The Impact of Endpoint Measures in Rheumatoid Clinical Trials
Arthritis
By Agnes van der Heide, Johannes W.G. Jacobs, Huibert J. Dinant, and Johannes W.J. Bijlsma In clinical trials on the effectiveness of diseasemodifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (DA), it is common to apply a large number of endpoint measures. This practice has several disadvantages. To determine which endpoint measures are most valuable, reports of 32 clinical trials on six DMARDs were reviewed. The frequency with which each endpoint measure was used is described and discussed, as well as the frequency with which the values of each endpoint were significantly different in statistical comparisons within or between groups, thus showing ability to discriminate between drugs not equally effective. The results of this review are discussed and compared with other reports in the literature on
the choice of endpoint measures in RA clinical trials. The authors conclude that it is still common practice to evaluate multiple outcome measures. The number of measures could be reduced by using only those that are generally considered important, are sensitive to change, and are able to differentiate between drugs in clinical trials. A joint count, assessment of pain, a questionnaire on functional status, and measurement of erythrocyte sedimentation rate are sufficient. Copyright o 1992 by W.B. Saunders Company
I
composite index that combines several endpoints; this approach increases statistical efficiency and allows sample size to be reduced.‘34-7 Disadvantages of composite indices are that the constituent measures may not be equally or appropriately weighted and that a composite index is not easil interpreted by clinicians.3 Recently developed arthritis-specific selfassessment questionnaires such as the Stanford Health Assessment Questionnaire (HAQ)” and the Arthritis Impact Measurement Scales (AIMS)9 provide a more comprehensive idea of the impact of RA on daily functioning and quality of life. Both the HAQ and the AIMS
T IS NOT EASY to accurately measure the efficacy of treatment with disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA). Appropriate endpoints must be selected that measure both the pathophysiological effects of the disease and the impact on symptoms, signs, and disability the therapeutic agent has the potential to improve.’ It is common practice in RA clinical trials to assess a large number of measures in order to detect all possible signs of benefit. Felson et al describe the major shortcomings of this approach that relies more on the quantity of measures than on their quality.* Among others, one problem with measuring multiple outcomes is that some will improve and others will not; therefore, conclusions are not easily drawn. Another difficulty is the multiplicity of statistical comparisons: in most trials, measures are considered to change independently and no adjustment is made for the number of comparisons to avoid type I errors.3 The use of numerous different measures also makes it difficult to compare results between studies because few trials use exactly the same criteria. Thus, it seems logical to reduce the number of measures by selecting those that are most relevant and sensitive. Some investigators advocate the use of a
INDEX WORDS: Endpoint measures; clinical trials; rheumatoid arthritis.
outcome;
From the cooperating Departments of Rheumatology of the University Hospital, Utrecht; St Antonius Hospital, Nieuwegein; Diakonessen Hospital, Utrecht; and Eemland Hospital, Amersfoort, the Netherlands. Dr van der Heide’s research is funded by the “Nationaal Reumafonds” (Dutch Arthritis Foundation). Agnes van der Heide, MD: Study coordinator, “Stichting Reumaonderzoek Utrecht” (Arthritis Research Foundation, Utrecht); Johannes W.G. Jacobs, MD: Rheumatologist; Huibert J. Dinant, MD: Rheumatologist; Johannes W.J. Bijlsma, MD: Professor of Rheumatology. Address reprint requests to Agnes van der Heide, Department of Rheumatology F 02.223, University Hospital Utrecht, PO Box 85500, 3508 GA Utrecht, the Netherlands. Copyright 0 1992 by W.B. Saunders Company 0049-0172/9212105-0002$5.00/O
Seminars in Arthritis andRheumatism, Vol21, No 5 (April), 1992: pp 287-294
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fulfill criteria of precision, reproducibility, and interobserver variation and correlate well with “traditional” clinical measures.8-‘o This article reviews recently published reports of clinical trials on the effectiveness of DMARD treatment of RA. The impact of each endpoint measure is assessed using the following questions: Which endpoint measures are being used in RA clinical trials? Which outcomes are most sensitive in detecting effects of treatment by showing statistically significant changes in DMARD-treated groups? Which measures are most decisive in differentiating the effectiveness of various treatments by showing statistically significant differences between groups treated with drugs not equally effective? Our results are discussed and compared with other literature reviews on this subject.
and for short-term ( < 24 weeks) and long-term ( > 24 weeks) trials. The relative impact of each endpoint measurement on conclusions about the effectiveness of a DMARD was analyzed by determining the frequency of finding a statistically significant change or difference. All types of statistical tests for differences within or between groups were included. The last point in time at which mean or median values of the endpoint measures or mean or median changes were available was considered. For studies that included within-group statistical analyses, the frequency with which each endpoint measure changed significantly within the DMARD treated group was determined. For studies in which the authors concluded on the basis of between-group statistical analyses that the effectiveness of studied drugs was different, the frequency with which each endpoint measure was statistically different was noted. RESULTS
MATERIALS
AND METHODS
Reports of clinical trials assessing the effectiveness of DMARD therapy published in English from 1986 through 1990 were selected for this review. This search was done using a CD-ROM computerized bibliography. Trials were included that studied patients with RA according to the American College of Rheumatology diagnostic criteria of 1958” or 1987’*; patients must have been randomly assigned to treatment regimens, and trials must either have been placebo controlled or compared two or more DMARDs or different dosages of one DMARD. The following DMARDs were included: hydroxychloroquine or chloroquine (CHL), auranofin (oAU), injectable gold (iAU), D-penicillamine (DPA), methotrexate (MTX), and sulphasalazine (SPS). Studies investigating the effect of steroid induction on DMARD therapy, as well as studies on the effect of stopping a DMARD, were excluded. Data obtained for each trial included source and year of publication, country where the trial was performed, DMARD investigated, duration of the trial, and characteristics of the study population (group sizes, age, gender, duration of RA). The frequency with which each endpoint measure was used was determined for all trials
Inclusion criteria were met by 32 clinical trials.‘3-48In three cases, several reports describe the same trial; reports describing the same trial are regarded as one in our review. Of the 32 trials, 7 were performed in the United Kingdom, 6 in the United States, 6 in Canada, 3 in Australia, and 10 in other countries. The reports were published rather equally over the 5-year period. Table 1 provides data on the trials and the study populations. The effectiveness of oAU was investigated in 15 studies; iAU, MTX, and SPS were also studied frequently. Nine trials compared the effectiveness of a DMARD with that of placebo. The mean duration of the trials was 52 weeks, with a range of 15 to 260 weeks. Eleven studies had a duration of 6 months or less, 10 lasted between 6 months and a year, and 11 had a duration of a year or more. The mean number of patients per treatment group was 33. The mean patient age was 54 years, on average 68% were women, and the mean disease duration was 6.3 years (not all studies report mean values on these variables). A joint count (number of joints that are tender on pressure), in some studies weighted for severity of tenderness, was assessed in 30 of the 32 trials (94%) (Table 2). The most frequently used joint count was the Ritchie or a
ENDPOINT MEASURES IN RA CLINICAL TRIALS
289
Table 1: Selected Data on Clinical Trials
modified Ritchie score (12 of 30), but other more or less standardized scores were also often used. In 11 trials, a joint count as well as a score that weighs the severity of tenderness was used. Joint swelling was used as an articular score in 21 trials (66%). Grip strength and morning stiffness were used in most trials (91%). The patient’s global assessment was an endpoint measure in 72%, and the physician’s global assessment was used in 50%. Of the traditional clinical endpoints, walking time and proximal interphalangeal joints (PIP) circumference were not common, and measures of fatigue and nonsteroidal antiinflammatory drug (NSAID) or analgesic intake were seldom used. Both walking time and physician’s global assessment are mentioned in the methods section of a single report; no results are given. The mean number of clinical measures is 7 (range, 0 to 17). Functional status was assessed in 14 trials (44%); in 10 of these, a HAQ or modified HAQ was used. Quality of life was assessed in only 4 trials. The erythrocyte sedimentation rate (ESR) was used in 88% of the trials, and serum level of C-reactive protein (CRP) was used in 31%. In
Reviewed No. of Patient DMARDs
Groups Studied
oAU
15
iAU
9
MTX
9
SPS
9
DPA
6
HC
5
Other/combination therapy
16 Mean
Range
52
15-260
33
IO-154
Duration of trials (wk) No. of patients per treatment group Patient characteristics Age (yr)” % Femalet Duration of RA (yr)*
54
50-60
68
50-84
6
1-13
*n = 25; 7 reports did not give mean age values. tn = 26; 6 reports did not give mean gender values. Sn = 20; 11 reports did not give mean duration of RA values.
Table 2: Frequency With Which Each Endpoint Measure was Used Short-Term
Trials*
Long-Term Trialst
All Trials
(n = 21)
(n = 32)
(n = 11) Endpoint Measure Morning stiffness Pain
%
(n)
%
(n)
%
(n)
100 91
(11) (10)
86 67
(18) (14)
91 75
(24)
(29)
Patient’s global assessment
73
(8)
71
(15)
72
(23)
Physician’s global assessment*
64
(7)
43
(9)
50
(16)
Joint count§ Joint swelling11
91 73
(10) (8)
95 62
(20) (13)
94 66
(21)
(30)
PIP circumference
46
(5)
24
(5)
31
(10)
Grip strength
91
(10)
90
(19)
91
(29)
Walking time* Functional status
55 55
(6) (6)
14 38
(3) (8)
28 44
(14)
Quality of life
18
(2)
10
(2)
13
(4)
Other clinical endpoints
18
(2)
24
(5)
22
(7)
ESR
91
(10)
86
(18)
88
(28)
CRP Other laboratory endpoints
27 73
(3) (8)
33 57
(7) (12)
31 63
(20)
Radiographs* Cost/effectiveness
18 9
(2) (1)
48 0
(IO) (0)
38 3
analysis
*24 weeks or less.
tMore than 24 weeks. *No results reported in 1 trial. §Tender joint count, sometimes weighted for severity. I/Swollen joint count, sometimes weighted for severity.
(9)
(IO) (12) (1)
VAN DER HEIDE ET AL
290
more than 60% of the trials, laboratory measures other than ESR and CRP were applied; most often these were hemoglobin, platelet count, rheumatoid factor titer, and immunoglobulin levels. Radiographs were obtained in 12 trials (38%) but results were reported in only 10. One study reported only radiographic changes. The choice of endpoints in short-term (5 24 weeks) and long-term (> 24 weeks) trials was similar (Table 2); almost every measure except radiographs was used slightly more often in short-term trials. In the DMARD-treated groups, statistically significant changes were found most frequently in joint count (70%) pain (61%) ESR (61%) and functional status (57%) (Table 3). Joint swelling and grip strength changed significantly in more than 50% of treatment groups, as did PIP circumference, although the number of groups tested was small (13). The number of significant changes in an endpoint in DMARDtreated groups could not be compared with those in placebo groups because none of the nine placebo-controlled studies included statistical analyses of changes within groups. Thirteen trials, 8 of which were placebo controlled, in which a between-group analysis was done report a difference in effectiveness of investigated drugs. This conclusion was most
Table
3:
Frequency
With
Which
Statistically Measure
frequently based on findings of statistically significant differences in joint count (58%) joint swelling (63%) and pain (56%) (Table 4). Functional status supported the conclusion that the study drug was different in 4 of 6 trials, and quality of life was different in 3 of 3 trials. ESR (56%) and CRP (67%) were also helpful in differentiating between groups, but the latter was used in only 3 of the 13 trials. Changes in radiographs were significantly different in 3 of 4 trials. DISCUSSION
In the endpoint measure literature, a distinction is often made between measurement of “process” and measurement of “outcome.” According to Fries, outcome is the end result of the disease, whereas process is merely what happens along the way to a certain outcome.‘9 Outcome measures can also be regarded as reflecting “the state of the patient” in contrast to process measures, which reflect “the state of the disease” and are mainly prognostic indicators of later outcome.5” Laboratory measures such as ESR and acute-phase protein levels primarily estimate the disease process. Most of the traditional clinical endpoints, such as joint count, grip strength, and pain reflect aspects of both process and outcome. These measures give insight into the severity of synovitis, which is
Significant in DMARD
n*
Differencest
Were
Found for Each Endpoint
No Significant
Significant Endpoint Measure
Differences Groups
(%)
Differencest
(%)
Not Tested Within Groups (%)
Morning stiffness
42
48
17
35
Pain
33
61
9
30
Patient’s global assessment
32
22
19
59
Physician’s global assessment
20
5
0
95
Joint count
44
70
5
25
Joint swelling
31
55
IO
35
PIP circumference
13
54
15
31
Grip strength
42
55
14
31
Walking time
12
17
17
66
Functional status
21
57
14
29
4
25
50
25
ESR
41
60
17
22
CRP
12
36
25
42
Radiographs
20
40
5
55
Quality of life
*Number of DMARD groups for which the endpoint measure is applied. tfksults
of zero time compared with last observation.
291
ENDPOINT MEASURES IN RA CLINICAL TRIALS
Table 4: Frequency With Which Statistically
probably related to the ultimate degree of joint damage and disability,5’ and thus may be of prognostic value. However, they also reflect disease impact on daily function and quality of life, serving as (incomplete) outcome measures also. Radiographic joint damage is a result of the disease but is also a parameter of disease process because radiographic changes may ultimately affect joint function. Because DMARD treatment is aimed at improving quality of life in the short and long term, measurement of both process and outcome is important in determining drug response. Several authors select the best endpoint measures. Some reduce the quantity of measures by using only the most sensitive ones or those that best reflect the values of all other tests used to evaluate the disease.43s2-54 Others use a judgmental approach and use measures that are considered relevant at consensus meetings or by leading rheumatologists.55-59 The recommendations of several authorities are summarized in Table 5. In this review, we attempt to establish the impact of various endpoint measures by showing the frequency with which they are used, their sensitivity to change, and their ability to distinguish between different
Significant Differences Between Groups Were Found for Each Endpoint Measure in Trials Reporting Differences in Efficacy of the Investigated
Drugs (n = 13)
Endpoint Measure Morning stiffness Pain Patient’s global assessment Physician’s global assessment Joint count Joint swelling PIP circumference Grip strength
n*
Significant Differences (% of n)
11
27
9
56
10
30
9
44
12
58
8
63
6
17
11
36
Walking time
6
17
Functional status
6
67
3
100
Quality of life ESR
10
56
CRP
3
67
Radiographs
4
75
NOTE. Only trials that report data on between group statistical analyses of mean or median endpoint values or mean or median changes are included. Eight trials were placebo controlled. *Number of studies in which the endpoint is used.
Table 5: Recommended
Endpoint Measures in RA Clinical Trials Source*
Endpoint Measure
I=
2=
3=
4’
5”
+ -
+
+ +
+ +
+ +
+ +
_
-
Morning stiffness Pain Patient’s global assessment Physician’s global assessment Joint count
+ +
Joint swelling
+
6%
757
+ +
+ +
+ + + + + +
+
+ + +
8”
9=
10
+ +
+
+
+
+
+
+
+
+ +
+
PIP circumference
+ +t +t +
Grip strength Walking time Functional status Quality of life ESR Acute-phase
+
reactants
+
Other laboratory measures
+ + +
+ +
+t
Radiographs I
NOTE. C, recommended;
+ + _
+
-, not recommended.
*Sources 1 through 4, recommendations
from other authors based on statistical considerations; sources 5 through 9, recommenda-
tions from other authors based on judgmental considerations; source 10, recommendations use, sensitivity to change, and ability to differentiate between drugs not equally effective. Wiecommendation
+
-
-
based on judgmental consideration.
from this review based on frequency of
292
VAN DER HEIDE ET AL
treatment groups. If we compare the results of our review with the recommendations given in Table 5, the usefulness of a joint count is apparent. Its validity is reflected in the frequency of its use and recommendation, its sensitivity to change, and its capacity to distinguish between treatments.60 The ARA Cooperating Clinics Index’jl and the Ritchie articular score”’ are currently the methods of choice. A recent publication shows that defining joint inflammation by the simultaneous presence of tenderness and swelling and weighing for joint size produces the most sensitive articular index’j3 and yields the highest correlation with serum CRP levels.” Grip strength and morning stiffness are used frequently but not recommended often. In the trials reviewed, they show moderate ability to distinguish between drugs not equally effective. Assessment of pain is considered important and is used in 75% of trials. Although pain assessment is not recommended on statistical grounds in the literature, our review indicates that it is a sensitive measure of within-group and betweengroup change. The less frequent use of the patient’s and physician’s global assessment is justified by their poor differentiating capacities; PIP circumference and walking time are even less sensitive measures. The use of self-assessment questionnaires to determine functional status is a step in the right
direction because they perform better than the traditional functional parameters of grip strength and walking time. Quality of life was assessed in only 3 of the 32 trials reviewed; however, its 100% accuracy in denoting differences between DMARD and placebo groups might indicate its potential value. ESR is often recommended and used and has good ability to differentiate between effective and ineffective therapy. Moreover, it is relatively inexpensive and easily performed. The small impact of laboratory measures makes the use of large numbers of tests undesirable; their prognostic value remains to be proven. We conclude that RA clinical trials still use many, sometimes poorly defined, endpoint measures. Different endpoints are chosen, making interpretation and comparison between trials difficult. Future studies should use selected, standardized endpoint measures whose sensitivity and accuracy have been validated. The number of outcome measures should be reduced by omitting those of lesser clinical importance and of lesser sensitivity to change. Our review indicates that joint count (preferably the Ritchie score or the Thompson score, which combines tenderness and swelling), assessment of pain, functional status (preferably measured by HAQ questionnaire), and ESR are sufficient endpoint measures.
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IN RA CLINICAL TRIALS
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tests used to monitor rheumatoid arthritis. Lancet 1:965967,1989 55. Bellamy N: Critical review of clinical assessment techniques for rheumatoid arthritis trials: New developments. Stand J Rheumatol S80:3-16, 1989 56. Scott DL, Spector TD. Pullar T, et al: What should we hope to achieve when treating rheumatoid arthritis’? Ann Rheum Dis 48:256-261,1989 57. Bombardier C, Tugwell P, Sinclair A. et al: Preference for endpoint measures in clinical trials: results of structured workshops. J Rheumatol 19:798-806, 1982 58. Wright V: Do we need so many assays to detect suppression of inflammation?, in Paulus HE, Ehrlich GE, Lindenlaub E (eds): Controversies in the Clinical Evaluation of Analgesic-Antiinflammatory-Antirheumatic Drugs. New York, NY, Schattauer, 1981, pp 208-210 59. Symmons DPM, Dawes PT: Summary and consensus view. Br J Rheumatol27(supplI):76-77, 1988 60. Tugwell P. Bombardier C: A methodologic framework for developing and selecting endpoints in clinical trials. J Rheumatol9:758-762, 1982 61. Cooperating Clinics Committee of the American Rheumatism Association: A seven-day variability study of 499 patients with peripheral rheumatoid arthritis. Arthritis Rheum 8:302-335, 1965 62. Ritchie DM. Boyle JA. Mclnnes JM, et al: Clinical studies with an articular index for the assessment of joint tenderness in patients with rheumatoid arthritis. Q J Med 37:393-406. 1968 63. Thompson PW, Kirwan JR, Currey HLF: A comparison of the ability of 28 articular indices to detect an induced flare of joint inflammation in rheumatoid arthritis. Br J Rheumatol27:375-380, 1988 64. Thompson PW, Silman AJ, Kirwan JR, et al: Articular indices of joint inflammation with rheumatoid arthritis. Correlation with the acute-phase response. Arthritis Rheum 30:618-623, 1987
Arthritis
By Agnes van der Heide, Johannes W.G. Jacobs, Huibert J. Dinant, and Johannes W.J. Bijlsma In clinical trials on the effectiveness of diseasemodifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (DA), it is common to apply a large number of endpoint measures. This practice has several disadvantages. To determine which endpoint measures are most valuable, reports of 32 clinical trials on six DMARDs were reviewed. The frequency with which each endpoint measure was used is described and discussed, as well as the frequency with which the values of each endpoint were significantly different in statistical comparisons within or between groups, thus showing ability to discriminate between drugs not equally effective. The results of this review are discussed and compared with other reports in the literature on
the choice of endpoint measures in RA clinical trials. The authors conclude that it is still common practice to evaluate multiple outcome measures. The number of measures could be reduced by using only those that are generally considered important, are sensitive to change, and are able to differentiate between drugs in clinical trials. A joint count, assessment of pain, a questionnaire on functional status, and measurement of erythrocyte sedimentation rate are sufficient. Copyright o 1992 by W.B. Saunders Company
I
composite index that combines several endpoints; this approach increases statistical efficiency and allows sample size to be reduced.‘34-7 Disadvantages of composite indices are that the constituent measures may not be equally or appropriately weighted and that a composite index is not easil interpreted by clinicians.3 Recently developed arthritis-specific selfassessment questionnaires such as the Stanford Health Assessment Questionnaire (HAQ)” and the Arthritis Impact Measurement Scales (AIMS)9 provide a more comprehensive idea of the impact of RA on daily functioning and quality of life. Both the HAQ and the AIMS
T IS NOT EASY to accurately measure the efficacy of treatment with disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA). Appropriate endpoints must be selected that measure both the pathophysiological effects of the disease and the impact on symptoms, signs, and disability the therapeutic agent has the potential to improve.’ It is common practice in RA clinical trials to assess a large number of measures in order to detect all possible signs of benefit. Felson et al describe the major shortcomings of this approach that relies more on the quantity of measures than on their quality.* Among others, one problem with measuring multiple outcomes is that some will improve and others will not; therefore, conclusions are not easily drawn. Another difficulty is the multiplicity of statistical comparisons: in most trials, measures are considered to change independently and no adjustment is made for the number of comparisons to avoid type I errors.3 The use of numerous different measures also makes it difficult to compare results between studies because few trials use exactly the same criteria. Thus, it seems logical to reduce the number of measures by selecting those that are most relevant and sensitive. Some investigators advocate the use of a
INDEX WORDS: Endpoint measures; clinical trials; rheumatoid arthritis.
outcome;
From the cooperating Departments of Rheumatology of the University Hospital, Utrecht; St Antonius Hospital, Nieuwegein; Diakonessen Hospital, Utrecht; and Eemland Hospital, Amersfoort, the Netherlands. Dr van der Heide’s research is funded by the “Nationaal Reumafonds” (Dutch Arthritis Foundation). Agnes van der Heide, MD: Study coordinator, “Stichting Reumaonderzoek Utrecht” (Arthritis Research Foundation, Utrecht); Johannes W.G. Jacobs, MD: Rheumatologist; Huibert J. Dinant, MD: Rheumatologist; Johannes W.J. Bijlsma, MD: Professor of Rheumatology. Address reprint requests to Agnes van der Heide, Department of Rheumatology F 02.223, University Hospital Utrecht, PO Box 85500, 3508 GA Utrecht, the Netherlands. Copyright 0 1992 by W.B. Saunders Company 0049-0172/9212105-0002$5.00/O
Seminars in Arthritis andRheumatism, Vol21, No 5 (April), 1992: pp 287-294
287
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fulfill criteria of precision, reproducibility, and interobserver variation and correlate well with “traditional” clinical measures.8-‘o This article reviews recently published reports of clinical trials on the effectiveness of DMARD treatment of RA. The impact of each endpoint measure is assessed using the following questions: Which endpoint measures are being used in RA clinical trials? Which outcomes are most sensitive in detecting effects of treatment by showing statistically significant changes in DMARD-treated groups? Which measures are most decisive in differentiating the effectiveness of various treatments by showing statistically significant differences between groups treated with drugs not equally effective? Our results are discussed and compared with other literature reviews on this subject.
and for short-term ( < 24 weeks) and long-term ( > 24 weeks) trials. The relative impact of each endpoint measurement on conclusions about the effectiveness of a DMARD was analyzed by determining the frequency of finding a statistically significant change or difference. All types of statistical tests for differences within or between groups were included. The last point in time at which mean or median values of the endpoint measures or mean or median changes were available was considered. For studies that included within-group statistical analyses, the frequency with which each endpoint measure changed significantly within the DMARD treated group was determined. For studies in which the authors concluded on the basis of between-group statistical analyses that the effectiveness of studied drugs was different, the frequency with which each endpoint measure was statistically different was noted. RESULTS
MATERIALS
AND METHODS
Reports of clinical trials assessing the effectiveness of DMARD therapy published in English from 1986 through 1990 were selected for this review. This search was done using a CD-ROM computerized bibliography. Trials were included that studied patients with RA according to the American College of Rheumatology diagnostic criteria of 1958” or 1987’*; patients must have been randomly assigned to treatment regimens, and trials must either have been placebo controlled or compared two or more DMARDs or different dosages of one DMARD. The following DMARDs were included: hydroxychloroquine or chloroquine (CHL), auranofin (oAU), injectable gold (iAU), D-penicillamine (DPA), methotrexate (MTX), and sulphasalazine (SPS). Studies investigating the effect of steroid induction on DMARD therapy, as well as studies on the effect of stopping a DMARD, were excluded. Data obtained for each trial included source and year of publication, country where the trial was performed, DMARD investigated, duration of the trial, and characteristics of the study population (group sizes, age, gender, duration of RA). The frequency with which each endpoint measure was used was determined for all trials
Inclusion criteria were met by 32 clinical trials.‘3-48In three cases, several reports describe the same trial; reports describing the same trial are regarded as one in our review. Of the 32 trials, 7 were performed in the United Kingdom, 6 in the United States, 6 in Canada, 3 in Australia, and 10 in other countries. The reports were published rather equally over the 5-year period. Table 1 provides data on the trials and the study populations. The effectiveness of oAU was investigated in 15 studies; iAU, MTX, and SPS were also studied frequently. Nine trials compared the effectiveness of a DMARD with that of placebo. The mean duration of the trials was 52 weeks, with a range of 15 to 260 weeks. Eleven studies had a duration of 6 months or less, 10 lasted between 6 months and a year, and 11 had a duration of a year or more. The mean number of patients per treatment group was 33. The mean patient age was 54 years, on average 68% were women, and the mean disease duration was 6.3 years (not all studies report mean values on these variables). A joint count (number of joints that are tender on pressure), in some studies weighted for severity of tenderness, was assessed in 30 of the 32 trials (94%) (Table 2). The most frequently used joint count was the Ritchie or a
ENDPOINT MEASURES IN RA CLINICAL TRIALS
289
Table 1: Selected Data on Clinical Trials
modified Ritchie score (12 of 30), but other more or less standardized scores were also often used. In 11 trials, a joint count as well as a score that weighs the severity of tenderness was used. Joint swelling was used as an articular score in 21 trials (66%). Grip strength and morning stiffness were used in most trials (91%). The patient’s global assessment was an endpoint measure in 72%, and the physician’s global assessment was used in 50%. Of the traditional clinical endpoints, walking time and proximal interphalangeal joints (PIP) circumference were not common, and measures of fatigue and nonsteroidal antiinflammatory drug (NSAID) or analgesic intake were seldom used. Both walking time and physician’s global assessment are mentioned in the methods section of a single report; no results are given. The mean number of clinical measures is 7 (range, 0 to 17). Functional status was assessed in 14 trials (44%); in 10 of these, a HAQ or modified HAQ was used. Quality of life was assessed in only 4 trials. The erythrocyte sedimentation rate (ESR) was used in 88% of the trials, and serum level of C-reactive protein (CRP) was used in 31%. In
Reviewed No. of Patient DMARDs
Groups Studied
oAU
15
iAU
9
MTX
9
SPS
9
DPA
6
HC
5
Other/combination therapy
16 Mean
Range
52
15-260
33
IO-154
Duration of trials (wk) No. of patients per treatment group Patient characteristics Age (yr)” % Femalet Duration of RA (yr)*
54
50-60
68
50-84
6
1-13
*n = 25; 7 reports did not give mean age values. tn = 26; 6 reports did not give mean gender values. Sn = 20; 11 reports did not give mean duration of RA values.
Table 2: Frequency With Which Each Endpoint Measure was Used Short-Term
Trials*
Long-Term Trialst
All Trials
(n = 21)
(n = 32)
(n = 11) Endpoint Measure Morning stiffness Pain
%
(n)
%
(n)
%
(n)
100 91
(11) (10)
86 67
(18) (14)
91 75
(24)
(29)
Patient’s global assessment
73
(8)
71
(15)
72
(23)
Physician’s global assessment*
64
(7)
43
(9)
50
(16)
Joint count§ Joint swelling11
91 73
(10) (8)
95 62
(20) (13)
94 66
(21)
(30)
PIP circumference
46
(5)
24
(5)
31
(10)
Grip strength
91
(10)
90
(19)
91
(29)
Walking time* Functional status
55 55
(6) (6)
14 38
(3) (8)
28 44
(14)
Quality of life
18
(2)
10
(2)
13
(4)
Other clinical endpoints
18
(2)
24
(5)
22
(7)
ESR
91
(10)
86
(18)
88
(28)
CRP Other laboratory endpoints
27 73
(3) (8)
33 57
(7) (12)
31 63
(20)
Radiographs* Cost/effectiveness
18 9
(2) (1)
48 0
(IO) (0)
38 3
analysis
*24 weeks or less.
tMore than 24 weeks. *No results reported in 1 trial. §Tender joint count, sometimes weighted for severity. I/Swollen joint count, sometimes weighted for severity.
(9)
(IO) (12) (1)
VAN DER HEIDE ET AL
290
more than 60% of the trials, laboratory measures other than ESR and CRP were applied; most often these were hemoglobin, platelet count, rheumatoid factor titer, and immunoglobulin levels. Radiographs were obtained in 12 trials (38%) but results were reported in only 10. One study reported only radiographic changes. The choice of endpoints in short-term (5 24 weeks) and long-term (> 24 weeks) trials was similar (Table 2); almost every measure except radiographs was used slightly more often in short-term trials. In the DMARD-treated groups, statistically significant changes were found most frequently in joint count (70%) pain (61%) ESR (61%) and functional status (57%) (Table 3). Joint swelling and grip strength changed significantly in more than 50% of treatment groups, as did PIP circumference, although the number of groups tested was small (13). The number of significant changes in an endpoint in DMARDtreated groups could not be compared with those in placebo groups because none of the nine placebo-controlled studies included statistical analyses of changes within groups. Thirteen trials, 8 of which were placebo controlled, in which a between-group analysis was done report a difference in effectiveness of investigated drugs. This conclusion was most
Table
3:
Frequency
With
Which
Statistically Measure
frequently based on findings of statistically significant differences in joint count (58%) joint swelling (63%) and pain (56%) (Table 4). Functional status supported the conclusion that the study drug was different in 4 of 6 trials, and quality of life was different in 3 of 3 trials. ESR (56%) and CRP (67%) were also helpful in differentiating between groups, but the latter was used in only 3 of the 13 trials. Changes in radiographs were significantly different in 3 of 4 trials. DISCUSSION
In the endpoint measure literature, a distinction is often made between measurement of “process” and measurement of “outcome.” According to Fries, outcome is the end result of the disease, whereas process is merely what happens along the way to a certain outcome.‘9 Outcome measures can also be regarded as reflecting “the state of the patient” in contrast to process measures, which reflect “the state of the disease” and are mainly prognostic indicators of later outcome.5” Laboratory measures such as ESR and acute-phase protein levels primarily estimate the disease process. Most of the traditional clinical endpoints, such as joint count, grip strength, and pain reflect aspects of both process and outcome. These measures give insight into the severity of synovitis, which is
Significant in DMARD
n*
Differencest
Were
Found for Each Endpoint
No Significant
Significant Endpoint Measure
Differences Groups
(%)
Differencest
(%)
Not Tested Within Groups (%)
Morning stiffness
42
48
17
35
Pain
33
61
9
30
Patient’s global assessment
32
22
19
59
Physician’s global assessment
20
5
0
95
Joint count
44
70
5
25
Joint swelling
31
55
IO
35
PIP circumference
13
54
15
31
Grip strength
42
55
14
31
Walking time
12
17
17
66
Functional status
21
57
14
29
4
25
50
25
ESR
41
60
17
22
CRP
12
36
25
42
Radiographs
20
40
5
55
Quality of life
*Number of DMARD groups for which the endpoint measure is applied. tfksults
of zero time compared with last observation.
291
ENDPOINT MEASURES IN RA CLINICAL TRIALS
Table 4: Frequency With Which Statistically
probably related to the ultimate degree of joint damage and disability,5’ and thus may be of prognostic value. However, they also reflect disease impact on daily function and quality of life, serving as (incomplete) outcome measures also. Radiographic joint damage is a result of the disease but is also a parameter of disease process because radiographic changes may ultimately affect joint function. Because DMARD treatment is aimed at improving quality of life in the short and long term, measurement of both process and outcome is important in determining drug response. Several authors select the best endpoint measures. Some reduce the quantity of measures by using only the most sensitive ones or those that best reflect the values of all other tests used to evaluate the disease.43s2-54 Others use a judgmental approach and use measures that are considered relevant at consensus meetings or by leading rheumatologists.55-59 The recommendations of several authorities are summarized in Table 5. In this review, we attempt to establish the impact of various endpoint measures by showing the frequency with which they are used, their sensitivity to change, and their ability to distinguish between different
Significant Differences Between Groups Were Found for Each Endpoint Measure in Trials Reporting Differences in Efficacy of the Investigated
Drugs (n = 13)
Endpoint Measure Morning stiffness Pain Patient’s global assessment Physician’s global assessment Joint count Joint swelling PIP circumference Grip strength
n*
Significant Differences (% of n)
11
27
9
56
10
30
9
44
12
58
8
63
6
17
11
36
Walking time
6
17
Functional status
6
67
3
100
Quality of life ESR
10
56
CRP
3
67
Radiographs
4
75
NOTE. Only trials that report data on between group statistical analyses of mean or median endpoint values or mean or median changes are included. Eight trials were placebo controlled. *Number of studies in which the endpoint is used.
Table 5: Recommended
Endpoint Measures in RA Clinical Trials Source*
Endpoint Measure
I=
2=
3=
4’
5”
+ -
+
+ +
+ +
+ +
+ +
_
-
Morning stiffness Pain Patient’s global assessment Physician’s global assessment Joint count
+ +
Joint swelling
+
6%
757
+ +
+ +
+ + + + + +
+
+ + +
8”
9=
10
+ +
+
+
+
+
+
+
+
+ +
+
PIP circumference
+ +t +t +
Grip strength Walking time Functional status Quality of life ESR Acute-phase
+
reactants
+
Other laboratory measures
+ + +
+ +
+t
Radiographs I
NOTE. C, recommended;
+ + _
+
-, not recommended.
*Sources 1 through 4, recommendations
from other authors based on statistical considerations; sources 5 through 9, recommenda-
tions from other authors based on judgmental considerations; source 10, recommendations use, sensitivity to change, and ability to differentiate between drugs not equally effective. Wiecommendation
+
-
-
based on judgmental consideration.
from this review based on frequency of
292
VAN DER HEIDE ET AL
treatment groups. If we compare the results of our review with the recommendations given in Table 5, the usefulness of a joint count is apparent. Its validity is reflected in the frequency of its use and recommendation, its sensitivity to change, and its capacity to distinguish between treatments.60 The ARA Cooperating Clinics Index’jl and the Ritchie articular score”’ are currently the methods of choice. A recent publication shows that defining joint inflammation by the simultaneous presence of tenderness and swelling and weighing for joint size produces the most sensitive articular index’j3 and yields the highest correlation with serum CRP levels.” Grip strength and morning stiffness are used frequently but not recommended often. In the trials reviewed, they show moderate ability to distinguish between drugs not equally effective. Assessment of pain is considered important and is used in 75% of trials. Although pain assessment is not recommended on statistical grounds in the literature, our review indicates that it is a sensitive measure of within-group and betweengroup change. The less frequent use of the patient’s and physician’s global assessment is justified by their poor differentiating capacities; PIP circumference and walking time are even less sensitive measures. The use of self-assessment questionnaires to determine functional status is a step in the right
direction because they perform better than the traditional functional parameters of grip strength and walking time. Quality of life was assessed in only 3 of the 32 trials reviewed; however, its 100% accuracy in denoting differences between DMARD and placebo groups might indicate its potential value. ESR is often recommended and used and has good ability to differentiate between effective and ineffective therapy. Moreover, it is relatively inexpensive and easily performed. The small impact of laboratory measures makes the use of large numbers of tests undesirable; their prognostic value remains to be proven. We conclude that RA clinical trials still use many, sometimes poorly defined, endpoint measures. Different endpoints are chosen, making interpretation and comparison between trials difficult. Future studies should use selected, standardized endpoint measures whose sensitivity and accuracy have been validated. The number of outcome measures should be reduced by omitting those of lesser clinical importance and of lesser sensitivity to change. Our review indicates that joint count (preferably the Ritchie score or the Thompson score, which combines tenderness and swelling), assessment of pain, functional status (preferably measured by HAQ questionnaire), and ESR are sufficient endpoint measures.
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IN RA CLINICAL TRIALS
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