding Study. Effect of tranexamic acid in traumatic brain injury: A nested randomised, placebo controlled trial (CRASH-2 intracranial bleeding study). BMJ. 2011 Jul 1;343:d3795. 115. Chesnut RM, Temkin N, Carney N, Dikmen S, Rondina C, Videtta W, et al. A trial of intracranial-pressure monitoring in traumatic brain injury. N Engl J Med. 2012 Dec 27;367(26):2471-81. 116. Chourdakis M, Kraus MM, Tzellos T, Sardeli C, Peftoulidou M, Vassilakos D, et al. Effect of early compared with delayed enteral nutrition on endocrine function in patients with traumatic brain injury: An open-labeled randomized trial. JPEN J Parenter Enteral Nutr. 2012 Jan;36(1):108-16.
30
ACCEPTED MANUSCRIPT
117. Hanks RA, Rapport LJ, Wertheimer J, Koviak C. Randomized controlled trial of peer mentoring for individuals with traumatic brain injury and their significant others. Arch Phys Med Rehabil. 2012 Aug;93(8):1297-304.
RI PT
118. Justo Meirelles CM, de Aguilar-Nascimento JE. Enteral or parenteral nutrition in traumatic brain injury: A prospective randomised trial. Nutr Hosp. 2011 SepOct;26(5):1120-4.
SC
119. Zafonte RD, Bagiella E, Ansel BM, Novack TA, Friedewald WT, Hesdorffer DC, et al. Effect of citicoline on functional and cognitive status among patients with traumatic brain injury: Citicoline brain injury treatment trial (COBRIT). JAMA. 2012 Nov 21;308(19):1993-2000.
M AN U
120. Hoffer ME, Balaban C, Slade MD, Tsao JW, Hoffer B. Amelioration of acute sequelae of blast induced mild traumatic brain injury by N-acetyl cysteine: A double-blind, placebo controlled study. PLoS One. 2013;8(1):e54163. 121. Matuseviciene G, Borg J, Stalnacke BM, Ulfarsson T, de Boussard C. Early intervention for patients at risk for persisting disability after mild traumatic brain injury: A randomized, controlled study. Brain Inj. 2013;27(3):318-24. 122. Sanchez-Aguilar M, Tapia-Perez JH, Sanchez-Rodriguez JJ, Vinas-Rios JM, Martinez-Perez P, de la Cruz-Mendoza E, et al. Effect of rosuvastatin on cytokines after traumatic head injury. J Neurosurg. 2013 Mar;118(3):669-75.
TE D
123. Shum D, Fleming J, Gill H, Gullo MJ, Strong J. A randomized controlled trial of prospective memory rehabilitation in adults with traumatic brain injury. J Rehabil Med. 2011 Feb;43(3):216-23.
EP
124. Brenner LA, Braden CA, Bates M, Chase T, Hancock C, Harrison-Felix C, et al. A health and wellness intervention for those with moderate to severe traumatic brain injury: A randomized controlled trial. J Head Trauma Rehabil. 2012 Nov-Dec;27(6):E57-68.
AC C
125. Freiman JA, Chalmers TC, Smith H,Jr, Kuebler RR. The importance of beta, the type II error and sample size in the design and interpretation of the randomized control trial. survey of 71 "negative" trials. N Engl J Med. 1978 Sep 28;299(13):690-4. 126. Schulz KF, Grimes DA. Sample size calculations in randomised trials: Mandatory and mystical. Lancet. 2005 Apr 9-15;365(9467):1348-53. 127. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995 Feb 1;273(5):408-12. 128. Chalmers TC, Celano P, Sacks HS, Smith H,Jr. Bias in treatment assignment in controlled clinical trials. N Engl J Med. 1983 Dec 1;309(22):1358-61. 31
ACCEPTED MANUSCRIPT
129. Pildal J, Hrobjartsson A, Jorgensen KJ, Hilden J, Altman DG, Gotzsche PC. Impact of allocation concealment on conclusions drawn from meta-analyses of randomized trials. Int J Epidemiol. 2007 Aug;36(4):847-57.
RI PT
130. Savovic J, Jones H, Altman D, Harris R, Juni P, Pildal J, et al. Influence of reported study design characteristics on intervention effect estimates from randomised controlled trials: Combined analysis of meta-epidemiological studies. Health Technol Assess. 2012 Sep;16(35):1-82. 131. Juni P, Altman DG, Egger M. Systematic reviews in health care: Assessing the quality of controlled clinical trials. BMJ. 2001 Jul 7;323(7303):42-6.
SC
132. Schulz KF, Grimes DA. Blinding in randomised trials: Hiding who got what. Lancet. 2002 Feb 23;359(9307):696-700.
M AN U
133. Wood L, Egger M, Gluud LL, Schulz KF, Juni P, Altman DG, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: Meta-epidemiological study. BMJ. 2008 Mar 15;336(7644):601-5. 134. Boutron I, Moher D, Altman DG, Schulz KF, Ravaud P, CONSORT Group. Extending the CONSORT statement to randomized trials of nonpharmacologic treatment: Explanation and elaboration. Ann Intern Med. 2008 Feb 19;148(4):295-309.
TE D
135. Falagas ME, Grigori T, Ioannidou E. A systematic review of trends in the methodological quality of randomized controlled trials in various research fields. J Clin Epidemiol. 2009 Mar;62(3):227,31, 231.e1-9.
EP
136. Agha R, Cooper D, Muir G. The reporting quality of randomised controlled trials in surgery: A systematic review. Int J Surg. 2007 Dec;5(6):413-22. 137. Carlton DA, Kocherginsky M, Langerman AJ. A systematic review of the quality of randomized controlled trials in head & neck oncology surgery. Laryngoscope. 2014 Apr 12.
AC C
138. Agha RA, Camm CF, Doganay E, Edison E, Siddiqui MR, Orgill DP. Randomised controlled trials in plastic surgery: A systematic review of reporting quality. Eur J Plast Surg. 2014;37:55-62. 139. Han C, Kwak KP, Marks DM, Pae CU, Wu LT, Bhatia KS, et al. The impact of the CONSORT statement on reporting of randomized clinical trials in psychiatry. Contemp Clin Trials. 2009 Mar;30(2):116-22. 140. Chauhan SP, Berghella V, Sanderson M, Siddiqui D, Hendrix NW, Magann EF. Randomized clinical trials behind level A recommendations in obstetric practice bulletins: Compliance with CONSORT statement. Am J Perinatol. 2009 Jan;26(1):69-80.
32
ACCEPTED MANUSCRIPT
141. Bath FJ, Owen VE, Bath PM. Quality of full and final publications reporting acute stroke trials: A systematic review. Stroke. 1998 Oct;29(10):2203-10.
RI PT
142. Bhandari M, Guyatt GH, Lochner H, Sprague S, Tornetta P,3rd. Application of the consolidated standards of reporting trials (CONSORT) in the fracture care literature. J Bone Joint Surg Am. 2002 Mar;84-A(3):485-9. 143. Prady SL, Richmond SJ, Morton VM, Macpherson H. A systematic evaluation of the impact of STRICTA and CONSORT recommendations on quality of reporting for acupuncture trials. PLoS One. 2008 Feb 13;3(2):e1577.
SC
144. Adetugbo K, Williams H. How well are randomized controlled trials reported in the dermatology literature? Arch Dermatol. 2000 Mar;136(3):381-5.
M AN U
145. Turner L, Shamseer L, Altman DG, Weeks L, Peters J, Kober T, et al. Consolidated standards of reporting trials (CONSORT) and the completeness of reporting of randomised controlled trials (RCTs) published in medical journals. Cochrane Database Syst Rev. 2012 Nov 14;11:MR000030. 146. Fung AE, Palanki R, Bakri SJ, Depperschmidt E, Gibson A. Applying the CONSORT and STROBE statements to evaluate the reporting quality of neovascular age-related macular degeneration studies. Ophthalmology. 2009 Feb;116(2):286-96.
AC C
EP
TE D
147. Chan L, Heinemann AW, Roberts J. Elevating the quality of disability and rehabilitation research: Mandatory use of the reporting guidelines. Arch Phys Med Rehabil. 2014 Mar;95(3):415-7.
Figure 1 legend
33
ACCEPTED MANUSCRIPT
Figure 1 shows the article identification process. A total of 105 RCT reports were included in the current review.
RI PT
Figure 2 legend
Figure 2 shows the comparison of RCTs published during 1976-2001(n=38) with those
published during 2002-2010 (n=51). A statistically significant improvement is observed
SC
between the two periods in reporting the pre-specified primary/secondary outcomes (RR:1.33, CI:1.15-1.75) and the method of randomization sequence generation (RR: 2.79, 95% CI: 1.45-
M AN U
5.39), details of the allocation concealment (RR: 2.31, 95% CI: 1.30-4.11) and attrition due to loss to follow up (RR 1.23, 95% CI 1.02-1.49).
Figure 3 legend
TE D
Figure 3 shows a further comparison of RCTs published during 2002-2010 (n=51) with those published during 2011-September, 2013 (n=16). A statistically significant improvement was observed between the two periods in reporting details in sample size calculation (RR 1.82, 95%
AC C
EP
CI 1.18-2.81) and intent to treat analysis (RR 1.18, 95% CI 1.05-1.34).
34
ACCEPTED MANUSCRIPT
M AN U
SC
RI PT
Table 1. Methodological Items and Definitions Used to Assess Reporting of Randomized Controlled Trials CONSORT Guidelines Items and Definitions 2010 2001 Primary outcome Study primary or main outcome(s) explicitly defined. √ √ Sample size Sample size calculation stated to be carried out. √ √ Randomization Sequence generation Method used to generate the random allocation sequence described. √ √ Allocation concealment Mechanism used to implement the random allocation sequence and /or steps used to conceal the sequence until interventions were assigned described. √ √ Implementation Personnel who generated the random allocation sequence, enrolled participants, and assigned participants to interventions specified. √ √ Blinding – who was blind Study participants, care providers, outcome assessors, or investigators with no knowledge of the participants’ group allocation stated to be blinded; or the trial stated to be blinded, single blind, double blind, or triple blind.
Blinding – how blinding was achieved
Similarities between interventions or procedures described, or the trial stated to be placebo controlled or unblinded.
AC C
EP
TE D
Attrition – loss to follow-up For each group, the numbers of participants who losses to follow-up listed, with reasons. Intention to treat analysis Randomized participants with available data stated as having been included in an intention to treat analysis.
√
√
√
-
√
√
√
√
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Table 2. General Characteristics of Randomized Controlled Trials in Adult Traumatic Brain Injury Trials by publication years All trials 1976-2001 2002 – 2010 2011 – Sept. 2013 N=105 N=38 N=51 N=16 Trial design Parallel 99 (94.3) 37 (97.4) 46(90.2) 16 (100.0) Crossover 4 (3.8) 0 (0.0) 4 (7.8) 0 (0.0) Other 2 (1.9) 1 (2.6) 1 (2.0) 0 (0.0) Intervention Drug 40 (38.1) 18 (47.4) 18 (35.3) 4 (25.0) Surgery or procedure 6 (5.7) 0 (0.0) 3 (5.9) 3 (18.8) Rehabilitation 34 (32.4) 12 (31.6) 19 (37.3) 3 (18.8) Others 25 (23.8) 8 (21.1) 11 (21.6) 6 (37.5) Trial locations U.S. trials 48 (45.7) 19 (50.0) 21 (41.2) 8 (50.0) Non-US trials 57 (54.3) 19 (50.0) 30 (58.8) 8 (50.0) Study centers Single 52 (49.5) 15 (38.5) 30 (58.8) 7 (43.8) Multiple 44 (41.9) 19 (50.0) 16 (31.4) 9 (56.3) Unclear 9 (8.6) 4 (10.5) 5 (9.8) 0 (0.0) Number of study groups Two 93 (88.6) 35 (92.1) 44 (86.3) 14 (87.5) Three or more 12 (11.4) 3 (7.9) 7 (13.7) 2 (12.5) Sample size 102.0 119.0 99.0 118.0 Median per trial (39.0-463.0) (30.0-693.0) (39.0-404.0) (39.0-433.0) (10th to 90th percentile)
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Table 3. Reporting Characteristics of Randomized Controlled Trials in Adult Traumatic Brain Injury Trials by publication years All trials 1976-2001 2002 – 2010 N=105 N=38 N=51 “Randomized” stated in the title Stated 52 (49.5) 13 (34.2) 31 (60.8) Location of the data collection Reported 85 (81.0) 32 (84.2) 37 (72.6) Predefined primary outcome Defined 82 (78.1) 24 (63.2) 43 (84.3) Sample size calculation Stated 43 (41.0) 10 (26.3) 21 (41.8) Method of random sequence generation Reported 49 (46.7) 8 (21.1) 30 (58.8) Method of allocation concealment Reported 48 (45.7) 10(26.3) 31 (60.8) Implementation 30 (28.6) 4 (10.5) 20 (39.2) Any report (personnel who generated sequence, administered intervention and/or assigned intervention groups) One of the three 13 (43.3) 1 (25.0) 11 (55.0) Two of the three 12 (40.0) 3 (75.0) 5 (25.0) All three 5 (16.7) 0 (0.0) 4 (20.0) Blinding-who was blinded Any blinding 61 (58.1) 21 (55.3) 32 (62.8) Details reported* 50 (82.0) 14 (66.7) 28 (87.5) 11 (18.0) 7 (33.3) 4 (12.5) Details not reported† ‡ 13 (12.4) 3 (7.9) 9 (17.7) Unblinded Not reported 31 (29.5) 14 (36.8) 10 (19.6) Blinding-how blinding was achieved Any blinding 55 (52.4) 21 (55.3) 29 (56.9) § 35 (63.6) 13 (61.9) 19 (65.5) Details reported || 20 (36.4) 8 (38.1) 10 (35.5) Details not reported Unblinded 13 (12.4) 3 (7.9) 9 (17.7) Not reported 37 (35.2) 14 (36.8) 13 (25.5) Participation diagram Included 49 (46.7) 25 (65.8) 31 (60.8) Period of the recruitment Reported 71 (67.6) 29 (76.3) 34 (66.7)
2011 – Sept. 2013 N=16 8 (50.0) 16 (100.0) 15 (93.8) 12 (75.0) 11 (68.8) 7 (43.8) 6 (37.5) 1 (16.7) 4 (66.7) 1 (16.7) 8 (50.0) 8 (100.0) 0 (0.0) 1 (6.3) 7 (43.8) 5 (31.3) 3 (60.0) 2 (40.0) 1 (6.3) 10 (62.5) 13 (81.3) 12 (75.0)
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Period of the follow-up Reported 87 (82.9) 29 (76.3) 43 (84.3) Attrition-Loss to follow-up for each group Reported 93 (88.6) 29 (76.3) 48 (94.1) Reasons given¶ 82 (88.2) 23 (79.3) 44 (91.7) Reasons not given 11 (11.8) 6 (20.7) 4 (8.3) Attrition-Intention to treat analysis Reported 89 (84.8) 30 (78.9) 43 (84.3) As all randomized participants 38 (42.7) 13 (43.3) 18 (41.9) As randomized with available data 51 (57.3) 17 (56.7) 25 (58.1) Trial registration Reported 17 (16.2) 2 (5.3) 8 (15.7) Trial protocol Reported 2 (1.9) 0 (0.0) 1 (2.0) Funding Reported 68 (64.8) 21 (75.3) 35 (68.6) Solely industry 12 (17.7) 6 (28.6) 4 (11.4) Part industry 6 (8.8) 2 (9.5) 2 (5.7) Non-industry 50 (73.5) 13 (61.9) 29 (82.9) *Article reports exactly who was blinded; † Report stated used the terms “blinded”, “single blind,” or “double blind,” or similar, without providing further details on who was blinded; ‡Trial stated as unblinded if explicitly stated as such or blinding clearly not possible; § Article reports similarities between interventions or procedures; || Trial stated as placebo controlled, without further details on how placebo control was achieved; ¶ Including trial reports stated that there was no loss to follow-up.
15 (93.8) 16 (100.0) 15 (93.8) 1 (6.3) 16 (100.0) 7 (43.8) 9 (56.3) 7 (43.8) 1 (6.3) 12 (75.0) 2 (16.7) 2 (16.7) 8 (66.7)
ACCEPTED MANUSCRIPT
Databases: MedLine, PsycINFO and CINAHL Through September 30, 3013
RI PT
Figure 1 Study Selections
9 trial reports added from Gordon et al. 2006, Cernich et al. 2010 and Maas et al. 2010
M AN U
1378 trial reports screened
SC
Search terms: “Traumatic Brain Injury OR Brain Injury” “AND” “Randomized Controlled Trials OR Randomized Controlled Trials”
TE D
Total 1387 reports identified
EP
122 reports eligible for full-text review
AC C
Final study inclusion 105 trials
1104 excluded on titles 161 excluded on abstract
Participants not predominately TBI (n=5) Focus on non-TBI related outcomes (n=6) Early phase trials (n=3) Not RCT (n=1) Duplicate studies (n=2)
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Text Box 1. Reporting Allocation Concealment and Blinding Allocation concealment - Report the mechanism of allocation concealment - Report the implementation process (i.e., the personnel who enrolled the participants, ascertain the intervention assignment and administered intervention) Blinding - Not only report the single-blind, double blind, or triple-blind terminology, but also explicitly state who is blinded and how blinding is achieved - Report all involved healthcare personnel for whom blinding may influence the validity of a trial (e.g., care providers, interventionist cointerventionist, outcome assessors and adjudicators)
S0003-9993(14)01280-5
DOI:
10.1016/j.apmr.2014.10.026
Reference:
YAPMR 56049
To appear in:
ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION
Received Date: 8 July 2014 Revised Date:
3 October 2014
Accepted Date: 31 October 2014
Please cite this article as: Lu J, Gary KW, Copolillo A, Ward J, Niemeier JP, Lapane KL, Randomized Controlled Trials in Adult Traumatic Brain Injury: A Review of Compliance to CONSORT Statement, ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION (2015), doi: 10.1016/ j.apmr.2014.10.026. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Running Title: Quality of RCT reports in TBI research
RI PT
Randomized Controlled Trials in Adult Traumatic Brain Injury: A Review of Compliance to CONSORT Statement
Juan Lu1, Kelli W. Gary2, Al Copolillo3, John Ward4, Janet P. Niemeier5, Kate L. Lapane6
3. 4. 5.
SC
EP
6.
M AN U
2.
Department of Family Medicine and Population Health, Division of Epidemiology, Virginia Commonwealth University, Richmond, VA, U.S.A. Email: [email protected]; Phone number: 8048289786 Department of Occupational Therapy, Virginia Commonwealth University, Richmond, VA, U.S.A. Email: [email protected]; Phone number: 8048283412 Department of Occupational Therapy, Virginia Commonwealth University, Richmond, VA, U.S.A. Email: [email protected]; Phone number: 8048282220 Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, U.S.A. Email: [email protected]; Phone number: 8048278400 Department of Physical Medicine and Rehabilitation, Carolinas Rehabilitation, 1100 Blythe Boulevard, Charlotte, NC, U.S.A. Email: [email protected]; Phone number:7043552046 Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA, U.S.A. Email: [email protected]; Phone number: 5088568999
TE D
1.
Juan Lu M.D., M.P.H., Ph.D.
AC C
Corresponding author: Address:
Email address: Phone number: Fax number:
Department of Family Medicine and Population Health, Division of Epidemiology, Virginia Commonwealth University, Richmond, VA, U.S.A. [email protected] 804 8289786 804 8289773
The authors report no declarations of interest. The work is supported by CTSA award No. UL1TR000058 from the National Center for Advancing Translational Sciences
1
ACCEPTED MANUSCRIPT
Abstract Objective: To describe extent to which adherence to Consolidated Standards of Reporting Trials (CONSORT) Statement in randomized controlled trials (RCTs) in adult traumatic brain injury
RI PT
(TBI) has improved over time. Data Sources: MedLine, PsycINFO and CINAHL databases were searched from inception to September, 2013.
SC
Study Selection: Primary report of randomized controlled trials in adult traumatic brain injury. The quality of reporting on CONSORT checklist items was examined and compared over time.
M AN U
Study selection was conducted by 2 researchers independently. Any disagreements were solved by discussion.
Data Extraction: Two reviewers independently conducted data extraction based on a set of structured data extraction forms. Data regarding the publication years, size, locations,
TE D
participation centers, intervention types, intervention groups and CONSORT checklist items were extracted from the including trials.
Data Synthesis: Of 105 trials reviewed, 38.1%, 5.7% and 32.4% investigated drugs, surgical
EP
procedures and rehabilitations as the intervention of interest, respectively. Among reports published between 2002-2010 (n=51) and 2011-September, 2013 (n=16), median sample size
AC C
was 99 and 118; 39.2% and 37.5% detailed implementation of randomization process; 60.8% and 43.8% of all reports provided information on method of allocation concealment; 56.9% and 31.3% stated how blinding was achieved; 15.7% and 43.8% reported information regarding trial registration and only 2.0% and 6.3% stated where full trial protocol could be accessed, respectively. Conclusions: Reporting of several important methodological aspects of RCTs conducted in adult TBI population improved over years; however, quality of reporting remains below an acceptable 1
ACCEPTED MANUSCRIPT
level. The small sample sizes suggest that many RCTs are likely underpowered. Further improvement is recommended in designing and reporting RCTS.
Randomized controlled trials – RCTs Traumatic brain injury - TBI
AC C
EP
TE D
M AN U
Consolidated Standards of Reporting Trials - CONSORT
SC
Abbreviations
RI PT
Key words: Randomized controlled trials, traumatic brain injury, CONSORT Statement
2
ACCEPTED MANUSCRIPT
1 2
Well-designed and properly conducted RCTs provide the most reliable evidence in health interventions. This, in turn, leads to improvement in the prevention or treatment of disease (1).
4
Many RCTs have been conducted with adequate methodological rigor to advance scientific
5
knowledge. The ability to evaluate and disseminate this knowledge directly rest on the
6
transparent and thorough reporting of trial methodology and findings. The lack of adequate
7
reporting influences readers’ interpretation of the evidence and makes it more difficult to
8
replicate the results for future research and follow recommended treatment options (2, 3). In
9
order to alleviate this problem, guidelines have been created to assist researcher, peer-reviewers
SC
M AN U
10
RI PT
3
and journal editors in complete reporting of RCTs.
The Consolidated Standards of Reporting Trials (CONSORT) Statement is a minimum
12
set of evidence-based recommendations designed to improve the quality of reporting RCTs. It
13
was initially published in 1996 (4), then revised twice subsequently in 2001 and 2010 (5, 6). The
14
revisions were each accompanied by a detailed explanation and elaboration document for the
15
purpose of enhancing the use, understanding, and dissemination of the Statement (7, 8). The
16
COSNORT provides structured guidance to help researchers prepare reports of trial findings,
17
facilitate complete and transparent reporting, and aid in critical appraisal and interpretation. The
18
most current version of the statement includes a 25 item checklist and a flow diagram. The
19
checklist provides standardized approaches to report the trial design, analysis and interpretation
20
and the diagram gives instructions to display the progress of all participants throughout the trial.
EP
AC C
21
TE D
11
Since the initial publication, the quality of clinical trial reporting has improved over the
22
years in general (9, 10) and in many medical specialties (11-13). However, far from satisfactory,
23
incompleteness and inaccurate reporting of trial results compounded with poor methodological
24
rigor remain a serious concern (10, 14-16). 3
ACCEPTED MANUSCRIPT
Thus far, there are limited assessments of CONSORT compliance and improved
26
reporting in randomized controlled trials (RCTs) in traumatic brain injury (TBI) literature. We
27
previously reported on 100 RCTs in adult TBI with the aims of synthesizing evidenced based
28
interventions and facilitating the effectiveness of interdisciplinary care (17). The current review
29
extends previous work by (1) examining the extent that these reports of RCTs adhere to the
30
CONSORT Statement and (2) assess whether the quality of reports has improved over time.
31
Methods
32
Study sample
SC
From our previous review (17), we searched databases of MedLine, PsycINFO and
M AN U
33
RI PT
25
CINAHL to identify all primary reports of RCTs in adult TBI populations through June 29th,
35
2011, using the search terms of ‘Traumatic Brain Injury or Brain Injury’ plus ‘Randomized
36
Controlled Trials or Randomised Controlled Trials’. Hand searches against published reviews
37
were also performed. Two authors independently assessed titles, abstract and full-texted articles
38
according the eligibility criteria. We excluded trials with (1) exclusive pediatric samples, (2)
39
acquired brain injury samples, unless the sample was predominantly TBI or the results were
40
reported separately for the TBI sample and met the search criteria, (3) a sample size less than 20,
41
(4) a focus on specific symptoms following TBI (e.g. elbow contractures, seizures, etc.), (5) a
42
focus on safety and pharmacokinetics solely, or (6) non-English languages. As a result, the
43
review selected 100 eligible studies, including 93 published RCT reports and seven studies with
44
unpublished results (18).
EP
AC C
45
TE D
34
For this review, we updated the initial research and further included 12 published RCT
46
reports up to September, 2013. After excluding seven studies with unpublished results from the
47
previous review, this review included a total of 105 RCT reports in adult TBI populations.
48
Data extraction 4
ACCEPTED MANUSCRIPT
49 50
Data extraction was carried out by three authors (J.L., A.E.C. and K.W.G.). For each article, at least two authors independently extracted data. To ensure the quality and consistency
52
of the data extraction, the process started with practice on the first ten reports reviewed, from
53
which authors extracted data based on a set of structured data extraction forms and discussed all
54
discrepancies. Most differences were due to differing interpretation of the data extraction form;
55
thus the form was modified and the exercise repeated using another ten articles until agreement
56
was reached for all data items listed on the form. Following the agreement on the data extraction
57
form, the same authors continued the process of data extraction and resolving discrepancies for
58
the remaining reports. The overall rater agreement on the assessment of checklist items is 96%.
59 60 61
CONSORT compliance
62
original 25 items, this study evaluated the items that can be assessed and compared objectively
63
across trials. The methodological items include: the use of the term ‘randomized trial’ in the title,
64
location of data collection, predefined primary outcome, sample size estimation, method of
65
randomization sequence generation, allocation concealment and implementation, who was blind
66
and how blinding was achieved, publication of a participant flow diagram, period of recruitment,
67
period of follow up, as well as the attrition due to loss to follow-up and intention to treat
68
analysis. Since more than half the trial reports in this review were published before CONSORT
69
revision in 2001 (5, 7), Table 1 provides methodological items and definitions used to assess
70
reporting of RCTs, and comparisons of these items in CONSORT versions 2001 and 2010. The
71
definitions were mainly adopted from Hopewell and colleagues (10) with some revision. In
72
addition, the information regarding the status of trial registration, accessibility of the full
M AN U
SC
RI PT
51
AC C
EP
TE D
We used the 2010 CONSORT reporting guideline (6, 8) to evaluate the studies. From the
5
ACCEPTED MANUSCRIPT
73
protocol and funding resources (i.e., reported as solely industry, part industry or non-industry, or
74
not reported) were also assessed. Table 1 here
75
Other data extraction
79
trials), participation centers (i.e., single or multicenter), intervention types (i.e., drug
80
intervention, rehabilitation or others) and intervention groups (i.e., two, or three or more groups).
SC
We also extracted data on the trial publication years, size, locations (i.e., U.S. or non-U.S.
Statistical analysis
M AN U
81 82 83 84
RI PT
76 77 78
We summarize the data descriptively. The numbers and proportions of the methodological items were reported by the publication years. The years were grouped into three periods: trial reports
86
published (1) before the CONSORT 2001 revision, (2) after the 2001 revision but before the
87
2010 revision and (3) after the 2010 revision. The descriptive summary statistics were used to
88
compare the quality of RCT reports published between the periods. Risk ratios and associated
89
95% confidence intervals were calculated and used to quantify changes in reporting between the
90
publication periods. Forest plots were used to illustrate the methodological compliance between
91
the publication years. SAS (Version 9.4, SAS Institute Inc., Cary, NC, US) was used for all
92
analyses.
93 94
Results
95
Study selections
EP
AC C
96
TE D
85
A total of 105 RCT reports were included in the current review. Figure 1 shows the
97
article identification process.
98 99 100
General trial characteristics
Figure 1 here 6
ACCEPTED MANUSCRIPT
101 102
Table 2 provides information on general trial characteristics, according to the publication periods of (1) 1976-2001 (before and up to the revision in 2001), (2) 2002-2010 (before and up
104
to the revision in 2010) and (3) 2011-September, 2013 (after the revision in 2010). Of 105
105
eligible trial reports reviewed, 38 (19-57) , 51 (58-108) and 16 (109-124) were published up to
106
the first, second and after the second waves of the revisions respectively. A vast majority
107
(94.3%) of trials used parallel group design (99/105), and the remaining 3.8% (4/105) and 1.9%
108
(2/105) used crossover and other types of designs respectively. Overall, 38.1% (40/105) of the
109
trials investigated drugs as the primary intervention of interest, 5.7% (6/105) assessed surgical
110
procedures, 32.4% (34/105) assessed rehabilitation related interventions and 23.8% (25/105)
111
studied other types of treatment, such as hypothermia treatment, nutritional treatments, etc.
112
Noticeably, the percentages of trials investigating drug treatments have decreased over the years,
113
with 47.4% (18/38), 35.3% (18/51) and 25.0% (4/16) reported during the periods of 1976-2001,
114
2002-2010 and 2011-September, 2013, respectively. The percentages of rehabilitation related
115
interventions were 31.6% (12/38), 37.3% (19/51) and 18.8% (3/16) during the accordance
116
periods, respectively.
SC
M AN U
TE D
EP
117
RI PT
103
Of all trial reports reviewed, 45.7% (48/105) of trials were conducted in the United Sates while 54.3% (57/105) were conducted abroad or internationally. The proportion of trials
119
conducted in the States decreased relatively from the period of 1976-2001 to the periods of 2002-
120
2010, and 2011-September, 2013 [from 50.0% (19/38) to 41.2% (21/51) and 50% (8/16)]. Close
121
to 50% (52/105) of all reports clearly stated that the trial was conducted at a single center and
122
41.9% (44/105) stated that the trial took place at multiple centers; the number of study centers
123
was not explicitly defined in 8.6% of the reports (9/105). Close to 89% (93/105) of all trials
124
consisted of two study groups, while 11.4% (12/105) consisted of three or more groups. The
AC C
118
7
ACCEPTED MANUSCRIPT
125
median number of participants recruited per trial was 102.0 (10th to 90th percentile: 39.0 to
126
463.0).
128
CONSORT compliances of the methodological items
RI PT
Table 2 here
127
Table 3 shows information on the CONSORT compliances of the methodological items,
129
according to the publication periods of (1) 1976-2001, (2) 2002-2010 and (3) 2011-September,
131
2013.
Table 3 here
M AN U
132 133 134 135 136 137
SC
130
Statement of ‘Randomization’ in the title and location of data collection About 50% (52/105) of all trial reports stated that the study was randomized in the title of the report. Compared with the reports published during the period of 1976-2001, an
139
improvement is observed in reports published during the periods of 2002-2010 and 2011-
140
September, 2013, from 34.2% (13/38) to 60.8% (31/51) and 50% (8/16). 81% (85/105) of all
141
reports provided location of the trial data collection, with 84.2% (32/38), 72.6% (37/51) and
142
100% (16/16) for the three periods respectively.
143 144 145
Predefined primary outcomes and sample size calculations
146
(43/105) stated that a sample size calculation had been undertaken. The proportions of pre-
147
specified primary outcomes among reports reviewed were relatively high and further improved
148
after the CONSORT revision in 2001. 84% (43/51) and 93.8% (15/16) of the trials reported the
149
primary outcomes during the periods of 2002-2010 and 2011-September, 2013 whereas 63.2%
150
(24/38) of the trials during the periods of 1976-2001. An improvement in reporting the study
151
sample size is also observed after 2001. 41.8% (21/51) and 75.0% (12/16) of the reports stated
EP
TE D
138
AC C
Of all reports, 78.1% (82/105) defined the primary outcome; whereas only 41.0%
8
ACCEPTED MANUSCRIPT
152
that sample size calculation had been undertaken during the periods of 2002-2010 and 2011-
153
September 2013, whereas only 26.3% (10/38) during the period of 1976-2001.
154 155 156
Methods of randomization sequence generation, allocation concealment and implementation
157
randomization sequence, 45.7% (48/105) reported the allocation concealment method and 28.6%
158
(30/105) provided information on who generated the sequence, administered the intervention
159
and/or assigned the intervention groups.
SC
RI PT
Overall, 46.7% (49/105) of the trials reported the methods used to generate the
A steady improvement is observed in reporting the methods that were used to generate
161
the randomization sequence after the revisions in 2001 and 2010. During the periods of 2002-
162
2010 and 2011-September 2013, 58.8% (30/51) and 68.8% (11/16) of trials reported the
163
methods, while only 21.1% (8/38) during the periods of 1976-2001. An improvement in
164
reporting the methods of allocation concealment and implementation of the randomization
165
process is also observed during the two later periods. For the periods of 1976-2001, 2002-201 0
166
and 2011-September 2013, 26.3% (10/38), 60.8% (31/51) and 43.8% (7/16) of trials reported the
167
allocation concealment methods; and 10.5% (4/38), 39.2% (20/51) and 37.5% (6/16) of trials
168
provided any information on who implemented the randomization process.
TE D
EP
169
M AN U
160
Moreover, among 30 trials that reported personnel who implemented the randomization process, only 16.7% (5/30) clearly stated all personnel who generated sequence, assigned
171
intervention groups and/or administered intervention; while 43.3% (13/30) and 40.0% (12/30)
172
reported personnel who implemented either one or two of the three randomization tasks stated
173
above. The reporting of individual personnel who implemented the randomization process was
174
poor across all observed publication periods.
175 176
Who was blinded and how blinding was achieved
AC C
170
9
ACCEPTED MANUSCRIPT
177
Among all reports, 58.1% (61/105) reported whether there was any blinding, 12.4% (13/105) stated that the trial was not blinded, and 29.5% (31/105) did not report who was blinded
179
at all. Of 61 trials reporting any blinding, 82.0% (50/61) provided specific details on who was
180
blinded after assignment to interventions (for example, study participants, care providers,
181
outcome assessors), whereas the remaining 18.0% (11/61) simply used the terms “blinded”,
182
“single blind”, or “double blind” without providing further details. The performance of the
183
reporting on any blinding was relatively consistent over time. However, among the trials
184
reporting any blinding, 87.5% (28/32) and 100.0% (8/8 ) of the reports published during 2002-
185
2010 and 2011-September, 2013 provided specific details on who was blinded, while only 61.9%
186
(13/21) during 1976-2001 provided such details.
SC
M AN U
187
RI PT
178
In addition to reporting who was blinded, 52.4% (55/105) of the trial reports provided information on how blinding was achieved. Of these, 63.6% (35/55) specifically described any
189
similarities between the interventions or procedures (e.g., identical in size, color, taste, or method
190
of administration), whereas the remaining 36.4% (20/55) simply used the term “placebo” without
191
providing further details. For the periods of 1976-2001, 2002-2010 and 2011-September 2013,
192
55.3% (21/38), 56.9% (29/51) and 31.3% (5/16) of the trial reports provided information on how
193
blinding was achieved. Among trials reporting any blinding, 61.9% (13/21), 65.5% (19/29) and
194
60.0% (3/5) of the trial reports provided specific details on how blinding was achieved.
195 196 197 198
Participation diagram, periods of recruitment and follow up and attritions of loss to follow ups and intention to treat analysis
199
inclusion of a participation diagram in trial reports has been improving since its revision in 2010,
200
from 65.8 (25/38) and 60.8% (31/51) for the reports published during 1976-2001 and 2002-2010
201
to 81.3% (13/16) during 2011-September, 2013.
AC C
EP
TE D
188
A participant flow diagram was given in 46.7% (49/105) of the trial reports. The
10
ACCEPTED MANUSCRIPT
202
Overall, more than two-thirds of the trial reports [67.6% (71/105)] supported information on the time of the recruitment period and most of the reports [82.9% (87/105)] provided
204
information on the follow up period. The reporting of trial recruitment period was relatively
205
consistent over the study periods [76.3% (29/38), 66.7% (34/51), and 75.0% (12/16)
206
respectively], but reporting on follow-up periods was improving [76.3% (29/38), 84.3% (43/51)
207
and 93.8% (15/16), respectively].
Of all trials, 88.6% (93/105) of the trial reports provided information on any loss to
SC
208
RI PT
203
follow-up for each study group or reported no loss to follow up; among 93 trials reporting such
210
information, 88.2% (82/93) provided the reasons for attrition or reported that there was no loss to
211
follow-up. Of the periods within which the reports were reviewed, the period of 1976-2001 did
212
the worst relative to the others, with 76.3% (29/38) of the trials reporting any loss of follow up or
213
reporting no loss to follow up; and of those 29 reports, 79.3% (23/29) providing the reasons for
214
attrition or reporting that there was no loss to follow up. Of the periods of 2002-2010 and 2011-
215
September, 2013, 94.1% (48/51) and 100% (16/16) provided such information, and 91.7%
216
(44/48) and 93.8% (15/16) provided the reasons for attrition or reported that there was no loss to
217
follow up, respectively.
TE D
EP
218
M AN U
209
Similar to performance of reporting of the attrition to loss to follow up, 84.8% (89/105) of all trial reports stated that intention to treat analysis was applied. Among 89 trials, 42.7%
220
(38/89) of the trials included all randomized participants in the analysis, 57.3% (51/89) included
221
randomized subjects with available outcomes only. Again, of the three periods, the period of
222
1976-2001 did worse relative to the others, with 78.9% (30/38) of the trials stating that intention
223
to treat analysis was applied. Further, of the 30 trials, 43.3% (13/30) included all randomized
224
participants in the analysis. Of the two later periods, 84.3% (43/51) and 100.0% (16/16) stated
AC C
219
11
ACCEPTED MANUSCRIPT
225
that the intention to treat analysis was applied, and 41.9% (18/43) and 43.8% (7/16) reported the
226
inclusion of all randomized participants in the analysis.
227 228 229
Trial registrations, protocols and funding resources
230
registration and where the full trial protocol could be accessed (1.9%, 2/105). Since the first
231
U.S. Federal law of requiring trial registration was established in 1997 and the registry of
232
ClinicalTrials.gov was released by National Institution of Health (NIH) in 2000, the trial report
233
regarding the information of the trial registration still well below the optimal level. For the two
234
later periods of 2002-2010 and 2011-September, 2013, only 15.7% (8/51) and 43.8% (7/16)
235
reported such information accordingly, although recognizing some trials conducted abroad may
236
not necessary having the same requirement.
RI PT
SC
M AN U
237
Of all reports reviewed, only 16.2% (17/105) of the trial reports provided details of trial
Overall, the details of the funding sources were provided in 64.8% (68/105) of all trial reports. Of these 68 trials, 26.5% (18/68) of the trials were funded solely [17.7% (12/68)] or
239
partially [8.8% (6/68)] by industry and the remaining 73.5% (50/68) were funded by non-
240
industry resources. Among all that reported the funding sources, 38.1% (8/21), 17.1% (6/35) and
241
33.4% (4/12) of the trials were fully or partially funded by industry during the periods of 1976-
242
2001, 2002-2010 and 2011-September, 2013, respectively.
243 244 245
RCTs published during 1976-2001 vs. those published during 2002-2010
246
first revision in 2001) with those (n=51) published during 2002-2010 (following the first revision
247
and up to the second revision in 2010). There was a statistically significant improvement
248
between the two periods in the proportion of trial reports that reported pre-specified
249
primary/secondary outcomes [Relative Risk (RR):1.33, 95% confidence interval (CI):1.15-1.75)]
AC C
EP
TE D
238
Figure 2 shows the comparison of RCTs (n=38) published during 1976-2001 (up to the
12
ACCEPTED MANUSCRIPT
and the method of randomization sequence generation (RR: 2.79, 95% CI: 1.45-5.39), details of
251
the allocation concealment (RR: 2.31, 95% CI: 1.30-4.11) and attrition due to loss to follow up
252
(RR 1.23, 95% CI 1.02-1.49). Various improvements between the two periods in the proportion
253
of the reports were also observed, although they did not reach statistical significance. The
254
improvements included providing sample size calculation (RR 1.41, 95% CI 0.84-2.92), blinding
255
after assignment of interventions (RR 1.27, 95% CI 0.96-1.68), and intent to treat analysis (RR
256
1.07, 95% CI 0.87-1.31). Figure 2 here
257
SC
RI PT
250
RCTs published during 2002-2010 vs. those published during 2011-September, 2013
261
(following the first revision and up to the second revision in 2010) with those (n=16) published
262
during 2011-September, 2013 (following the second revision). There was a statistically
263
significant improvement between the two periods in the proportion of trial reports including
264
details in sample size calculation (RR 1.82, 95% CI 1.18-2.81) and intent to treat analysis (RR
265
1.18, 95% CI 1.05-1.34). The improvements between the two periods were also observed in the
266
proportion of the reports including details of the primary outcome (RR 1.11, 95% CI 0.93-1.32)
267
and the methods of random sequence generation (RR 1.17, 95% CI 0.78-1.75) and loss to follow
268
up (RR: 1.06: 95% CI: 0.99-1.14), but did not reach statistical significance. There was no
269
difference in the proportion of trials that provided specific details on the method of allocation
270
concealment (RR 0.72, 95% CI 0.40-1.31) and on who was blinded after assignment to
271
interventions (RR 0.70, 95% CI 0.44-1.10).
M AN U
258 259 260
AC C
EP
TE D
Figure 3 shows a further comparison of RCTs (n=51) published during 2002-2010
Figure 3 here
272 273
Discussion
13
ACCEPTED MANUSCRIPT
274 275
Study findings We performed comprehensive assessment of the quality of reports from105 RCTs in adult TBI research published in databases of MedLine, PsycINFO and CINAHL between 1976
277
and September, 2013. The quality of reports was examined against the CONSORT reporting
278
guidelines and compared over time. We specifically compared (1) RCT reports (n=38) published
279
during 1976-2001 (up to the first CONSORT revision in 2001) with those (n=51) published
280
during 2002-2010 (following the first revision and up to the second revision in 2010), and (2)
281
reports published during 2002-2010 with those (n=16) published during 2011-September, 2013
282
(following the second revision in 2010). Over the past 3 decades, the quality of RCT reports has
283
improved over time in the field of TBI research. From the period of 1976-2001 to the period of
284
2002-2010, a significant improvement was observed in reporting the pre-specified primary and
285
secondary outcomes, methods of randomization sequence generation and allocation concealment,
286
and trial attritions due to loss to follow-up. From the period of 2002-2010 to the period of 2011-
287
September, 2013, significant improvements continued in reporting the details of sample size
288
calculation and intent to treat analysis. Various improvements were also noticed in other
289
CONSORT checklist items, although the improvements were not statistically significant.
SC
M AN U
TE D
EP
290
RI PT
276
Of 105 eligible trials reviewed in adult TBI research, 38.1% of the trials investigated drugs as the primary intervention of interest, 5.7% assessed surgical procedures, 32.4% assessed
292
rehabilitation related interventions and 23.8% studied other types of treatment. A vast majority
293
of trials in adult TBI used parallel group design (94.3%, 99/105), mostly with two study groups
294
(88.6%, 93/105). In this cohort, the median size per trial is 102 subjects with the 10th and 90th
295
percentile ranging between 39 and 463. Little improvement in reporting has been seen over time.
296
The small size observed in this review is of concern. In general, for a trial with two comparison
AC C
291
14
ACCEPTED MANUSCRIPT
groups, a sample size of 102 (or 51 per group) has only 56% power to detect a difference
298
between an event rate of 40% and 60% (e.g., an improvement of 20% from an unfavorable
299
outcome to a favorable outcome in the treatment group) at a 0.05 significance level. In practice,
300
the effect size could be even smaller than the absolute differences as given in our example; and
301
the power determined a priori could be further compromised by study attrition. As pointed out by
302
other studies, trials with inadequate power could result in a high false-negative error rate and are
303
likely associated with publication bias (9, 125, 126).
SC
304
RI PT
297
Among all CONSORT checklist items examined, the improvement in reporting the methods of randomization sequence generation and allocation concealment noticed in this study
306
are of great importance, as studies have shown that it is strongly associated with effect estimates
307
(127-130). For any RCTs, the method of randomization is a key component to minimize any
308
measured and unmeasured differences between the comparison groups. A successful
309
randomization process relies on three different steps: sequence generation, allocation
310
concealment and implementation. After generation of unpredictable allocation sequence, it is
311
important to conceal this sequence from the investigators enrolling participants. Proper designed
312
allocation concealment mechanism prevents selection bias and can always be successfully
313
implemented (8).
TE D
EP
After participants received treatment assignment, blinding is another important safeguard
AC C
314
M AN U
305
315
against bias in RCTs although may not feasible in some situation (131). Blinding refers to
316
withholding information about the assigned intervention from people involved in the trial who
317
may potentially be influenced by this knowledge. Blinding usually reduces differential
318
assessment of outcomes, therefore the information bias, but can also improve compliance and
319
retention of trial participants while reducing biased supplemental care or treatment (132). A
15
ACCEPTED MANUSCRIPT
320
recent review by Wood and colleagues (133) found that, for subjective outcomes, trials that used
321
inadequate or unclear allocation concealment yield 31% larger estimates of effect than those that
322
used adequate concealment and trials that were not blinded yield 25% larger estimates. A portion of trials reviewed by this study are non-pharmacological trials (32.4% of all
RI PT
323
trials are rehabilitation-related interventions, 5.7% are surgical trials), for these trials, blinding of
325
intervention allocation status from the participants and caregivers may not be feasible depending
326
on the study design and nature of intervention studied. However, it is recommended that the
327
outcome assessors be blinded whenever possible, particularly for those subjective outcome
328
measurements. Further, if blinded, the trials should explicitly report method of blinding (i.e.,
329
who and how), description of the similarity of the interventions, and whether or not those
330
administering co-interventions were blinded (134).
M AN U
331
SC
324
Although the data suggest that there has been significant improvement in reporting the quality parameters of allocation concealment, we should also point out that the current quality of
333
reporting RCTs is still below an acceptable level. Among the most recent reports published in the
334
period between 2011-September, 2013, less than half of all reports provided information on the
335
method of allocation concealment; detailed the implementation of the randomization process;
336
stated how blinding was achieved; and provided information regarding the trial registration. As
337
these quality parameters are associated with potential biased estimation of intervention effect, we
338
further highlighted some recommendations in Text Box 1 to facilitate the future awareness and
339
improvement in these areas.
341
EP
AC C
340
TE D
332
Text Box 1 here
Comparison to clinical trial reports in other areas of medicine
16
ACCEPTED MANUSCRIPT
342
The observation from our review on the quality of RCT reports trials is, in general, consistent with the current literature in other specialties. Many studies review the quality in
344
reporting RCTs through use of the CONSORT statement. They represent a wide range of areas
345
of medicine and span over the past couple of decades (135). More recent reviews demonstrate
346
greater adherence to CONSORT criteria (10, 15, 136-138). Like our study, most of the published
347
reviews relied on use of CONSORT 2000, but some used 1996 CONSORT guidelines to judge
348
the quality of RCTs. Comparable with our study, findings from these reviews point to overall
349
improvement in the quality of RCT reports over time as indicated by adherence to CONSORT
350
guidelines. However, most conclude that the quality of reports on RCTs has yet to reach
351
acceptable levels.
M AN U
SC
RI PT
343
A variety of methods have been used to judge the quality of RCTs and explore whether
353
improvements had occurred over time. Similar to our procedures, most studies engaged two or
354
more reviewers in a process of identifying the presence or absence of CONSORT criteria in
355
systematically identified research publications. Researchers typically searched for articles
356
identified as RCTs or clinical trials within a medical specialty area, e.g., endoscopy, psychiatry,
357
obstetrics/gynecology (12, 139, 140). Other reviews focused on a particular diagnosis or
358
intervention procedure, e.g., fractures, acupuncture, stroke (141-143). PubMed/Medline was the
359
most commonly used source; the second most popular source was the Cochrane Database of
360
Systematic Reviews. Most studies calculated the percentage of CONSORT criteria met per
361
study, a median or mean percent score, and the number of studies that reached a certain level of
362
CONSORT compliance.
363 364
AC C
EP
TE D
352
To our knowledge, our study is the only study that provided a comprehensive methodological assessment of randomized trials in adult TBI that covers more than three decades
17
ACCEPTED MANUSCRIPT
of publications. Comparing the quality of reports among the publication periods allows us to
366
examine the extent to which the quality of RCT reports in TBI research has improved over time.
367
Our sample is acquired from three large online databases and with no restriction to any specific
368
journals. Therefore, we are confident that it contains the majority of the RCT publications in
369
adult TBI. Relatively unique to our study is that we calculated risk ratios with 95% confidence
370
intervals for several key methodological items which allow quantifying changes in reporting
371
between the publication periods.
SC
372
RI PT
365
It is difficult to ascertain specific improvements or areas of neglect in use of the CONSORT across a wide range of studies. Some studies noted improvement in allocation
374
concealment (139) while others reported limited adherence in this area (142). Some saw ongoing
375
deficiency in describing the randomization process and blinding following assignment to
376
intervention group (138, 139) while others noted improvement or strength in these areas (144).
377
These differences in findings may be related to the search procedures, topic of interest and time
378
period from which the trial reports were published. Relatively consistent across all studies and in
379
agreement with our study is the recognition of improvements over time but ongoing need for
380
better adherence to CONSORT guidelines as an indicator of high quality research. The
381
endorsement by professional journals of the CONSORT Statement may influence the
382
completeness of reporting RCTs (137, 145, 146). Currently, Archives of Physical Medicine and
383
Rehabilitation, Journal of Neurosurgery, and Neurosurgery are among the TBI specialty journals
384
that endorse the CONSORT guidelines. To extend the effort, 28 rehabilitation journals recently
385
published editorial acknowledgements (147) calling for further elevation of the quality of
386
disability and rehabilitation research and mandatory use the reporting guidelines, not only for
AC C
EP
TE D
M AN U
373
18
ACCEPTED MANUSCRIPT
387
reporting RCTs, but also for other study designs. Future studies should follow up with the
388
impact of such mandatory effort on the quality of reporting RCTs in these journals.
389 390 391
Limitations
392
inclusion/exclusion criteria from our previous report (17), and these procedures could have
393
limited inclusion of all published RCT reports in TBI during the search period. However, such
394
exclusion would be minimal. Studies included in the review allowed us to fulfill our primary aim
395
to describe methodological compliance with the CONSORT recommendation and compare
396
improvement in trial reporting over time among a representative sample. Some CONSORT
397
checklist items were not assessed in this review since they could not be objectively compared
398
across trials even though they are all of equal importance in evaluating the quality of the report.
399
We agree with Hopewell and colleagues (10) on the point that poor reporting does not
400
necessarily mirror the actual methods that were carried out in a trial. In practice, there might be
401
studies that had better quality of design in the study protocol than that in the final publication.
402
Conversely, there might be studies that have shown more information about the trial design and
403
conduct in the published reports than that in the actual protocols.
404
Conclusions
405
Reporting of several important methodological aspects of RCTs conducted in adult TBI
406
population improved over the years, however, quality of reporting remains below an acceptable
407
level. The small sample sizes suggest that many RCTs are likely underpowered. Further
408
methodological improvement is recommended in both designing and reporting RCTs. Currently,
409
only limited TBI specialty journals endorsed CONSORT guidelines. More journals are
410
encouraged to join the effort to promote transparent and high quality reporting of RCTs.
AC C
EP
TE D
M AN U
SC
RI PT
Our search technique relied on MeSH key words and terms and certain
19
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
References
1. Altman DG, Moher D, Schulz KF. Improving the reporting of randomised trials: The CONSORT statement and beyond. Stat Med. 2012 Nov 10;31(25):2985-97. 2. Chalmers I, Glasziou P. Avoidable waste in the production and reporting of research evidence. Obstet Gynecol. 2009 Dec;114(6):1341-5. 20
ACCEPTED MANUSCRIPT
3. Laine C, Goodman SN, Griswold ME, Sox HC. Reproducible research: Moving toward research the public can really trust. Ann Intern Med. 2007 Mar 20;146(6):450-3.
RI PT
4. Begg C, Cho M, Eastwood S, Horton R, Moher D, Olkin I, et al. Improving the quality of reporting of randomized controlled trials. the CONSORT statement. JAMA. 1996 Aug 28;276(8):637-9. 5. Moher D, Schulz KF, Altman DG. The CONSORT statement: Revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet. 2001 Apr 14;357(9263):1191-4.
SC
6. Schulz KF, Altman DG, Moher D, CONSORT Group. CONSORT 2010 statement: Updated guidelines for reporting parallel group randomised trials. BMC Med. 2010 Mar 24;8:18,7015-8-18.
M AN U
7. Altman DG, Schulz KF, Moher D, Egger M, Davidoff F, Elbourne D, et al. The revised CONSORT statement for reporting randomized trials: Explanation and elaboration. Ann Intern Med. 2001 Apr 17;134(8):663-94. 8. Moher D, Hopewell S, Schulz KF, Montori V, Gotzsche PC, Devereaux PJ, et al. CONSORT 2010 explanation and elaboration: Updated guidelines for reporting parallel group randomised trials. BMJ. 2010 Mar 23;340:c869.
TE D
9. Chan AW, Altman DG. Epidemiology and reporting of randomised trials published in PubMed journals. Lancet. 2005 Mar 26-Apr 1;365(9465):1159-62. 10. Hopewell S, Dutton S, Yu LM, Chan AW, Altman DG. The quality of reports of randomised trials in 2000 and 2006: Comparative study of articles indexed in PubMed. BMJ. 2010 Mar 23;340:c723.
EP
11. Ladd BO, McCrady BS, Manuel JK, Campbell W. Improving the quality of reporting alcohol outcome studies: Effects of the CONSORT statement. Addict Behav. 2010 Jul;35(7):660-6.
AC C
12. Areia M, Soares M, Dinis-Ribeiro M. Quality reporting of endoscopic diagnostic studies in gastrointestinal journals: Where do we stand on the use of the STARD and CONSORT statements? Endoscopy. 2010 Feb;42(2):138-47. 13. Ziogas DC, Zintzaras E. Analysis of the quality of reporting of randomized controlled trials in acute and chronic myeloid leukemia, and myelodysplastic syndromes as governed by the CONSORT statement. Ann Epidemiol. 2009 Jul;19(7):494-500. 14. Smith BA, Lee HJ, Lee JH, Choi M, Jones DE, Bausell RB, et al. Quality of reporting randomized controlled trials (RCTs) in the nursing literature: Application of the consolidated standards of reporting trials (CONSORT). Nurs Outlook. 2008 JanFeb;56(1):31-7. 21
ACCEPTED MANUSCRIPT
15. Kane RL, Wang J, Garrard J. Reporting in randomized clinical trials improved after adoption of the CONSORT statement. J Clin Epidemiol. 2007 Mar;60(3):241-9.
RI PT
16. Sut N, Senocak M, Uysal O, Koksalan H. Assessing the quality of randomized controlled trials from two leading cancer journals using the CONSORT statement. Hematol Oncol Stem Cell Ther. 2008 Jan-Mar;1(1):38-43. 17. Lu J, Gary KW, Neimeier JP, Ward J, Lapane KL. Randomized controlled trials in adult traumatic brain injury. Brain Inj. 2012;26(13-14):1523-48.
SC
18. Maas AI, Roozenbeek B, Manley GT. Clinical trials in traumatic brain injury: Past experience and current developments. Neurotherapeutics. 2010 Jan;7(1):115-26. 19. Kitamura K. Therapeutic effect of pyritinol on sequelae of head injuries. J Int Med Res. 1981;9(3):215-21.
M AN U
20. Saul TG, Ducker TB, Salcman M, Carro E. Steroids in severe head injury: A prospective randomized clinical trial. J Neurosurg. 1981 May;54(5):596-600. 21. Braakman R, Schouten HJ, Blaauw-van Dishoeck M, Minderhoud JM. Megadose steroids in severe head injury. results of a prospective double-blind clinical trial. J Neurosurg. 1983 Mar;58(3):326-30.
TE D
22. Ward JD, Becker DP, Miller JD, Choi SC, Marmarou A, Wood C, et al. Failure of prophylactic barbiturate coma in the treatment of severe head injury. J Neurosurg. 1985 Mar;62(3):383-8.
EP
23. Dearden NM, Gibson JS, McDowall DG, Gibson RM, Cameron MM. Effect of highdose dexamethasone on outcome from severe head injury. J Neurosurg. 1986 Jan;64(1):818.
AC C
24. Smith HP, Kelly DL,Jr, McWhorter JM, Armstrong D, Johnson R, Transou C, et al. Comparison of mannitol regimens in patients with severe head injury undergoing intracranial monitoring. J Neurosurg. 1986 Dec;65(6):820-4. 25. Artru F, Chacornac R, Deleuze R. Hyperbaric oxygenation for severe head injuries. preliminary results of a controlled study. Eur Neurol. 1976;14(4):310-8. 26. Young B, Ott L, Twyman D, Norton J, Rapp R, Tibbs P, et al. The effect of nutritional support on outcome from severe head injury. J Neurosurg. 1987 Nov;67(5):668-76. 27. Eisenberg HM, Frankowski RF, Contant CF, Marshall LF, Walker MD. High-dose barbiturate control of elevated intracranial pressure in patients with severe head injury. J Neurosurg. 1988 Jul;69(1):15-23.
22
ACCEPTED MANUSCRIPT
28. Niemann H, Ruff RM, Baser CA. Computer-assisted attention retraining in headinjured individuals: A controlled efficacy study of an outpatient program. J Consult Clin Psychol. 1990 Dec;58(6):811-7.
RI PT
29. Ruff RM, Niemann H. Cognitive rehabilitation versus day treatment in head-injured adults: Is there an impact on emotional and psychosocial adjustment? Brain Inj. 1990 OctDec;4(4):339-47. 30. Bailey I, Bell A, Gray J, Gullan R, Heiskanan O, Marks PV, et al. A trial of the effect of nimodipine on outcome after head injury. Acta Neurochir (Wien). 1991;110(3-4):97-105.
SC
31. Calatayud Maldonado V, Calatayud Perez JB, Aso Escario J. Effects of CDP-choline on the recovery of patients with head injury. J Neurol Sci. 1991 Jul;103 Suppl:S15-8.
M AN U
32. Muizelaar JP, Marmarou A, Ward JD, Kontos HA, Choi SC, Becker DP, et al. Adverse effects of prolonged hyperventilation in patients with severe head injury: A randomized clinical trial. J Neurosurg. 1991 Nov;75(5):731-9. 33. Rockswold GL, Ford SE, Anderson DC, Bergman TA, Sherman RE. Results of a prospective randomized trial for treatment of severely brain-injured patients with hyperbaric oxygen. J Neurosurg. 1992 Jun;76(6):929-34.
TE D
34. Gaab MR, Trost HA, Alcantara A, Karimi-Nejad A, Moskopp D, Schultheiss R, et al. "Ultrahigh" dexamethasone in acute brain injury. results from a prospective randomized double-blind multicenter trial (GUDHIS). german ultrahigh dexamethasone head injury study group. Zentralbl Neurochir. 1994;55(3):135-43.
EP
35. A multicenter trial of the efficacy of nimodipine on outcome after severe head injury. the european study group on nimodipine in severe head injury. J Neurosurg. 1994 May;80(5):797-804. 36. Neistadt ME. The effects of different treatment activities on functional fine motor coordination in adults with brain injury. Am J Occup Ther. 1994 Oct;48(10):877-82.
AC C
37. Smith KR,Jr, Goulding PM, Wilderman D, Goldfader PR, Holterman-Hommes P, Wei F. Neurobehavioral effects of phenytoin and carbamazepine in patients recovering from brain trauma: A comparative study. Arch Neurol. 1994 Jul;51(7):653-60. 38. Grumme T, Baethmann A, Kolodziejczyk D, Krimmer J, Fischer M, von Eisenhart Rothe B, et al. Treatment of patients with severe head injury by triamcinolone: A prospective, controlled multicenter clinical trial of 396 cases. Res Exp Med (Berl). 1995;195(4):217-29. 39. Harders A, Kakarieka A, Braakman R. Traumatic subarachnoid hemorrhage and its treatment with nimodipine. german tSAH study group. J Neurosurg. 1996 Jul;85(1):82-9.
23
ACCEPTED MANUSCRIPT
40. Young B, Runge JW, Waxman KS, Harrington T, Wilberger J, Muizelaar JP, et al. Effects of pegorgotein on neurologic outcome of patients with severe head injury. A multicenter, randomized controlled trial. JAMA. 1996 Aug 21;276(7):538-43.
RI PT
41. Young B, Ott L, Kasarskis E, Rapp R, Moles K, Dempsey RJ, et al. Zinc supplementation is associated with improved neurologic recovery rate and visceral protein levels of patients with severe closed head injury. J Neurotrauma. 1996 Jan;13(1):25-34. 42. Couser RJ, Hoekstra RE, Ferrara TB, Wright GB, Cabalka AK, Connett JE. Neurodevelopmental follow-up at 36 months' corrected age of preterm infants treated with prophylactic indomethacin. Arch Pediatr Adolesc Med. 2000 Jun;154(6):598-602.
SC
43. Marion DW, Penrod LE, Kelsey SF, Obrist WD, Kochanek PM, Palmer AM, et al. Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med. 1997 Feb 20;336(8):540-6.
M AN U
44. Wade DT, King NS, Wenden FJ, Crawford S, Caldwell FE. Routine follow up after head injury: A second randomised controlled trial. J Neurol Neurosurg Psychiatry. 1998 Aug;65(2):177-83. 45. Marshall LF, Maas AI, Marshall SB, Bricolo A, Fearnside M, Iannotti F, et al. A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury. J Neurosurg. 1998 Oct;89(4):519-25.
TE D
46. Paniak C, Toller-Lobe G, Durand A, Nagy J. A randomized trial of two treatments for mild traumatic brain injury. Brain Inj. 1998 Dec;12(12):1011-23.
EP
47. Marmarou A, Nichols J, Burgess J, Newell D, Troha J, Burnham D, et al. Effects of the bradykinin antagonist bradycor (deltibant, CP-1027) in severe traumatic brain injury: Results of a multi-center, randomized, placebo-controlled trial. american brain injury consortium study group. J Neurotrauma. 1999 Jun;16(6):431-44.
AC C
48. Morris GF, Bullock R, Marshall SB, Marmarou A, Maas A, Marshall LF. Failure of the competitive N-methyl-D-aspartate antagonist selfotel (CGS 19755) in the treatment of severe head injury: Results of two phase III clinical trials. the selfotel investigators. J Neurosurg. 1999 Nov;91(5):737-43. 49. Levine B, Robertson IH, Clare L, Carter G, Hong J, Wilson BA, et al. Rehabilitation of executive functioning: An experimental-clinical validation of goal management training. J Int Neuropsychol Soc. 2000 Mar;6(3):299-312. 50. Paniak C, Toller-Lobe G, Reynolds S, Melnyk A, Nagy J. A randomized trial of two treatments for mild traumatic brain injury: 1 year follow-up. Brain Inj. 2000 Mar;14(3):219-26.
24
ACCEPTED MANUSCRIPT
51. Salazar AM, Warden DL, Schwab K, Spector J, Braverman S, Walter J, et al. Cognitive rehabilitation for traumatic brain injury: A randomized trial. defense and veterans head injury program (DVHIP) study group. JAMA. 2000 Jun 21;283(23):3075-81.
RI PT
52. Bateman A, Culpan FJ, Pickering AD, Powell JH, Scott OM, Greenwood RJ. The effect of aerobic training on rehabilitation outcomes after recent severe brain injury: A randomized controlled evaluation. Arch Phys Med Rehabil. 2001 Feb;82(2):174-82. 53. Cruz J, Minoja G, Okuchi K. Improving clinical outcomes from acute subdural hematomas with the emergency preoperative administration of high doses of mannitol: A randomized trial. Neurosurgery. 2001 Oct;49(4):864-71.
SC
54. Shiel A, Burn JP, Henry D, Clark J, Wilson BA, Burnett ME, et al. The effects of increased rehabilitation therapy after brain injury: Results of a prospective controlled trial. Clin Rehabil. 2001 Oct;15(5):501-14.
M AN U
55. Shiozaki T, Hayakata T, Taneda M, Nakajima Y, Hashiguchi N, Fujimi S, et al. A multicenter prospective randomized controlled trial of the efficacy of mild hypothermia for severely head injured patients with low intracranial pressure. mild hypothermia study group in japan. J Neurosurg. 2001 Jan;94(1):50-4. 56. Chen B, Liu YS. Randomized double-blind clinical trial of moderate dosage naloxone in acute moderate and severe traumatic brain injury]. Hunan Yi Ke Da Xue Xue Bao. 2002 Feb 28;27(1):58-60.
TE D
57. Dirette DK, Hinojosa J, Carnevale GJ. Comparison of remedial and compensatory interventions for adults with acquired brain injuries. J Head Trauma Rehabil. 1999 Dec;14(6):595-601.
EP
58. Chen L, Zeng F, Yang L, Chai J, Li K, Lu M, et al. Curative effect of wilsonii injecta on severe head injury. Chin J Traumatol. 2002 Apr;5(2):82-5.
AC C
59. Clifton GL, Miller ER, Choi SC, Levin HS, McCauley S, Smith KR,Jr, et al. Hypothermia on admission in patients with severe brain injury. J Neurotrauma. 2002 Mar;19(3):293-301. 60. Cruz J, Minoja G, Okuchi K. Major clinical and physiological benefits of early high doses of mannitol for intraparenchymal temporal lobe hemorrhages with abnormal pupillary widening: A randomized trial. Neurosurgery. 2002 Sep;51(3):628,37; discussion 637-8. 61. de Kruijk JR, Leffers P, Meerhoff S, Rutten J, Twijnstra A. Effectiveness of bed rest after mild traumatic brain injury: A randomised trial of no versus six days of bed rest. J Neurol Neurosurg Psychiatry. 2002 Aug;73(2):167-72.
25
ACCEPTED MANUSCRIPT
62. Lee H, Kim SW, Kim JM, Shin IS, Yang SJ, Yoon JS. Comparing effects of methylphenidate, sertraline and placebo on neuropsychiatric sequelae in patients with traumatic brain injury. Hum Psychopharmacol. 2005 Mar;20(2):97-104.
RI PT
63. Powell J, Heslin J, Greenwood R. Community based rehabilitation after severe traumatic brain injury: A randomised controlled trial. J Neurol Neurosurg Psychiatry. 2002 Feb;72(2):193-202. 64. Lu LQ, Jiang JY, Yu MK, Hou LJ, Chen ZG, Zhang GJ, et al. Standard large trauma craniotomy for severe traumatic brain injury. Chin J Traumatol. 2003 Oct;6(5):302-4.
SC
65. Zhi D, Zhang S, Lin X. Study on therapeutic mechanism and clinical effect of mild hypothermia in patients with severe head injury. Surg Neurol. 2003 May;59(5):381-5.
M AN U
66. Cooper DJ, Myles PS, McDermott FT, Murray LJ, Laidlaw J, Cooper G, et al. Prehospital hypertonic saline resuscitation of patients with hypotension and severe traumatic brain injury: A randomized controlled trial. JAMA. 2004 Mar 17;291(11):13507. 67. Whyte J, Hart T, Vaccaro M, Grieb-Neff P, Risser A, Polansky M, et al. Effects of methylphenidate on attention deficits after traumatic brain injury: A multidimensional, randomized, controlled trial. Am J Phys Med Rehabil. 2004 Jun;83(6):401-20.
TE D
68. Aquilani R, Iadarola P, Contardi A, Boselli M, Verri M, Pastoris O, et al. Branchedchain amino acids enhance the cognitive recovery of patients with severe traumatic brain injury. Arch Phys Med Rehabil. 2005 Sep;86(9):1729-35.
EP
69. Bell KR, Temkin NR, Esselman PC, Doctor JN, Bombardier CH, Fraser RT, et al. The effect of a scheduled telephone intervention on outcome after moderate to severe traumatic brain injury: A randomized trial. Arch Phys Med Rehabil. 2005 May;86(5):851-6.
AC C
70. Brown TH, Mount J, Rouland BL, Kautz KA, Barnes RM, Kim J. Body weightsupported treadmill training versus conventional gait training for people with chronic traumatic brain injury. J Head Trauma Rehabil. 2005 Sep-Oct;20(5):402-15. 71. Edwards P, Arango M, Balica L, Cottingham R, El-Sayed H, Farrell B, et al. Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months. Lancet. 2005 Jun 410;365(9475):1957-9. 72. Jha A, Weintraub A, Allshouse A, Morey C, Cusick C, Kittelson J, et al. A randomized trial of modafinil for the treatment of fatigue and excessive daytime sleepiness in individuals with chronic traumatic brain injury. J Head Trauma Rehabil. 2008 JanFeb;23(1):52-63.
26
ACCEPTED MANUSCRIPT
73. Jiang JY, Xu W, Li WP, Gao GY, Bao YH, Liang YM, et al. Effect of long-term mild hypothermia or short-term mild hypothermia on outcome of patients with severe traumatic brain injury. J Cereb Blood Flow Metab. 2006 Jun;26(6):771-6.
RI PT
74. Maas AI, Murray G, Henney H,3rd, Kassem N, Legrand V, Mangelus M, et al. Efficacy and safety of dexanabinol in severe traumatic brain injury: Results of a phase III randomised, placebo-controlled, clinical trial. Lancet Neurol. 2006 Jan;5(1):38-45. 75. McDonald S, Tate R, Togher L, Bornhofen C, Long E, Gertler P, et al. Social skills treatment for people with severe, chronic acquired brain injuries: A multicenter trial. Arch Phys Med Rehabil. 2008 Sep;89(9):1648-59.
SC
76. Wilson DJ, Powell M, Gorham JL, Childers MK. Ambulation training with and without partial weightbearing after traumatic brain injury: Results of a randomized, controlled trial. Am J Phys Med Rehabil. 2006 Jan;85(1):68-74.
M AN U
77. Elgmark Andersson E, Emanuelson I, Bjorklund R, Stalhammar DA. Mild traumatic brain injuries: The impact of early intervention on late sequelae. A randomized controlled trial. Acta Neurochir (Wien). 2007 Feb;149(2):151,9; discussion 160. 78. Dahlberg CA, Cusick CP, Hawley LA, Newman JK, Morey CE, Harrison-Felix CL, et al. Treatment efficacy of social communication skills training after traumatic brain injury: A randomized treatment and deferred treatment controlled trial. Arch Phys Med Rehabil. 2007 Dec;88(12):1561-73.
TE D
79. Qiu W, Zhang Y, Sheng H, Zhang J, Wang W, Liu W, et al. Effects of therapeutic mild hypothermia on patients with severe traumatic brain injury after craniotomy. J Crit Care. 2007 Sep;22(3):229-35.
EP
80. Tiersky LA, Anselmi V, Johnston MV, Kurtyka J, Roosen E, Schwartz T, et al. A trial of neuropsychologic rehabilitation in mild-spectrum traumatic brain injury. Arch Phys Med Rehabil. 2005 Aug;86(8):1565-74.
AC C
81. Wilson BA, Emslie H, Quirk K, Evans J, Watson P. A randomized control trial to evaluate a paging system for people with traumatic brain injury. Brain Inj. 2005 Oct;19(11):891-4. 82. Jiang JY, Xu W, Li WP, Xu WH, Zhang J, Bao YH, et al. Efficacy of standard trauma craniectomy for refractory intracranial hypertension with severe traumatic brain injury: A multicenter, prospective, randomized controlled study. J Neurotrauma. 2005 Jun;22(6):623-8. 83. Moein H, Khalili HA, Keramatian K. Effect of methylphenidate on ICU and hospital length of stay in patients with severe and moderate traumatic brain injury. Clin Neurol Neurosurg. 2006 Sep;108(6):539-42.
27
ACCEPTED MANUSCRIPT
84. Qiu WS, Liu WG, Shen H, Wang WM, Hang ZL, Zhang Y, et al. Therapeutic effect of mild hypothermia on severe traumatic head injury. Chin J Traumatol. 2005 Feb;8(1):2732.
RI PT
85. Temkin NR, Anderson GD, Winn HR, Ellenbogen RG, Britz GW, Schuster J, et al. Magnesium sulfate for neuroprotection after traumatic brain injury: A randomised controlled trial. Lancet Neurol. 2007 Jan;6(1):29-38. 86. Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, et al. ProTECT: A randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med. 2007 Apr;49(4):391,402, 402.e1-2.
SC
87. Zhu XL, Poon WS, Chan CC, Chan SS. Does intensive rehabilitation improve the functional outcome of patients with traumatic brain injury (TBI)? A randomized controlled trial. Brain Inj. 2007 Jun;21(7):681-90.
M AN U
88. Bell KR, Hoffman JM, Temkin NR, Powell JM, Fraser RT, Esselman PC, et al. The effect of telephone counselling on reducing post-traumatic symptoms after mild traumatic brain injury: A randomised trial. J Neurol Neurosurg Psychiatry. 2008 Nov;79(11):127581. 89. Bilotta F, Caramia R, Cernak I, Paoloni FP, Doronzio A, Cuzzone V, et al. Intensive insulin therapy after severe traumatic brain injury: A randomized clinical trial. Neurocrit Care. 2008;9(2):159-66.
TE D
90. Cicerone KD, Mott T, Azulay J, Sharlow-Galella MA, Ellmo WJ, Paradise S, et al. A randomized controlled trial of holistic neuropsychologic rehabilitation after traumatic brain injury. Arch Phys Med Rehabil. 2008 Dec;89(12):2239-49.
EP
91. Constantinidou F, Thomas RD, Robinson L. Benefits of categorization training in patients with traumatic brain injury during post-acute rehabilitation: Additional evidence from a randomized controlled trial. J Head Trauma Rehabil. 2008 Sep-Oct;23(5):312-28.
AC C
92. Vanderploeg RD, Schwab K, Walker WC, Fraser JA, Sigford BJ, Date ES, et al. Rehabilitation of traumatic brain injury in active duty military personnel and veterans: Defense and veterans brain injury center randomized controlled trial of two rehabilitation approaches. Arch Phys Med Rehabil. 2008 Dec;89(12):2227-38. 93. Xiao G, Wei J, Yan W, Wang W, Lu Z. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: A randomized controlled trial. Crit Care. 2008;12(2):R61. 94. Bombardier CH, Bell KR, Temkin NR, Fann JR, Hoffman J, Dikmen S. The efficacy of a scheduled telephone intervention for ameliorating depressive symptoms during the first year after traumatic brain injury. J Head Trauma Rehabil. 2009 Jul-Aug;24(4):230-8.
28
ACCEPTED MANUSCRIPT
95. Novack TA, Banos JH, Brunner R, Renfroe S, Meythaler JM. Impact of early administration of sertraline on depressive symptoms in the first year after traumatic brain injury. J Neurotrauma. 2009 Nov;26(11):1921-8.
RI PT
96. Harris OA, Muh CR, Surles MC, Pan Y, Rozycki G, Macleod J, et al. Discrete cerebral hypothermia in the management of traumatic brain injury: A randomized controlled trial. J Neurosurg. 2009 Jun;110(6):1256-64. 97. Tenovuo O, Alin J, Helenius H. A randomized controlled trial of rivastigmine for chronic sequels of traumatic brain injury-what it showed and taught? Brain Inj. 2009 Jun;23(6):548-58.
SC
98. Willmott C, Ponsford J. Efficacy of methylphenidate in the rehabilitation of attention following traumatic brain injury: A randomised, crossover, double blind, placebo controlled inpatient trial. J Neurol Neurosurg Psychiatry. 2009 May;80(5):552-7.
M AN U
99. Yang M, Guo Q, Zhang X, Sun S, Wang Y, Zhao L, et al. Intensive insulin therapy on infection rate, days in NICU, in-hospital mortality and neurological outcome in severe traumatic brain injury patients: A randomized controlled trial. Int J Nurs Stud. 2009 Jun;46(6):753-8.
TE D
100. Banos JH, Novack TA, Brunner R, Renfroe S, Lin HY, Meythaler J. Impact of early administration of sertraline on cognitive and behavioral recovery in the first year after moderate to severe traumatic brain injury. J Head Trauma Rehabil. 2010 SepOct;25(5):357-61.
EP
101. Bernard SA, Nguyen V, Cameron P, Masci K, Fitzgerald M, Cooper DJ, et al. Prehospital rapid sequence intubation improves functional outcome for patients with severe traumatic brain injury: A randomized controlled trial. Ann Surg. 2010 Dec;252(6):959-65.
AC C
102. Bulger EM, May S, Brasel KJ, Schreiber M, Kerby JD, Tisherman SA, et al. Out-ofhospital hypertonic resuscitation following severe traumatic brain injury: A randomized controlled trial. JAMA. 2010 Oct 6;304(13):1455-64. 103. Coester A, Neumann CR, Schmidt MI. Intensive insulin therapy in severe traumatic brain injury: A randomized trial. J Trauma. 2010 Apr;68(4):904-11. 104. Hoffman JM, Bell KR, Powell JM, Behr J, Dunn EC, Dikmen S, et al. A randomized controlled trial of exercise to improve mood after traumatic brain injury. PM R. 2010 Oct;2(10):911-9. 105. Rapoport MJ, Mitchell RA, McCullagh S, Herrmann N, Chan F, Kiss A, et al. A randomized controlled trial of antidepressant continuation for major depression following traumatic brain injury. J Clin Psychiatry. 2010 Sep;71(9):1125-30.
29
ACCEPTED MANUSCRIPT
106. Yurkewicz L, Weaver J, Bullock MR, Marshall LF. The effect of the selective NMDA receptor antagonist traxoprodil in the treatment of traumatic brain injury. J Neurotrauma. 2005 Dec;22(12):1428-43.
RI PT
107. Carnevale GJ, Anselmi V, Johnston MV, Busichio K, Walsh V. A natural setting behavior management program for persons with acquired brain injury: A randomized controlled trial. Arch Phys Med Rehabil. 2006 Oct;87(10):1289-97.
SC
108. Hassett LM, Moseley AM, Tate RL, Harmer AR, Fairbairn TJ, Leung J. Efficacy of a fitness centre-based exercise programme compared with a home-based exercise programme in traumatic brain injury: A randomized controlled trial. J Rehabil Med. 2009 Mar;41(4):247-55.
M AN U
109. Bell KR, Brockway JA, Hart T, Whyte J, Sherer M, Fraser RT, et al. Scheduled telephone intervention for traumatic brain injury: A multicenter randomized controlled trial. Arch Phys Med Rehabil. 2011 Oct;92(10):1552-60. 110. Clifton GL, Valadka A, Zygun D, Coffey CS, Drever P, Fourwinds S, et al. Very early hypothermia induction in patients with severe brain injury (the national acute brain injury study: Hypothermia II): A randomised trial. Lancet Neurol. 2011 Feb;10(2):131-9. 111. Cooper DJ, Rosenfeld JV. Does decompressive craniectomy improve outcomes in patients with diffuse traumatic brain injury? Med J Aust. 2011 May 2;194(9):437-8.
TE D
112. Cottenceau V, Masson F, Mahamid E, Petit L, Shik V, Sztark F, et al. Comparison of effects of equiosmolar doses of mannitol and hypertonic saline on cerebral blood flow and metabolism in traumatic brain injury. J Neurotrauma. 2011 Oct;28(10):2003-12.
EP
113. McFadden KL, Healy KM, Dettmann ML, Kaye JT, Ito TA, Hernandez TD. Acupressure as a non-pharmacological intervention for traumatic brain injury (TBI). J Neurotrauma. 2011 Jan;28(1):21-34.
AC C
114. CRASH-2 Collaborators, Intracranial Bleeding Study. Effect of tranexamic acid in traumatic brain injury: A nested randomised, placebo controlled trial (CRASH-2 intracranial bleeding study). BMJ. 2011 Jul 1;343:d3795. 115. Chesnut RM, Temkin N, Carney N, Dikmen S, Rondina C, Videtta W, et al. A trial of intracranial-pressure monitoring in traumatic brain injury. N Engl J Med. 2012 Dec 27;367(26):2471-81. 116. Chourdakis M, Kraus MM, Tzellos T, Sardeli C, Peftoulidou M, Vassilakos D, et al. Effect of early compared with delayed enteral nutrition on endocrine function in patients with traumatic brain injury: An open-labeled randomized trial. JPEN J Parenter Enteral Nutr. 2012 Jan;36(1):108-16.
30
ACCEPTED MANUSCRIPT
117. Hanks RA, Rapport LJ, Wertheimer J, Koviak C. Randomized controlled trial of peer mentoring for individuals with traumatic brain injury and their significant others. Arch Phys Med Rehabil. 2012 Aug;93(8):1297-304.
RI PT
118. Justo Meirelles CM, de Aguilar-Nascimento JE. Enteral or parenteral nutrition in traumatic brain injury: A prospective randomised trial. Nutr Hosp. 2011 SepOct;26(5):1120-4.
SC
119. Zafonte RD, Bagiella E, Ansel BM, Novack TA, Friedewald WT, Hesdorffer DC, et al. Effect of citicoline on functional and cognitive status among patients with traumatic brain injury: Citicoline brain injury treatment trial (COBRIT). JAMA. 2012 Nov 21;308(19):1993-2000.
M AN U
120. Hoffer ME, Balaban C, Slade MD, Tsao JW, Hoffer B. Amelioration of acute sequelae of blast induced mild traumatic brain injury by N-acetyl cysteine: A double-blind, placebo controlled study. PLoS One. 2013;8(1):e54163. 121. Matuseviciene G, Borg J, Stalnacke BM, Ulfarsson T, de Boussard C. Early intervention for patients at risk for persisting disability after mild traumatic brain injury: A randomized, controlled study. Brain Inj. 2013;27(3):318-24. 122. Sanchez-Aguilar M, Tapia-Perez JH, Sanchez-Rodriguez JJ, Vinas-Rios JM, Martinez-Perez P, de la Cruz-Mendoza E, et al. Effect of rosuvastatin on cytokines after traumatic head injury. J Neurosurg. 2013 Mar;118(3):669-75.
TE D
123. Shum D, Fleming J, Gill H, Gullo MJ, Strong J. A randomized controlled trial of prospective memory rehabilitation in adults with traumatic brain injury. J Rehabil Med. 2011 Feb;43(3):216-23.
EP
124. Brenner LA, Braden CA, Bates M, Chase T, Hancock C, Harrison-Felix C, et al. A health and wellness intervention for those with moderate to severe traumatic brain injury: A randomized controlled trial. J Head Trauma Rehabil. 2012 Nov-Dec;27(6):E57-68.
AC C
125. Freiman JA, Chalmers TC, Smith H,Jr, Kuebler RR. The importance of beta, the type II error and sample size in the design and interpretation of the randomized control trial. survey of 71 "negative" trials. N Engl J Med. 1978 Sep 28;299(13):690-4. 126. Schulz KF, Grimes DA. Sample size calculations in randomised trials: Mandatory and mystical. Lancet. 2005 Apr 9-15;365(9467):1348-53. 127. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995 Feb 1;273(5):408-12. 128. Chalmers TC, Celano P, Sacks HS, Smith H,Jr. Bias in treatment assignment in controlled clinical trials. N Engl J Med. 1983 Dec 1;309(22):1358-61. 31
ACCEPTED MANUSCRIPT
129. Pildal J, Hrobjartsson A, Jorgensen KJ, Hilden J, Altman DG, Gotzsche PC. Impact of allocation concealment on conclusions drawn from meta-analyses of randomized trials. Int J Epidemiol. 2007 Aug;36(4):847-57.
RI PT
130. Savovic J, Jones H, Altman D, Harris R, Juni P, Pildal J, et al. Influence of reported study design characteristics on intervention effect estimates from randomised controlled trials: Combined analysis of meta-epidemiological studies. Health Technol Assess. 2012 Sep;16(35):1-82. 131. Juni P, Altman DG, Egger M. Systematic reviews in health care: Assessing the quality of controlled clinical trials. BMJ. 2001 Jul 7;323(7303):42-6.
SC
132. Schulz KF, Grimes DA. Blinding in randomised trials: Hiding who got what. Lancet. 2002 Feb 23;359(9307):696-700.
M AN U
133. Wood L, Egger M, Gluud LL, Schulz KF, Juni P, Altman DG, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: Meta-epidemiological study. BMJ. 2008 Mar 15;336(7644):601-5. 134. Boutron I, Moher D, Altman DG, Schulz KF, Ravaud P, CONSORT Group. Extending the CONSORT statement to randomized trials of nonpharmacologic treatment: Explanation and elaboration. Ann Intern Med. 2008 Feb 19;148(4):295-309.
TE D
135. Falagas ME, Grigori T, Ioannidou E. A systematic review of trends in the methodological quality of randomized controlled trials in various research fields. J Clin Epidemiol. 2009 Mar;62(3):227,31, 231.e1-9.
EP
136. Agha R, Cooper D, Muir G. The reporting quality of randomised controlled trials in surgery: A systematic review. Int J Surg. 2007 Dec;5(6):413-22. 137. Carlton DA, Kocherginsky M, Langerman AJ. A systematic review of the quality of randomized controlled trials in head & neck oncology surgery. Laryngoscope. 2014 Apr 12.
AC C
138. Agha RA, Camm CF, Doganay E, Edison E, Siddiqui MR, Orgill DP. Randomised controlled trials in plastic surgery: A systematic review of reporting quality. Eur J Plast Surg. 2014;37:55-62. 139. Han C, Kwak KP, Marks DM, Pae CU, Wu LT, Bhatia KS, et al. The impact of the CONSORT statement on reporting of randomized clinical trials in psychiatry. Contemp Clin Trials. 2009 Mar;30(2):116-22. 140. Chauhan SP, Berghella V, Sanderson M, Siddiqui D, Hendrix NW, Magann EF. Randomized clinical trials behind level A recommendations in obstetric practice bulletins: Compliance with CONSORT statement. Am J Perinatol. 2009 Jan;26(1):69-80.
32
ACCEPTED MANUSCRIPT
141. Bath FJ, Owen VE, Bath PM. Quality of full and final publications reporting acute stroke trials: A systematic review. Stroke. 1998 Oct;29(10):2203-10.
RI PT
142. Bhandari M, Guyatt GH, Lochner H, Sprague S, Tornetta P,3rd. Application of the consolidated standards of reporting trials (CONSORT) in the fracture care literature. J Bone Joint Surg Am. 2002 Mar;84-A(3):485-9. 143. Prady SL, Richmond SJ, Morton VM, Macpherson H. A systematic evaluation of the impact of STRICTA and CONSORT recommendations on quality of reporting for acupuncture trials. PLoS One. 2008 Feb 13;3(2):e1577.
SC
144. Adetugbo K, Williams H. How well are randomized controlled trials reported in the dermatology literature? Arch Dermatol. 2000 Mar;136(3):381-5.
M AN U
145. Turner L, Shamseer L, Altman DG, Weeks L, Peters J, Kober T, et al. Consolidated standards of reporting trials (CONSORT) and the completeness of reporting of randomised controlled trials (RCTs) published in medical journals. Cochrane Database Syst Rev. 2012 Nov 14;11:MR000030. 146. Fung AE, Palanki R, Bakri SJ, Depperschmidt E, Gibson A. Applying the CONSORT and STROBE statements to evaluate the reporting quality of neovascular age-related macular degeneration studies. Ophthalmology. 2009 Feb;116(2):286-96.
AC C
EP
TE D
147. Chan L, Heinemann AW, Roberts J. Elevating the quality of disability and rehabilitation research: Mandatory use of the reporting guidelines. Arch Phys Med Rehabil. 2014 Mar;95(3):415-7.
Figure 1 legend
33
ACCEPTED MANUSCRIPT
Figure 1 shows the article identification process. A total of 105 RCT reports were included in the current review.
RI PT
Figure 2 legend
Figure 2 shows the comparison of RCTs published during 1976-2001(n=38) with those
published during 2002-2010 (n=51). A statistically significant improvement is observed
SC
between the two periods in reporting the pre-specified primary/secondary outcomes (RR:1.33, CI:1.15-1.75) and the method of randomization sequence generation (RR: 2.79, 95% CI: 1.45-
M AN U
5.39), details of the allocation concealment (RR: 2.31, 95% CI: 1.30-4.11) and attrition due to loss to follow up (RR 1.23, 95% CI 1.02-1.49).
Figure 3 legend
TE D
Figure 3 shows a further comparison of RCTs published during 2002-2010 (n=51) with those published during 2011-September, 2013 (n=16). A statistically significant improvement was observed between the two periods in reporting details in sample size calculation (RR 1.82, 95%
AC C
EP
CI 1.18-2.81) and intent to treat analysis (RR 1.18, 95% CI 1.05-1.34).
34
ACCEPTED MANUSCRIPT
M AN U
SC
RI PT
Table 1. Methodological Items and Definitions Used to Assess Reporting of Randomized Controlled Trials CONSORT Guidelines Items and Definitions 2010 2001 Primary outcome Study primary or main outcome(s) explicitly defined. √ √ Sample size Sample size calculation stated to be carried out. √ √ Randomization Sequence generation Method used to generate the random allocation sequence described. √ √ Allocation concealment Mechanism used to implement the random allocation sequence and /or steps used to conceal the sequence until interventions were assigned described. √ √ Implementation Personnel who generated the random allocation sequence, enrolled participants, and assigned participants to interventions specified. √ √ Blinding – who was blind Study participants, care providers, outcome assessors, or investigators with no knowledge of the participants’ group allocation stated to be blinded; or the trial stated to be blinded, single blind, double blind, or triple blind.
Blinding – how blinding was achieved
Similarities between interventions or procedures described, or the trial stated to be placebo controlled or unblinded.
AC C
EP
TE D
Attrition – loss to follow-up For each group, the numbers of participants who losses to follow-up listed, with reasons. Intention to treat analysis Randomized participants with available data stated as having been included in an intention to treat analysis.
√
√
√
-
√
√
√
√
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Table 2. General Characteristics of Randomized Controlled Trials in Adult Traumatic Brain Injury Trials by publication years All trials 1976-2001 2002 – 2010 2011 – Sept. 2013 N=105 N=38 N=51 N=16 Trial design Parallel 99 (94.3) 37 (97.4) 46(90.2) 16 (100.0) Crossover 4 (3.8) 0 (0.0) 4 (7.8) 0 (0.0) Other 2 (1.9) 1 (2.6) 1 (2.0) 0 (0.0) Intervention Drug 40 (38.1) 18 (47.4) 18 (35.3) 4 (25.0) Surgery or procedure 6 (5.7) 0 (0.0) 3 (5.9) 3 (18.8) Rehabilitation 34 (32.4) 12 (31.6) 19 (37.3) 3 (18.8) Others 25 (23.8) 8 (21.1) 11 (21.6) 6 (37.5) Trial locations U.S. trials 48 (45.7) 19 (50.0) 21 (41.2) 8 (50.0) Non-US trials 57 (54.3) 19 (50.0) 30 (58.8) 8 (50.0) Study centers Single 52 (49.5) 15 (38.5) 30 (58.8) 7 (43.8) Multiple 44 (41.9) 19 (50.0) 16 (31.4) 9 (56.3) Unclear 9 (8.6) 4 (10.5) 5 (9.8) 0 (0.0) Number of study groups Two 93 (88.6) 35 (92.1) 44 (86.3) 14 (87.5) Three or more 12 (11.4) 3 (7.9) 7 (13.7) 2 (12.5) Sample size 102.0 119.0 99.0 118.0 Median per trial (39.0-463.0) (30.0-693.0) (39.0-404.0) (39.0-433.0) (10th to 90th percentile)
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Table 3. Reporting Characteristics of Randomized Controlled Trials in Adult Traumatic Brain Injury Trials by publication years All trials 1976-2001 2002 – 2010 N=105 N=38 N=51 “Randomized” stated in the title Stated 52 (49.5) 13 (34.2) 31 (60.8) Location of the data collection Reported 85 (81.0) 32 (84.2) 37 (72.6) Predefined primary outcome Defined 82 (78.1) 24 (63.2) 43 (84.3) Sample size calculation Stated 43 (41.0) 10 (26.3) 21 (41.8) Method of random sequence generation Reported 49 (46.7) 8 (21.1) 30 (58.8) Method of allocation concealment Reported 48 (45.7) 10(26.3) 31 (60.8) Implementation 30 (28.6) 4 (10.5) 20 (39.2) Any report (personnel who generated sequence, administered intervention and/or assigned intervention groups) One of the three 13 (43.3) 1 (25.0) 11 (55.0) Two of the three 12 (40.0) 3 (75.0) 5 (25.0) All three 5 (16.7) 0 (0.0) 4 (20.0) Blinding-who was blinded Any blinding 61 (58.1) 21 (55.3) 32 (62.8) Details reported* 50 (82.0) 14 (66.7) 28 (87.5) 11 (18.0) 7 (33.3) 4 (12.5) Details not reported† ‡ 13 (12.4) 3 (7.9) 9 (17.7) Unblinded Not reported 31 (29.5) 14 (36.8) 10 (19.6) Blinding-how blinding was achieved Any blinding 55 (52.4) 21 (55.3) 29 (56.9) § 35 (63.6) 13 (61.9) 19 (65.5) Details reported || 20 (36.4) 8 (38.1) 10 (35.5) Details not reported Unblinded 13 (12.4) 3 (7.9) 9 (17.7) Not reported 37 (35.2) 14 (36.8) 13 (25.5) Participation diagram Included 49 (46.7) 25 (65.8) 31 (60.8) Period of the recruitment Reported 71 (67.6) 29 (76.3) 34 (66.7)
2011 – Sept. 2013 N=16 8 (50.0) 16 (100.0) 15 (93.8) 12 (75.0) 11 (68.8) 7 (43.8) 6 (37.5) 1 (16.7) 4 (66.7) 1 (16.7) 8 (50.0) 8 (100.0) 0 (0.0) 1 (6.3) 7 (43.8) 5 (31.3) 3 (60.0) 2 (40.0) 1 (6.3) 10 (62.5) 13 (81.3) 12 (75.0)
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Period of the follow-up Reported 87 (82.9) 29 (76.3) 43 (84.3) Attrition-Loss to follow-up for each group Reported 93 (88.6) 29 (76.3) 48 (94.1) Reasons given¶ 82 (88.2) 23 (79.3) 44 (91.7) Reasons not given 11 (11.8) 6 (20.7) 4 (8.3) Attrition-Intention to treat analysis Reported 89 (84.8) 30 (78.9) 43 (84.3) As all randomized participants 38 (42.7) 13 (43.3) 18 (41.9) As randomized with available data 51 (57.3) 17 (56.7) 25 (58.1) Trial registration Reported 17 (16.2) 2 (5.3) 8 (15.7) Trial protocol Reported 2 (1.9) 0 (0.0) 1 (2.0) Funding Reported 68 (64.8) 21 (75.3) 35 (68.6) Solely industry 12 (17.7) 6 (28.6) 4 (11.4) Part industry 6 (8.8) 2 (9.5) 2 (5.7) Non-industry 50 (73.5) 13 (61.9) 29 (82.9) *Article reports exactly who was blinded; † Report stated used the terms “blinded”, “single blind,” or “double blind,” or similar, without providing further details on who was blinded; ‡Trial stated as unblinded if explicitly stated as such or blinding clearly not possible; § Article reports similarities between interventions or procedures; || Trial stated as placebo controlled, without further details on how placebo control was achieved; ¶ Including trial reports stated that there was no loss to follow-up.
15 (93.8) 16 (100.0) 15 (93.8) 1 (6.3) 16 (100.0) 7 (43.8) 9 (56.3) 7 (43.8) 1 (6.3) 12 (75.0) 2 (16.7) 2 (16.7) 8 (66.7)
ACCEPTED MANUSCRIPT
Databases: MedLine, PsycINFO and CINAHL Through September 30, 3013
RI PT
Figure 1 Study Selections
9 trial reports added from Gordon et al. 2006, Cernich et al. 2010 and Maas et al. 2010
M AN U
1378 trial reports screened
SC
Search terms: “Traumatic Brain Injury OR Brain Injury” “AND” “Randomized Controlled Trials OR Randomized Controlled Trials”
TE D
Total 1387 reports identified
EP
122 reports eligible for full-text review
AC C
Final study inclusion 105 trials
1104 excluded on titles 161 excluded on abstract
Participants not predominately TBI (n=5) Focus on non-TBI related outcomes (n=6) Early phase trials (n=3) Not RCT (n=1) Duplicate studies (n=2)
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
Text Box 1. Reporting Allocation Concealment and Blinding Allocation concealment - Report the mechanism of allocation concealment - Report the implementation process (i.e., the personnel who enrolled the participants, ascertain the intervention assignment and administered intervention) Blinding - Not only report the single-blind, double blind, or triple-blind terminology, but also explicitly state who is blinded and how blinding is achieved - Report all involved healthcare personnel for whom blinding may influence the validity of a trial (e.g., care providers, interventionist cointerventionist, outcome assessors and adjudicators)
