Inflammatory bowel disease maintenance of remission trials that use placebo controls are potentially harmful to patients, warranting counselling before trial entry and more serious consideration of alternative trial designs, researchers say.
Their systematic review and meta-analysis included 45 randomised placebo-controlled trials of licensed biologics and small molecules for maintenance of remission in 16,562 adults with IBD (62% receiving active drug, 38% placebo).
Half of the trials had defined exit strategies for patients not responding to placebo during the maintenance period, allowing access to an open-label active drug.
Findings showed the relative risk of any infection (39.9% vs 35.6%; RR 1.14) or drug-related adverse event (36.5% vs 31.2%; RR 1.24) was significantly higher in patients receiving an active drug compared with patients on placebo.
Treatment-emergent adverse events occurred in 76.4% and 75.5% (RR 1.01) of patients, respectively, serious infection occurred in 2.5% and 2.5% (RR 0.97) and venous thromboembolic events occurred in 0.25% and 0.33% (RR 0.72).
Importantly, patients receiving an active drug were significantly less likely to have any worsening of IBD activity (12.8% vs 22.8%; RR 0.58), withdrawal due to adverse events (5.9% vs 9.0%; RR 0.71), serious adverse events (10.4% vs 12.0%; RR 0.85), or serious worsening of IBD activity (1.8% vs 3.9%; RR 0.55).
Writing in the Lancet Gastroenterology and Hepatology [link here], the international group of researchers said there were also ethical concerns regarding re-randomisation trials requiring withdrawal of an active drug that appeared to be working as patients might have limited alternatives remaining.
“Furthermore, adverse events (eg, development of immunogenicity and hypersensitivity), especially with anti-TNF drugs, are more likely to occur when drug concentrations are low or if the active drug is interrupted, which are additional harms that patients receiving placebo after re-randomisation might encounter if they are exposed to anti-TNF drug in the future,” said the authors, which included Melbourne gastroenterologist Associate Professor Jonathan Segal.
“However, we acknowledge that several of these trials were done more than 20 years ago. At that time, many questions regarding the optimal use of these drugs, the risk of immunogenicity, and the required dose and length of therapy, were unanswered. These trials have, therefore, contributed to an improved understanding of how to use biologics and small molecules and have shaped clinical practice.”
The authors urged careful consideration of the need to reassess safety of a drug compared with placebo if safety had already been established in other conditions.
They also said while the default position for IBD trials remained placebo-controlled trials, other approaches, such as adaptive trial designs or stringent exit strategies for patients not responding to placebo, should be used to minimise harms.
“We advocate for robust conversations between regulatory organisations, industry, health-care providers and, more importantly, with patients to mitigate these harms, ensuring that future research endeavours in IBD prioritise patient safety while continuing to advance our understanding and treatment options in these complex diseases.”