Microbiota Restoration Therapy for Recurrent Clostridium Difficile Infection (PUNCHCD3)

A Phase 3 Prospective, Randomized, Double-blinded, Placebo-controlled Clinical Study to Evaluate the Efficacy and Safety of RBX2660 (Microbiota Suspension) for the Prevention of Clostridium Difficile Infection

This is a prospective, multicenter, randomized, double-blinded, placebo-controlled Phase 3 study of a microbiota suspension of intestinal microbes. Patients who have had at least one recurrence after a primary episode and have completed at least one round of standard-of-care oral antibiotic therapy or have had at least two episodes of severe Clostridioides difficile infection (CDI) resulting in hospitalization within the last year may be eligible for the study. Subjects who are deemed failures following the blinded treatment per the pre-specified treatment failure definition may elect to receive an unblinded dose of RBX2660.

Study Overview

• Status: Completed
• Conditions: Clostridium Difficile Infection (CDI)
• Intervention / Treatment: Drug: Placebo; Drug: Open label RBX2660 (only for confirmed CDI recurrence); Drug: RBX2660

Detailed Description

This is a prospective, multicenter, randomized, double-blinded, placebo-controlled Phase 3 study of a microbiota suspension of intestinal microbes. The primary assessments for this study are (i) efficacy of RBX2660 as compared to a Placebo in preventing recurrent episodes of CDI and (ii) safety via assessment of adverse events. The primary efficacy analysis of the study will be a Bayesian hierarchical model, which formally incorporates data from a previous randomized Phase 2b study (Protocol 2014-01, NCT02299570) of RBX2660.

Follow-up office visits occur at weeks 1-, 4- and 8 after completing the blinded study treatment. Telephone assessments for adverse events occur during weeks 2, 3 and 6 after the study treatment and at months 3 and 6. Patients who have had at least one recurrence after a primary episode and have completed at least one round of standard-of-care oral antibiotic therapy or have had at least two episodes of severe CDI resulting in hospitalization within the last year may be eligible for the study. Study Subjects who are deemed failures following the blinded treatment per the pre-specified treatment failure definition may elect to receive an unblinded dose of RBX2660.

• Study Type: Interventional
• Enrollment (Actual): 320
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N2T9
      • Calgary
    • Edmonton, Alberta, Canada, TG2X8
      • Edmonton
  • British Columba
    • Vancouver, British Columba, Canada, V5Z1M9
      • Vancouver
  • British Columbia
    • Victoria, British Columbia, Canada, BC V8R 1J8
      • Victoria
  • New Brunswick
    • Fredericton, New Brunswick, Canada, E3B 4R3
      • Fredericton
    • Moncton, New Brunswick, Canada, E1C628
      • Moncton
• United States
  • Alabama
    • Athens, Alabama, United States, 35611
      • Athens
    • Dothan, Alabama, United States, 36305
      • Dothan
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Phoenix
  • Arkansas
    • North Little Rock, Arkansas, United States, 72117
      • North Little Rock
  • California
    • Lancaster, California, United States, 93534
      • Lancaster
    • Los Angeles, California, United States, 90095
      • Los Angeles
    • Oxnard, California, United States, 93030
      • Oxnard
    • Sacramento, California, United States, 95817
      • Sacramento
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Aurora
  • Connecticut
    • Hamden, Connecticut, United States, 06518
      • Hamden
  • Florida
    • Gainesville, Florida, United States, 32610
      • Gainesville
    • Jacksonville, Florida, United States, 32224
      • Jacksonville
    • Miami, Florida, United States, 33176
      • Miami
    • Port Orange, Florida, United States, 32127
      • Port Orange
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Atlanta
    • Atlanta, Georgia, United States, 30342
      • Atlanta
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Idaho Falls
  • Illinois
    • Gurnee, Illinois, United States, 60031
      • Gurnee
    • Highland Park, Illinois, United States, 60035
      • Highland Park
    • Maywood, Illinois, United States, 60153
      • Maywood
  • Indiana
    • Lafayette, Indiana, United States, 47904
      • Lafayette
  • Kansas
    • Topeka, Kansas, United States, 66606
      • Topeka
    • Wichita, Kansas, United States, 67214
      • Wichita
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • Lexington
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • New Orleans
    • Shreveport, Louisiana, United States, 71105
      • Shreveport
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Boston
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Detroit
  • Minnesota
    • Plymouth, Minnesota, United States, 55446
      • Plymouth
    • Rochester, Minnesota, United States, 55902
      • Rochester
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • St. Louis
  • Nebraska
    • Omaha, Nebraska, United States, 68198-4031
      • Omaha
    • Omaha, Nebraska, United States, 68198
      • Omaha
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • Las Vegas
  • New Jersey
    • Teaneck, New Jersey, United States, 07666
      • Teaneck
  • New York
    • New York, New York, United States, 10016
      • New York
    • North Massapequa, New York, United States, 11758
      • North Massapequa
    • Rochester, New York, United States, 14618
      • Rochester
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Durham
    • Greenville, North Carolina, United States, 27834
      • Greenville
    • Wilmington, North Carolina, United States, 28401
      • Wilmington
  • North Dakota
    • Fargo, North Dakota, United States, 58102
      • Fargo
  • Ohio
    • Toledo, Ohio, United States, 43608
      • Toledo
  • Oregon
    • Portland, Oregon, United States, 97701
      • Portland
  • Pennsylvania
    • Flourtown, Pennsylvania, United States, 19031
      • Flourtown
    • Philadelphia, Pennsylvania, United States, 19102
      • Philadelphia
    • Philadelphia, Pennsylvania, United States, 19107-5244
      • Philadelphia
    • Uniontown, Pennsylvania, United States, 15401
      • Uniontown
    • Wyomissing, Pennsylvania, United States, 19610
      • Wyomissing
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Charleston
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Rapid City
  • Tennessee
    • Hixson, Tennessee, United States, 37434
      • Hixson
  • Texas
    • Dallas, Texas, United States, 75246
      • Dallas
    • Houston, Texas, United States, 77030
      • Houston
  • Utah
    • West Jordan, Utah, United States, 84088
      • West Jordan
  • Virginia
    • Springfield, Virginia, United States, 22150
      • Springfield
    • Winchester, Virginia, United States, 22601
      • Winchester
  • Washington
    • Seattle, Washington, United States, 98104
      • Seattle
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • Madison
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. ≥ 18 years old.
2. Medical record documentation of recurrent CDI per the study definition, that includes either: a) at least one recurrence after a primary episode and has completed at least one round of standard-of-care oral antibiotic therapy or b) has had at least two episodes of severe CDI resulting in hospitalization within the last year.
3. A positive stool test for the presence of toxigenic C. difficile within 30 days prior to or on the date of enrollment.
4. Is currently taking or was just prescribed antibiotics to control CDI related diarrhea at the time of enrollment.

[Note: Subject's CDI diarrhea must be controlled (<3 unformed/loose stools/day) while taking this course of antibiotics]

Exclusion Criteria:

1. Currently has continued CDI diarrhea despite being on antibiotics prescribed for CDI treatment.
2. Previous fecal transplant
3. History of inflammatory bowel disease (IBD), e.g., ulcerative colitis, Crohn's disease, or microscopic colitis.
4. Diagnosis of irritable bowel syndrome (IBS) as determined by Rome III criteria.
5. Compromised immune system (e.g. immunosuppressed due to a medical condition or medication; current or recent (< 90 days) treatment with chemotherapy)
6. An absolute neutrophil count of <1000 cells/µL during screening.
7. Pregnant, breastfeeding, or intends to become pregnant during study participation.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo is an suspension of normal saline. Packaging and labeling are identical to the packaging and labeling for RBX2660 to support the study blinding	Drug: Placebo; Placebo is normal saline solution administered rectally; Other Names: saline solution; Drug: Open label RBX2660 (only for confirmed CDI recurrence); RBX2660 administered as a second treatment after confirmed CDI recurrence following the initial dose of placebo or RBX2660; Other Names: microbiota suspension
Experimental: RBX2660; RBX2660 is a rectally administered microbiota suspension in a 0.9% sodium chloride irrigation United States Pharmacopeia (USP) solution and cryoprotectant	Drug: Open label RBX2660 (only for confirmed CDI recurrence); RBX2660 administered as a second treatment after confirmed CDI recurrence following the initial dose of placebo or RBX2660; Other Names: microbiota suspension; Drug: RBX2660; RBX2660 is a rectally administered microbiota suspension; Other Names: microbiota suspension

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of RBX2660 Compared to Placebo Through 8 Weeks	The primary efficacy endpoint was the absence of CDI diarrhea for 8 weeks after study treatment. The model-estimated rate of treatment success, that is the model-estimated percentage of participants that met the primary efficacy endpoint, was estimated using a Bayesian hierarchical model, which formally incorporated data from a previous randomized Phase 2B study (NCT02299570) of RBX2660.	8 weeks after completing the study treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sustained Clinical Response Through 6 Months After Blinded Treatment	The rates of Sustained Clinical Response (i.e., the occurrence of new CDI infections from baseline through 6 months) was assessed by either the rate of new CDI infections after treatment success at 8 weeks (durability) or the frequency of total CDI infections from baseline through 6 months. Sustained Clinical Response was compared between the RBX2660 group and the control group using a chi-square test. Patients who exited prior to their 6-month follow-up were conservatively counted as a Treatment Failure	6 months after completing the study treatment

Collaborators and Investigators

• Sponsor: Rebiotix Inc.
• Investigators: Study Chair: Teena Chopra, M.D., M.P.H., Wayne State University

Publications and helpful links

General Publications

• EISEMAN B, SILEN W, BASCOM GS, KAUVAR AJ. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery. 1958 Nov;44(5):854-9. No abstract available.
• Bakken JS. Feces transplantation for recurrent Clostridium difficile infection: US experience and recommendations. Microb Ecol Health Dis. 2015 May 29;26:27657. doi: 10.3402/mehd.v26.27657. eCollection 2015. No abstract available.
• Miller MA, Louie T, Mullane K, Weiss K, Lentnek A, Golan Y, Kean Y, Sears P. Derivation and validation of a simple clinical bedside score (ATLAS) for Clostridium difficile infection which predicts response to therapy. BMC Infect Dis. 2013 Mar 25;13:148. doi: 10.1186/1471-2334-13-148.
• Khanna S, Assi M, Lee C, Yoho D, Louie T, Knapple W, Aguilar H, Garcia-Diaz J, Wang GP, Berry SM, Marion J, Su X, Braun T, Bancke L, Feuerstadt P. Efficacy and Safety of RBX2660 in PUNCH CD3, a Phase III, Randomized, Double-Blind, Placebo-Controlled Trial with a Bayesian Primary Analysis for the Prevention of Recurrent Clostridioides difficile Infection. Drugs. 2022 Oct;82(15):1527-1538. doi: 10.1007/s40265-022-01797-x. Epub 2022 Oct 26. Erratum In: Drugs. 2022 Oct;82(15):1539. doi: 10.1007/s40265-022-01805-0.

Helpful Links

• Sponsor website
• Rebyota sponsor briefing book
• Centers for Disease Control page last reviewed March 15, 2021; accessed March 01, 2022.

Study record dates

Study Major Dates

• Study Start (Actual): July 31, 2017
• Primary Completion (Actual): April 2, 2020
• Study Completion (Actual): August 3, 2020

Study Registration Dates

• First Submitted: August 2, 2017
• First Submitted That Met QC Criteria: August 8, 2017
• First Posted (Actual): August 9, 2017

Study Record Updates

• Last Update Posted (Actual): July 10, 2024
• Last Update Submitted That Met QC Criteria: July 8, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: Diarrhea; FMT; Clostridium Difficile; CDI; Microbiota Restoration Therapy; Fecal Microbiota Transplant (FMT); C Difficile Colitis; C.Difficile Diarrhea; Fecal Transplant; Microbial Suspension
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Infections; Communicable Diseases; Clostridium Infections
• Other Study ID Numbers: 2017-01

Drug and device information, study documents

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