AAC Accepted Manuscript Posted Online 18 May 2015 Antimicrob. Agents Chemother. doi:10.1128/AAC.00679-15 Copyright © 2015, American Society for Microbiology. All Rights Reserved.
1
Antibacterial treatment effect estimation in acute bacterial skin and skin structure infection:
2
systematic review and meta-analysis.
3 4 5
Jordan E. Cates,a Fanny S. Mitrani-Gold,b,# Gang Li,c,* Linda M. Mundyc
6 7
University of North Carolina, Chapel Hill, NCa; GlaxoSmithKline (GSK), Research Triangle
8
Park, NCb; GSK, Collegeville, PAc.
9 10 11 12 13
Running title: Antibacterial treatment effect estimation in ABSSSI
14 15 16 17
# Address correspondence to [email protected]
18 19
* Present address: Gang Li, Pfizer, Collegeville, PA
20 21 22 23
1
24
ABSTRACT
25
A systematic literature review and meta-analysis were conducted to estimate the antibacterial
26
treatment effect for linezolid and ceftaroline to inform on the design of acute bacterial skin and
27
skin structure infection (ABSSSI) non-inferiority trials. The primary endpoints included an early
28
clinical treatment response (ECTR) defined as cessation of lesion spread at 48-72 hours post-
29
randomization and the test of cure (TOC) response defined as total resolution of the infection at
30
7-14 days post-treatment. The systematic review identified no placebo-controlled trials in
31
ABSSSI, four placebo-controlled trials in uncomplicated skin and soft tissue infection as a proxy
32
for placebo in ABSSSI, 12 linezolid ABSSSI trials, three ceftaroline ABSSSI trials, and two
33
trials for non-antibacterial treatment. The ECTR rates at 48-72 hours, and corresponding 95%
34
confidence intervals (CI), were 78.7% (95% CI 61.1, 96.3%) for linezolid, 74.0% (95% CI
35
69.7,78.3%) for ceftaroline, and 59.0% (95% CI 52.8, 65.3%) for non-antibacterial treatment.
36
Early clinical treatment effect could not be estimated, given no available placebo or proxy for
37
placebo data for this endpoint. Clinical, methodological, and statistical heterogeneity influenced
38
the selection of trials for the meta-analysis of the TOC treatment effect estimation. The pooled
39
estimates of TOC treatment response were 31.0% (95% CI 6.2, 55.9%) for the proxy for placebo,
40
88.1% (95% CI 81.0, 95.1%) for linezolid, and 86.1% (95% CI 83.7, 88.6%) for ceftaroline. The
41
TOC clinical treatment effect estimation was 25.1% for linezolid and 27.8% for ceftaroline. The
42
antibacterial treatment effect estimation at TOC will inform on the design and analysis of future
43
non-inferiority ABSSSI clinical trials.
44
Abstract word count: 249
2
45
Key words: acute bacterial skin and skin structure infection (ABSSSI), complicated skin and soft
46
tissue infection (cSSTI), complicated skin and skin structure infection (cSSSI), treatment effect,
47
abscess, skin infection
3
48
Introduction
49
Over the past decade, robust clinical, scientific, and regulatory debate has ensued for initiatives
50
to improve the design, execution, and analysis of antibacterial clinical trials (1-4). New trials for
51
acute bacterial skin and skin structure infections (ABSSSI), previously referred to as complicated
52
skin and skin structure infections (cSSTI), remain important given the rise in incidence of
53
methicillin-resistant Staphylococcus aureus infections and reports of treatment failure (5-8). Per
54
guidance from the United States (US) Food and Drug Administration (FDA), patient eligibility
55
for enrollment in ABSSSI trials should be restricted to those with erysipelas, cellulitis, major
56
cutaneous abscesses, and wound infections having a minimal lesion surface area involvement of
57
75 cm2 (9). For trial endpoints, the traditional test of cure (TOC) endpoint, with the treatment
58
success defined as total resolution of the infection at 7-14 days post-treatment, remains aligned
59
with European regulatory guidance, yet the treatment success for the primary efficacy endpoint
60
aligned with the FDA guidance is defined as cessation of lesion spread after 48-72 hours of
61
treatment (9-11). Revisions to the enrollment and endpoint criteria in recent regulatory guidance
62
for ABSSSI trials necessitate re-evaluation of the antibacterial treatment effect estimation
63
calculated from across-trials comparison of existing data for non-inferiority trial design (4, 12-
64
16).
65 66
To inform on future non-inferiority ABSSSI trial design, we conducted a systematic review and
67
meta-analysis of antibacterial treatment effect estimation. Linezolid and ceftaroline were a
68
priori selected as drugs representative of potential active comparators for hospitalized adults
69
with ABSSSI in a global phase 3 clinical development program. The trial data extracted for the
70
systematic review were aligned with regulatory guidance for the enrollment and endpoint criteria
4
71
in ABSSSI. A pre-defined meta-analysis plan defined the efficacy variables, primary endpoints
72
of interest, and computational methods for antibacterial treatment effect estimation in ABSSSI
73
historical trials for non-inferiority margin justification.
74 75
Materials and Methods
76
Study design. The systematic review and meta-analysis were designed and executed in
77
compliance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis
78
(PRISMA) (17-19). Two independent reviewers conducted computer-based literature searches
79
and a systematic review using the MEDLINE search engine (PubMed, US National Library of
80
Medicine, National Institute of Health; http://www.ncbi.nlm.nih.gov). Ideally, treatment effect
81
estimation for a non-inferiority antibacterial trial should be calculated from placebo-controlled
82
trials to allow for within trial comparison of the antibacterial treatment response as compared to
83
placebo treatment response (11, 14). Given prior report that placebo-controlled trials were non-
84
existent for complicated skin infections (20), we partitioned the literature searches to identify
85
placebo-controlled trials of any antibacterial treatment for ABSSSI (search A1) as well as
86
randomized clinical trials of active comparators in ABSSSI for linezolid (search B1) and
87
ceftaroline (search B2). Due to nomenclature changes over time, studies were included that
88
assessed ABSSSI, complicated skin and soft tissue infections (cSSTI), or complicated skin and
89
skin structure infections (cSSSI). While it was previously reported that there were no historical
90
data for placebo-controlled trials of any antibacterial treatment in complicated skin infections,
91
our search strategy, by design, would have captured any placebo-controlled ABSSSI trials,
92
inclusive of trials for linezolid and ceftaroline. The placebo search was extended to include
93
clinical trials reporting a placebo treatment response in uncomplicated skin and soft tissue
5
94
infections (uSSTI) as a proxy for placebo in ABSSSI (search A2). This strategy, which
95
comprised using a proxy for placebo effect estimation, has been recommended in FDA guidance
96
for non-inferiority trials and has been used for placebo treatment effect estimation for trials in
97
complicated urinary tract infection (13, 21, 22). Given that historical studies published in 1937
98
reported relatively high response rates in treatment of erysipelas with ultraviolet (UV) light, an
99
additional search (search C) was conducted to identify clinical trials of non-antibacterial
100
treatment in uSSTI and in ABSSSI (4, 23, 24). This search was a priori conducted to identify
101
potentially informative data and not as a proxy for placebo treatment response estimation.
102 103
Identification of trials and full-screen review for eligibility
104
For each search, the publications were restricted to dates before 28 February 2013. Search terms
105
included abbreviations, plural and full phrase versions of the selected search terms (listed in
106
Appendix 1) combined with Boolean operators (AND, OR) used in succession to narrow or
107
widen the respective searches. Two reviewers independently assessed the identified publications
108
for trial eligibility, data quality, and efficacy data. Eligible studies included randomized clinical
109
trials for the respective searches of placebo-controlled trials (search A1), active comparator trials
110
of linezolid (search B1) and ceftaroline (search B2) in ABSSSI, and trials of non-antibacterial
111
treatment in uSSTI and ABSSSI (search C). Case series, observational studies, review papers,
112
duplicate studies, and studies with incomplete data were not eligible for full text review.
113
Publications identified in searches A1, B1, B2, and C were excluded for one or more of the
114
following criteria: pediatric exclusivity, lack of reported measure of endpoints of interest, more
115
than 15% of subjects with either diabetic foot infections, animal or human bites, necrotizing
116
fasciitis, decubitus ulcer infection, myonecrosis, or ecthyma gangrenosum, and pooled treatment
6
117
response rates for multiple infection types. Publications of uSSTI in search A2 were eligible for
118
full review if the report was a placebo-controlled trial in impetigo, furunculosis, carbunculosis,
119
folliculitis, ecthyma, erysipelas, or secondarily-infected traumatic lesions (SITL). Publications
120
of uSSTI studies were excluded for one of the following criteria: placebo add-on treatment,
121
pediatric-exclusive studies, prevention or colonization trials, or inclusion of subjects with simple
122
abscesses treated via incision and drainage as surgical treatment in minor cutaneous abscesses.
123
The latter group was excluded as any potential estimate of placebo effect could not be
124
independently assessed of the surgical treatment effect (25-27).
125 126
Primary endpoints
127
For the meta-analysis, the two primary endpoints of interest were in the intention to treat (ITT)
128
population and defined as the early clinical treatment response at 48-72 hours after
129
randomization and the TOC clinical treatment response. Outcome definitions of clinical success,
130
cure, or treatment failure were evaluated from each of the published studies on the basis of
131
criteria available and assessed for methodological and clinical heterogeneity. Early clinical
132
treatment response was defined as the proportion of subjects who experienced cessation of
133
spread or the reduction in the total surface area of the lesion at 48-72 hours after randomization
134
or after the first dose of study drug (9). The TOC clinical treatment response varied in definition
135
based on location and year of the trial execution, but was typically defined as the proportion of
136
subjects who experienced total resolution of all signs and symptoms of the infection at 1-2 weeks
137
after completion of therapy (9). Studies that incorporated improvement in the definition of
138
success were included in the meta-analysis, yet noted for this composite definition of success.
139
Treatment was divided into three broad categories: placebo (with extension to proxy for
7
140
placebo), antibacterial and non- antibacterial treatment for the ITT population unless otherwise
141
noted.
142
143
Data extraction
144
Data were systematically extracted for general study characteristics which included author,
145
publication date, study drug and duration of therapy, active comparator, study population
146
description, study years, countries or regions, study centers, and outcomes. Baseline
147
demographic data were abstracted to assess age, gender, geographic region, proportion of
148
baseline infection types and lesions size when available. Methodological details were abstracted
149
to assess randomization procedures, sequence generation, blinding in subjects and in
150
investigators, eligibility criteria, inclusion and exclusion criteria, subject withdrawals, allocation
151
concealment, primary outcome variable, secondary outcome variable, study definitions, timing of
152
outcome assessment (including early clinical treatment response at 48-72 hours after
153
randomization and TOC clinical treatment response), incomplete reporting of outcomes, and
154
other potential sources of bias.
155 156
Assessments of trial heterogeneity and publication bias
157
Publications reporting trials meeting inclusion criteria were assessed for clinical, methodological,
158
and statistical heterogeneity. Clinical heterogeneity was defined by patient selection,
159
interventions, and outcomes; methodological heterogeneity was defined by study design and
160
execution; statistical heterogeneity was defined as variation in the results beyond sampling
161
variability (28-31). Given the qualitative decisions associated with clinical and methodological
162
heterogeneity, each trial meeting the eligibility criteria was systematically assessed by each 8
163
reviewer for inclusion and exclusion criteria, types and distribution of skin infections, timing of
164
the outcome assessments, treatment duration, inclusion of lesion improvement as an indicator of
165
success, and the proportion of subjects with MRSA pathogens. Each of two independent
166
reviewers employed the Cochrane Risk of Bias Tool for assessment of publication bias and any
167
potential discrepancies were adjudicated via consensus with a third assessor (32).
168 169
Study selection for meta-analysis
170
Extensive clinical, methodological, and statistical heterogeneity influenced the selection of
171
studies included in the meta-analysis (31). The proxy for placebo trials selected for inclusion in
172
the meta-analysis were restricted to studies that did not exclusively enroll subjects with SITL,
173
given differential regulatory approval of antibacterial agents for this infection type. For the
174
linezolid and ceftaroline trials, selection for inclusion in the meta-analysis was based on trial
175
parameters in the historical data that approximated recent ABSSSI guidance, to minimize clinical
176
and methodological heterogeneity of studies pooled in the meta-analysis (9, 31). These selection
177
criteria were trials with total surface lesion area >75 cm2, a non-MRSA specific population, and
178
abscesses in
1
Antibacterial treatment effect estimation in acute bacterial skin and skin structure infection:
2
systematic review and meta-analysis.
3 4 5
Jordan E. Cates,a Fanny S. Mitrani-Gold,b,# Gang Li,c,* Linda M. Mundyc
6 7
University of North Carolina, Chapel Hill, NCa; GlaxoSmithKline (GSK), Research Triangle
8
Park, NCb; GSK, Collegeville, PAc.
9 10 11 12 13
Running title: Antibacterial treatment effect estimation in ABSSSI
14 15 16 17
# Address correspondence to [email protected]
18 19
* Present address: Gang Li, Pfizer, Collegeville, PA
20 21 22 23
1
24
ABSTRACT
25
A systematic literature review and meta-analysis were conducted to estimate the antibacterial
26
treatment effect for linezolid and ceftaroline to inform on the design of acute bacterial skin and
27
skin structure infection (ABSSSI) non-inferiority trials. The primary endpoints included an early
28
clinical treatment response (ECTR) defined as cessation of lesion spread at 48-72 hours post-
29
randomization and the test of cure (TOC) response defined as total resolution of the infection at
30
7-14 days post-treatment. The systematic review identified no placebo-controlled trials in
31
ABSSSI, four placebo-controlled trials in uncomplicated skin and soft tissue infection as a proxy
32
for placebo in ABSSSI, 12 linezolid ABSSSI trials, three ceftaroline ABSSSI trials, and two
33
trials for non-antibacterial treatment. The ECTR rates at 48-72 hours, and corresponding 95%
34
confidence intervals (CI), were 78.7% (95% CI 61.1, 96.3%) for linezolid, 74.0% (95% CI
35
69.7,78.3%) for ceftaroline, and 59.0% (95% CI 52.8, 65.3%) for non-antibacterial treatment.
36
Early clinical treatment effect could not be estimated, given no available placebo or proxy for
37
placebo data for this endpoint. Clinical, methodological, and statistical heterogeneity influenced
38
the selection of trials for the meta-analysis of the TOC treatment effect estimation. The pooled
39
estimates of TOC treatment response were 31.0% (95% CI 6.2, 55.9%) for the proxy for placebo,
40
88.1% (95% CI 81.0, 95.1%) for linezolid, and 86.1% (95% CI 83.7, 88.6%) for ceftaroline. The
41
TOC clinical treatment effect estimation was 25.1% for linezolid and 27.8% for ceftaroline. The
42
antibacterial treatment effect estimation at TOC will inform on the design and analysis of future
43
non-inferiority ABSSSI clinical trials.
44
Abstract word count: 249
2
45
Key words: acute bacterial skin and skin structure infection (ABSSSI), complicated skin and soft
46
tissue infection (cSSTI), complicated skin and skin structure infection (cSSSI), treatment effect,
47
abscess, skin infection
3
48
Introduction
49
Over the past decade, robust clinical, scientific, and regulatory debate has ensued for initiatives
50
to improve the design, execution, and analysis of antibacterial clinical trials (1-4). New trials for
51
acute bacterial skin and skin structure infections (ABSSSI), previously referred to as complicated
52
skin and skin structure infections (cSSTI), remain important given the rise in incidence of
53
methicillin-resistant Staphylococcus aureus infections and reports of treatment failure (5-8). Per
54
guidance from the United States (US) Food and Drug Administration (FDA), patient eligibility
55
for enrollment in ABSSSI trials should be restricted to those with erysipelas, cellulitis, major
56
cutaneous abscesses, and wound infections having a minimal lesion surface area involvement of
57
75 cm2 (9). For trial endpoints, the traditional test of cure (TOC) endpoint, with the treatment
58
success defined as total resolution of the infection at 7-14 days post-treatment, remains aligned
59
with European regulatory guidance, yet the treatment success for the primary efficacy endpoint
60
aligned with the FDA guidance is defined as cessation of lesion spread after 48-72 hours of
61
treatment (9-11). Revisions to the enrollment and endpoint criteria in recent regulatory guidance
62
for ABSSSI trials necessitate re-evaluation of the antibacterial treatment effect estimation
63
calculated from across-trials comparison of existing data for non-inferiority trial design (4, 12-
64
16).
65 66
To inform on future non-inferiority ABSSSI trial design, we conducted a systematic review and
67
meta-analysis of antibacterial treatment effect estimation. Linezolid and ceftaroline were a
68
priori selected as drugs representative of potential active comparators for hospitalized adults
69
with ABSSSI in a global phase 3 clinical development program. The trial data extracted for the
70
systematic review were aligned with regulatory guidance for the enrollment and endpoint criteria
4
71
in ABSSSI. A pre-defined meta-analysis plan defined the efficacy variables, primary endpoints
72
of interest, and computational methods for antibacterial treatment effect estimation in ABSSSI
73
historical trials for non-inferiority margin justification.
74 75
Materials and Methods
76
Study design. The systematic review and meta-analysis were designed and executed in
77
compliance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis
78
(PRISMA) (17-19). Two independent reviewers conducted computer-based literature searches
79
and a systematic review using the MEDLINE search engine (PubMed, US National Library of
80
Medicine, National Institute of Health; http://www.ncbi.nlm.nih.gov). Ideally, treatment effect
81
estimation for a non-inferiority antibacterial trial should be calculated from placebo-controlled
82
trials to allow for within trial comparison of the antibacterial treatment response as compared to
83
placebo treatment response (11, 14). Given prior report that placebo-controlled trials were non-
84
existent for complicated skin infections (20), we partitioned the literature searches to identify
85
placebo-controlled trials of any antibacterial treatment for ABSSSI (search A1) as well as
86
randomized clinical trials of active comparators in ABSSSI for linezolid (search B1) and
87
ceftaroline (search B2). Due to nomenclature changes over time, studies were included that
88
assessed ABSSSI, complicated skin and soft tissue infections (cSSTI), or complicated skin and
89
skin structure infections (cSSSI). While it was previously reported that there were no historical
90
data for placebo-controlled trials of any antibacterial treatment in complicated skin infections,
91
our search strategy, by design, would have captured any placebo-controlled ABSSSI trials,
92
inclusive of trials for linezolid and ceftaroline. The placebo search was extended to include
93
clinical trials reporting a placebo treatment response in uncomplicated skin and soft tissue
5
94
infections (uSSTI) as a proxy for placebo in ABSSSI (search A2). This strategy, which
95
comprised using a proxy for placebo effect estimation, has been recommended in FDA guidance
96
for non-inferiority trials and has been used for placebo treatment effect estimation for trials in
97
complicated urinary tract infection (13, 21, 22). Given that historical studies published in 1937
98
reported relatively high response rates in treatment of erysipelas with ultraviolet (UV) light, an
99
additional search (search C) was conducted to identify clinical trials of non-antibacterial
100
treatment in uSSTI and in ABSSSI (4, 23, 24). This search was a priori conducted to identify
101
potentially informative data and not as a proxy for placebo treatment response estimation.
102 103
Identification of trials and full-screen review for eligibility
104
For each search, the publications were restricted to dates before 28 February 2013. Search terms
105
included abbreviations, plural and full phrase versions of the selected search terms (listed in
106
Appendix 1) combined with Boolean operators (AND, OR) used in succession to narrow or
107
widen the respective searches. Two reviewers independently assessed the identified publications
108
for trial eligibility, data quality, and efficacy data. Eligible studies included randomized clinical
109
trials for the respective searches of placebo-controlled trials (search A1), active comparator trials
110
of linezolid (search B1) and ceftaroline (search B2) in ABSSSI, and trials of non-antibacterial
111
treatment in uSSTI and ABSSSI (search C). Case series, observational studies, review papers,
112
duplicate studies, and studies with incomplete data were not eligible for full text review.
113
Publications identified in searches A1, B1, B2, and C were excluded for one or more of the
114
following criteria: pediatric exclusivity, lack of reported measure of endpoints of interest, more
115
than 15% of subjects with either diabetic foot infections, animal or human bites, necrotizing
116
fasciitis, decubitus ulcer infection, myonecrosis, or ecthyma gangrenosum, and pooled treatment
6
117
response rates for multiple infection types. Publications of uSSTI in search A2 were eligible for
118
full review if the report was a placebo-controlled trial in impetigo, furunculosis, carbunculosis,
119
folliculitis, ecthyma, erysipelas, or secondarily-infected traumatic lesions (SITL). Publications
120
of uSSTI studies were excluded for one of the following criteria: placebo add-on treatment,
121
pediatric-exclusive studies, prevention or colonization trials, or inclusion of subjects with simple
122
abscesses treated via incision and drainage as surgical treatment in minor cutaneous abscesses.
123
The latter group was excluded as any potential estimate of placebo effect could not be
124
independently assessed of the surgical treatment effect (25-27).
125 126
Primary endpoints
127
For the meta-analysis, the two primary endpoints of interest were in the intention to treat (ITT)
128
population and defined as the early clinical treatment response at 48-72 hours after
129
randomization and the TOC clinical treatment response. Outcome definitions of clinical success,
130
cure, or treatment failure were evaluated from each of the published studies on the basis of
131
criteria available and assessed for methodological and clinical heterogeneity. Early clinical
132
treatment response was defined as the proportion of subjects who experienced cessation of
133
spread or the reduction in the total surface area of the lesion at 48-72 hours after randomization
134
or after the first dose of study drug (9). The TOC clinical treatment response varied in definition
135
based on location and year of the trial execution, but was typically defined as the proportion of
136
subjects who experienced total resolution of all signs and symptoms of the infection at 1-2 weeks
137
after completion of therapy (9). Studies that incorporated improvement in the definition of
138
success were included in the meta-analysis, yet noted for this composite definition of success.
139
Treatment was divided into three broad categories: placebo (with extension to proxy for
7
140
placebo), antibacterial and non- antibacterial treatment for the ITT population unless otherwise
141
noted.
142
143
Data extraction
144
Data were systematically extracted for general study characteristics which included author,
145
publication date, study drug and duration of therapy, active comparator, study population
146
description, study years, countries or regions, study centers, and outcomes. Baseline
147
demographic data were abstracted to assess age, gender, geographic region, proportion of
148
baseline infection types and lesions size when available. Methodological details were abstracted
149
to assess randomization procedures, sequence generation, blinding in subjects and in
150
investigators, eligibility criteria, inclusion and exclusion criteria, subject withdrawals, allocation
151
concealment, primary outcome variable, secondary outcome variable, study definitions, timing of
152
outcome assessment (including early clinical treatment response at 48-72 hours after
153
randomization and TOC clinical treatment response), incomplete reporting of outcomes, and
154
other potential sources of bias.
155 156
Assessments of trial heterogeneity and publication bias
157
Publications reporting trials meeting inclusion criteria were assessed for clinical, methodological,
158
and statistical heterogeneity. Clinical heterogeneity was defined by patient selection,
159
interventions, and outcomes; methodological heterogeneity was defined by study design and
160
execution; statistical heterogeneity was defined as variation in the results beyond sampling
161
variability (28-31). Given the qualitative decisions associated with clinical and methodological
162
heterogeneity, each trial meeting the eligibility criteria was systematically assessed by each 8
163
reviewer for inclusion and exclusion criteria, types and distribution of skin infections, timing of
164
the outcome assessments, treatment duration, inclusion of lesion improvement as an indicator of
165
success, and the proportion of subjects with MRSA pathogens. Each of two independent
166
reviewers employed the Cochrane Risk of Bias Tool for assessment of publication bias and any
167
potential discrepancies were adjudicated via consensus with a third assessor (32).
168 169
Study selection for meta-analysis
170
Extensive clinical, methodological, and statistical heterogeneity influenced the selection of
171
studies included in the meta-analysis (31). The proxy for placebo trials selected for inclusion in
172
the meta-analysis were restricted to studies that did not exclusively enroll subjects with SITL,
173
given differential regulatory approval of antibacterial agents for this infection type. For the
174
linezolid and ceftaroline trials, selection for inclusion in the meta-analysis was based on trial
175
parameters in the historical data that approximated recent ABSSSI guidance, to minimize clinical
176
and methodological heterogeneity of studies pooled in the meta-analysis (9, 31). These selection
177
criteria were trials with total surface lesion area >75 cm2, a non-MRSA specific population, and
178
abscesses in
