Placebo response and remission rates in randomised trials of induction and maintenance therapy for ulcerative colitis

Jairath V, Zou G, Parker CE, MacDonald JK, AlAmeel T, Al Beshir M, Almadi MA, Al-Taweel T, Atkinson NSS, Biswas S, Chapman T, Dulai PS, Glaire MA, Hoekman DR, Koutsoumpas A, Minas E, Mosli MH, Samaan M, Khanna R, Travis S, D'Haens G, Sandborn WJ, Feagan BG

What is ulcerative colitis?

Ulcerative colitis (UC) is a recurrent, chronic inflammatory bowel disease that usually affects the large intestine (colon). Symptoms include abdominal pain, urgency to pass stools, bloody diarrhoea, weight loss and fatigue. When symptoms stop patients are considered to be in remission. Clinical trials for UC are usually designed to assess whether a drug treatment brings about a clinical response (an improvement of disease symptoms) or remission (typically measured within eight weeks of treatment) or helps to maintain a clinical response or remission over a longer period of time (typically measured after one year of treatment).

What is the placebo effect?

The placebo effect occurs when a patient experiences an actual or perceived improvement in health after receiving a dummy (non-active) treatment. The factors influencing this are not completely understood but may be due to the psychological effect of receiving treatment, rather than the treatment itself. Understanding the size of the placebo effect and the factors that influence it is important, because the placebo response rate is used to calculate the number of patients needed when designing a clinical trial of new drug treatment. Ideally when designing a clinical trial researchers aim to minimize the size of the placebo effect to best detect the true difference between the active drug and dummy treatment with the minimum number of patients. This means that clinical trials, which are costly to conduct, could be designed with fewer numbers of patients, greater efficiency, lower cost and ultimately bring new drugs to patients more quickly.

What did the researchers investigate?

The researchers reviewed published randomised placebo-controlled trials in UC of several classes of drugs to quantify what the placebo response rates were overall, and how these response rates have evolved over time. They also investigated how factors related to the study design, participants, treatments or outcomes influenced the placebo rates in UC trials. The medical literature was searched and analysed up to 1 March 2017.

What did the researchers find?

Sixty-one trials were included which evaluated 58 induction phases (5111 patients randomised to placebo) and 12 maintenance phases (1579 patients randomised to placebo). The researchers found that placebo response and remission rates varied according to which class of drug was being tested with the highest placebo response rates observed for biological drugs (genetically engineered medications made from living organisms). The highest placebo remission rates were observed for trials evaluating aminosalicylates (a type of anti-inflammatory drug). The lowest placebo response and remission rates were in trials that assessed corticosteroids (drugs that suppress inflammation and immunity). The requirement of a minimum rectal bleeding score for study eligibility was associated with an increased placebo response rate compared to studies that did not use rectal bleeding for trial eligibility. The time point of primary outcome assessment was found to be significantly associated with placebo remission rates such that every one week increment in endpoint assessment was associated with an increase in the placebo remission rate. There were several trial design features that were associated with lower placebo response and remission rates. A key finding was that trials enrolling patients with more severe endoscopic disease (i.e. inflammation of the colon as confirmed by a colonoscopy) at trial entry were associated with lower placebo response and remission rates, which underpins the importance of objectively ensuring that patients enrolled into UC trials have sufficient disease severity. Disease duration of greater than five years prior to trial enrolment was associated with a significantly lower placebo response rate compared to disease duration of less than or equal to five years. The researchers also found that placebo rates have remained stable from 2008 to 2015.

In conclusion, placebo response and remission rates vary according to endoscopic disease severity and rectal bleeding score at trial entry, drug class, disease duration, and the time point at which the primary outcome was measured. The overall findings will help researchers conducting trials to design their studies, determine the number of patients required for their planned trials and also provide useful information about trial design features which should be considered when planning new trials.

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