Clostridium Difficile Infection (CDI)
Conditions
Keywords
C Difficile Colitis, Clostridium Difficile, CDI, C.Difficile Diarrhea, Fecal Transplant, Fecal Microbiota Transplant (FMT), Microbiota Restoration Therapy, Diarrhea, FMT, Microbial Suspension
Brief summary
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
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.
Interventions
DRUGPlacebo
Placebo is normal saline solution administered rectally
DRUGRBX2660
RBX2660 is a rectally administered microbiota suspension
DRUGOpen 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
Sponsors
Rebiotix Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of RBX2660 Compared to Placebo Through 8 Weeks | 8 weeks after completing the study treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Sustained Clinical Response Through 6 Months After Blinded Treatment | 6 months after completing the study 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 |
Countries
Canada, United States
Participant flow
Recruitment details
Recruitment was from July 2017 to February 2020 at 44 medical clinics in the United States and Canada. Recruitment was performed by trained investigators and study coordinators.
Pre-assignment details
A total of 320 subjects were enrolled (signed consent) of which 31 were screen failures. 289 subjects were randomized: 193 to RBX2660 and 96 to placebo. Of the 289, 22 did not receive the allocated treatment. Therefore, a total of 267 subjects were randomized and treated: 180 subjects were treated with blinded RBX2660 treatment and 87 subjects were treated with blinded Placebo treatment.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo is normal saline administered rectally. Packaging and labeling are identical to the packaging and labeling for RBX2660 to support the study blinding
Placebo: Placebo is normal saline solution administered rectally | 87 |
| RBX2660 RBX2660 is a rectally administered microbiota suspension in a 0.9% sodium chloride irrigation USP solution and cryoprotectant
RBX2660: RBX2660 is a microbiota suspension administered rectally | 180 |
| Total | 267 |
Baseline characteristics
| Characteristic | RBX2660 | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 89 Participants | 33 Participants | 122 Participants |
| Age, Categorical Between 18 and 65 years | 91 Participants | 54 Participants | 145 Participants |
| Age, Continuous | 64.0 years | 60.0 years | 63.0 years |
| Antibiotic Screening Fidaxomicin | 12 Participants | 5 Participants | 17 Participants |
| Antibiotic Screening Other | 6 Participants | 2 Participants | 8 Participants |
| Antibiotic Screening Vancomycin alone | 157 Participants | 78 Participants | 235 Participants |
| Antibiotic Screening Vancomycin in combination | 5 Participants | 2 Participants | 7 Participants |
| Clostridioides difficile infection (CDI) History <=3 | 111 Participants | 59 Participants | 170 Participants |
| Clostridioides difficile infection (CDI) History >3 | 69 Participants | 28 Participants | 97 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 4 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 168 Participants | 80 Participants | 248 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 10 Participants | 3 Participants | 13 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 6 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) White | 168 Participants | 78 Participants | 246 Participants |
| Region of Enrollment Canada | 51 participants | 26 participants | 77 participants |
| Region of Enrollment United States | 129 participants | 61 participants | 190 participants |
| Sex: Female, Male Female | 123 Participants | 60 Participants | 183 Participants |
| Sex: Female, Male Male | 57 Participants | 27 Participants | 84 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 63 | 1 / 139 | 0 / 24 | 0 / 41 | 0 / 24 | 1 / 41 |
| other Total, other adverse events | 23 / 63 | 56 / 139 | 5 / 24 | 3 / 41 | 10 / 24 | 19 / 41 |
| serious Total, serious adverse events | 5 / 63 | 9 / 139 | 1 / 24 | 3 / 41 | 1 / 24 | 5 / 41 |
Outcome results
Primary
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.
Time frame: 8 weeks after completing the study treatment
Population: The modified Intent-To-Treat (mITT) Population included all randomized patients who successfully received blinded treatment, excluding those who discontinued from the study for reasons not related to CDI symptoms prior to evaluation of Treatment Success for the primary endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Efficacy of RBX2660 Compared to Placebo Through 8 Weeks | 57.5 Model-estimated percent of participants |
| RBX2660 | Efficacy of RBX2660 Compared to Placebo Through 8 Weeks | 70.6 Model-estimated percent of participants |
Comparison: A hierarchical, closed-testing procedure (Bayesian hierarchical model) was utilized for the primary endpoint. The Bayesian hierarchical model formally incorporated data from the previous Phase 2B study (NCT02299570) of RBX2660. This analysis tested the hypothesis that the response rate of RBX2660 was superior to Placebo and was performed at the nominal 0.00125 and 0.025 one-sided levels.95% CI: [2.3, 24]
Secondary
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
Time frame: 6 months after completing the study treatment
Population: The mITT population included all randomized patients who successfully received blinded treatment, excluding those who discontinued from the study for reasons not related to CDI symptoms prior to evaluation of Treatment Success for the primary endpoint.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Sustained Clinical Response Through 6 Months After Blinded Treatment | From 8 weeks through 6 months (Durability) | 48 Participants |
| Placebo | Sustained Clinical Response Through 6 Months After Blinded Treatment | Through 6 months | 48 Participants |
| RBX2660 | Sustained Clinical Response Through 6 Months After Blinded Treatment | From 8 weeks through 6 months (Durability) | 116 Participants |
| RBX2660 | Sustained Clinical Response Through 6 Months After Blinded Treatment | Through 6 months | 116 Participants |
p-value: 0.156Chi-squared