Washed Microbiota Transplantation for Chronic Constipation in Adults

Study Overview
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Brief Summary
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This is a single-center, randomized, double-blind, placebo-controlled, dose-exploring clinical study to explore the safety and efficacy of washed microbiota transplantation (WMT) for patients with chronic constipation.

Detailed Description
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At least 18 subjects who meet all the inclusion criteria but do not meet any exclusion criteria will be enrolled in this study. They will be randomly assigned to the high-dose group (high dose of washed microbiota suspension), the low-dose group (low dose of washed microbiota suspension) and the control group (placebo). Data of demographic characteristics, intestinal symptoms，medicine treatment usage and clinical outcomes will be collected. After treatment (D1-D4), they will enter the double-blind visit (D5, D18) for safety and efficacy evaluation. Open follow-up periods will be performed on days 32 and 60 after administration.

Official Title
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Washed Microbiota Transplantation for Chronic Constipation in Adults: a Single-center, Randomized, Double-blind, Placebo-controlled, Dose-exploring Clinical Study

Conditions
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Constipation

Intervention / Treatment
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* Drug: High-dose washed microbiota suspension
* Drug: Low-dose washed microbiota suspension
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Meet all of the following inclusion criteria : Voluntary sign informed consent, age 18-70 years old (including the threshold), male and female. For subjects diagnosed with chronic constipation, the duration of the disease is at least 6 months, and the following conditions are met: Frequency of spontaneous defecation <3 times/week (spontaneous defecation refers to spontaneous defecation without the aid of remedial purgatives or manual assistance). Dry and hard stool: More than a quarter of the stool is type 1 or 2 on the Bristol Fecal Trait Scale. The subject or his/her legal representative has given informed consent, is fully aware of the purpose of the study, is able to communicate well with the investigator, and is able to understand and comply with the requirements of the study. Exclusion Criteria: - All exclusion criteria below are not met: Outlet obstruction constipation, such as rectal mucosal prolapse. History of abdominal and pelvic surgery, except for no intestinal complications after cholecystectomy, caesarean section, appendectomy, and treatment of intestinal polyps. Combined with the colonoscopy results in the past 24 months, patients with intestinal stenosis caused by organic lesions of the digestive tract (such as tumor, inflammation, anal fissure, Crohn's disease, intestinal adhesion, ulcerative colitis, intestinal tuberculosis, etc.) and constipation. Other systemic diseases involving the digestive tract (such as neurological diseases (such as Parkinson's disease, spinal cord injury, multiple sclerosis, etc.), muscle diseases (such as amyloidosis, dermatomyositis, etc.), mental disorders (such as depression, etc.), metabolic endocrine disorders (such as diabetes, hypothyroidism, etc.), or constipation caused by opioids. Have a history of major surgery or severe trauma within 3 months and have not fully recovered. There are contraindications for endoscopic intestinal catheterization via colonic approach, such as severe intestinal stenosis, obstruction, deep ulcer, and high risk of perforation. There are serious ulcers or a large number of false polyps in the fixation area, which is not suitable for fixation. The subject's behavior is seriously out of control. Cardiac function and cardiac performance have any of the following abnormalities: According to the New York Heart Association (NYHA) heart function rating, the heart function rating is grade III and above. Subjects with new myocardial infarction or unstable angina pectoris within 6 months. Electrocardiogram indicated prolonged corrected QT interval (QTc) (male QTc≥450ms, female QTc≥470ms). Atrial arrhythmias that cannot be stably controlled by drugs and ventricular arrhythmias that require drug control (including grade 2 and above atrioventricular block). Poor lung function that the investigator assessed as having an impact on study treatment, such as in subjects with acute chronic obstructive pulmonary disease or long-term oral, intravenous hormone control (other than inhalant/spray hormone use). Uncontrolled immune disease and/or the need for long-term use of hormones (except for topical use). Subjects with poorly controlled metabolic disease (e.g., thyroid dysfunction) or metabolic disease with gastrointestinal complications (e.g., gastrointestinal autonomic dysfunction, diabetic gastroparesis, etc.); Patients with reproductive system diseases (including but not limited to ovarian cysts, endometriosis, primary dysmenorrhea, etc.) that are prone to abdominal pain. Significant abnormalities in laboratory tests that, in the investigator's judgment, may affect subject safety or completion of the clinical study include: Hemoglobin <100g/L. Serum creatinine ≥1.5 times the upper limit of normal (ULN) Abnormal liver function, defined as Glutamic oxalacetic transaminase >1.5×ULN and/or Glutamic-pyruvic transaminase>1.5×ULN and/or total bilirubin >1.5×ULN. Coagulation function: PLT≤80×109/L, activated partial thromboplastin time > 1.5×ULN, prothrombin time > 1.5×ULN, International Normalized Ratio > 1.5×ULN. The results of routine stool or fecal occult blood are abnormal and have clinical significance to indicate gastrointestinal disease. Subjects with active hepatitis who require or are on long-term use of therapeutic drugs, HIV, or active tuberculosis. Subjects with a history of drug or alcohol abuse (i.e., consuming more than 14 servings (1 serving is 360mL) of beer, 45mL of 40% spirits, or 150mL of wine per week) or substance abuse. Known allergy to the investigational drug, similar drugs or excipients. Anti-infective drugs (antibiotics, antifungal, antiviral) were used within 14 days prior to enrollment, or anti-infective therapy was required at the time of enrollment evaluation. Drugs and supplements that affect gastrointestinal motility and function that cannot be discontinued in trials, including but not limited to: antibiotics, such as erythromycin; Drugs that regulate intestinal microecology, such as probiotics such as Bifidobacterium; Parasympathetic inhibitors, such as scopolamine, atropine, belladonna, etc. Muscle relaxants such as succinylcholine; Antidiarrheal agents such as loperamide, Smecta, etc. Opioid preparations; Inhibition of gastric acid secretion drugs. Those who use hydrotherapy for defecation/bowel cleansing within one month prior to treatment. Women who are pregnant or breastfeeding, or who refuse to use effective contraception within 3 months after the last dose of medication. Participants who had participated in clinical trials of drug intervention within 3 months before drug administration. Patients with malignant tumors. There are other situations in which the investigator deems it inappropriate to participate in this study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High-dose group<br>The participant will receive a high dose of the washed microbiota suspension, with a bacterial quantity that is 10 times higher than the conventional clinical treatment dose, once daily for a duration of 4 days. | Drug: High-dose washed microbiota suspension<br>* The high-dose group will be administered a high dose of washed microbiota suspension。<br>* Other names: WMT-001;|
| Experimental: Low-dose group<br>The participant will receive a low-dose washed microbiota suspension, with a bacterial quantity equivalent to the conventional clinical treatment dose. The washed microbiota suspension will be administered once on the first day, followed by placebo of equal volume for the next 3 days. | Drug: Low-dose washed microbiota suspension<br>* The low-dose group will be administered a low dose of washed microbiota suspension.<br>|
| Placebo Comparator: Control group<br>The patient will receive a placebo of equal volume once daily for a duration of 4 days. | Drug: Placebo<br>* The control group will be given equal volume placebo (120ml carrier solution matching the volume of WMT-001), which contains 10% sterile glycerol and saline injection. The drug was administered once a day for 4 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of treatment-related adverse events (AE) assessed by CTCAE, Version 5.0 | The severity of AE was graded as mild (grade 1), moderate (grade 2), severe/disabling (grade 3), life threatening (grade 4), and death (grade 5). All AE were divided in definitely, probably and possibly related to treatment. The treatment-related AE we focused on included microbiota-related AEs (e.g., infection, diarrhea, abdominal pain, etc.) and route of delivery related AEs (e.g., nausea, vomiting, etc.). | Two-week post-WMT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of treatment-related adverse events (AE) assessed by CTCAE, Version 5.0 | The severity of AE was graded as mild (grade 1), moderate (grade 2), severe/disabling (grade 3), life threatening (grade 4), and death (grade 5). All AE were divided in definitely, probably and possibly related to treatment. The treatment-related AE we focused on included microbiota-related AEs (e.g., infection, diarrhea, abdominal pain, etc.) and route of delivery related AEs (e.g., nausea, vomiting, etc.). | Day 5，Four-week post-WMT，Eight-week post-WMT | 
| The clinical response rate after treatment | A clinical response was defined as a patient achieving complete spontaneous bowel movement (CSBM) at least 50% of the time after receiving WMT. CSBM was defined as the number of spontaneous defecation with complete exhaust feeling without taking remedial purgative or manual assistance. | One-week post-WMT，two-week post-WMT，Four-week post-WMT，Eight-week post-WMT | 
| The weekly usage rate of assisted defecation drugs. | Percentage of days per week after WMT that assisted defecation drugs were used, which was compared to baseline. | One-week post-WMT，Two-week post-WMT, Four-week post-WMT，Eight-week post-WMT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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washed microbiota transplantation, constipation, difficult defecation