Are We Ready to Abandon Placebo in Randomised Clinical Trials for Inflammatory Bowel Disease? Pros and Cons.

The role of placebo in clinical trials for drug development in inflammatory bowel disease [IBD] was the topic of a panel discussion held during the 10th Congress of the European Crohn's and Colitis Organisation [ECCO], in Barcelona, Spain, in 2015. Panellists discussed a number of issues around placebo-controlled trials in IBD, noting issues such as difficulties with recruitment, leading to less then representative patient populations in clinical studies. It was noted that, whereas the easiest answer may be to drop placebo, it is much more complicated than that. The relevance of placebo is affected by a number of factors, including the phase of the trial, as well as the nature of the drug. In most cases where placebo has been left out in drug development, it has been for trials involving a new formulation, a new dosing schedule, or a biosimilar, for example. The panel agreed that placebo-controlled trials are of particular importance early in the development programme, perhaps not so much in phase III, although placebo is important for monitoring safety. The current trial paradigm, in which patients remain on a plethora of, likely ineffective and toxic, background medication, was also questioned. The applicability of placebo in the paediatric population was also discussed. The overall consensus from this panel discussion was that placebo is still necessary in clinical trials in inflammatory bowel disease, but there remain questions as to how and when placebo should be used.

Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study.

OBJECTIVE: Budesonide MMX is a novel oral formulation of budesonide that uses Multi-Matrix System (MMX) technology to extend release to the colon. This study compared the efficacy of budesonide MMX with placebo in patients with active, mild-to-moderate ulcerative colitis (UC). DESIGN: Patients were randomised 1:1:1:1 to receive budesonide MMX 9 mg or 6 mg, or Entocort EC 9 mg (budesonide controlled ileal-release capsules; reference arm) or placebo once daily for 8 weeks. The primary endpoint was combined clinical and endoscopic remission, defined as UC Disease Activity Index score ≤1 with a score of 0 for rectal bleeding and stool frequency, no mucosal friability on colonoscopy, and a ≥1-point reduction in endoscopic index score from baseline. RESULTS: 410 patients were evaluated for efficacy. Combined clinical and endoscopic remission rates with budesonide MMX 9 mg or 6 mg, Entocort EC and placebo were 17.4%, 8.3%, 12.6% and 4.5%, respectively. The difference between budesonide MMX 9 mg and placebo was significant (OR 4.49; 95% CI 1.47 to 13.72; p=0.0047). Budesonide MMX 9 mg was associated with numerically higher rates of clinical (42.2% vs 33.7%) and endoscopic improvement (42.2% vs 31.5%) versus placebo. The rate of histological healing (16.5% vs 6.7%; p=0.0361) and proportion of patients with symptom resolution (23.9% vs 11.2%; p=0.0220) were significantly higher for budesonide MMX 9 mg than placebo. Adverse event profiles were similar across groups. CONCLUSION: Budesonide MMX 9 mg was safe and more effective than placebo at inducing combined clinical and endoscopic remission in patients with active, mild-to-moderate UC.

A health economic model to assess the long-term effects and cost-effectiveness of orlistat in obese type 2 diabetic patients.

OBJECTIVES: Obesity is a common condition in type 2 diabetic patients. Treating obesity may enhance hypoglycemic treatment and contribute to the reduction of long-term microvascular and macrovascular complications. Orlistat reduces cardiovascular risk factors in obese type 2 diabetic patients. The objectives of this study were to estimate the long-term clinical consequences of this weight loss and the resulting cost-effectiveness of treating obese type 2 diabetic patients with orlistat. RESEARCH DESIGN AND METHODS: A Markov model was developed to predict, over a 10-year period, the complication rates and mortality with and without a 2-year orlistat treatment, assuming a 5-year catch-up period after treatment. A stepwise approach was used to obtain the clinical data. First, the impact of weight loss with orlistat on HbA(1c), blood pressure, and cholesterol was assessed; then, the impact on mortality and micro- and macrovascular complications of decreasing these risk factors was applied. Four subgroups were studied based on the presence of risk factors. RESULTS: Cost-effectiveness varies between 3,462 Euro/life-year gained (LYG) for obese diabetic patients with hypertension and hypercholesterolemia and 19,986 Euro/LYG for obese diabetic patients without other risk factors. The latter result is not robust according to sensitivity analyses. CONCLUSIONS: Our results suggest that orlistat is cost-effective in the management of obese type 2 diabetic patients, especially in those with the presence of hypercholesterolemia and/or hypertension. Evidence on longer-term benefits of orlistat (>2 years) will be of importance for future decision-making.