Rifaximin and Misoprostol Combination Therapy for Healing of Small Bowel Ulcers in Aspirin Users

Rifaximin and Misoprostol Combination Therapy for Healing of Small Bowel Ulcers in Aspirin Users With Small Bowel Bleeding: A Double Blind Randomized Trial

Background: Investigators have previously shown that misoprostol can heal small bowel ulcers in aspirin users with small bowel bleeding. However, the rate of small-bowel mucosal healing was low with use of misoprostol alone. There is evidence to suggest that bacteria contribute to the development aspirin-induced ulcers and antibiotics may be useful in its treatment. Rifaximin, a non-absorbed oral antibiotic that target the gastrointestinal tract have been shown to be safe and effective in a few other gastrointestinal conditions.

Small bowel capsule is the most sensitive and non-invasive way to investigate the small bowel. It plays an important role in obscure GIB investigations.

Aims: The aim of this randomized study is to test the hypothesis that misoprostol combined with rifaximin is superior to misoprostol alone for healing of small bowel ulcers in aspirin users complicated by small bowel bleeding.

Study design: 8-week double-blind randomized trial

Study Overview

• Status: Recruiting
• Conditions: Small Bowel Disease; Rifaximin
• Intervention / Treatment: Drug: Rifaximin; Drug: Placebo oral tablet

Detailed Description

Aspirin is one of the most commonly prescribed drugs worldwide It is widely used as the first line agent for prevention and treatment of heart diseases and stroke. It is well recognized that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are associated with risk of upper gastrointestinal (the stomach) bleeding. It is increasingly recognized to have adverse effects in the small bowel, including ulcers resulting in bleeding.

Bleeding from the small bowel has been very difficult to diagnose as it is beyond the reach of the conventional endoscopy. But with advances in endoscopic technique, video capsule endoscopy is now available to visualize the whole of the digestive tract. Capsule endoscopy is the size and shape of a pill which contains a tiny camera. After ingesting the capsule, pictures are taken inside of the gastrointestinal tract. Capsule endoscopy is now recommended to be a noninvasive test to identify source of small bowel bleeding.

Investigators have recently shown that misoprostol can heal small bowel ulcers in aspirin users with small bowel bleeding. However, the complete healing rate with misoprostol alone was only 40%. This suggests that we should continue to investigate for additional therapies in order to achieve higher success rate of healing of aspirin-induced small bowel ulcers.

Rifaximin is a non-absorbed oral antibiotic that targets the gastrointestinal tract. It was first described in 1982 and introduced into the Italian market 5 years later. Since then, rifaximin has had U.S. Food and Drug Administration (FDA) approval for treatment of travellers' diarrhea (year approved = 2004), hepatic encephalopathy (year approved=2010), irritable bowel syndrome (IBS) with diarrhea (year approved= 2015). Unlike the systematically available antibiotics, it allows localized enteric targeting of pathogens and is associated with minimal risk of systemic toxicity or side effects. In addition, the restricted use of non-absorbed oral antibiotics should also reduce the development of wide spread resistance.

The aim of this study is to test the hypothesis that the combination therapy of rifaximin and misoprostol is superior to misoprostol alone for healing of small bowel ulcers in aspirin users complicated by small bowel bleeding.

Participants are invited to this study because some predefined lesions are detected by the small bowel capsule endoscopy. Participants will be randomly assigned to receive either a combination therapy of misoprostol and rifaximin or misoprostol and rifaximin placebo for 8 weeks. Participants will be contacted by telephone after 1 week for any adverse events. Participants will then return at Week 8 to undergo a follow-up capsule endoscopy. Lab tests, drug compliance, and adverse events will be assessed.

• Study Type: Interventional
• Enrollment (Anticipated): 78
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Jessica CHING, MPH; Phone Number: +852 3505 3524; Email: jessicaching@cuhk.edu.hk
• Study Contact Backup: Name: Pui Kuan Cheong, MPH; Phone Number: +852 3505 3476; Email: jcheong@cuhk.edu.hk

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 000
      • Recruiting
      • Beijing Friendship Hospital, Capital Medical University
      • Contact: Rui Cheng, MD; Phone Number: 86-15901103303; Email: 15901103303@163.com
• Hong Kong
  • Hong Kong, Hong Kong, 000
    • Recruiting
    • Prince of Wales Hospital
    • Contact: Pui Kuan Cheong, MPH; Phone Number: 852-35053476; Email: jcheong@cuhk.edu.hk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Suspected small bowel overt bleeding - melena or hematochezia with or without a source of bleeding from gastroscopy and colonoscopy or suspected small bowel occult blood loss - defined as a significant decrease in hemoglobin (> 2g/dL), without a source of bleeding from gastroscopy and colonoscopy, confirmed iron deficiency anemia, and absence of other identifiable causes for hemoglobin decrease (e.g. fluid overload, progressive renal failure, malnutrition, or other hematological disorders such as hemolysis or malignancies)
• Continuous use of aspirin for the duration of the trial
• Age ≥ 18
• Written informed consent obtained

Exclusion Criteria:

• Increased risk of capsule retention (e.g. gastric outlet obstruction, bypass surgery, Crohn's disease or suspected small bowel stricture)
• Abnormal findings on gastroscopy that may account for bleeding episode: clean-based ulcer >2 cm or >5 erosions, esophageal varices, grade C or D erosive esophagitis, vascular malformations
• Unable to swallow the capsule endoscopy
• Terminal illness
• Concomitant use of NSAIDs, sucralfate, rebamepide, antibiotics, corticosteroids (prednisolone >7.5 mg daily or equivalent), and iron supplement
• Pregnancy (except LMP within 7 days) or women of child-bearing age without regular use of contraception
• Contraindications to colonoscopy or capsule endoscopy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Rifaximin; ASA daily + misoprostol + Rifaximin (Rifaximin group)	Drug: Rifaximin; Rifaximin 200mcg four times daily
PLACEBO_COMPARATOR: Rifaximin Placebo; ASA daily + misoprostol + Placebo Rifaximin (Placebo group)	Drug: Placebo oral tablet; Placebo Rifaximin four times daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Healing of small bowel ulcers	Capsule endoscopy will be performed to check if there is complete healing of small bowel ulcers, with or without red spots.	8 weeks after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in numbers of ulcer/erosions	Change in numbers of ulcer/erosions from baseline within and between groups	8 weeks after randomization
Change in blood hemoglobin level	Change in blood hemoglobin level from baseline within and between groups	8 weeks after randomization

Collaborators and Investigators

• Sponsor: Chinese University of Hong Kong
• Collaborators: Beijing Friendship Hospital
• Investigators: Principal Investigator: Francis Chan, MD, Chinese University of Hong Kong

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 2, 2019
• Primary Completion (ANTICIPATED): June 30, 2022
• Study Completion (ANTICIPATED): June 30, 2023

Study Registration Dates

• First Submitted: May 19, 2019
• First Submitted That Met QC Criteria: May 23, 2019
• First Posted (ACTUAL): May 24, 2019

Study Record Updates

• Last Update Posted (ACTUAL): July 1, 2020
• Last Update Submitted That Met QC Criteria: June 29, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Anti-Infective Agents; Gastrointestinal Agents; Anti-Bacterial Agents; Rifaximin
• Other Study ID Numbers: MISO RF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No