Efficacy and Safety of Rifaximin for Patients With Chronic Intestinal Pseudo-obstruction: a Phase 2 Trial

Efficacy and Safety of Rifaximin for Patients With Chronic Intestinal Pseudo-obstruction: a Single Center, Randomized, Placebo Controlled, Double-blind Phase 2 Trial

The objective of the study is to investigate efficacy and safety of rifaximin (L-105) in patients with chronic idiopathic intestinal pseudo-obstruction(CIIPO) or patients with chronic intestinal pseudo-obstruction (CIPO), secondary to systemic scleroderma

Study Overview

• Status: Active, not recruiting
• Conditions: Chronic Intestinal Pseudo-obstruction
• Intervention / Treatment: Drug: Rifaximin oral tablet; Drug: Placebo oral tablet

Detailed Description

This is a placebo-controlled, randomized, double-blind, parallel group, comparative study, when patients with chronic idiopathic intestinal pseudo-obstruction(CIIPO) or patients with chronic intestinal pseudo-obstruction (CIPO), secondary to the onset of systemic scleroderma, are administered rifaximin at 400 mg 3 times daily for 4 weeks. In addition, the time course of symptoms of the patients are to be confirmed for 8 weeks after the end of administration.

• Study Type: Interventional
• Enrollment (Anticipated): 12
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Kanagawa
    • Yokohama, Kanagawa, Japan, 236-0004
      • Yokohama city university

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Outpatients aged ≥20 and <75 on the day of informed consent (IC)
• Patients with CIIPO (designated intractable disease 99) at enrollment, satisfying all the criteria specified in (1) to (7) of the CIIPO Diagnostic Criteria issued in 2014 by the MHLW Research Group, or patients with CIPO, secondary to systemic scleroderma, satisfying all the same criteria specified in (1) to (6)
• Patients' levels of abdominal bloating symptoms, 4 scales of GSS, should be score 2 or 3 at the time of IC acquisition and enrollment.

Exclusion Criteria:

• Patients with malignant diseases (excluding those whose symptoms are stable and who do not require aggressive treatments such as chemotherapy and/or surgical therapy)
• Patients with psychiatric diseases (excluding those whose symptoms are stable, and the investigator or coinvestigator concludes that efficacy of the patient can be assessed without any issue)
• Patients with severe diabetes within 5 weeks before enrollment (HbA1c >10%)
• Patients who have already had gastrostomy (including percutaneousendoscopic gastro -jejunostomy, PEG-J), enterostomy, or colostomy
• Patients who underwent intestinal decompression therapy not associated with surgical procedures (trans-nasal ileus tube) within 4weeks before enrollment
• Patients who used antimicrobials, antiparasitics or antifungals (excluding topical use) within 4 weeks before enrollment
• Patients who have changed the doses of the following concomitantly administered drugs within 4 weeks before enrollment: mosapride, daikenchuto, metoclopramide, acotiamide
• Patients with severe hepatic disorders within 5 weeks before enrollment (who meet either one of the following criteria: AST≥ 5 x the upper limit of the common reference value specified in the Japanese Committee for Clinical Laboratory Standards (JCCLS), ALT≥ 5 x the upper limit of the common reference value specified in JCCLS, total bilirubin ≥ 3 x the upper limit of the common reference value specified in JCCLS, decompensated hematic cirrhosis, or jaundice)
• Patients who are pregnant, breastfeeding, possibly pregnant, or those who wish to become pregnant
• Patients with a previous history of hypersensitivity to any investigational product ingredients
• Patients with active tuberculosis
• Patients who participated in other clinical trial (including a trial with an investigational product) within 12 weeks before this enrollment and who received an intervention with a test drug
• Other patients whose participation in the trial is concluded to be inappropriate by the investigator or coinvestigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rifaximin; Two tablets of the investigational product per dosing (400 mg of rifaximin) are orally administered 3 times daily for 4 weeks.	Drug: Rifaximin oral tablet; Patients with chronic idiopathic intestinal pseudo-obstruction (CIIPO) or patients with chronic intestinal pseudo-obstruction (CIPO), secondary to systemic scleroderma, are administered investigational product (rifaximin) for 4 weeks; Other Names: L-105
Placebo Comparator: Placebo; Two tablets of the placebo are orally administered 3 times daily for 4 weeks.	Drug: Placebo oral tablet; Patients with chronic idiopathic intestinal pseudo-obstruction (CIIPO) or patients with chronic intestinal pseudo-obstruction (CIPO), secondary to systemic scleroderma, are administered placebo for 4 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement ratio (%) in abdominal bloating score in Global Symptomatic Score (GSS)	Abdominal bloating score in Global Symptomatic Score (GSS) is used. GSS is a 4-point Likert scale ranging from 0 (no symptom) to 3 (severe, incapacitating with inability to perform normal activities), with lower scores reflecting better symptoms. Score 0 or 1 is defined as improvement.	at the end of administration (4 weeks)
Improvement ratio (%) in Gastrointestinal (GI) symptoms score	Gastrointestinal score (GI score) is a 5-point Likert scale (0; greatly improved, 1; improved, 2; no change, 3; worsened, 4; severely worsened), with lower scores reflecting more improved symptoms. Score 0 or 1 is defined as improvement.	at the end of administration (4 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes of the improvement ratio (%) in abdominal bloating score	Abdominal bloating score in Global Symptomatic Score (GSS) is used. GSS is a 4-point likert scale ranging from 0 (no symptom) to 3 (severe, incapacitating with inability to perform normal activities), with lower scores reflecting better symptoms. Score 0 or 1 is defined as improvement.	Before, 2 and 4 weeks after administration;and 4 and 8 weeks after the end of administration
Changes of abdominal bloating score	Abdominal bloating score in Global Symptomatic Score (GSS) is used. GSS is a 4-point likert scale ranging from 0 (no symptom) to 3 (severe, incapacitating with inability to perform normal activities), with lower scores reflecting better symptoms.	Before, 2 and 4 weeks after administration;and 4 and 8 weeks after the end of administration
Changes of the improvement ratio (%) in gastrointestinal symptoms score	Gastrointestinal score (GI score), a 5-point likert scale (0; greatly improved, 1; improved, 2; no change, 3; worsened, 4; severely worsened), with lower scores reflecting more improved symptoms, is used. Score 0 or 1 is defined as improvement.	Before, 2 and 4 weeks after administration;and 4 and 8 weeks after the end of administration
Changes of the "good" ratio (%) in gastrointestinal symptoms score	Gastrointestinal score (GI score), 5-point likert scale (0; very good, 1; good, 2; average, 3; bad, 4; extremely bad), with lower scores reflecting better conditions, is used. Score 0 or 1 is defined as ''good''.	Before, 2 and 4 weeks after administration;and 4 and 8 weeks after the end of administration
Changes of each score in Global Symptomatic Score other than abdominal bloating score	Global Symptomatic Score (GSS), a 4-point likert scale ranging from 0 (no symptom) to 3 (severe), of the following symptoms are assessed; (a. diarrhea, b. epigastric pain/ discomfort, c. pain in the lower quadrant/discomfort, d. tenderness, e. nausea, f. vomiting).	Before, 2 and 4 weeks after administration;and 4 and 8 weeks after the end of administration
Changes of total scores in Global Symptomatic Score	Sum of Global Symptomatic Score (GSS) of the following 7 symptoms, 0 to maximum of 21, are assessed; (a. diarrhea, b. epigastric pain/discomfort, c. abdominal distention, d. pain in the lower quadrant/discomfort, e. tenderness, f. nausea, g. vomiting).	Before, 2 and 4 weeks after administration;and 4 and 8 weeks after the end of administration
Changes of the improvement ratio (%) in General health condition (symptoms) score	General health condition (symptoms) score, a 5-point likert scale (0; greatly improved, 1; improved, 2; no change, 3; worsened, 4; severely worsened), with lower scores reflecting more improved symptoms, is used. Score 0 or 1 is defined as improvement.	Before, 2 and 4 weeks after administration;and 4 and 8 weeks after the end of administration
Changes of the "good" ratio (%) in General health condition (symptoms) score	General health condition (symptoms) score, 5-point scale (0; very good, 1; good, 2; average, 3; bad, 4; extremely bad), with lower scores reflecting better conditions, is used. Score 0 or 1 is defined as ''good''.	Before, 2 and 4 weeks after administration;and 4 and 8 weeks after the end of administration
Patient satisfaction score	% of the "satisfaction" ratio in patient satisfaction score	At the end of the administration (4 weeks)
Changes of Short Form (SF)-8 health survey score	SF-8(short form-8), a self-reporting health survey ranging from 8 to maximum of 42, with lower scores reflecting better conditions, is used.	Before, 2 and 4 weeks after administration;and 4 and 8 weeks after the end of administration
Small intestinal volume measured by abdominal CT scan	Changes of small intestinal volume measured by abdominal CT scan	Before, 2 and 4 weeks after administration;and 4 and 8 weeks after the end of administration
Changes from baseline of serum albumin level	Serum albumin level is calculated for nutritional assessment	Before, 2 and 4 weeks after administration;and 4 and 8 weeks after the end of administration
Changes from baseline of prealbumin (transthyretin)	Prealbumin (transthyretin) is calculated for nutritional assessment	Before, 2 and 4 weeks after administration;and 4 and 8 weeks after the end of administration
Changes from baseline of cholinesterase	Cholinesterase is calculated for nutritional assessment	Before, 2 and 4 weeks after administration;and 4 and 8 weeks after the end of administration
Changes from baseline of folic acid	Folic acid is calculated for nutritional assessment	Before, 2 and 4 weeks after administration;and 4 and 8 weeks after the end of administration
Changes from baseline of vitamin B12 (cobalamin)	Vitamin B12 (cobalamin) is calculated for nutritional assessment	Before, 2 and 4 weeks after administration;and 4 and 8 weeks after the end of administration
Changes from baseline of serum iron	Serum iron is calculated for nutritional assessment	Before, 2 and 4 weeks after administration;and 4 and 8 weeks after the end of administration

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Small intestinal bacterial overgrowth (SIBO) in a glucose-hydrogen breath test	Elimination rate of SIBO in a glucose-hydrogen breath test	Before, 4 weeks after administration;and 8 weeks after the end of administration
Changes of Serum endotoxin activity	Serum endotoxin activity, ranging from 0.00-1.00, is assessed using EAA® (endotoxin activity assay, Toray Medical Co., Ltd.), FDA approved rapid whole blood assay for detection of human endotoxemia. 0.00-0.39 means low level, 0.40-0.59 means middle level, and ≥0.60 means high level.	Before, 2 and 4 weeks after administration;and 4 and 8 weeks after the end of administration
Fecal test (intestinal flora)	Changes of intestinal flora detected by 16SrDNA amplicon analysis using next generation sequencing.	Before and 4 weeks after administration
Adverse events	Incidence of adverse events	From the start of administration to 8 weeks after the end of administration
Changes from baseline of hematological parameters	Hematological parameters (red blood cell count, hematocrit, white blood cell count, platelet count) are calculated for safety assessment	Before, 2 and 4 weeks after administration; and 4 and 8 weeks after the end of administration
Changes from the baseline of total protein	Total protein is calculated for safety assessment	Before, 2 and 4 weeks after administration; and 4 and 8 weeks after the end of administration
Changes from the baseline of liver function	Liver function parameters (aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, alkaline phosphatase, total bilirubin) are calculated for safety assessment.	Before, 2 and 4 weeks after administration; and 4 and 8 weeks after the end of administration
Changes from the baseline of renal function	Creatinine and blood urea nitrogen are calculated for safety assessment.	Before, 2 and 4 weeks after administration; and 4 and 8 weeks after the end of administration
Changes from the baseline of electrolytes	Electrolytes (sodium, potassium, chlorine, calcium) are calculated for safety assessment.	Before, 2 and 4 weeks after administration; and 4 and 8 weeks after the end of administration
Changes from the baseline of blood lipid level	Blood lipid level (total cholesterol, triglyceride, and high-density lipoprotein cholesterol) is calculated for safety assessment.	Before, 2 and 4 weeks after administration; and 4 and 8 weeks after the end of administration
Changes from the baseline of C reactive protein	C reactive protein is calculated for safety assessment.	Before, 2 and 4 weeks after administration; and 4 and 8 weeks after the end of administration
Changes from the baseline of serum glucose level	Serum glucose level is calculated for safety assessment.	Before, 2 and 4 weeks after administration; and 4 and 8 weeks after the end of administration

Collaborators and Investigators

• Sponsor: Yokohama City University
• Collaborators: ASKA Pharmaceutical Co., Ltd.

Publications and helpful links

General Publications

• Ohkubo H, Iida H, Takahashi H, Yamada E, Sakai E, Higurashi T, Sekino Y, Endo H, Sakamoto Y, Inamori M, Sato H, Fujimoto K, Nakajima A. An epidemiologic survey of chronic intestinal pseudo-obstruction and evaluation of the newly proposed diagnostic criteria. Digestion. 2012;86(1):12-9. doi: 10.1159/000337528. Epub 2012 Jun 15.
• Parodi A, Sessarego M, Greco A, Bazzica M, Filaci G, Setti M, Savarino E, Indiveri F, Savarino V, Ghio M. Small intestinal bacterial overgrowth in patients suffering from scleroderma: clinical effectiveness of its eradication. Am J Gastroenterol. 2008 May;103(5):1257-62. doi: 10.1111/j.1572-0241.2007.01758.x. Epub 2008 Apr 16.

Study record dates

Study Major Dates

• Study Start (Actual): December 25, 2019
• Primary Completion (Anticipated): November 1, 2021
• Study Completion (Anticipated): January 1, 2022

Study Registration Dates

• First Submitted: September 23, 2019
• First Submitted That Met QC Criteria: October 4, 2019
• First Posted (Actual): October 8, 2019

Study Record Updates

• Last Update Posted (Actual): June 21, 2021
• Last Update Submitted That Met QC Criteria: June 18, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Rifaximin; phase 2 trial; systemic scleroderma; small intestinal bacterial overgrowth; L-105; CIPO
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Obstruction; Ileus; Intestinal Pseudo-Obstruction; Anti-Infective Agents; Gastrointestinal Agents; Anti-Bacterial Agents; Rifaximin
• Other Study ID Numbers: YCU19001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No