Y-ECCO Literature Review: Samuel Majna
Harms with placebo in trials of biological therapies and small molecules as maintenance therapy in inflammatory bowel disease: a systematic review and meta-analysis
Gros B, Blackwell J, Segal J, et al.
Lancet Gastroenterol Hepatol 2024;9:1030–40.
Introduction
Although the estimated life expectancy of people with inflammatory bowel disease (IBD) in developed countries is nowadays almost the same as for healthy populations [1, 2], IBD and associated complications may still be life threatening—especially in cases without suitable treatment. After many years of few effective treatment options, the number of drugs approved for the treatment of IBD is gradually rising [3]. Along with the widening of therapeutic options, there have been significant advances in treatment strategies and therapeutic goals [4, 5]. Broadly, the performance of placebo-controlled trials has in the past been considered justified in cases where there are no treatments of high efficacy, where a common standard of care is lacking or when the standard of care can result in unacceptable levels of toxicity [6]. However, in the face of progress/improvements in IBD care, it has increasingly been questioned whether the widespread ongoing use of placebo-controlled trials in IBD is still appropriate. Gros and colleagues aimed to examine the potential harms associated with receiving a placebo in trials of licensed biologics and small molecules for maintenance of remission of Ulcerative Colitis (UC) and luminal Crohn’s Disease (CD).
Methods and key findings
Gros and colleagues conducted a systematic review and meta-analysis. They searched through multiple databases from their inception to May 31, 2024, looked for unpublished trials and supplementary data and also investigated conference proceedings to identify trials published only as abstracts. Randomised controlled trials (RCTs) were selected which assessed the efficacy of biological therapies and small molecules for maintenance of IBD remission at the doses taken through into phase 3 clinical trials and in addition reported detailed adverse events. Included RCTs had to randomly assign participants to active drug or placebo at baseline. Trial designs which included subsequent re-randomisation or those without re-randomisation (treat-through), were both included. RCTs needed to recruit ambulatory adult patients (at least 16 years old) with UC or CD and compare biological therapies or small molecules with placebo over a period of 20 weeks or more. Outcomes of interest were any treatment-emergent adverse event, any drug-related adverse event, any infection, any worsening of IBD activity, any withdrawal due to adverse events, any serious adverse event, any serious infection, any serious worsening of IBD activity and any venous thromboembolic event (VTE).
Forty-five RCTs were included (24 RCTs in UC and 21 RCTs in CD) with a total of 16,562 participants, comprising 10,319 (62.3%) randomly assigned to the active drug and 6243 (37.7%) randomly assigned to a placebo.
In total, 7297 (76.4%) of 9546 patients receiving the active drug had any treatment-emergent adverse event (AE), compared with 4415 (75.5%) of 5850 patients receiving placebo (RR 1.01, 95% CI 0.99–1.04, I2=47%). Results were similar for trials in CD and UC. According to 15 trials providing data for any drug-related AEs, 1094 (36.5%) of 2997 patients receiving active drug had any drug-related AE vs 609 (31.2%) of 1950 patients receiving placebo (RR 1.24, 95% CI 1.02–1.50; I2=75%).
According to 38 trials, 3208 (39.9%) of 8038 patients receiving active drug had any infection, compared with 1713 (35.6%) of 4809 patients receiving placebo (RR 1.14, 95% CI 1.05–1.23; I2=60%). The RR of infection was significantly higher with active drug in trials of both designs (treat-through or randomised) in UC, but not in CD. Otherwise, when looking at the data for serious infections, 260 (2.5%) of 10,242 patients receiving active drug had any serious infection, compared to 155 (2.5%) of 6149 patients receiving a placebo (RR 0.97, 95% CI 0.79–1.19; I2=0%).
Overall, 1038 of 8090 patients (12.8%) receiving active drug had any worsening of IBD activity, compared to 1181 of 5191 patients (22.8%) receiving placebo (RR 0.58, 95% CI 0.52–0.64; I2=40%). One hundred and one (1.8%) of 5707 patients receiving active drug had any serious worsening of IBD activity, compared with 143 (3.9%) of 3640 receiving placebo (RR 0.55, 95% CI 0.42–0.71; I2=0%).
Overall, 610 of 10,282 (5.9%) participants receiving active drug had to withdraw due to an adverse event, compared with 561 of 6207 (9.0%) participants receiving placebo (RR 0.71, 95% CI 0.60–0.84; I2=43%). Altogether 1066 (10.4%) of 10,292 patients on active drug had any serious adverse event compared with 742 (12.0%) of 6198 patients on placebo (RR 0.85, 95% CI 0.77–0.94; I2=17%). VTE risk was low, with 12 (0.25%) of 4729 patients receiving active drug having a VTE, compared with 9 (0.33%) of 2691 patients receiving placebo (RR 0.72, 95% CI 0.31–1.66; I2=0%).
In summary, although risk of infection or drug-related AE was higher in patients receiving active drug, the risks of placebo included worsening of IBD activity, serious worsening of IBD activity, trial withdrawal due to AEs and more serious AEs.
Discussion
It is important to highlight the pivotal role of placebo-controlled RCTs to date in providing evidence to support the use of current therapies in IBD. On the other hand, there are clear ethical issues associated with the provision of placebo with no active treatment, bearing in mind the increasing number of safe and effective treatment options in IBD.
The findings from Gros and colleagues are even more stark when considering recent evidence that inadequate control of inflammation is the key driver of complications and worse outcomes in IBD, including higher risk of flares, infections, hospitalisations and surgeries with inadequately controlled inflammation [7]. It is also important to consider that there is an increasing number of trial design options that can help to minimise placebo exposure for patients. These include, among many others, the use of open-label active drug comparator groups for patients, either from the outset or for those who do not show a prompt response to the therapy. It might also be possible to use historical control information obtained from patients assigned to the placebo group in previous trials, either generated from meta-analyses or potentially using Bayesian statistical methods. A further promising approach that could combine some or all of the above options would be to increase the use of master protocol trials [8], i.e. clinical trials where more than one primary research question can be answered within a trial protocol.
This systematic review and meta-analysis did not consider early-phase trials and clinical trials conducted for therapies which did not subsequently become licensed—an important limitation because for most clinical trials it is not possible to determine at the outset whether the therapy will demonstrate sufficient efficacy and safety for data to be used for licensing purposes.
Conclusion
The authors of this study demonstrate the potential harms of using a placebo control arm in RCTs in maintenance therapy, building on previous evidence showing potential harms also in the induction phase of IBD trials [9]. However, it is crucial to appreciate that this systematic review did not include clinical trials conducted for therapies which did not subsequently become licensed. This article highlights the importance of engaging all relevant stakeholders in the IBD field to work together and improve the design of clinical trials, including consideration of novel strategies and innovative designs to help minimise exposure to placebo for patients taking part in IBD clinical trials.
References
- Kuenzig ME, Manuel DG, Donelle J, Benchimol EI. Life expectancy and health-adjusted life expectancy in people with inflammatory bowel disease. CMAJ 2020;192:1394–1402.
- Gros B, Kaplan GG. Ulcerative colitis in adults: a review. JAMA 2023;330:951–65.
- Zurba Y, Gros B, Shehab M. Exploring the pipeline of novel therapies for inflammatory bowel disease; state of the art review. Biomedicines 2023;11:747.
- Peyrin-Biroulet L, Sandborn W, Sands BE, et al. Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining therapeutic goals for treat-to-target. Am J Gastroenterol 2015;110:1324–38.
- Turner D, Ricciuto A, Lewis A, et al. STRIDE-II: An update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative of the International Organization for the Study of IBD (IOIBD): Determining therapeutic goals for treat-to-target strategies in IBD. Gastroenterology 2021;160:1570–83.
- Sachar DB. Placebo-controlled clinical trials in gastroenterology. A position paper of the American College of Gastroenterology. Am J Gastroenterol 1984;79:913–7.
- Noor NM, Lee JC, Bond S, et al. A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open-label randomised controlled trial. Lancet Gastroenterol Hepatol 2024;9:415–27.
- Honap S, Sands BE, Jairath V, Danese S, Vicaut E, Peyrin-Biroulet L. Basket, umbrella, and platform trials: The potential for master protocol-based trials in inflammatory bowel disease. Gastroenterology 2024;167:636–42.
- Din S, Segal J, Blackwell J, Gros B, Black CJ, Ford AC. Harms with placebo in trials of biological therapies and small molecules as induction therapy in inflammatory bowel disease: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2024;9:1020–9.
Profile
Samuel Majna is a clinical fellow at the Department of Gastroenterology, Bezrucova Clinic in Bratislava, Slovakia, and a PhD student at Comenius University in Bratislava. His main interests are endoscopic therapy of strictures caused by IBD and the potential role of dietary interventions and microbiome modulation in the treatment of IBD.