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

Study Overview
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Brief Summary
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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

Detailed Description
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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.

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

Conditions
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Chronic Intestinal Pseudo-obstruction

Intervention / Treatment
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* Drug: Rifaximin oral tablet
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rifaximin<br>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<br>* 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<br>* Other names: L-105;|
| Placebo Comparator: Placebo<br>Two tablets of the placebo are orally administered 3 times daily for 4 weeks. | Drug: Placebo oral tablet<br>* 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<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rifaximin, L-105, phase 2 trial, CIPO, small intestinal bacterial overgrowth, systemic scleroderma