Microbiota trAnSplant ThERaPy In hEpatiC Encephalopathy (MASTERPIECE) (MASTERPIECE)

Microbiota Transplant Therapy to Prevent HE Recurrence in a Phase 2B Multi-Center Trial of Veterans With Cirrhosis

The goal of this clinical trial is to find out whether changing the microbes in the bowels of Veterans with cirrhosis and hepatic encephalopathy (a condition that affects the brain as a result of liver problems) using capsules made from microbes from healthy people can prevent future episodes of hepatic encephalopathy.

Study Overview

• Status: Not yet recruiting
• Conditions: Hepatic Encephalopathy; Cirrhosis
• Intervention / Treatment: Other: Placebo capsule; Biological: Microbiota transplant therapy (MTT) capsules

Detailed Description

Wartime injuries as well as metabolic disorders can result in liver injury directly or indirectly through PTSD, metabolic disorders, and/or alcohol misuse. These liver injuries culminate in cirrhosis, which affects 4.9 million patients in the US, >80,000 of whom are Veterans. Moreover, numerous Veterans with cirrhosis remain undiagnosed, suggesting these numbers are an underestimation. A major complication of cirrhosis, which is exacerbated by alcohol misuse and PTSD, is hepatic encephalopathy (HE), which affects >50% of Veterans with cirrhosis. Current HE therapies are lactulose (inexpensive but difficult to tolerate) and rifaximin (expensive and second line). However, despite these therapies, a large group of patients have recurrent HE episodes. These recurrences worsen clinical (readmissions, falls, death), psychosocial (cumulative brain injury, poor quality of life, disability, stress on the family), and financial outcomes to the patients, families, and the VHA. Microbiota transplant therapy (MTT) or fecal microbiota transplant (FMT) has the potential to interrupt this cycle. There are Phase 1 and Phase 2a randomized controlled trials (RCTs) published that defined safe and acceptable MTT routes for Veterans with HE. MTT was acceptable to most Veterans who were approached. However, the impact of MTT in preventing HE recurrence in a multi-center context is unclear, especially in those on lactulose only versus those on rifaximin.

The central hypothesis is: Microbial transplant therapy delivered through capsules will significantly reduce the rate of HE recurrence regardless of lactulose or rifaximin use compared to placebo in a multi-center double-blind, placebo-controlled, randomized clinical trial of Veterans with cirrhosis.

In a 6-month double-blind, multi-center, placebo-controlled, randomized clinical trial in Veterans with cirrhosis and HE on lactulose or rifaximin, these specific aims will be used to test this hypothesis:

Aim 1:Determine the rate of HE recurrence in MTT versus placebo-randomized groups: Patients from each site will be randomized 1:1 into receiving MTT or placebo capsules, which will be administered twice a day for 2 weeks. Patients will be followed monthly for 6 months. Recurrence of HE will be defined using standard criteria and will be the primary outcome. Stratification by lactulose use alone or lactulose and rifaximin will be performed.

Aim 2: Determine the effect of MTT on all-cause hospitalizations, death, and liver transplant compared to placebo. This analysis will study safety outcomes other than HE between the groups.

Aim 3: Determine the impact of MTT on systemic inflammation, microbial community structure and function, and donor engraftment over time compared to placebo. In MTT and placebo groups, stool microbiome will be studied for donor engraftment, microbiome structure (stool metagenomics), and microbiome function (targeted and untargeted metabolomics from stool and blood) to determine impact of MTT on recipients and clinical outcomes. Systemic inflammatory changes and antibiotic resistance microbial genes will be analyzed. Individual donor-recipient matching will be studied to evaluate best combinations.

Aim 4: Determine the impact of MTT on cognitive testing, health-related quality of life, and daily function. Cognitive testing, validated PROs, and Veterans' input on FMT and the trial will be analyzed.

Based on favorable results of our single-center phase 2A trial, 162 patients (half on lactulose alone and half on rifaximin) across the three sites will be included. Compound MTP-101C, which is a standardized form of MTT targeting delivery into the distal intestine, will be used. Three rationally selected donors with high Lachnospiraceae relative abundance to maximize engraftment and study donor-recipient matching will be selected.

• Study Type: Interventional
• Enrollment (Estimated): 162
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jasmohan S Bajaj, MD MS; Phone Number: (804) 675-5802; Email: Jasmohan.Bajaj@va.gov
• Study Contact Backup: Name: Brian C Davis, MD; Phone Number: (804) 675-5802; Email: brian.davis5@va.gov

Study Locations

• United States
  • Connecticut
    • West Haven, Connecticut, United States, 06516-2770
      • CERC (VISN1, West Haven, CT)
      • Contact: Lynn Buchwalder; Phone Number: 5338 203-932-5711; Email: Lynn.Buchwalder@va.gov
  • Texas
    • Dallas, Texas, United States, 75216-7167
      • VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
      • Contact: Elizabeth Hernandez; Phone Number: 469-231-9343; Email: elizabeth.hernandez4@va.gov
  • Virginia
    • Richmond, Virginia, United States, 23249-0001
      • Richmond VA Medical Center, Richmond, VA
      • Contact: Haley Obolewicz; Phone Number: 804-675-5705; Email: haley.obolewicz@va.gov
      • Principal Investigator: Jasmohan S. Bajaj, MD MS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 21 years of age

  • Cirrhosis diagnosed by any of the following in a patient with chronic liver disease

    • Liver Biopsy
    • Radiologic evidence of varices, cirrhosis or portal hypertension
    • Laboratory evidence of platelet count <110,000 or AST/ALT ratio>1
    • Endoscopic evidence of varices or portal hypertensive gastropathy
  • Prior overt HE (patient can be on lactulose and/or rifaximin 4 weeks stable dosing)
  • Able to give written, informed consent [mini-mental status exam (MMSE)]>25 at the time of consenting)
  • For lactulose only group: Prior HE not on rifaximin

Exclusion Criteria:

• Disease-related:

  • MELD3.0 score>22
  • WBC count<1000
  • non-elective hospitalization or overt HE episode within 1 month
  • on dialysis
  • known untreated, luminal GI cancer
  • chronic intrinsic GI diseases (ulcerative colitis, Crohn's disease, microscopic colitis, eosinophilic gastroenteritis or celiac disease)

• Safety-related:

  • Current dysphagia
  • History of aspiration, intestinal obstruction or non-medication induced gastroparesis
  • Ongoing absorbable antibiotic use
  • History of anaphylactic food allergy
  • Allergy to ingredients in the capsules (glycerol, sodium chloride, hypromellose, gellan gum, titanium dioxide, theobroma oil)
• Adverse event attributable to prior FMT (7) ASA Class V
• Pregnant or nursing patients
• Acute illness or fever on the day of planned FMT
• History of spontaneous bacterial peritonitis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo capsule	Other: Placebo capsule; Placebo capsule
Experimental: MTT; Microbiota transplant therapy (MTT) capsules	Biological: Microbiota transplant therapy (MTT) capsules; MTP-101-C is manufactured using cGMP protocols in the Molecular and Cellular Therapeutics (MCT) facility at the University of Minnesota.; Other Names: MTP-101-C

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrence of Hepatic Encephalopathy (HE)	HE episodes that requires hospitalization, ER visits, or medication changes prompted under medical supervision.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death	Death	6 months
Non-elective Hospitalizations	Cirrhosis-related, relatedness to MTT or all-cause	6 months
Liver transplant	Liver transplant	6 months
Health-related quality of life (HRQOL) assessment: Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29)	PROMIS-29 used 29 items that are scored using T-scores (mean = 50, SD = 10) Maximum 100, minimum 0. Changes in t-scores between and within groups will be studied. High score=better	6 months
Health-related quality of life (HRQOL) assessment: Sickness Impact Profile (SIP)	SIP is a 136-item self-report questionnaire assessing health-related dysfunction, yielding a total score (0-100%) and 12 category scores. Higher scores indicate greater dysfunction (worse health). Items are yes/no, weighted based on severity, and sum into physical and psychosocial dimensions.	6 months
Cognitive testing: Psychometric Hepatic Encephalopathy score (PHES)	Psychometric Hepatic Encephalopathy score is a battery of 5 paper-and-pencil tests (NCT-A, NCT-B, SDT, LTT, DST) used to detect minimal hepatic encephalopathy (MHE), often requiring 15 minutes to complete. It measures cognitive speed, attention, and motor skills, with results adjusted for age and education, typically yielding a sum score -4 indicating impairment. Low score indicates worse performance.	6 months
Cognitive testing: EncephalApp Stroop	Stroop testing results: measures response times in two phases-"OFF" (simple) and "ON" (complex/incongruent)-to detect covert hepatic encephalopathy (CHE). A total OffTime+OnTime based on local norms suggests impairment, with higher scores indicating worse performance	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety laboratories: Model for End-stage Liver Disease 3.0 (MELD3.0 score)	MELD3.0 score is a validated blood laboratory score of INR, bilirubin, creatinine, albumin and gender. High score=worse prognosis	6 months
Serum ammonia	Serum ammonia levels will be drawn and analyzed using local clinical laboratories.	6 months
Pathophysiological: Microbiota changes	Stool microbiota composition and functional change including serum metabolomics	6 months
Pathophysiological: Inflammation	Serum inflammatory cytokines	6 months

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Jasmohan S. Bajaj, MD MS, Richmond VA Medical Center, Richmond, VA

Study record dates

Study Major Dates

• Study Start (Estimated): October 30, 2026
• Primary Completion (Estimated): October 31, 2030
• Study Completion (Estimated): March 3, 2031

Study Registration Dates

• First Submitted: April 2, 2026
• First Submitted That Met QC Criteria: April 9, 2026
• First Posted (Actual): April 14, 2026

Study Record Updates

• Last Update Posted (Actual): April 14, 2026
• Last Update Submitted That Met QC Criteria: April 9, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: hepatic encephalopathy; cirrhosis; rifaximin; lactulose; microbiota transplant therapy
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Metabolic Diseases; Digestive System Diseases; Liver Diseases; Brain Diseases, Metabolic; Liver Failure; Hepatic Insufficiency; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Fibrosis; Hepatic Encephalopathy; Pharmaceutical Preparations; Dosage Forms; Capsules; monooxyethylene trimethylolpropane tristearate
• Other Study ID Numbers: GAST-006-25S; IRBnet1909366 (Other Identifier: VA Central IRB)

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