In clinical trials evaluating treatments for inflammatory bowel disease (IBD), patients receiving placebo experienced a significantly higher risk of adverse outcomes, according to two systematic reviews published in The Lancet Gastroenterology & Hepatology. The findings raise ethical questions about the continued use of placebo groups in IBD trials and suggest exploring alternative study designs.
Increased Risk with Placebo
One meta-analysis of 47 induction therapy trials, involving approximately 21,000 adults with moderate to severe IBD, demonstrated that patients on active treatment had a significantly lower risk of worsening disease activity compared to those receiving placebo (4.2% vs 8.5%; HR 0.48, 95% CI 0.40-0.59). The research was led by Alex Ford, MD, of St. James University Hospital.
Furthermore, the active treatment groups were significantly less likely to experience serious adverse events (4.8% vs 7.2%; HR 0.69, 95% CI 0.59-0.80) or venous thromboembolism (0.2% vs 0.4%; HR 0.45, 95% CI 0.21-0.94). The numbers needed to treat to avoid adverse events were 23 for worsening IBD activity and 452 for venous thromboembolism.
A second meta-analysis, encompassing 45 maintenance therapy trials with roughly 16,500 patients, yielded similar results. Patients receiving active treatment showed a significantly reduced risk of serious worsening of IBD, serious adverse events, and withdrawal due to adverse events.
Implications for Trial Design
The study authors suggest that these findings should prompt a re-evaluation of the current clinical trial model in IBD. They advocate for critical thinking regarding strategies to minimize placebo exposure and consideration of alternative trial designs for future IBD drug development. "These findings clearly show that in moderately to severely active ulcerative colitis and Crohn's disease, even over the relatively short duration of an induction of remission RCT, there were small but statistically significant harms associated with not receiving an active drug and being assigned to placebo," the authors wrote.
Potential alternative trial designs include platform studies, Bayesian analysis of existing data on expected placebo response rates, or open-label active treatment. The researchers noted that the harms associated with placebo were likely due to a lower risk of adverse outcomes in patients receiving an active drug, rather than a true increase in risk associated with receiving placebo.
Expert Commentary
Fernando Gomollón, MD, of Zaragoza University in Spain, highlighted the rising prevalence of IBD, potentially reaching 1% of the global population by 2030, in an accompanying editorial. He noted that the increased prevalence will drive further drug development and necessitate more clinical trials. However, the inclusion of a placebo group is a key factor for many patients declining to participate in clinical trials, obstructing recruitment processes and slowing down studies.
Gomollón emphasized that the information from these studies will be fundamental for the design of future trials in the field. "Moreover, considering these data for improving participant consent will be mandatory: patients and trialists should have access to them for making the right decisions."
Study Details and Limitations
The meta-analyses included randomized, placebo-controlled drug trials reporting data on adverse events in adults with moderate to severe ulcerative colitis or luminal Crohn's disease. The minimum treatment period was 4 weeks for induction therapy and 20 weeks for maintenance therapy. The investigators searched MEDLINE, the Cochrane Central Register of Controlled Trials, and other databases to identify relevant trials.
Both meta-analyses included only clinical trials of drugs shown to be effective for IBD, which may have overestimated the potential harm for patients in placebo groups. Additionally, not all adverse events associated with a placebo are captured over the course of a trial, especially if rare, and these events might not have been fully assessed.
