Review
Annals of Internal Medicine
Biological Agents for Moderately to Severely Active Ulcerative Colitis A Systematic Review and Network Meta-analysis Silvio Danese, MD, PhD; Gionata Fiorino, MD, PhD; Laurent Peyrin-Biroulet, MD, PhD; Ersilia Lucenteforte, ScD, PhD; Gianni Virgili, MD; Lorenzo Moja, MD, MSc, DrPH; and Stefanos Bonovas, MD, MSc, PhD
Background: Biological agents are emerging treatment options for the management of ulcerative colitis (UC). Purpose: To assess the comparative efficacy and harm of biological agents in adult patients with moderately to severely active UC who are naive to biological agents. Data Sources: MEDLINE, EMBASE, and Cochrane Library from inception through December 2013, without language restrictions, and ClinicalTrials.gov, European Medicines Agency, and U.S. Food and Drug Administration Web sites. Study Selection: Randomized, placebo-controlled or head-to-head trials assessing biological agents as induction or maintenance therapy for moderately to severely active UC. Data Extraction: Two reviewers independently abstracted study data and outcomes and rated each trial’s risk of bias. Data Synthesis: There were no head-to-head trials. There were 7 double-blind, placebo-controlled trials that were rated as low risk of bias and showed that all biological agents (adalimumab, golimumab, infliximab, and vedolizumab) resulted in more clinical responses, clinical remissions, and mucosal healings than placebo for
U
lcerative colitis (UC) is an idiopathic, remitting and relapsing, chronic inflammatory bowel disease. It is characterized by mucosal ulceration, rectal bleeding, diarrhea, abdominal cramps, urgency or tenesmus, fever, malaise, weight loss and fatigue, depending on the extent and severity of the disease. Worldwide, the estimated incidence of UC ranges from 1.2 to 20.3 cases per 100 000 personyears and its prevalence ranges from 7.6 to 246.0 per 100 000 persons (1– 4). Pharmacologic management of UC aims at reducing inflammation and maintaining remission of symptoms and includes sulfasalazine, 5-aminosalicylates (mesalamine, olsalazine, and balsalazide), glucocorticoids, and immunosuppressants (azathioprine, 6-mercaptopurine, and cyclosporine) (5, 6). Despite progress, treatment options for moderately to severely active UC remain limited because conventional therapies inadequately control the disease in a substantial proportion of patients and often lead to adverse events (AEs). However, a series of biological agents have recently received regulatory approval or are under scrutiny; in 2013, those included the monoclonal antibodies adalimumab, golimumab, infliximab, and vedolizumab.
See also: Editorial comment. . . . . . . . . . . . . . . . . . . . . . . . . . 733 704 © 2014 American College of Physicians
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induction therapy. The results of network meta-analysis suggested that infliximab is more effective to induce clinical response (odds ratio, 2.36 [95% credible interval, 1.22 to 4.63]) and mucosal healing (odds ratio, 2.02 [95% credible interval, 1.13 to 3.59]) than adalimumab. No other indirect comparison reached statistical significance. For maintenance, 6 double-blind, placebo-controlled trials that were rated high risk of bias showed that all biological agents have greater clinical efficacy than placebo. The occurrence of adverse events was not different between biological agents and placebo. Limitation: Few trials, no head-to-head comparisons, and inadequate follow-up in maintenance trials. Conclusion: Biological agents are effective treatments for UC, but head-to-head trials are warranted to establish the best therapeutic option. Primary Funding Source: Centro Ricerca e Cura delle Malattie Infiammatorie Croniche Intestinali, IRCCS Istituto Clinico Humanitas. (PROSPERO registration number: CRD42013005459) Ann Intern Med. 2014;160:704-711. For author affiliations, see end of text.
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Evidence on comparative effectiveness and harms of those treatments would be very useful to inform clinical decision making. We conducted a systematic review of randomized, controlled trials (RCTs) assessing biological agents as induction or maintenance therapy for moderately to severely active UC in adults to address this issue. We assessed their comparative clinical efficacy and harm using the method of multiple-treatment meta-analysis, also known as network meta-analysis or mixed-treatment comparison (7–10), based on the available evidence from RCTs. We aimed to compare the different treatment options and provide a clinically useful summary that can be used to support optimal decision making.
METHODS Our study protocol (11) was registered on PROSPERO (CRD42013005459). We followed standard methods for conducting and reporting systematic reviews and network meta-analyses (12, 13). Data Sources and Searches
We systematically searched MEDLINE and EMBASE databases from inception to 31 December 2013. Search terms included biologic(al) agent(s), biologic(s), adalimumab, golimumab, infliximab, or vedolizumab, combined with ulcerative colitis. The search was limited to RCTs and humans. Language or age restrictions were not imposed.
Biological Agents for Ulcerative Colitis
We also searched the Cochrane Library for any recent systematic review on the subject, the ClinicalTrials.gov database for completed but unpublished studies, and the European Medicines Agency and U.S. Food and Drug Administration Web sites to obtain details on study characteristics or outcomes if these data were missing or unclearly presented in the original articles. Study Selection
The titles and abstracts of identified published articles were scanned to exclude irrelevant studies. The full text of the selected articles was retrieved and read. The bibliographies of the articles and of reviews and meta-analyses were scanned. We further asked field experts to provide additional evidence. Studies were eligible for inclusion if they were randomized, placebo-controlled or head-to-head trials assessing the efficacy or harm of biological agents for the treatment of adult patients with moderately to severely active UC. We considered only biological agents that were market-authorized by either the U.S. Food and Drug Administration or European Medicines Agency, as well as agents under review for the new drug application (United States) or marketing authorisation application (European Union). We defined moderately to severely active UC as a Mayo Clinic score (MCS) of 6 to 12 points, with an endoscopic subscore of 2 or 3. An MCS is a composite activity index ranging from 0 to 12, with higher scores indicating more severe disease activity. It is calculated as the sum of 4 items: stool frequency, rectal bleeding, endoscopic findings, and physician’s global assessment (14). Randomized, controlled trials were eligible for inclusion in the network regardless of country, phase (2 or 3), or support. Data Extraction and Quality Assessment
Two reviewers abstracted the data independently. The following information was collected from each study: publication data; trial’s acronym and identifier; first author’s last name; geographic location of study; year of publication; study design; number of participants and population characteristics; and interventions’ variables, including drug, dose, and administration. We extracted data specific for patients who were naive to treatment with biological agents because the relative efficacy of biological agents should not be assessed by pooling patients for whom standard therapies were unsuccessful with patients for whom biological agents were unsuccessful (15, 16). Different doses of the same treatment were treated as separate interventions, and for biological agents that received regulatory approval, only data for dose and administration as approved in the respective summary of product characteristics were considered. The outcome measures were the odds ratios (ORs) for clinical response (primary outcome), clinical remission, and mucosal healing at the end of induction and at completion of each trial’s maintenance phase, calculated in acwww.annals.org
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Review
cordance with the intention-to-treat principle (that is, total number of randomly assigned participants, regardless of how the original study investigators analyzed the data). Clinical response was defined as a decrease from baseline in the MCS of at least 3 points and at least 30%, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point, or an absolute rectal bleeding subscore of 0 or 1. Clinical remission was defined as an MCS of 2 points or lower, with no individual subscore exceeding 1 point. Mucosal healing was defined as an absolute subscore for endoscopy of 0 or 1. We also examined the occurrence of serious adverse events (SAEs), which are defined as any untoward medical occurrence that results in death, requires hospital admission or prolongation of an existing hospital stay, causes persistent or significant disability or incapacity, or is lifethreatening (17); the AEs leading to discontinuation of the study drug; the total number of AEs; the total number of infectious AEs; the number of serious infections; tuberculosis; and congestive heart failure. Reviewers assessed the risk of bias in the results of included studies by using the Cochrane Collaboration’s tool (18), which addresses the following key domains: sequence generation, allocation concealment, blinding of participants and personnel, incomplete outcome data, selective outcome reporting, and other sources of bias. These items are considered as key domains for risk-of-bias assessment and reclassified as adequate (low risk of bias), inadequate (high risk of bias), or unclear. Studies with adequate procedures in all domains are considered to have a low risk of bias, ones with inadequate procedures in 1 or more domains are considered to have a high risk of bias, and those with unclear procedures in 1 or more domains are considered to have unclear risk of bias. Disagreements among reviewers were discussed and agreement was reached by consensus. Data Synthesis and Analysis
We conducted the network meta-analysis within a Bayesian framework using Markov chain Monte Carlo methods in WinBUGS (Medical Research Council Biostatistics Unit, Cambridge, United Kingdom) (19). Analysis was based on noninformative priors for relative-effect parameters (flat normal with mean of 0 and precision of 0.001) and between-study SD (a flat uniform distribution between 0 and 2). Convergence and lack of autocorrelation were checked and confirmed after a 5000-simulation burn-in phase without any thinning and using 4 chains with different initial values. Then, a burn-in phase of 20 000 iterations was used, followed by 50 000 iterations to estimate parameters. We did sensitivity analyses by setting the prior on the heterogeneity equal to a uniform (0, 100) and on the precision parameter equal to a ␥ (0.001, 0.001) to check the robustness of the model to different sets of priors. Model choice was based on the deviance information criterion, and a lower deviance information 20 May 2014 Annals of Internal Medicine Volume 160 • Number 10 705
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Identification
Figure 1. Summary of evidence search and selection.
Records identified (n = 479) MEDLINE database search: 141 EMBASE database search: 335 Knowledgeable expert: 3
Screening
Duplicates removed (n = 55)
Records screened (n = 424)
Eligibility
Articles excluded based on title/abstract (n = 406)
Articles retrieved for detailed evaluation (n = 18)
RCTs excluded (n = 11) Not placebo-controlled or head-to-head trials: 3 Biologics that are not market-authorized or under evaluation: 2 Not moderate to severe UC (as defined with MCS): 7 Different definitions and measurements of outcomes: 7 Not in adults: 1
Included
RCT identified through ClinicalTrials.gov (n = 1)
Eligible RCTs included (n = 8)
MCS ⫽ Mayo Clinic score; RCT ⫽ randomized, controlled trial; UC ⫽ ulcerative colitis.
criterion by 5 or more units suggested a better model fit. We report estimates only for the default model because we did not find differences in model fit according to deviance information criterion. We used the resulting ORs and 95% credible intervals (CrIs), the Bayesian equivalent to CIs, to assess treatment effects. We also calculated fixed-effects ORs and 95% CIs (frequentist approach). Given that each pairwise comparison included a limited number of RCTs, we could not formally assess statistical heterogeneity and publication bias. Role of the Funding Source
This study was funded by the Centro Ricerca e Cura delle Malattie Infiammatorie Croniche Intestinali, IRCCS Istituto Clinico Humanitas. The funding source had no role in the design of the study; the collection, analysis, and interpretation of the data; or the decision to submit the manuscript for publication. 706 20 May 2014 Annals of Internal Medicine Volume 160 • Number 10
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RESULTS Figure 1 summarizes the search and selection of evidence. We identified 6 publications (20 –25) reporting the results of 7 trials (ACT [Active Ulcerative Colitis Trial] 1, ACT 2, ULTRA [Ulcerative Colitis Long-Term Remission and Maintenance With Adalimumab] 1, ULTRA 2, PURSUIT-SC [Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment– Subcutaneous], PURSUIT-M [Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment–Maintenance], and GEMINI 1). One additional study, the NCT00853099 trial, was initially identified through ClinicalTrials.gov (26) and later in full-text publication (27). In total, 8 trials met the eligibility criteria, none of which were head-to-head comparisons of biological agents. All 8 studies were multicenter, randomized, doubleblind, placebo-controlled trials assessing the efficacy and www.annals.org
Biological Agents for Ulcerative Colitis
harm of 4 biological agents (adalimumab, golimumab, infliximab, and vedolizumab) as induction or maintenance therapy for adult patients with moderately to severely active UC (that is, MCS of 6 to 12 points with an endoscopic subscore of at least 2). In most studies, patients were randomly assigned once, at the beginning of the trial, to receive either 6- to 8-week experimental therapy or matching placebo (induction phase) followed by a longer phase during which experimental treatments were given at maintenance schemes (maintenance phase of the trial). However, in 2 trials (PURSUIT-M [24] and GEMINI 1 [25]), only patients who responded to induction were eligible for continued (maintenance) therapy and were reassigned at the beginning of the maintenance study. A summary of the design characteristics of the trials is presented in Appendix Figure 1 (available at www.annals .org). The mean age of patients ranged from 40 to 43 years, whereas the mean previous disease duration ranged from 6 to 8 years. The studies were conceptually homogeneous in terms of outcome definitions and measurements (all trials used the Mayo Clinic activity index to define clinical response, clinical remission, and mucosal healing). In 6 of those RCTs (ACT 1, ACT 2, ULTRA 1, NCT00853099, PURSUIT-SC, and PURSUIT-M), any patient previously exposed to biological agents had been excluded as per protocol, whereas in the other 2 trials (ULTRA 2 and GEMINI 1), randomization had been stratified by previous exposure to anti–tumor necrosis factor-␣ agents, and we specifically extracted only the data for patients who were naive to biological agents. Thus, randomization was maintained. Further outcome data were retrieved from the U.S. Food and Drug Administration Web site (28) for the ULTRA 1 trial (the intention-to-treat population, original protocol) and from conference abstracts (29 –31) for the GEMINI 1 study. All trials contributed to all efficacy outcomes except mucosal healing: The GEMINI 1 study (25) has not published any data about mucosal healing, referring to the subgroup of patients without any previous anti– tumor necrosis factor-␣ exposure, whereas the respective data for the PURSUIT-M trial (24) were not reported. For biological agents that received regulatory approval for the treatment of UC (adalimumab, golimumab, and infliximab), only dose and administration as approved in the respective summary of product characteristics for each agent were considered in the analysis (Table 1). For vedolizumab, for which a license application was under evaluation by the regulatory authorities (32, 33) during our analysis, both schemes for maintenance therapy (300 mg intravenously every 8 weeks or every 4 weeks) were included. Assessment of the RCTs using the Cochrane Collaboration tool revealed low risk of bias across the induction trials (ACT 1, ACT 2, ULTRA 1, ULTRA 2, NCT00853099, PURSUIT-SC, and GEMINI 1) but high risk of bias across maintenance phases (ACT 1, ACT 2, www.annals.org
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Review
Table 1. Biological Agents for Treatment of Moderately to Severely Active Ulcerative Colitis in Adult Patients* Biological Agent
Dose
ADA
160 mg SC at 0 wk, followed by 80 mg at 2 wk and then 40 mg every other wk 200 mg SC at 0 wk, followed by 100 mg at 2 wk and then 100 mg every 4 wk 5 mg/kg IV at 0 wk, followed by 5 mg/kg at 2 and 6 wk and every 8 wk thereafter 300 mg IV at 0 and 2 wk and every 8 wk or every 4 wk thereafter
GLM IFX VDZ
ADA ⫽ adalimumab; GLM ⫽ golimumab; IFX ⫽ infliximab; IV ⫽ intravenous; SC ⫽ subcutaneous; VDZ ⫽ vedolizumab. * Dose and administration included in the analysis.
ULTRA 2, NCT00853099, PURSUIT-M, and GEMINI 1) with regard to the “incomplete outcome data” domain. Although follow-up was as high as 91% to 97% for induction trials, equally balanced between the study groups, rates of complete follow-up were lower in maintenance studies (55% to 76%) with significant imbalances across intervention groups and unequal dropout rates due to AEs. This pattern is of concern. If patients with poorer clinical outcomes are more likely to drop out because of AEs and this happens mainly in the experimental group, then the results may be biased in favor of the experimental drug. Premature treatment discontinuation due to “inefficacy” may also introduce bias if the numbers excluded are not balanced across intervention groups. We considered the whole group of maintenance trials to have a high risk of bias with regard to the “incomplete outcome data” domain for these reasons. Quality assessment items are summarized in Figure 2 for the induction trials and in Appendix Figure 2 (available at www.annals.org) for the maintenance trials. Efficacy of Biological Agents as Induction Therapy
Ten randomized (2-group) comparisons of biological agents versus placebo contributed to this analysis (Figure 3 and Appendix Figure 1). They provided only indirect comparative evidence. In total, 2282 adult patients who were naive to biological agents had been randomly assigned to placebo (n ⫽ 1115) or a biological agent (adalimumab, golimumab, infliximab, or vedolizumab in doses described in Table 1) (n ⫽ 1167) as induction therapy (6 to 8 weeks) for moderately to severely active UC.
Treatments Compared With Placebo
All biological agents (adalimumab, golimumab, infliximab, and vedolizumab) demonstrated superiority over placebo for induction of clinical response, remission, and mucosal healing, except adalimumab for clinical remission. The estimated relative efficacies (expressed as ORs) are shown in Table 2. 20 May 2014 Annals of Internal Medicine Volume 160 • Number 10 707
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Figure 2. Summary of risk-of-bias assessments for
Random sequence generation
Allocation concealment
Blinding of participants and personnel
Incomplete outcome data
Free of selective outcome reporting
Free of other sources of bias
randomized, controlled trials of induction therapy.
ACT 1
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Green circles signify low risk of bias. ACT ⫽ Active Ulcerative Colitis Trial; PURSUIT-SC ⫽ Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment–Subcutaneous; ULTRA ⫽ Ulcerative Colitis Long-Term Remission and Maintenance With Adalimumab.
izumab in doses described in Table 1) (n ⫽ 782) as maintenance treatment. However, 2 of the trials (PURSUIT-M [24] and GEMINI 1 [25]) had included only persons who responded to induction in their maintenance phases (Appendix Figure 1). Therefore, 2 distinct groups of maintenance trials were formed: group A, with adalimumab and infliximab trials (ACT 1, ACT 2, ULTRA 2, and NCT00853099), and group B, with golimumab and vedolizumab trials (PURSUIT-M and GEMINI 1), restricted to persons who responded to induction. Given the mixture of study designs involved in the maintenance trials and the fact that persons who responded to induction may be more likely to achieve a positive clinical outcome in the long term than those who did not respond (34), we decided not to synthesize indirect effect estimates but simply summarize the available direct evidence using frequentist fixedeffects models. In group A, infliximab and adalimumab were better than placebo for clinical response (ORs, 2.89 [95% CI, 1.96 to 4.28] and 1.90 [CI, 1.27 to 2.86], respectively), clinical remission (ORs, 2.78 [CI, 1.75 to 4.41] and 2.30 [CI, 1.37 to 3.86]), and mucosal healing (ORs, 2.65 [CI, 1.79 to 3.92] and 1.99 [CI, 1.30 to 3.06]). In group B, both schemes of vedolizumab (300 mg intravenously every 4 weeks or every 8 weeks) and golimumab were better than placebo for clinical response (ORs for vedolizumab every 4 weeks, vedolizumab every 8 weeks, and golimumab were 3.54 [CI, 1.79 to 6.99], 5.19 [CI, 2.59 to 10.42], and 2.24 [CI, 1.41 to 3.56], respectively) and clinical remission (ORs, 3.93 [CI, 1.90 to 8.12], 3.61 [CI, 1.74 to 7.48], and 1.81 [CI, 1.10 to 3.00], respectively).
Figure 3. Network geometry for induction treatment.
Treatments Compared With Each Other
The results of our Bayesian network meta-analysis suggested that infliximab is more likely to induce a favorable clinical outcome than adalimumab. The OR was 2.36 (95% CrI, 1.22 to 4.63) for the primary outcome of induction of clinical response. The ORs were 2.79 (CrI, 0.95 to 8.83) and 2.02 (CrI, 1.13 to 3.59) for the secondary outcomes of clinical remission and mucosal healing, respectively. However, this evidence needs to be interpreted with caution because it is based on indirect comparisons. None of the other indirect comparisons reached statistical significance. Results are summarized in Appendix Figure 3 (available at www.annals.org). Efficacy of Biological Agents as Maintenance Therapy
Six randomized trials contributed to this analysis (Appendix Figure 1). In total, 1502 patients who were naive to biological agents received placebo (n ⫽ 720) or a biological agent (adalimumab, golimumab, infliximab, or vedol708 20 May 2014 Annals of Internal Medicine Volume 160 • Number 10
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ADA
4 trials (928 patients)
PBO
3 trials (662 patients)
GLM
1 trial (206 patients)
VDZ
2 trials (486 patients)
IFX
Compared treatments are connected indirectly through the placebo, the “common comparator.” The number of independent randomized, controlled trials and number of patients who were naive to biological agents (in parenthesis) for each comparison in the induction treatment network are informed by head-to-head evidence. To calculate the numbers of patients, we considered only persons assigned to a dose as approved in the summary of product characteristics and those assigned to placebo. ADA ⫽ adalimumab; GLM ⫽ golimumab; IFX ⫽ infliximab; PBO ⫽ placebo; VDZ ⫽ vedolizumab. www.annals.org
Biological Agents for Ulcerative Colitis
Table 2. Comparative Efficacy of Biological Agents as Induction Therapy for Moderately to Severely Active Ulcerative Colitis in Adult Patients* Network Comparator Treatment
OR (95% CrI)
Clinical response ADA (160/80/40 mg SC) vs. placebo GLM (200/100 mg SC) vs. placebo IFX (5 mg/kg IV) vs. placebo VDZ (300 mg IV) vs. placebo
1.76 (1.19–2.56) 2.11 (1.18–3.28) 4.13 (2.39–7.16) 3.23 (1.42–7.42)
Clinical remission ADA (160/80/40 mg SC) vs. placebo GLM (200/100 mg SC) vs. placebo IFX (5 mg/kg IV) vs. placebo VDZ (300 mg IV) vs. placebo
1.91 (0.98–3.72) 2.90 (1.19–6.54) 5.33 (2.28–13.63) 4.51 (1.13–20.76)
Mucosal healing ADA (160/80/40 mg SC) vs. placebo GLM (200/100 mg SC) vs. placebo IFX (5 mg/kg IV) vs. placebo VDZ (300 mg IV) vs. placebo
1.64 (1.18–2.31) 1.84 (1.18–2.81) 3.31 (2.07–5.32) –
ADA ⫽ adalimumab; CrI ⫽ credible interval; GLM ⫽ golimumab; IFX ⫽ infliximab; IV ⫽ intravenous; OR ⫽ odds ratio; SC ⫽ subcutaneous; VDZ ⫽ vedolizumab. * Treatment effect estimates come from Bayesian network meta-analysis.
Harms
This analysis used randomized data on AEs from both induction and maintenance phases. Because AE data specific for patients who were naive to biological agents were not available for the 2 studies having also recruited patients with previous exposure to biological agents (ULTRA 2 [22] and GEMINI 1 [25]), data on harms for the whole randomly assigned populations were included instead. The median rates of AEs for patients using biological agents were 107 events per 1000 patients for SAEs, 814 events per 1000 patients for total AEs, 83 events per 1000 patients for AEs leading to discontinuation of the study drug, and 17 events per 1000 patients for serious infections. The corresponding event rates for placebo were 123 events per 1000 patients, 698 events per 1000 patients, 64 events per 1000 patients, and 19 events per 1000 patients (Table 3). There were very few cases of tuberculosis and congestive heart failure. Numbers were rather small for comparison of individual biological agents with placebo (Appendix Table, available at www.annals.org). Of note, the maintenance trials had high rates of incomplete follow-up and thus inadequate ascertainment of harms may have occurred. For information on sensitivity analysis after the retrospective exclusion of patients in the final publications of the PURSUIT-SC and PURSUIT-M trials, see the Appendix (available at www.annals.org).
DISCUSSION In this systematic review of RCTs assessing biological agents for the treatment of moderately to severely active UC in adult patients, 8 trials were incorporated, none of www.annals.org
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which were head-to-head comparisons of biological agents. Meta-analysis of induction studies showed that all agents (adalimumab, golimumab, infliximab, and vedolizumab) were superior to placebo. Indirect comparisons from our network meta-analysis suggested that infliximab is more likely to induce a favorable clinical outcome than adalimumab. Synthesis of the available studies demonstrated that all biological agents had greater efficacy than placebo for maintenance therapy. The occurrence of AEs was not different between biological agents and placebo. The internal validity of our analysis is supported by 3 factors. First, having conducted a rigorous and extensive literature search, we are confident that all relevant RCTs have been properly identified. Second, the induction trials included in the network are characterized by low risk of bias, as assessed with the Cochrane Collaboration approach, and allowed a reliable synthesis of Bayesian indirect treatment effect estimates. Third, all RCTs are conceptually homogeneous in terms of study design (randomized, double-blind, placebo-controlled, and common use of the MCS to define and measure the clinical outcomes) and patient characteristics (adults with a mean age of 40 to 43 years; moderately to severely active UC, defined by an MCS of 6 to 12 points, with an endoscopic subscore of at least 2; previous disease duration of 6 to 8 years; and naive to treatment with biological agents). Differences in key characteristics across trials that may act as effect modifiers, possibly causing bias in the analysis, seem to be small. However, the strengths of this network meta-analysis should be weighed against some limitations. First, the limited number of trials and the absence of head-to-head comparisons increase the uncertainty of the findings and conclusions. Second, all studies of this network were registration trials for regulatory purposes. As such, they have enrolled selective homogeneous populations, a fact that may compromise external validity (35). We further limited
Table 3. Occurrence of AEs in RCTs of Biological Agents for Moderately to Severely Active Ulcerative Colitis in Adult Patients Outcome
Any AE SAEs AEs leading to discontinuation of study drug Infectious AEs Serious infection TB CHF
RCTs With Data, n
Patients, n
8 8 7
8 8 7 3
Median Event Rates (Range), % Biological Agents
Placebo
3354 3354 2607
81.4 (37.5–87.6) 10.7 (2.2–21.5) 8.3 (0.3–13.2)
69.8 (38.2–85.1) 12.3 (6.1–25.6) 6.4 (0.9–13.1)
3354 3354 2607 1150
39.0 (11.8–71.7) 1.7 (0.0–5.5) 0.0 (0.0–1.9) 0.0 (0.0–0.4)
28.2 (12.1–70.6) 1.9 (0.8–4.1) 0.0 (0.0–0.6) 0.0 (0.0–0.0)
AE ⫽ adverse event; CHF ⫽ congestive heart failure; RCT ⫽ randomized, controlled trial; SAE ⫽ serious adverse event; TB ⫽ tuberculosis. 20 May 2014 Annals of Internal Medicine Volume 160 • Number 10 709
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the network to patients who were naive to biological agents and had moderately to severely active disease. Policymakers should be cautious in extrapolating our results to persons for whom biological agents were unsuccessful or those with mild disease, as well as for follow-up longer than 1 year because the trials lasted only up to 1 year. Third, we could not assess publication bias. Fourth, the maintenance trials included in our review were at high risk of bias for incomplete outcome data. Fifth, an issue remaining beyond our control is the potential presence of sponsorship bias in the studies included in the network (that is, the bias associated with the commercial interests of industrial sponsors) (36, 37). They were registration trials, supported by the pharmaceutical companies marketing these compounds. It is also important to note that in a network meta-analysis of RCTs, the value of randomization does not hold across trials. Hence, a network meta-analysis of RCTs is a form of observational evidence and may be biased if differences in unmeasured covariates among trials are modifiers of relative treatment effects. For example, differences in history of treatment may constitute effect modifiers. Moreover, although the MCS was used to define and measure the clinical outcomes, there may be still ascertainment bias among the trials arising from frequency of follow-up visits. Also, the geographic regions where the studies were done may reflect additional differences between patient populations not reflected in reported patient characteristics. It remains important to have head-to-head comparative trials with the same recruitment strategy and follow-up protocol across groups for these reasons. In conclusion, the results of our meta-analysis showed that all biological agents had superior clinical efficacy compared with placebo, both in induction and maintenance phases. It also provides indirect evidence that infliximab is better than adalimumab as induction therapy to obtain clinical response. Data on SAEs are limited. Given the efficacy of the available treatments and severity of the disease, further use of placebo controls should be considered as unethical. Direct head-to-head comparisons between biological agents should be the top priority on the research agenda, as well as studies in the real-world setting and evaluation in terms of cost, which is a key consideration in determining the comparative effectiveness of alternative treatments for UC. Meanwhile, national and international registries, long-term epidemiologic studies, and clinical audits (such as the United Kingdom Inflammatory Bowel Disease audit [38]), may serve as complementary sources of data about the beneficial and harmful effects of alternative therapies for UC. From Inflammatory Bowel Disease Center, IRCCS Humanitas Research Hospital, University of Milan, IRCCS Galeazzi Orthopedic Institute, and Laboratory of Drug Regulatory Policies, IRCCS Mario Negri Institute for Pharmacologic Research, Milan, Italy; University Hospital of Nancy, Universite´ de Lorraine, Vandoeuvre-le`s-Nancy, France; Univer710 20 May 2014 Annals of Internal Medicine Volume 160 • Number 10
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sity of Florence, Florence, Italy; and School of Medicine, University of Athens, Athens, Greece. Grant Support: By the Centro Ricerca e Cura delle Malattie Infiammatorie Croniche Intestinali, IRCCS Istituto Clinico Humanitas. Disclosures: Disclosures can be viewed at www.acponline.org/authors /icmje/ConflictOfInterestForms.do?msNum⫽M13-2403. Requests for Single Reprints: Silvio Danese, MD, PhD, Inflammatory Bowel Disease Center, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy; e-mail, [email protected].
Current author addresses and author contributions are available at www.annals.org.
References 1. Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med. 2011;365:1713-25. [PMID: 22047562] 2. Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology. 2004;126:1504-17. [PMID: 15168363] 3. Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet. 2007;369:1641-57. [PMID: 17499606] 4. Stange EF, Travis SP, Vermeire S, Reinisch W, Geboes K, Barakauskiene A, et al; European Crohn’s and Colitis Organisation (ECCO). European evidencebased Consensus on the diagnosis and management of ulcerative colitis: Definitions and diagnosis. J Crohns Colitis. 2008;2:1-23. [PMID: 21172194] 5. Travis SP, Stange EF, Le´mann M, Oresland T, Bemelman WA, Chowers Y, et al; European Crohn’s and Colitis Organisation (ECCO). European evidencebased consensus on the management of ulcerative colitis: current management. J Crohns Colitis. 2008;2:24-62. [PMID: 21172195] 6. Kornbluth A, Sachar DB; Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010;105:501-23. [PMID: 20068560] 7. Mills EJ, Thorlund K, Ioannidis JP. Demystifying trial networks and network meta-analysis. BMJ. 2013;346:f2914. [PMID: 23674332] 8. Salanti G, Higgins JP, Ades AE, Ioannidis JP. Evaluation of networks of randomized trials. Stat Methods Med Res. 2008;17:279-301. [PMID: 17925316] 9. Caldwell DM, Ades AE, Higgins JP. Simultaneous comparison of multiple treatments: combining direct and indirect evidence. BMJ. 2005;331:897-900. [PMID: 16223826] 10. Lu G, Ades AE. Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med. 2004;23:3105-24. [PMID: 15449338] 11. Danese S, Fiorino G, Peyrin-Biroulet L, Lucenteforte E, Virgili G, Moja L, et al. Biological agents for the treatment of moderately-to-severely active ulcerative colitis in adults: a network meta-analysis of randomised controlled trials [study protocol]. PROSPERO 2013:CRD42013005459. Accessed at www.crd .york.ac.uk/PROSPERO/display_record.asp?ID⫽CRD42013005459 on 20 February 2014. 12. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151:264-9. [PMID: 19622511] 13. Cipriani A, Higgins JP, Geddes JR, Salanti G. Conceptual and technical challenges in network meta-analysis. Ann Intern Med. 2013;159:130-7. [PMID: 23856683] 14. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med. 1987;317:1625-9. [PMID: 3317057] 15. Wells GA, Sultan SA, Chen L, Khan M, Coyle D. Indirect Evidence: Indirect Treatment Comparisons in Meta-Analysis. Ottawa, Ontario, Canada: www.annals.org
Biological Agents for Ulcerative Colitis Canadian Agency for Drugs and Technologies in Health; 2009. Accessed at www.cadth.ca/media/pdf/H0462_itc_tr_e.pdf on 20 February 2014. 16. Dias S, Welton NJ, Sutton AJ, Ades AE. NICE DSU Technical Support Document 1: Introduction to Evidence Synthesis for Decision Making. 2011 (last updated April 2012). Accessed at www.nicedsu.org.uk/TSD1%20 Introduction.final.08.05.12.pdf on 20 February 2014. 17. Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet. 2000;356:1255-9. [PMID: 11072960] 18. Higgins JP, Altman DG, Gøtzsche PC, Ju¨ni P, Moher D, Oxman AD, et al; Cochrane Bias Methods Group. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. [PMID: 22008217] 19. Lunn DJ, Thomas A, Best N, Spiegelhalter D. WinBUGS—a Bayesian modelling framework: concepts, structure, and extensibility. Stat Comput. 2000; 10:325-37. 20. Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353:2462-76. [PMID: 16339095] 21. Reinisch W, Sandborn WJ, Hommes DW, D’Haens G, Hanauer S, Schreiber S, et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut. 2011;60:780-7. [PMID: 21209123] 22. Sandborn WJ, van Assche G, Reinisch W, Colombel JF, D’Haens G, Wolf DC, et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2012;142:257-65.e1-3. [PMID: 22062358] 23. Sandborn WJ, Feagan BG, Marano C, Zhang H, Strauss R, Johanns J, et al; PURSUIT-SC Study Group. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146:85-95; quiz e14-5. [PMID: 23735746] 24. Sandborn WJ, Feagan BG, Marano C, Zhang H, Strauss R, Johanns J, et al; PURSUIT-Maintenance Study Group. Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146:96-109.e1. [PMID: 23770005] 25. Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, et al; GEMINI 1 Study Group. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369:699-710. [PMID: 23964932] 26. A study of adalimumab in Japanese subjects with moderately to severely active ulcerative colitis [clinical trial]. ClinicalTrials.gov Identifier: NCT00853099. Accessed at http://clinicaltrials.gov/show/NCT00853099 on 20 February 2014. 27. Suzuki Y, Motoya S, Hanai H, Matsumoto T, Hibi T, Robinson AM, et al. Efficacy and safety of adalimumab in Japanese patients with moderately to severely active ulcerative colitis. J Gastroenterol. 2014;49:283-94. [PMID: 24363029]
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28. U.S. Food and Drug Administration. FDA GIDAC briefing document on Humira (adalimumab). Gastrointestinal Drugs Advisory Committee Meeting, BLA 125057/232. 28 August 2012. Accessed at www.fda.gov/downloads /AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Gastrointestinal DrugsAdvisoryCommittee/UCM316786.pdf on 20 February 2014. 29. Feagan BG, Rutgeerts PJ, Sands BE. Vedolizumab induction therapy for ulcerative colitis: results of GEMINI 1, a randomized, placebo-controlled, double-blind, multicenter, phase III trial. Presented at Digestive Disease Week, San Diego, CA, 19 –22 May 2012. Abstract no. 943b. 30. Rutgeerts P. Vedolizumab induction therapy for ulcerative colitis: results of GEMINI I, a randomized, placebo-controlled, double-blind, multicenter, phase 3 trial. 20th United European Gastroenterology Week, Amsterdam, the Netherlands, 20 –24 October 2012. Abstract no. OP280. 31. Feagan BG, Rutgeerts P, Sands BE, Sandborn WJ, Colombel JF, Hanauer S, et al. Vedolizumab maintenance therapy for ulcerative colitis: Results of GEMINI I, a randomized, placebo-controlled, double-blind, multicenter phase 3 trial. Am J Gastroenterol. 2012;107:S609. 32. Takeda submits marketing authorisation application for vedolizumab in moderately to severely active ulcerative colitis and Crohn’s disease in the European Union [press release]. Osaka, Japan: Takeda; 7 March 2013. Accessed at www.takeda.com/news/2013/20130308_5677.html on 20 February 2014. 33. Takeda submits biologics license application for a new investigational drug vedolizumab, in moderately to severely active Crohn’s disease and ulcerative colitis in the United States [press release]. Osaka, Japan: Takeda; 21 June 2013. Accessed at www.takeda.com/news/2013/20130624_5844.html on 20 February 2014. 34. Sandborn WJ, Colombel JF, D’Haens G, Van Assche G, Wolf D, Kron M, et al. One-year maintenance outcomes among patients with moderately-toseverely active ulcerative colitis who responded to induction therapy with adalimumab: subgroup analyses from ULTRA 2. Aliment Pharmacol Ther. 2013;37: 204-13. [PMID: 23173821] 35. Rothwell PM. Factors that can affect the external validity of randomised controlled trials. PLoS Clin Trials. 2006;1:e9. [PMID: 16871331] 36. Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflicts of interest in biomedical research: a systematic review. JAMA. 2003;289:454-65. [PMID: 12533125] 37. Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373:746-58. [PMID: 19185342] 38. Biological therapies audit subgroup. National clinical audit report of biological therapies: UK Inflammatory Bowel Disease (IBD) audit. Adult national report. London, United Kingdom: Royal College of Physicians; 2013. Accessed at www.rcplondon.ac.uk/sites/default/files/national_clinical_audit_report_of _biological_therapies_-_adult_report._29_august_2013.pdf on 20 February 2014.
20 May 2014 Annals of Internal Medicine Volume 160 • Number 10 711
Annals of Internal Medicine Current Author Addresses: Drs. Danese and Fiorino: Inflammatory Bowel Disease Center, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy. Dr. Peyrin-Biroulet: Inserm U954 and Department of HepatoGastroenterology, University Hospital of Nancy, Universite´ de Lorraine, Vandoeuvre-le`s-Nancy, France. Dr. Lucenteforte: Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy. Dr. Virgili: Department of Specialised Surgical Sciences, University of Florence, Via le Morgagni 85, 50134 Florence, Italy. Dr. Moja: Clinical Epidemiology Unit, IRCCS Orthopedic Institute Galeazzi, Via R. Galeazzi 4, 20161 Milan, Italy. Dr. Bonovas: Department of Pharmacology, School of Medicine, University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece. Author Contributions: Conception and design: S. Danese, G. Fiorino, L. Peyrin-Biroulet, L. Moja, S. Bonovas. Analysis and interpretation of the data: S. Danese, E. Lucenteforte, G. Virgili, L. Moja, S. Bonovas. Drafting of the article: S. Danese, L. Peyrin-Biroulet, L. Moja, S. Bonovas. Critical revision of the article for important intellectual content: S. Danese, G. Fiorino, L. Peyrin-Biroulet, E. Lucenteforte, G. Virgili, L. Moja, S. Bonovas. Final approval of the article: S. Danese, G. Fiorino, L. Peyrin-Biroulet, E. Lucenteforte, G. Virgili, L. Moja, S. Bonovas. Provision of study materials or patients: G. Fiorino. Statistical expertise: E. Lucenteforte, G. Virgili, S. Bonovas. Administrative, technical, or logistic support: S. Danese. Collection and assembly of data: S. Danese, G. Fiorino, S. Bonovas.
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Web-Only Reference 39. Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. The Cochrane Collaboration [updated March 2011]; 2011. Accessed at http://handbook.cochrane.org on 20 February 2014.
APPENDIX: SENSITIVITY ANALYSIS AFTER RETROSPECTIVE EXCLUSION OF PATIENTS IN THE FINAL PUBLICATIONS OF THE PURSUIT-SC AND PURSUIT-M TRIALS During the revision of this article, 2 publications of RCTs included in the network meta-analysis changed their status from “ahead of print” to “in print.” The PURSUIT-SC (23) and PURSUIT-M (24) trials were published in the January 2014 issue of Gastroenterology. The primary efficacy populations analyzed in the final publications slightly differed from those in the originally accepted ahead-of-print versions. PURSUIT-SC analyzed 761 instead of 774 patients, and PURSUIT-M analyzed 456 instead of 464 patients. The reason was a retrospective exclusion of many patients after identification of nonadherence to good clinical practice (source documentation and informed consent process) at the study site at which they participated. After extensive discussion, we decided to present the results of the analysis based on all randomly assigned patients, adhering to the intention-to-treat principle, because it is recommended (39). Nevertheless, we did a sensitivity analysis by rerunning our metaanalysis on the basis of new data. Exclusion of these data had a minimal effect on our efficacy results— however, in the direction of more conservative effect estimates for golimumab—and does not alter the conclusions of our study.
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Appendix Figure 1. Summary of methodological characteristics of trials. Wk 0
ACT 1 R
ACT 2 R
ULTRA 1 (ITT-A3)
ULTRA 1 (ITT-E)
6
8
30
PBO
PBO
IFX 5 mg/kg IV IFX 10 mg/kg IV
IFX 5 mg/kg IV q8w IFX 10 mg/kg IV q8w
PBO
PBO
IFX 5 mg/kg IV IFX 10 mg/kg IV
IFX 5 mg/kg IV q8w IFX 10 mg/kg IV q8w
52
54
60
PBO R
ADA 80/40 mg SC ADA 160/80/40 mg SC
PBO R
ULTRA 2
ADA 160/80/40 mg SC
PBO
PBO R
ADA 160/80/40 mg SC ADA 40 mg SC eow
PBO
NCT00853099 R
PBO
ADA 80/40 mg SC ADA 40 mg SC eow ADA 160/80/40 mg SC ADA 40 mg SC eow
PBO
PURSUIT-SC (phase 2) R
GLM 100/50 mg SC GLM 200/100 mg SC GLM 400/200 mg SC
PURSUIT-SC (phase 2, additional)
PBO R
GLM 100/50 mg SC GLM 200/100 mg SC GLM 400/200 mg SC
PURSUIT-SC (phase 3)
PBO R
GLM 200/100 mg SC GLM 400/200 mg SC
PBO
PURSUIT-M
GLM induction responders from PURSUIT-SC and PURSUIT-IV
GEMINI 1 R
R
GLM 50 mg SC q4w GLM 100 mg SC q4w
PBO VDZ 300 mg IV
VDZ induction responders from the randomized and the open-label cohorts
PBO R
VDZ 300 mg IV q8w VDZ 300 mg IV q4w
Induction phases are represented in blue, whereas maintenance phases are represented in green. ACT ⫽ Active Ulcerative Colitis Trial; ADA ⫽ adalimumab; eow ⫽ every other week; GLM ⫽ golimumab; IFX ⫽ infliximab; ITT-A3 ⫽ intention-to-treat population, after protocol amendment 3; ITT-E ⫽ intention-to-treat population, original protocol; IV ⫽ intravenous; PBO ⫽ placebo; PURSUIT-M ⫽ Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment–Maintenance; PURSUIT-SC ⫽ Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment–Subcutaneous; q8w ⫽ every 8 wk; q4w ⫽ every 4 wk; R ⫽ randomization; SC ⫽ subcutaneous; ULTRA ⫽ Ulcerative Colitis Long-Term Remission and Maintenance With Adalimumab; VDZ ⫽ vedolizumab. 20 May 2014 Annals of Internal Medicine Volume 160 • Number 10
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Appendix Figure 2. Summary of risk-of-bias assessments for
Random sequence generation
Allocation concealment
Blinding of participants and personnel
Incomplete outcome data
Free of selective outcome reporting
Free of other sources of bias
randomized, controlled trials of maintenance therapy.
ACT 1
+
+
+
–
+
+
ACT 2
+
+
+
–
+
+
ULTRA 2
+
+
+
–
+
+
NCT00853099
+
+
+
–
+
+
PURSUIT-M
+
+
+
–
+
+
GEMINI 1
+
+
+
–
+
+
Green circles indicate low risk of bias, and red circles signify high risk of bias. ACT ⫽ Active Ulcerative Colitis Trial; PURSUIT-M ⫽ Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment–Maintenance; ULTRA ⫽ Ulcerative Colitis Long-Term Remission and Maintenance With Adalimumab.
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Appendix Figure 3. Comparative efficacy of biological agents as induction therapy for moderately to severely active ulcerative colitis.
IFX
OR, 1.28 (95% CrI, 0.48–3.45)
VDZ
OR, 1.96 (95% CrI, 0.99–4.48)
OR, 1.53 (95% CrI, 0.62–4.32)
GLM
OR, 2.36 (95% CrI, 1.22–4.63)
OR, 1.84 (95% CrI, 0.74–4.66)
OR, 1.20 (95% CrI, 0.60–2.12)
ADA
Clinical Response
IFX
OR, 1.18 (95% CrI, 0.21–6.32)
VDZ
OR, 1.84 (95% CrI, 0.58–6.92)
OR, 1.56 (95% CrI, 0.32–9.19)
GLM
OR, 2.79 (95% CrI, 0.95–8.83)
OR, 2.39 (95% CrI, 0.51–12.40)
OR, 1.52 (95% CrI, 0.50–4.28)
ADA
Clinical Remission
IFX
—
VDZ
OR, 1.80 (95% CrI, 0.96–3.46)
—
GLM
OR, 2.02 (95% CrI, 1.13–3.59)
—
OR, 1.12 (95% CrI, 0.64–1.92)
ADA
Mucosal Healing
Treatment effect estimates come from Bayesian network meta-analysis. Odds ratios ⬎1.0 favor the treatment in the left upper square. To obtain ORs for comparisons in the opposite direction, reciprocals should be calculated. ADA ⫽ adalimumab; CrI ⫽ credible interval; GLM ⫽ golimumab; IFX ⫽ infliximab; OR ⫽ odds ratio; VDZ ⫽ vedolizumab.
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Appendix Table. AE Rates in RCTs of Biological Agents for Moderately to Severely Active Ulcerative Colitis* Event Rates, %
Outcome
Any AE SAEs AEs leading to discontinuation of study drug Infectious AEs Serious infection TB CHF
ADA Biological Group†
ADA Placebo Group†
IFX Biological Group‡
IFX Placebo Group‡
GLM Biological Group§
GLM Placebo Group§
VDZ Biological Group㥋
VDZ Placebo Group㥋
70.1 8.8 8.2
67.9 10.5 8.8
84.7 16.1 5.0
79.1 22.5 9.4
48.9 6.4 3.1
47.1 6.6 2.7
61.7 5.5 –
63.6 10.9 –
32.7 1.6 0.2 0.2
28.8 1.7 0.0 0.0
35.5 2.1 0.0 –
31.1 2.5 0.0 –
20.4 1.2 0.6 –
17.3 1.9 0.2 –
44.1 1.3 – –
40.4 2.5 – –
ADA ⫽ adalimumab; AE ⫽ adverse event; CHF ⫽ congestive heart failure; GLM ⫽ golimumab; IFX ⫽ infliximab; RCT ⫽ randomized, controlled trial; SAE ⫽ serious adverse event; TB ⫽ tuberculosis; VDZ ⫽ vedolizumab. * Event rates are based on the number of AEs in the included RCTs. The GEMINI 1 trial did not report TB or AEs leading to discontinuation of the study drug. Congestive heart failure was reported only in the ADA trials (ULTRA 1 and 2 [Ulcerative Colitis Long-Term Remission and Maintenance With Adalimumab 1 and 2] and the NCT00853099 trial). † Data for 1150 patients from 3 RCTs. ‡ Data for 486 patients from 2 RCTs. § Data for 971 patients from 2 RCTs. 㛳 Data for 747 patients from 1 RCT.
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20 May 2014 Annals of Internal Medicine Volume 160 • Number 10
Annals of Internal Medicine
Biological Agents for Moderately to Severely Active Ulcerative Colitis A Systematic Review and Network Meta-analysis Silvio Danese, MD, PhD; Gionata Fiorino, MD, PhD; Laurent Peyrin-Biroulet, MD, PhD; Ersilia Lucenteforte, ScD, PhD; Gianni Virgili, MD; Lorenzo Moja, MD, MSc, DrPH; and Stefanos Bonovas, MD, MSc, PhD
Background: Biological agents are emerging treatment options for the management of ulcerative colitis (UC). Purpose: To assess the comparative efficacy and harm of biological agents in adult patients with moderately to severely active UC who are naive to biological agents. Data Sources: MEDLINE, EMBASE, and Cochrane Library from inception through December 2013, without language restrictions, and ClinicalTrials.gov, European Medicines Agency, and U.S. Food and Drug Administration Web sites. Study Selection: Randomized, placebo-controlled or head-to-head trials assessing biological agents as induction or maintenance therapy for moderately to severely active UC. Data Extraction: Two reviewers independently abstracted study data and outcomes and rated each trial’s risk of bias. Data Synthesis: There were no head-to-head trials. There were 7 double-blind, placebo-controlled trials that were rated as low risk of bias and showed that all biological agents (adalimumab, golimumab, infliximab, and vedolizumab) resulted in more clinical responses, clinical remissions, and mucosal healings than placebo for
U
lcerative colitis (UC) is an idiopathic, remitting and relapsing, chronic inflammatory bowel disease. It is characterized by mucosal ulceration, rectal bleeding, diarrhea, abdominal cramps, urgency or tenesmus, fever, malaise, weight loss and fatigue, depending on the extent and severity of the disease. Worldwide, the estimated incidence of UC ranges from 1.2 to 20.3 cases per 100 000 personyears and its prevalence ranges from 7.6 to 246.0 per 100 000 persons (1– 4). Pharmacologic management of UC aims at reducing inflammation and maintaining remission of symptoms and includes sulfasalazine, 5-aminosalicylates (mesalamine, olsalazine, and balsalazide), glucocorticoids, and immunosuppressants (azathioprine, 6-mercaptopurine, and cyclosporine) (5, 6). Despite progress, treatment options for moderately to severely active UC remain limited because conventional therapies inadequately control the disease in a substantial proportion of patients and often lead to adverse events (AEs). However, a series of biological agents have recently received regulatory approval or are under scrutiny; in 2013, those included the monoclonal antibodies adalimumab, golimumab, infliximab, and vedolizumab.
See also: Editorial comment. . . . . . . . . . . . . . . . . . . . . . . . . . 733 704 © 2014 American College of Physicians
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induction therapy. The results of network meta-analysis suggested that infliximab is more effective to induce clinical response (odds ratio, 2.36 [95% credible interval, 1.22 to 4.63]) and mucosal healing (odds ratio, 2.02 [95% credible interval, 1.13 to 3.59]) than adalimumab. No other indirect comparison reached statistical significance. For maintenance, 6 double-blind, placebo-controlled trials that were rated high risk of bias showed that all biological agents have greater clinical efficacy than placebo. The occurrence of adverse events was not different between biological agents and placebo. Limitation: Few trials, no head-to-head comparisons, and inadequate follow-up in maintenance trials. Conclusion: Biological agents are effective treatments for UC, but head-to-head trials are warranted to establish the best therapeutic option. Primary Funding Source: Centro Ricerca e Cura delle Malattie Infiammatorie Croniche Intestinali, IRCCS Istituto Clinico Humanitas. (PROSPERO registration number: CRD42013005459) Ann Intern Med. 2014;160:704-711. For author affiliations, see end of text.
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Evidence on comparative effectiveness and harms of those treatments would be very useful to inform clinical decision making. We conducted a systematic review of randomized, controlled trials (RCTs) assessing biological agents as induction or maintenance therapy for moderately to severely active UC in adults to address this issue. We assessed their comparative clinical efficacy and harm using the method of multiple-treatment meta-analysis, also known as network meta-analysis or mixed-treatment comparison (7–10), based on the available evidence from RCTs. We aimed to compare the different treatment options and provide a clinically useful summary that can be used to support optimal decision making.
METHODS Our study protocol (11) was registered on PROSPERO (CRD42013005459). We followed standard methods for conducting and reporting systematic reviews and network meta-analyses (12, 13). Data Sources and Searches
We systematically searched MEDLINE and EMBASE databases from inception to 31 December 2013. Search terms included biologic(al) agent(s), biologic(s), adalimumab, golimumab, infliximab, or vedolizumab, combined with ulcerative colitis. The search was limited to RCTs and humans. Language or age restrictions were not imposed.
Biological Agents for Ulcerative Colitis
We also searched the Cochrane Library for any recent systematic review on the subject, the ClinicalTrials.gov database for completed but unpublished studies, and the European Medicines Agency and U.S. Food and Drug Administration Web sites to obtain details on study characteristics or outcomes if these data were missing or unclearly presented in the original articles. Study Selection
The titles and abstracts of identified published articles were scanned to exclude irrelevant studies. The full text of the selected articles was retrieved and read. The bibliographies of the articles and of reviews and meta-analyses were scanned. We further asked field experts to provide additional evidence. Studies were eligible for inclusion if they were randomized, placebo-controlled or head-to-head trials assessing the efficacy or harm of biological agents for the treatment of adult patients with moderately to severely active UC. We considered only biological agents that were market-authorized by either the U.S. Food and Drug Administration or European Medicines Agency, as well as agents under review for the new drug application (United States) or marketing authorisation application (European Union). We defined moderately to severely active UC as a Mayo Clinic score (MCS) of 6 to 12 points, with an endoscopic subscore of 2 or 3. An MCS is a composite activity index ranging from 0 to 12, with higher scores indicating more severe disease activity. It is calculated as the sum of 4 items: stool frequency, rectal bleeding, endoscopic findings, and physician’s global assessment (14). Randomized, controlled trials were eligible for inclusion in the network regardless of country, phase (2 or 3), or support. Data Extraction and Quality Assessment
Two reviewers abstracted the data independently. The following information was collected from each study: publication data; trial’s acronym and identifier; first author’s last name; geographic location of study; year of publication; study design; number of participants and population characteristics; and interventions’ variables, including drug, dose, and administration. We extracted data specific for patients who were naive to treatment with biological agents because the relative efficacy of biological agents should not be assessed by pooling patients for whom standard therapies were unsuccessful with patients for whom biological agents were unsuccessful (15, 16). Different doses of the same treatment were treated as separate interventions, and for biological agents that received regulatory approval, only data for dose and administration as approved in the respective summary of product characteristics were considered. The outcome measures were the odds ratios (ORs) for clinical response (primary outcome), clinical remission, and mucosal healing at the end of induction and at completion of each trial’s maintenance phase, calculated in acwww.annals.org
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cordance with the intention-to-treat principle (that is, total number of randomly assigned participants, regardless of how the original study investigators analyzed the data). Clinical response was defined as a decrease from baseline in the MCS of at least 3 points and at least 30%, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point, or an absolute rectal bleeding subscore of 0 or 1. Clinical remission was defined as an MCS of 2 points or lower, with no individual subscore exceeding 1 point. Mucosal healing was defined as an absolute subscore for endoscopy of 0 or 1. We also examined the occurrence of serious adverse events (SAEs), which are defined as any untoward medical occurrence that results in death, requires hospital admission or prolongation of an existing hospital stay, causes persistent or significant disability or incapacity, or is lifethreatening (17); the AEs leading to discontinuation of the study drug; the total number of AEs; the total number of infectious AEs; the number of serious infections; tuberculosis; and congestive heart failure. Reviewers assessed the risk of bias in the results of included studies by using the Cochrane Collaboration’s tool (18), which addresses the following key domains: sequence generation, allocation concealment, blinding of participants and personnel, incomplete outcome data, selective outcome reporting, and other sources of bias. These items are considered as key domains for risk-of-bias assessment and reclassified as adequate (low risk of bias), inadequate (high risk of bias), or unclear. Studies with adequate procedures in all domains are considered to have a low risk of bias, ones with inadequate procedures in 1 or more domains are considered to have a high risk of bias, and those with unclear procedures in 1 or more domains are considered to have unclear risk of bias. Disagreements among reviewers were discussed and agreement was reached by consensus. Data Synthesis and Analysis
We conducted the network meta-analysis within a Bayesian framework using Markov chain Monte Carlo methods in WinBUGS (Medical Research Council Biostatistics Unit, Cambridge, United Kingdom) (19). Analysis was based on noninformative priors for relative-effect parameters (flat normal with mean of 0 and precision of 0.001) and between-study SD (a flat uniform distribution between 0 and 2). Convergence and lack of autocorrelation were checked and confirmed after a 5000-simulation burn-in phase without any thinning and using 4 chains with different initial values. Then, a burn-in phase of 20 000 iterations was used, followed by 50 000 iterations to estimate parameters. We did sensitivity analyses by setting the prior on the heterogeneity equal to a uniform (0, 100) and on the precision parameter equal to a ␥ (0.001, 0.001) to check the robustness of the model to different sets of priors. Model choice was based on the deviance information criterion, and a lower deviance information 20 May 2014 Annals of Internal Medicine Volume 160 • Number 10 705
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Identification
Figure 1. Summary of evidence search and selection.
Records identified (n = 479) MEDLINE database search: 141 EMBASE database search: 335 Knowledgeable expert: 3
Screening
Duplicates removed (n = 55)
Records screened (n = 424)
Eligibility
Articles excluded based on title/abstract (n = 406)
Articles retrieved for detailed evaluation (n = 18)
RCTs excluded (n = 11) Not placebo-controlled or head-to-head trials: 3 Biologics that are not market-authorized or under evaluation: 2 Not moderate to severe UC (as defined with MCS): 7 Different definitions and measurements of outcomes: 7 Not in adults: 1
Included
RCT identified through ClinicalTrials.gov (n = 1)
Eligible RCTs included (n = 8)
MCS ⫽ Mayo Clinic score; RCT ⫽ randomized, controlled trial; UC ⫽ ulcerative colitis.
criterion by 5 or more units suggested a better model fit. We report estimates only for the default model because we did not find differences in model fit according to deviance information criterion. We used the resulting ORs and 95% credible intervals (CrIs), the Bayesian equivalent to CIs, to assess treatment effects. We also calculated fixed-effects ORs and 95% CIs (frequentist approach). Given that each pairwise comparison included a limited number of RCTs, we could not formally assess statistical heterogeneity and publication bias. Role of the Funding Source
This study was funded by the Centro Ricerca e Cura delle Malattie Infiammatorie Croniche Intestinali, IRCCS Istituto Clinico Humanitas. The funding source had no role in the design of the study; the collection, analysis, and interpretation of the data; or the decision to submit the manuscript for publication. 706 20 May 2014 Annals of Internal Medicine Volume 160 • Number 10
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RESULTS Figure 1 summarizes the search and selection of evidence. We identified 6 publications (20 –25) reporting the results of 7 trials (ACT [Active Ulcerative Colitis Trial] 1, ACT 2, ULTRA [Ulcerative Colitis Long-Term Remission and Maintenance With Adalimumab] 1, ULTRA 2, PURSUIT-SC [Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment– Subcutaneous], PURSUIT-M [Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment–Maintenance], and GEMINI 1). One additional study, the NCT00853099 trial, was initially identified through ClinicalTrials.gov (26) and later in full-text publication (27). In total, 8 trials met the eligibility criteria, none of which were head-to-head comparisons of biological agents. All 8 studies were multicenter, randomized, doubleblind, placebo-controlled trials assessing the efficacy and www.annals.org
Biological Agents for Ulcerative Colitis
harm of 4 biological agents (adalimumab, golimumab, infliximab, and vedolizumab) as induction or maintenance therapy for adult patients with moderately to severely active UC (that is, MCS of 6 to 12 points with an endoscopic subscore of at least 2). In most studies, patients were randomly assigned once, at the beginning of the trial, to receive either 6- to 8-week experimental therapy or matching placebo (induction phase) followed by a longer phase during which experimental treatments were given at maintenance schemes (maintenance phase of the trial). However, in 2 trials (PURSUIT-M [24] and GEMINI 1 [25]), only patients who responded to induction were eligible for continued (maintenance) therapy and were reassigned at the beginning of the maintenance study. A summary of the design characteristics of the trials is presented in Appendix Figure 1 (available at www.annals .org). The mean age of patients ranged from 40 to 43 years, whereas the mean previous disease duration ranged from 6 to 8 years. The studies were conceptually homogeneous in terms of outcome definitions and measurements (all trials used the Mayo Clinic activity index to define clinical response, clinical remission, and mucosal healing). In 6 of those RCTs (ACT 1, ACT 2, ULTRA 1, NCT00853099, PURSUIT-SC, and PURSUIT-M), any patient previously exposed to biological agents had been excluded as per protocol, whereas in the other 2 trials (ULTRA 2 and GEMINI 1), randomization had been stratified by previous exposure to anti–tumor necrosis factor-␣ agents, and we specifically extracted only the data for patients who were naive to biological agents. Thus, randomization was maintained. Further outcome data were retrieved from the U.S. Food and Drug Administration Web site (28) for the ULTRA 1 trial (the intention-to-treat population, original protocol) and from conference abstracts (29 –31) for the GEMINI 1 study. All trials contributed to all efficacy outcomes except mucosal healing: The GEMINI 1 study (25) has not published any data about mucosal healing, referring to the subgroup of patients without any previous anti– tumor necrosis factor-␣ exposure, whereas the respective data for the PURSUIT-M trial (24) were not reported. For biological agents that received regulatory approval for the treatment of UC (adalimumab, golimumab, and infliximab), only dose and administration as approved in the respective summary of product characteristics for each agent were considered in the analysis (Table 1). For vedolizumab, for which a license application was under evaluation by the regulatory authorities (32, 33) during our analysis, both schemes for maintenance therapy (300 mg intravenously every 8 weeks or every 4 weeks) were included. Assessment of the RCTs using the Cochrane Collaboration tool revealed low risk of bias across the induction trials (ACT 1, ACT 2, ULTRA 1, ULTRA 2, NCT00853099, PURSUIT-SC, and GEMINI 1) but high risk of bias across maintenance phases (ACT 1, ACT 2, www.annals.org
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Table 1. Biological Agents for Treatment of Moderately to Severely Active Ulcerative Colitis in Adult Patients* Biological Agent
Dose
ADA
160 mg SC at 0 wk, followed by 80 mg at 2 wk and then 40 mg every other wk 200 mg SC at 0 wk, followed by 100 mg at 2 wk and then 100 mg every 4 wk 5 mg/kg IV at 0 wk, followed by 5 mg/kg at 2 and 6 wk and every 8 wk thereafter 300 mg IV at 0 and 2 wk and every 8 wk or every 4 wk thereafter
GLM IFX VDZ
ADA ⫽ adalimumab; GLM ⫽ golimumab; IFX ⫽ infliximab; IV ⫽ intravenous; SC ⫽ subcutaneous; VDZ ⫽ vedolizumab. * Dose and administration included in the analysis.
ULTRA 2, NCT00853099, PURSUIT-M, and GEMINI 1) with regard to the “incomplete outcome data” domain. Although follow-up was as high as 91% to 97% for induction trials, equally balanced between the study groups, rates of complete follow-up were lower in maintenance studies (55% to 76%) with significant imbalances across intervention groups and unequal dropout rates due to AEs. This pattern is of concern. If patients with poorer clinical outcomes are more likely to drop out because of AEs and this happens mainly in the experimental group, then the results may be biased in favor of the experimental drug. Premature treatment discontinuation due to “inefficacy” may also introduce bias if the numbers excluded are not balanced across intervention groups. We considered the whole group of maintenance trials to have a high risk of bias with regard to the “incomplete outcome data” domain for these reasons. Quality assessment items are summarized in Figure 2 for the induction trials and in Appendix Figure 2 (available at www.annals.org) for the maintenance trials. Efficacy of Biological Agents as Induction Therapy
Ten randomized (2-group) comparisons of biological agents versus placebo contributed to this analysis (Figure 3 and Appendix Figure 1). They provided only indirect comparative evidence. In total, 2282 adult patients who were naive to biological agents had been randomly assigned to placebo (n ⫽ 1115) or a biological agent (adalimumab, golimumab, infliximab, or vedolizumab in doses described in Table 1) (n ⫽ 1167) as induction therapy (6 to 8 weeks) for moderately to severely active UC.
Treatments Compared With Placebo
All biological agents (adalimumab, golimumab, infliximab, and vedolizumab) demonstrated superiority over placebo for induction of clinical response, remission, and mucosal healing, except adalimumab for clinical remission. The estimated relative efficacies (expressed as ORs) are shown in Table 2. 20 May 2014 Annals of Internal Medicine Volume 160 • Number 10 707
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Figure 2. Summary of risk-of-bias assessments for
Random sequence generation
Allocation concealment
Blinding of participants and personnel
Incomplete outcome data
Free of selective outcome reporting
Free of other sources of bias
randomized, controlled trials of induction therapy.
ACT 1
+
+
+
+
+
+
ACT 2
+
+
+
+
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+
ULTRA 1
+
+
+
+
+
+
ULTRA 2
+
+
+
+
+
+
NCT00853099
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PURSUIT-SC
+
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GEMINI 1
+
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Green circles signify low risk of bias. ACT ⫽ Active Ulcerative Colitis Trial; PURSUIT-SC ⫽ Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment–Subcutaneous; ULTRA ⫽ Ulcerative Colitis Long-Term Remission and Maintenance With Adalimumab.
izumab in doses described in Table 1) (n ⫽ 782) as maintenance treatment. However, 2 of the trials (PURSUIT-M [24] and GEMINI 1 [25]) had included only persons who responded to induction in their maintenance phases (Appendix Figure 1). Therefore, 2 distinct groups of maintenance trials were formed: group A, with adalimumab and infliximab trials (ACT 1, ACT 2, ULTRA 2, and NCT00853099), and group B, with golimumab and vedolizumab trials (PURSUIT-M and GEMINI 1), restricted to persons who responded to induction. Given the mixture of study designs involved in the maintenance trials and the fact that persons who responded to induction may be more likely to achieve a positive clinical outcome in the long term than those who did not respond (34), we decided not to synthesize indirect effect estimates but simply summarize the available direct evidence using frequentist fixedeffects models. In group A, infliximab and adalimumab were better than placebo for clinical response (ORs, 2.89 [95% CI, 1.96 to 4.28] and 1.90 [CI, 1.27 to 2.86], respectively), clinical remission (ORs, 2.78 [CI, 1.75 to 4.41] and 2.30 [CI, 1.37 to 3.86]), and mucosal healing (ORs, 2.65 [CI, 1.79 to 3.92] and 1.99 [CI, 1.30 to 3.06]). In group B, both schemes of vedolizumab (300 mg intravenously every 4 weeks or every 8 weeks) and golimumab were better than placebo for clinical response (ORs for vedolizumab every 4 weeks, vedolizumab every 8 weeks, and golimumab were 3.54 [CI, 1.79 to 6.99], 5.19 [CI, 2.59 to 10.42], and 2.24 [CI, 1.41 to 3.56], respectively) and clinical remission (ORs, 3.93 [CI, 1.90 to 8.12], 3.61 [CI, 1.74 to 7.48], and 1.81 [CI, 1.10 to 3.00], respectively).
Figure 3. Network geometry for induction treatment.
Treatments Compared With Each Other
The results of our Bayesian network meta-analysis suggested that infliximab is more likely to induce a favorable clinical outcome than adalimumab. The OR was 2.36 (95% CrI, 1.22 to 4.63) for the primary outcome of induction of clinical response. The ORs were 2.79 (CrI, 0.95 to 8.83) and 2.02 (CrI, 1.13 to 3.59) for the secondary outcomes of clinical remission and mucosal healing, respectively. However, this evidence needs to be interpreted with caution because it is based on indirect comparisons. None of the other indirect comparisons reached statistical significance. Results are summarized in Appendix Figure 3 (available at www.annals.org). Efficacy of Biological Agents as Maintenance Therapy
Six randomized trials contributed to this analysis (Appendix Figure 1). In total, 1502 patients who were naive to biological agents received placebo (n ⫽ 720) or a biological agent (adalimumab, golimumab, infliximab, or vedol708 20 May 2014 Annals of Internal Medicine Volume 160 • Number 10
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ADA
4 trials (928 patients)
PBO
3 trials (662 patients)
GLM
1 trial (206 patients)
VDZ
2 trials (486 patients)
IFX
Compared treatments are connected indirectly through the placebo, the “common comparator.” The number of independent randomized, controlled trials and number of patients who were naive to biological agents (in parenthesis) for each comparison in the induction treatment network are informed by head-to-head evidence. To calculate the numbers of patients, we considered only persons assigned to a dose as approved in the summary of product characteristics and those assigned to placebo. ADA ⫽ adalimumab; GLM ⫽ golimumab; IFX ⫽ infliximab; PBO ⫽ placebo; VDZ ⫽ vedolizumab. www.annals.org
Biological Agents for Ulcerative Colitis
Table 2. Comparative Efficacy of Biological Agents as Induction Therapy for Moderately to Severely Active Ulcerative Colitis in Adult Patients* Network Comparator Treatment
OR (95% CrI)
Clinical response ADA (160/80/40 mg SC) vs. placebo GLM (200/100 mg SC) vs. placebo IFX (5 mg/kg IV) vs. placebo VDZ (300 mg IV) vs. placebo
1.76 (1.19–2.56) 2.11 (1.18–3.28) 4.13 (2.39–7.16) 3.23 (1.42–7.42)
Clinical remission ADA (160/80/40 mg SC) vs. placebo GLM (200/100 mg SC) vs. placebo IFX (5 mg/kg IV) vs. placebo VDZ (300 mg IV) vs. placebo
1.91 (0.98–3.72) 2.90 (1.19–6.54) 5.33 (2.28–13.63) 4.51 (1.13–20.76)
Mucosal healing ADA (160/80/40 mg SC) vs. placebo GLM (200/100 mg SC) vs. placebo IFX (5 mg/kg IV) vs. placebo VDZ (300 mg IV) vs. placebo
1.64 (1.18–2.31) 1.84 (1.18–2.81) 3.31 (2.07–5.32) –
ADA ⫽ adalimumab; CrI ⫽ credible interval; GLM ⫽ golimumab; IFX ⫽ infliximab; IV ⫽ intravenous; OR ⫽ odds ratio; SC ⫽ subcutaneous; VDZ ⫽ vedolizumab. * Treatment effect estimates come from Bayesian network meta-analysis.
Harms
This analysis used randomized data on AEs from both induction and maintenance phases. Because AE data specific for patients who were naive to biological agents were not available for the 2 studies having also recruited patients with previous exposure to biological agents (ULTRA 2 [22] and GEMINI 1 [25]), data on harms for the whole randomly assigned populations were included instead. The median rates of AEs for patients using biological agents were 107 events per 1000 patients for SAEs, 814 events per 1000 patients for total AEs, 83 events per 1000 patients for AEs leading to discontinuation of the study drug, and 17 events per 1000 patients for serious infections. The corresponding event rates for placebo were 123 events per 1000 patients, 698 events per 1000 patients, 64 events per 1000 patients, and 19 events per 1000 patients (Table 3). There were very few cases of tuberculosis and congestive heart failure. Numbers were rather small for comparison of individual biological agents with placebo (Appendix Table, available at www.annals.org). Of note, the maintenance trials had high rates of incomplete follow-up and thus inadequate ascertainment of harms may have occurred. For information on sensitivity analysis after the retrospective exclusion of patients in the final publications of the PURSUIT-SC and PURSUIT-M trials, see the Appendix (available at www.annals.org).
DISCUSSION In this systematic review of RCTs assessing biological agents for the treatment of moderately to severely active UC in adult patients, 8 trials were incorporated, none of www.annals.org
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which were head-to-head comparisons of biological agents. Meta-analysis of induction studies showed that all agents (adalimumab, golimumab, infliximab, and vedolizumab) were superior to placebo. Indirect comparisons from our network meta-analysis suggested that infliximab is more likely to induce a favorable clinical outcome than adalimumab. Synthesis of the available studies demonstrated that all biological agents had greater efficacy than placebo for maintenance therapy. The occurrence of AEs was not different between biological agents and placebo. The internal validity of our analysis is supported by 3 factors. First, having conducted a rigorous and extensive literature search, we are confident that all relevant RCTs have been properly identified. Second, the induction trials included in the network are characterized by low risk of bias, as assessed with the Cochrane Collaboration approach, and allowed a reliable synthesis of Bayesian indirect treatment effect estimates. Third, all RCTs are conceptually homogeneous in terms of study design (randomized, double-blind, placebo-controlled, and common use of the MCS to define and measure the clinical outcomes) and patient characteristics (adults with a mean age of 40 to 43 years; moderately to severely active UC, defined by an MCS of 6 to 12 points, with an endoscopic subscore of at least 2; previous disease duration of 6 to 8 years; and naive to treatment with biological agents). Differences in key characteristics across trials that may act as effect modifiers, possibly causing bias in the analysis, seem to be small. However, the strengths of this network meta-analysis should be weighed against some limitations. First, the limited number of trials and the absence of head-to-head comparisons increase the uncertainty of the findings and conclusions. Second, all studies of this network were registration trials for regulatory purposes. As such, they have enrolled selective homogeneous populations, a fact that may compromise external validity (35). We further limited
Table 3. Occurrence of AEs in RCTs of Biological Agents for Moderately to Severely Active Ulcerative Colitis in Adult Patients Outcome
Any AE SAEs AEs leading to discontinuation of study drug Infectious AEs Serious infection TB CHF
RCTs With Data, n
Patients, n
8 8 7
8 8 7 3
Median Event Rates (Range), % Biological Agents
Placebo
3354 3354 2607
81.4 (37.5–87.6) 10.7 (2.2–21.5) 8.3 (0.3–13.2)
69.8 (38.2–85.1) 12.3 (6.1–25.6) 6.4 (0.9–13.1)
3354 3354 2607 1150
39.0 (11.8–71.7) 1.7 (0.0–5.5) 0.0 (0.0–1.9) 0.0 (0.0–0.4)
28.2 (12.1–70.6) 1.9 (0.8–4.1) 0.0 (0.0–0.6) 0.0 (0.0–0.0)
AE ⫽ adverse event; CHF ⫽ congestive heart failure; RCT ⫽ randomized, controlled trial; SAE ⫽ serious adverse event; TB ⫽ tuberculosis. 20 May 2014 Annals of Internal Medicine Volume 160 • Number 10 709
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the network to patients who were naive to biological agents and had moderately to severely active disease. Policymakers should be cautious in extrapolating our results to persons for whom biological agents were unsuccessful or those with mild disease, as well as for follow-up longer than 1 year because the trials lasted only up to 1 year. Third, we could not assess publication bias. Fourth, the maintenance trials included in our review were at high risk of bias for incomplete outcome data. Fifth, an issue remaining beyond our control is the potential presence of sponsorship bias in the studies included in the network (that is, the bias associated with the commercial interests of industrial sponsors) (36, 37). They were registration trials, supported by the pharmaceutical companies marketing these compounds. It is also important to note that in a network meta-analysis of RCTs, the value of randomization does not hold across trials. Hence, a network meta-analysis of RCTs is a form of observational evidence and may be biased if differences in unmeasured covariates among trials are modifiers of relative treatment effects. For example, differences in history of treatment may constitute effect modifiers. Moreover, although the MCS was used to define and measure the clinical outcomes, there may be still ascertainment bias among the trials arising from frequency of follow-up visits. Also, the geographic regions where the studies were done may reflect additional differences between patient populations not reflected in reported patient characteristics. It remains important to have head-to-head comparative trials with the same recruitment strategy and follow-up protocol across groups for these reasons. In conclusion, the results of our meta-analysis showed that all biological agents had superior clinical efficacy compared with placebo, both in induction and maintenance phases. It also provides indirect evidence that infliximab is better than adalimumab as induction therapy to obtain clinical response. Data on SAEs are limited. Given the efficacy of the available treatments and severity of the disease, further use of placebo controls should be considered as unethical. Direct head-to-head comparisons between biological agents should be the top priority on the research agenda, as well as studies in the real-world setting and evaluation in terms of cost, which is a key consideration in determining the comparative effectiveness of alternative treatments for UC. Meanwhile, national and international registries, long-term epidemiologic studies, and clinical audits (such as the United Kingdom Inflammatory Bowel Disease audit [38]), may serve as complementary sources of data about the beneficial and harmful effects of alternative therapies for UC. From Inflammatory Bowel Disease Center, IRCCS Humanitas Research Hospital, University of Milan, IRCCS Galeazzi Orthopedic Institute, and Laboratory of Drug Regulatory Policies, IRCCS Mario Negri Institute for Pharmacologic Research, Milan, Italy; University Hospital of Nancy, Universite´ de Lorraine, Vandoeuvre-le`s-Nancy, France; Univer710 20 May 2014 Annals of Internal Medicine Volume 160 • Number 10
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sity of Florence, Florence, Italy; and School of Medicine, University of Athens, Athens, Greece. Grant Support: By the Centro Ricerca e Cura delle Malattie Infiammatorie Croniche Intestinali, IRCCS Istituto Clinico Humanitas. Disclosures: Disclosures can be viewed at www.acponline.org/authors /icmje/ConflictOfInterestForms.do?msNum⫽M13-2403. Requests for Single Reprints: Silvio Danese, MD, PhD, Inflammatory Bowel Disease Center, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy; e-mail, [email protected].
Current author addresses and author contributions are available at www.annals.org.
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28. U.S. Food and Drug Administration. FDA GIDAC briefing document on Humira (adalimumab). Gastrointestinal Drugs Advisory Committee Meeting, BLA 125057/232. 28 August 2012. Accessed at www.fda.gov/downloads /AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Gastrointestinal DrugsAdvisoryCommittee/UCM316786.pdf on 20 February 2014. 29. Feagan BG, Rutgeerts PJ, Sands BE. Vedolizumab induction therapy for ulcerative colitis: results of GEMINI 1, a randomized, placebo-controlled, double-blind, multicenter, phase III trial. Presented at Digestive Disease Week, San Diego, CA, 19 –22 May 2012. Abstract no. 943b. 30. Rutgeerts P. Vedolizumab induction therapy for ulcerative colitis: results of GEMINI I, a randomized, placebo-controlled, double-blind, multicenter, phase 3 trial. 20th United European Gastroenterology Week, Amsterdam, the Netherlands, 20 –24 October 2012. Abstract no. OP280. 31. Feagan BG, Rutgeerts P, Sands BE, Sandborn WJ, Colombel JF, Hanauer S, et al. Vedolizumab maintenance therapy for ulcerative colitis: Results of GEMINI I, a randomized, placebo-controlled, double-blind, multicenter phase 3 trial. Am J Gastroenterol. 2012;107:S609. 32. Takeda submits marketing authorisation application for vedolizumab in moderately to severely active ulcerative colitis and Crohn’s disease in the European Union [press release]. Osaka, Japan: Takeda; 7 March 2013. Accessed at www.takeda.com/news/2013/20130308_5677.html on 20 February 2014. 33. Takeda submits biologics license application for a new investigational drug vedolizumab, in moderately to severely active Crohn’s disease and ulcerative colitis in the United States [press release]. Osaka, Japan: Takeda; 21 June 2013. Accessed at www.takeda.com/news/2013/20130624_5844.html on 20 February 2014. 34. Sandborn WJ, Colombel JF, D’Haens G, Van Assche G, Wolf D, Kron M, et al. One-year maintenance outcomes among patients with moderately-toseverely active ulcerative colitis who responded to induction therapy with adalimumab: subgroup analyses from ULTRA 2. Aliment Pharmacol Ther. 2013;37: 204-13. [PMID: 23173821] 35. Rothwell PM. Factors that can affect the external validity of randomised controlled trials. PLoS Clin Trials. 2006;1:e9. [PMID: 16871331] 36. Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflicts of interest in biomedical research: a systematic review. JAMA. 2003;289:454-65. [PMID: 12533125] 37. Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373:746-58. [PMID: 19185342] 38. Biological therapies audit subgroup. National clinical audit report of biological therapies: UK Inflammatory Bowel Disease (IBD) audit. Adult national report. London, United Kingdom: Royal College of Physicians; 2013. Accessed at www.rcplondon.ac.uk/sites/default/files/national_clinical_audit_report_of _biological_therapies_-_adult_report._29_august_2013.pdf on 20 February 2014.
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Annals of Internal Medicine Current Author Addresses: Drs. Danese and Fiorino: Inflammatory Bowel Disease Center, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy. Dr. Peyrin-Biroulet: Inserm U954 and Department of HepatoGastroenterology, University Hospital of Nancy, Universite´ de Lorraine, Vandoeuvre-le`s-Nancy, France. Dr. Lucenteforte: Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy. Dr. Virgili: Department of Specialised Surgical Sciences, University of Florence, Via le Morgagni 85, 50134 Florence, Italy. Dr. Moja: Clinical Epidemiology Unit, IRCCS Orthopedic Institute Galeazzi, Via R. Galeazzi 4, 20161 Milan, Italy. Dr. Bonovas: Department of Pharmacology, School of Medicine, University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece. Author Contributions: Conception and design: S. Danese, G. Fiorino, L. Peyrin-Biroulet, L. Moja, S. Bonovas. Analysis and interpretation of the data: S. Danese, E. Lucenteforte, G. Virgili, L. Moja, S. Bonovas. Drafting of the article: S. Danese, L. Peyrin-Biroulet, L. Moja, S. Bonovas. Critical revision of the article for important intellectual content: S. Danese, G. Fiorino, L. Peyrin-Biroulet, E. Lucenteforte, G. Virgili, L. Moja, S. Bonovas. Final approval of the article: S. Danese, G. Fiorino, L. Peyrin-Biroulet, E. Lucenteforte, G. Virgili, L. Moja, S. Bonovas. Provision of study materials or patients: G. Fiorino. Statistical expertise: E. Lucenteforte, G. Virgili, S. Bonovas. Administrative, technical, or logistic support: S. Danese. Collection and assembly of data: S. Danese, G. Fiorino, S. Bonovas.
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Web-Only Reference 39. Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. The Cochrane Collaboration [updated March 2011]; 2011. Accessed at http://handbook.cochrane.org on 20 February 2014.
APPENDIX: SENSITIVITY ANALYSIS AFTER RETROSPECTIVE EXCLUSION OF PATIENTS IN THE FINAL PUBLICATIONS OF THE PURSUIT-SC AND PURSUIT-M TRIALS During the revision of this article, 2 publications of RCTs included in the network meta-analysis changed their status from “ahead of print” to “in print.” The PURSUIT-SC (23) and PURSUIT-M (24) trials were published in the January 2014 issue of Gastroenterology. The primary efficacy populations analyzed in the final publications slightly differed from those in the originally accepted ahead-of-print versions. PURSUIT-SC analyzed 761 instead of 774 patients, and PURSUIT-M analyzed 456 instead of 464 patients. The reason was a retrospective exclusion of many patients after identification of nonadherence to good clinical practice (source documentation and informed consent process) at the study site at which they participated. After extensive discussion, we decided to present the results of the analysis based on all randomly assigned patients, adhering to the intention-to-treat principle, because it is recommended (39). Nevertheless, we did a sensitivity analysis by rerunning our metaanalysis on the basis of new data. Exclusion of these data had a minimal effect on our efficacy results— however, in the direction of more conservative effect estimates for golimumab—and does not alter the conclusions of our study.
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Appendix Figure 1. Summary of methodological characteristics of trials. Wk 0
ACT 1 R
ACT 2 R
ULTRA 1 (ITT-A3)
ULTRA 1 (ITT-E)
6
8
30
PBO
PBO
IFX 5 mg/kg IV IFX 10 mg/kg IV
IFX 5 mg/kg IV q8w IFX 10 mg/kg IV q8w
PBO
PBO
IFX 5 mg/kg IV IFX 10 mg/kg IV
IFX 5 mg/kg IV q8w IFX 10 mg/kg IV q8w
52
54
60
PBO R
ADA 80/40 mg SC ADA 160/80/40 mg SC
PBO R
ULTRA 2
ADA 160/80/40 mg SC
PBO
PBO R
ADA 160/80/40 mg SC ADA 40 mg SC eow
PBO
NCT00853099 R
PBO
ADA 80/40 mg SC ADA 40 mg SC eow ADA 160/80/40 mg SC ADA 40 mg SC eow
PBO
PURSUIT-SC (phase 2) R
GLM 100/50 mg SC GLM 200/100 mg SC GLM 400/200 mg SC
PURSUIT-SC (phase 2, additional)
PBO R
GLM 100/50 mg SC GLM 200/100 mg SC GLM 400/200 mg SC
PURSUIT-SC (phase 3)
PBO R
GLM 200/100 mg SC GLM 400/200 mg SC
PBO
PURSUIT-M
GLM induction responders from PURSUIT-SC and PURSUIT-IV
GEMINI 1 R
R
GLM 50 mg SC q4w GLM 100 mg SC q4w
PBO VDZ 300 mg IV
VDZ induction responders from the randomized and the open-label cohorts
PBO R
VDZ 300 mg IV q8w VDZ 300 mg IV q4w
Induction phases are represented in blue, whereas maintenance phases are represented in green. ACT ⫽ Active Ulcerative Colitis Trial; ADA ⫽ adalimumab; eow ⫽ every other week; GLM ⫽ golimumab; IFX ⫽ infliximab; ITT-A3 ⫽ intention-to-treat population, after protocol amendment 3; ITT-E ⫽ intention-to-treat population, original protocol; IV ⫽ intravenous; PBO ⫽ placebo; PURSUIT-M ⫽ Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment–Maintenance; PURSUIT-SC ⫽ Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment–Subcutaneous; q8w ⫽ every 8 wk; q4w ⫽ every 4 wk; R ⫽ randomization; SC ⫽ subcutaneous; ULTRA ⫽ Ulcerative Colitis Long-Term Remission and Maintenance With Adalimumab; VDZ ⫽ vedolizumab. 20 May 2014 Annals of Internal Medicine Volume 160 • Number 10
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Appendix Figure 2. Summary of risk-of-bias assessments for
Random sequence generation
Allocation concealment
Blinding of participants and personnel
Incomplete outcome data
Free of selective outcome reporting
Free of other sources of bias
randomized, controlled trials of maintenance therapy.
ACT 1
+
+
+
–
+
+
ACT 2
+
+
+
–
+
+
ULTRA 2
+
+
+
–
+
+
NCT00853099
+
+
+
–
+
+
PURSUIT-M
+
+
+
–
+
+
GEMINI 1
+
+
+
–
+
+
Green circles indicate low risk of bias, and red circles signify high risk of bias. ACT ⫽ Active Ulcerative Colitis Trial; PURSUIT-M ⫽ Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment–Maintenance; ULTRA ⫽ Ulcerative Colitis Long-Term Remission and Maintenance With Adalimumab.
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Appendix Figure 3. Comparative efficacy of biological agents as induction therapy for moderately to severely active ulcerative colitis.
IFX
OR, 1.28 (95% CrI, 0.48–3.45)
VDZ
OR, 1.96 (95% CrI, 0.99–4.48)
OR, 1.53 (95% CrI, 0.62–4.32)
GLM
OR, 2.36 (95% CrI, 1.22–4.63)
OR, 1.84 (95% CrI, 0.74–4.66)
OR, 1.20 (95% CrI, 0.60–2.12)
ADA
Clinical Response
IFX
OR, 1.18 (95% CrI, 0.21–6.32)
VDZ
OR, 1.84 (95% CrI, 0.58–6.92)
OR, 1.56 (95% CrI, 0.32–9.19)
GLM
OR, 2.79 (95% CrI, 0.95–8.83)
OR, 2.39 (95% CrI, 0.51–12.40)
OR, 1.52 (95% CrI, 0.50–4.28)
ADA
Clinical Remission
IFX
—
VDZ
OR, 1.80 (95% CrI, 0.96–3.46)
—
GLM
OR, 2.02 (95% CrI, 1.13–3.59)
—
OR, 1.12 (95% CrI, 0.64–1.92)
ADA
Mucosal Healing
Treatment effect estimates come from Bayesian network meta-analysis. Odds ratios ⬎1.0 favor the treatment in the left upper square. To obtain ORs for comparisons in the opposite direction, reciprocals should be calculated. ADA ⫽ adalimumab; CrI ⫽ credible interval; GLM ⫽ golimumab; IFX ⫽ infliximab; OR ⫽ odds ratio; VDZ ⫽ vedolizumab.
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Appendix Table. AE Rates in RCTs of Biological Agents for Moderately to Severely Active Ulcerative Colitis* Event Rates, %
Outcome
Any AE SAEs AEs leading to discontinuation of study drug Infectious AEs Serious infection TB CHF
ADA Biological Group†
ADA Placebo Group†
IFX Biological Group‡
IFX Placebo Group‡
GLM Biological Group§
GLM Placebo Group§
VDZ Biological Group㥋
VDZ Placebo Group㥋
70.1 8.8 8.2
67.9 10.5 8.8
84.7 16.1 5.0
79.1 22.5 9.4
48.9 6.4 3.1
47.1 6.6 2.7
61.7 5.5 –
63.6 10.9 –
32.7 1.6 0.2 0.2
28.8 1.7 0.0 0.0
35.5 2.1 0.0 –
31.1 2.5 0.0 –
20.4 1.2 0.6 –
17.3 1.9 0.2 –
44.1 1.3 – –
40.4 2.5 – –
ADA ⫽ adalimumab; AE ⫽ adverse event; CHF ⫽ congestive heart failure; GLM ⫽ golimumab; IFX ⫽ infliximab; RCT ⫽ randomized, controlled trial; SAE ⫽ serious adverse event; TB ⫽ tuberculosis; VDZ ⫽ vedolizumab. * Event rates are based on the number of AEs in the included RCTs. The GEMINI 1 trial did not report TB or AEs leading to discontinuation of the study drug. Congestive heart failure was reported only in the ADA trials (ULTRA 1 and 2 [Ulcerative Colitis Long-Term Remission and Maintenance With Adalimumab 1 and 2] and the NCT00853099 trial). † Data for 1150 patients from 3 RCTs. ‡ Data for 486 patients from 2 RCTs. § Data for 971 patients from 2 RCTs. 㛳 Data for 747 patients from 1 RCT.
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20 May 2014 Annals of Internal Medicine Volume 160 • Number 10
