Tag Archives: placebo

Moving Away From Placebo-Controlled Trials in Crohn’s Disease

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Din, Shahida et al. The Lancet Gastroenterology & Hepatology; 2024: DOI: 10.1016/S2468-1253(24)00264-4.  Open Access! Harms with placebo in trials of biological therapies and small molecules as induction therapy in inflammatory bowel disease: a systematic review and meta-analysis

Background: “Placebo-controlled trials are especially important during the early phases of drug development, as use of placebo aids early detection of efficacy or futility.”

Methods: The authors performed a systematic review which identified 47 trials including 20,987 patients (14 267 [68·0%] receiving active drug and 6720 [32·0%] receiving placebo) were eligible. The studies involved multiple RCTs of biologics and small molecules in IBD.

Key findings:

  • The risks of worsening of IBD activity (Active treatment vs placebo: 563/13,473 [4·2%] vs 530/6252 [8·5%];RR 0·48)
  • Withdrawal due to adverse event (Active treatment vs placebo: 401/13 363 [3·0%] vs 299/6267 [4·8%]; RR 0·62)
  • Serious adverse event (Active treatment vs placebo: 682/14,267 [4·8%] vs 483/6720 [7·2%]; RR 0·69)
  • Serious infection (Active treatment vs placebo: 140/14 ,194 [1·0%] vs 91/6647 [1·4%]; RR 0·67)
  • Serious worsening of IBD activity (Active treatment vs placebo: 187/11,271 [1·7%] vs 189/5056 [3·7%]; RR 0·4)
  • VTEs (Active treatment vs placebo: 13/7542 [0·2%] vs 12/2981 [0·4%]; RR 0·45)
  • All of these adverse outcomes were significantly lower with active drug than placebo. 

My take: Now that there are proven medications that are effective for moderate-to-severe Crohn’s disease, head-to-head trials of novel drugs against existing drugs with proven efficacy, rather than placebo-controlled trials, should be prioritized.

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Windy day at Isle of Palms, SC. There streams of sand flowing over the beach.

Good Study, Bad Practice: Placebo for IBS and Functional Abdominal Pain

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Have a great day (Mt Yonah, Cleveland GA)

S Nurko et al. JAMA Pediatr. 2022;176(4):349-356. doi:10.1001/jamapediatrics.2021.5750. Adolescents With Functional Abdominal Pain or Irritable Bowel Syndrome

Design: Patients completed 1 week of observation prior to randomization to 1 of 2 counterbalanced groups: OLP for 3 weeks followed by a 3-week control period or control period for 3 weeks followed by OLP for 3 weeks. During the OLP period, participants took 1.5 mL of an inert liquid placebo twice a day.

Key findings:

  • The mean (SD) pain scores were significantly lower during open label placebo (OLP) treatment compared with the control period (39.9 [18.9] vs 45.0 [14.7]; difference, 5.2; 95% CI, 0.2-10.1; P = .03)
  • Patients took nearly twice as many hyoscyamine pills during the control period compared with during the OLP period (mean [SD] number, 3.8 [5.1] pills vs 2.0 [3.0] pills; difference, 1.8 pills; 95% CI, 0.5-3.1 pills)

My take: It is a mistake to consider placebo as a treatment for functional abdominal pain. In many children, pain fluctuates and may improve with reassurance, distraction, healthier diets, and physical activity. However, we also need more effective therapies including pain psychology, dietary approaches and medications. The idea that placebo helps is misleading and undermines the fact that patients with functional disorders need effective treatment.

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How to Get Rid of the Placebo Effect in Inflammatory Bowel Disease Trials

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A recent study (M Duijvestein et al. Clin Gastroenterol Hepatol 2020; 18: 1121-32, editorial 1030-32) analyzed data from recent randomized, double-blind, placebo-controlled trials for Crohn’s disease (CD).  In these induction trials fro eldelumab, filgotinib, risankizumab, and ustekinumab, the authors found very low rates of placebo response (n=188 in placebo arms).

Key findings:

  • Based on endoscopic assessment of CD activity, response rate to placebo was 16.2%; response indicated >50% reduction in the simple endoscopic score for CD.
  • The rate of remission was 5.2%
  • Even lower rates of response were noted in those with elevated CRP at baseline (OR 0.93) and those with history of anti-TNF therapy (OR 0.31)

Commentary:

  • The key to lowering the placebo response are to use objective biologic markers rather than relying exclusively on clinical symptoms.
  • Central reading of endoscopic endpoints also is thought to minimize placebo effect
  • The editorial notes that the use of placebo in clinical trials “must be justified by the importance of the additional scientific value gained, and placebo should be used in trials only if there is genuine equipoise between the active treatment and placebo.”
  • “Because of ethical questions concerning placebo and the emergence of head-to-head trials, placebo arms may disappear from future IBD trials.”

My take: In reality, very few individuals with CD improve without adequate treatment.  Use of objective criteria is crucial to finding out what really works, both in clinical trials and in clinical practice.

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