Microbiota Restoration Therapy for Recurrent Clostridium Difficile Infection (PUNCHCD3)

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Clostridium Difficile Infection (CDI)

Intervention / Treatment
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* Drug: RBX2660
* Drug: Placebo
* Drug: Open label RBX2660 (only for confirmed CDI recurrence)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 18 years old. 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. A positive stool test for the presence of toxigenic C. difficile within 30 days prior to or on the date of enrollment. 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: Currently has continued CDI diarrhea despite being on antibiotics prescribed for CDI treatment. Previous fecal transplant History of inflammatory bowel disease (IBD), e.g., ulcerative colitis, Crohn's disease, or microscopic colitis. Diagnosis of irritable bowel syndrome (IBS) as determined by Rome III criteria. Compromised immune system (e.g. immunosuppressed due to a medical condition or medication; current or recent (< 90 days) treatment with chemotherapy) An absolute neutrophil count of <1000 cells/µL during screening. Pregnant, breastfeeding, or intends to become pregnant during study participation.

Ages Eligible for Study
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Minimum Age: 18 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>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<br>* Placebo is normal saline solution administered rectally<br>* Other names: saline solution;Drug: Open label RBX2660 (only for confirmed CDI recurrence)<br>* RBX2660 administered as a second treatment after confirmed CDI recurrence following the initial dose of placebo or RBX2660<br>* Other names: microbiota suspension;|
| Experimental: RBX2660<br>RBX2660 is a rectally administered microbiota suspension in a 0.9% sodium chloride irrigation United States Pharmacopeia (USP) solution and cryoprotectant | Drug: RBX2660<br>* RBX2660 is a rectally administered microbiota suspension<br>* Other names: microbiota suspension;Drug: Open label RBX2660 (only for confirmed CDI recurrence)<br>* RBX2660 administered as a second treatment after confirmed CDI recurrence following the initial dose of placebo or RBX2660<br>* Other names: microbiota suspension;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CDI, C Difficile Colitis, Clostridium Difficile, C.Difficile Diarrhea, Fecal Transplant, Fecal Microbiota Transplant (FMT), Microbiota Restoration Therapy, Diarrhea, FMT, Microbial Suspension