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.

Related blog posts:

Is It Safe for Me to Go to Work?

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Just for fun —YouTube (~3 minute video): The Swish Machine: 70 Step Basketball Trickshot (Rube Goldberg Machine)

Full text —MR Larochelle. DOI: 10.1056/NEJMp2013413. NEJM: Is It Safe for Me to Go to Work?

An excerpt:

I believe that a strategy to protect at-risk workers needs at least three components: a framework for counseling patients about the risks posed by continuing to work, urgent policy changes to ensure financial protections for people who are kept out of work, and a data-driven plan for safe reentry into the workforce…

The Occupational Safety and Health Administration has published guidance and proposed a scheme for classifying the risk of SARS-CoV-2 infection as high, medium, or low based on potential contact with persons who may or do have the virus (www.osha.gov/Publications/OSHA3990.pdf. opens in new tab). Low-, medium-, and high-risk categories of individual risk of death from Covid-19 are based on age and the presence of high-risk chronic conditions identified by the CDC…

As states move to reopen their economies, millions of nonessential employees will join essential employees in putting themselves at risk for contracting SARS-CoV-2 at work. Physicians should engage patients in individualized risk assessments. Our society has the moral imperative and means to provide vulnerable employees a financial safety net until we can better ensure their workplace safety.

Related blog post: @Atul_Gawande: How to Reopen

“Coronavirus Disease 2019 and the Pediatric Gastroenterologist”

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Full Text: KF Murray, BD Gold, R Shamir et al. JPGN 2020; 70: 720-6. Coronavirus Disease 2019 and the Pediatric Gastroenterologist. This article includes CME availability too!

Some excerpts:

  • The latest global count updates can be found at: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports/.
  • SARS-CoV-2 is a positive-sense, single-stranded RNA virus belonging to the genus Betacoronavirus, and phylogenetically related (88%–89% similarity) to the two bat-derived SARS-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21….
  • Routine gastroenterology practice poses increased risk of exposure and potential viral transmission during ambulatory interaction, especially during endoscopic procedures…
  • The use of telemedicine is now a critical tool for the pediatric gastroenterologists and their patients, whether in the academic setting or private practice…The recently published AAP guideline, entitled Telehealth Payer Policy in Response to COVID-19 (https://downloads.aap.org/DOPA/Telehealth_2_rev.pdf and https://www.aap.org/en-us/professional-resources/practice-transformation/telehealth/Pages/compendium.aspx), which outlines policy changes aiming to alleviate barriers to telehealth care, along with a webinar on telehealth and guidance on structuring your practice during the pandemic are tools that can be employed in both the academic and private practice pediatric gastroenterologist office to facilitate ongoing quality care of their patients

My take: This article provides a concise update and numerous resources.  As the information about the coronavirus is rapidly changing, the recommendations will continue to evolve.

Also, JPGN has a large number of articles available on its COVID-19 page: Link: COVID-19 page This page includes articles related to endoscopy, PPE, telemedicine, and central line infections.  Also, based on a personal communication, there will be a link to a recently published article soon on “Pediatric Crohn’s Disease and Multisystem Inflammatory Syndrome in Children (MIS-C) and COVID-19 Treated With Infliximab.”(Dolinger M T, Person H, Smith R, et al. Journal of Pediatric Gastroenterology & Nutrition 2020;  PMID: 32452979 DOI: 10.1097/MPG.0000000000002809)

“Channelopathy of the Pancreas Causes Chronic Pancreatitis” and SARS-CoV-2 in Sewage

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Interesting article: Full Text: SARS-CoV-2 RNA concentrations in primary municipal sewage sludge as a leading indicator of COVID-19 outbreak dynamics 

___________________________________________________________________

M Sahin-Toth. Gastroenterology 2020; 158: 1538-40. Full Text Link: Channelopathy of the Pancreas Causes Chronic Pancreatitis

Excerpt from editorial:

In this issue of Gastroenterology, Masamune et al report a landmark discovery, the genetic association of functionally defective TRPV6 channel variants and chronic pancreatitis. The authors investigated the TRPV6 gene in Japanese and European patients with nonalcoholic chronic pancreatitis using targeted sequencing followed by functional analysis of the identified variants. In the Japanese discovery cohort, they found functionally defective variants in 4.3% of the patients and in 0.1% of the controls (odds ratio 48). In the European replication cohort, 2% of the patients carried a defective variant and none was found in controls.

Original research study: A Masamune et al. Gastroenterology 2020; 158: 1626-41. Full text: Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis

An excerpt:

TRPV6 variants are globally associated with early-onset nonalcoholic CP. To our knowledge, TRPV6 is a novel pancreatitis-associated gene beyond the pancreatic digestive enzyme/enzyme inhibitor system, and it is the first gene that directly regulates Ca2+ homeostasis. Our findings open a completely new avenue by emphasizing the potential role of ductal cells and, especially, calcium channels in the pathophysiology of pancreatitis, which might lead to the development of personalized medicine targeting TRPV6 channel activity.

From editorial by Sahin-Toth

Visual abstract for research study by Masamne et al.

 

Rifabutin-based Triple Therapy for H pylori

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From NEJM Journal Watch (5/8/20): A New First-Line Treatment Regimen for H. pylori Infection

In this industry-funded, phase III trial conducted in the U.S., 455 H. pylori-treatment–naive patients with dyspepsia and a confirmed H. pylori diagnosis were randomized to treatment with capsules containing rifabutin, amoxicillin, and omeprazole or capsules containing amoxicillin and omeprazole for 14 days. Participants took 4 capsules every 8 hours. The eradication rate in the rifabutin-based therapy group was significantly higher (84%) compared with the comparison group (58%). In patients with confirmed adherence to treatment, the eradication rates were 90% versus 65%, respectively. No H. pylori resistance to rifabutin was detected, and side effects were similar between groups.

My take: More treatment options are needed due to drug resistance.  Also, “further studies are needed to compare this new triple therapy with current quadruple therapies.”

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@AllergyKidsDoc: Deep Down the Rabbit Hole of Bias, Plus Two

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NPR: From Camping To Dining Out: Here’s How Experts Rate The Risks Of 14 Summer Activities

This article describes the potential risks for dining out, staying at hotels, getting a haircut (ask your stylist to focus on cutting and not talking), going to the beach/pool and other activities.

Moving NY Times Graphic on coronavirus toll in U.S. (May 24, 2020): An Incalculable Loss: Remembering the Nearly 100,000 Lives Lost to Coronavirus in America

A recent lecture by Dave Stukus: Deep Down the Rabbit Hole of Biases, Conspiracies, and Echo Chambers (50 minutes). Thanks to Ben Gold for this reference.

This lecture summarizes some of the challenges of misinformation and quackery.

Some interesting points:

  • Explains common biases which lead us to faulty conclusions
  • Illustrates some far-fetched claims for Himalayan Salt Lamp as a treatment for asthma as well as Dr. Oz’s unproven recommendations for the coronavirus
  • Provides several books for those interested in learning a lot more (see last slide)

Some slides:

 

 

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Not Curing Obesity with Fecal Microbiota Transplantation & More on Remdesivir

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A recent pilot (n=22) double-blind study (JR Allegrett et al. Clin Gastroenterol Hepatol 2020; 18: 855-63) pours cold water on the idea that repopulating one’s microbiome would be helpful in treating obesity.

In this study, the authors examined obese patients without diabetes, nonalcoholic steatohepatitis, or metabolic syndrome.  In the treatment group, patients received FMT by capsules: 30 capsules at week 4 and then a maintenance dose of 12 capsules at week 8.  All FMT was derived from a single lean donor.

Key findings:

  • There were no significant changes in mean BMI at week 12 in either group.
  • Patients in the FMT group had sustained shifts in microbiomes associated with obesity toward those of the donor (P<.001).  In addition, bile acid profiles became more similar to the donor.

My take: Though this was a small study, it suggests that changing the microbiome by itself is likely insufficient to result in significant weight loss.

Related blog posts:

JH Beigel et al. NEJM DOI: 10.1056/NEJMoa2007764 (May 22, 2020): Full text: Remdesivir for the Treatment of Covid-19 — Preliminary Report

This was a a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement (n=1063).

Key findings:

  • Faster recovery for remdesivir recipients: 11 days vs 15 days
  • Lower mortality rate: 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70, 95% CI, 0.47 to 1.04) (mortality difference did not reach statistical significance)

 

 

Prevalence of Rome IV Functional Bowel Disorders in Adults (US, UK, Canada) & Largest Study to Date on Hydroxychloroquine for COVId-19

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OS Palsson et al. Gastoenterol 2020; 158: 1262-73.  The authors note that the switch from Rome III to Rome IV criteria reduces the prevalence of IBS by half, but increases the prevalence of functional constipation and functional diarrhea.

Full text PDF: Prevalence of Rome IV Functional Bowel Disorders Among Adults in the United States, Canada, and the United Kingdom

Abstract

BACKGROUND & AIMS:

Little is known about the population prevalence or demographic distributions of Rome IV functional bowel disorders (FBDs) or their effects on quality of life. We examined these in a multinational survey.

METHODS:

We analyzed data from a population-based [online] survey of adults in the United States, Canada, and United Kingdom (5931 valid responders; 49.2% female; mean age, 47.4 years; range, 18-92 years). The survey included the Rome IV Diagnostic Questionnaire, Rome III irritable bowel syndrome (IBS) and constipation questions, and the SF-8 quality of life questionnaire.

RESULTS:

The prevalence values of census-adjusted Rome IV FBDs were similar among the 3 countries; ranges were: 4.4%-4.8% for IBS, 7.9%-8.6% for functional constipation, 3.6%-5.3% for functional diarrhea, 2.0%-3.9% for functional bloating or distention, 1.1%-1.9% for opioid-induced constipation, 7.5%-10.0% for unspecified FBDs, and 28.6%-31.7% for any Rome IV FBD. FBDs were less common in older individuals, and all except functional diarrhea were more common in women. IBS was only half as prevalent by Rome IV as by Rome III criteria (4.6% vs 9.0% overall), primarily due to higher Rome IV minimum pain frequency. Functional diarrhea and functional constipation were more prevalent by Rome IV than Rome III criteria. Subjects with FBD had significant reductions in quality of life and reported more gastrointestinal doctor consultations than other subjects.

CONCLUSIONS:

More than 1 in 4 adults in the general population meet the Rome IV criteria for FBDs. These disorders affect quality of life and increase use of gastrointestinal health care. The switch from Rome III to Rome IV criteria reduces the prevalence of IBS by half, but increases the prevalence of functional constipation and functional diarrhea.

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From @EricTopol: Just published @TheLancet The largest study of hydroxychloroquine shows a significant increase in death (~35%) and >2-fold increase of serious heart arrhythmias. ~96,000 patients, ~15,000 on HCQ or CQ from 671 hospitals, 6 continents.

More Jokes: