Clostridium Difficile Infection Recurrence, Clostridium Difficile Infection, Clostridium Difficile, Clostridioides Difficile Infection Recurrence, Clostridioides Difficile Infection, Clostridioides Difficile, CDI
Conditions
Keywords
Clostridium Difficile Infection Recurrence, Clostridium Difficile Infection, Clostridium Difficile, VE303, Consortium, Vedanta, CDI, C. Diff, CDiff, Clostridiodes Difficile Infection Recurrence, Clostridiodes Difficile Infection, Clostridioides Difficile
Brief summary
This study evaluated the safety and efficacy of VE303 for participants with primary C. difficile infection (pCDI) at high risk for recurrence or subjects with recurrent C. difficile infections (rCDI).
Detailed description
CONSORTIUM was a randomized, placebo-controlled double-blind Phase 2 study to evaluate safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy of VE303 in prevention of subsequent Clostridioides difficile infection (CDI) -associated diarrhea compared with placebo following completion of at least 1 successful course of standard-of-care (SOC) antibiotics. VE303 or placebo capsules were taken orally for 14 days after completion of a course of SOC antibiotics. The proportions of subjects experiencing a confirmed CDI recurrence within 8 weeks after the first dose of study treatment were compared across the study arms, to understand the efficacy of VE303 in preventing rCDI. The study originally planned to enroll 146 subjects but through a protocol amendment was revised to an enrollment target of 60 to 80 subjects with a prior history of CDI diarrhea or first occurrence of CDI diarrhea with a higher risk for recurrence. Subjects must have had a positive C. difficile stool sample and have responded to SOC antibiotic treatment.
Interventions
DRUGVE303
VE303 is a live biotherapeutic product containing 8 clonal human commensal bacterial strains manufactured under Good Manufacturing Practices (GMP) conditions.
DRUGPlacebo
Placebo capsules contained microcrystalline cellulose and were visually identical to VE303 capsules. Placebo capsules did not contain any VE303 Drug Product.
Sponsors
Vedanta Biosciences, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
To reduce potential bias and increase study data integrity, study participants, care providers, site investigators, and study outcomes assessors were masked to study treatment assignment.
Intervention model description
This Phase 2 study evaluated the safety and efficacy of the study drug, VE303, at preventing subsequent CDI-associated diarrhea compared with placebo, following completion of at least 1 successful course of SOC antibiotics for subjects with pCDI at high risk for recurrence or subjects with rCDI. Participants in the study were randomized into 3 arms in a 1:1:1 ratio of high dose VE303, low dose VE303, and placebo.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Partial Inclusion Criteria: 1. Able and willing to provide written informed consent 2. Subjects with a qualifying CDI episode who had a prior history of CDI diarrhea (≥ 18 years of age) or first occurrence of CDI diarrhea with a higher risk for recurrence (≥ 75 years of age, or ≥ 65 years of age with one or more prespecified conditions) 3. CDI symptoms must have started within 30 days (inclusive) prior to the day of randomization 4. The diarrhea was considered unlikely to have another etiology. 5. Completed an Investigator's choice SOC antibiotic regimen of a minimum of 10 days and up to 21 days of total duration 6. Have a positive C. difficile stool 7. Recovered from any complications of severe or fulminant CDI and clinically stable by the time of randomization. Partial
Exclusion criteria
1. History of diarrhea (defined as 3 or more loose stools per day lasting for at least 4 weeks) that was not related to C. difficile infection within the 3 months prior to randomization. 2. Known or suspected toxic megacolon and/or known small bowel ileus at the time of randomization. 3. Contraindication to oral/enteral therapy (e.g., severe reflux, severe nausea/vomiting, or ileus). 4. Prior administration of genetically modified investigational live bacterial/fungal/bacteriophage/viral isolates for CDI-associated diarrhea 5. History of administration of fecally-derived investigational live biotherapeutic products, or fecally-derived live bacterial isolates for CDI-associated diarrhea including fecal microbiota transplantation (FMT) within the last 6 months. 6. Use of drugs that alter gut motility 7. History of acute leukemia or hematopoietic stem cell transplantation or myelosuppressive chemotherapy within 2 months prior to randomization. 8. Subjects with compromised immune system 9. Major gastrointestinal surgery (e.g., significant bowel resection or diversion) within 3 months prior to randomization or any history of total colectomy or bariatric surgery that disrupts the gastrointestinal lumen. 10. History of confirmed celiac disease, inflammatory bowel disease, short gut, gastrointestinal tract fistulas, or ischemia.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CDI Recurrence Week 8 | 8 weeks | Percentage of participants with toxin-positive, laboratory-confirmed, or clinically diagnosed and treated CDI recurrence before or at Week 8 (i.e., 8 weeks after the first dose of study treatment). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| VE303 Strains Detected | 24 weeks | Characterize the number of VE303 strains detected in the fecal microbiome at week 24. |
| VE303 Relative Abundance | 24 weeks | Proportion of VE303 strains is defined as the abundance proportion of all 8 VE303 strains relative to the total microbial composition of the sample. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Microbiota Diversity | 24 weeks | Characterize the fecal microbiome Shannon Diversity at week 24. |
| Determine the Recommended VE303 Phase 3 Dose Regimen(s). | 31 Months 1 Week | Determine the recommended VE303 phase 3 dose regimen(s) based on safety and efficacy, as indicated by the CDI recurrence rate for the duration of the study. |
| CDI Recurrence Week 4 | 4 Weeks | Percentage of participants with toxin-positive, laboratory-confirmed, or clinically diagnosed and treated CDI recurrence before or at Week 4 (i.e., 4 weeks after the first dose of study treatment). |
| Taxonomic Composition | 31 Months, 1 Week | Characterize Taxonomic Composition |
| Changes in the Fecal Metabolomic Profile, Including Short-chain Fatty Acids and Bile Acids. | 31 Months 1 Week | Changes in the fecal metabolomic profile, including short-chain fatty acids and bile acids for the duration of the study. |
| CDI Recurrence Week 12 | 12 Weeks | Percentage of participants with toxin-positive, laboratory-confirmed, or clinically diagnosed and treated CDI recurrence before or at Week 12 (i.e., 12 weeks after the first dose of study treatment). |
| CDI Recurrence Week 24 | 24 Weeks | Percentage of participants with toxin-positive, laboratory-confirmed, or clinically diagnosed and treated CDI recurrence before or at Week 24 (i.e., 24 weeks after the first dose of study treatment). |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| VE303 High Dose Study subjects assigned to the high dose VE303 arm took 10 capsules containing VE303 per day for 14 days.
VE303: VE303 is a live biotherapeutic product containing 8 clonal human commensal bacterial strains manufactured under GMP conditions. | 30 |
| VE303 Low Dose Study subjects assigned to the low dose VE303 arm took 2 capsules containing VE303 per day for 14 days.
VE303: VE303 is a live biotherapeutic product containing 8 clonal human commensal bacterial strains manufactured under GMP conditions. | 27 |
| Placebo Study subjects assigned to the placebo dose arm took placebo capsules each day for 14 days. The capsules did not contain any VE303.
Placebo: Placebo capsules contained microcrystalline cellulose and were visually identical to VE303 capsules. | 22 |
| Total | 79 |
Baseline characteristics
| Characteristic | VE303 Low Dose | Placebo | Total | VE303 High Dose |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 15 Participants | 10 Participants | 39 Participants | 14 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 12 Participants | 40 Participants | 16 Participants |
| Age, Continuous | 62.9 years STANDARD_DEVIATION 17.85 | 60.8 years STANDARD_DEVIATION 15.98 | 62.1 years STANDARD_DEVIATION 16.12 | 62.3 years STANDARD_DEVIATION 14.99 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants | 22 Participants | 77 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 25 Participants | 22 Participants | 76 Participants | 29 Participants |
| Region of Enrollment Canada | 10 participants | 8 participants | 30 participants | 12 participants |
| Region of Enrollment United States | 17 participants | 14 participants | 49 participants | 18 participants |
| Sex: Female, Male Female | 20 Participants | 17 Participants | 56 Participants | 19 Participants |
| Sex: Female, Male Male | 7 Participants | 5 Participants | 23 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 27 | 0 / 22 |
| other Total, other adverse events | 28 / 29 | 27 / 27 | 21 / 22 |
| serious Total, serious adverse events | 1 / 29 | 4 / 27 | 2 / 22 |
Outcome results
Primary
CDI Recurrence Week 8
Percentage of participants with toxin-positive, laboratory-confirmed, or clinically diagnosed and treated CDI recurrence before or at Week 8 (i.e., 8 weeks after the first dose of study treatment).
Time frame: 8 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| VE303 High Dose | CDI Recurrence Week 8 | C. difficile recurrences (laboratory-confirmed) | 4 Participants |
| VE303 High Dose | CDI Recurrence Week 8 | C. difficile recurrences (toxin-positive) | 4 Participants |
| VE303 High Dose | CDI Recurrence Week 8 | C. difficile recurrences (laboratory-confirmed or clinically diagnosed and treated) | 4 Participants |
| VE303 Low Dose | CDI Recurrence Week 8 | C. difficile recurrences (laboratory-confirmed) | 10 Participants |
| VE303 Low Dose | CDI Recurrence Week 8 | C. difficile recurrences (toxin-positive) | 9 Participants |
| VE303 Low Dose | CDI Recurrence Week 8 | C. difficile recurrences (laboratory-confirmed or clinically diagnosed and treated) | 10 Participants |
| Placebo | CDI Recurrence Week 8 | C. difficile recurrences (toxin-positive) | 5 Participants |
| Placebo | CDI Recurrence Week 8 | C. difficile recurrences (laboratory-confirmed or clinically diagnosed and treated) | 10 Participants |
| Placebo | CDI Recurrence Week 8 | C. difficile recurrences (laboratory-confirmed) | 8 Participants |
Secondary
VE303 Relative Abundance
Proportion of VE303 strains is defined as the abundance proportion of all 8 VE303 strains relative to the total microbial composition of the sample.
Time frame: 24 weeks
Population: Enrolled subjects who provided stool samples for analysis at week 24.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VE303 High Dose | VE303 Relative Abundance | 0.01186 Proportion of VE303 strains | Standard Deviation 0.013897 |
| VE303 Low Dose | VE303 Relative Abundance | 0.00775 Proportion of VE303 strains | Standard Deviation 0.016007 |
| Placebo | VE303 Relative Abundance | 0.00097 Proportion of VE303 strains | Standard Deviation 0.002297 |
Secondary
VE303 Strains Detected
Characterize the number of VE303 strains detected in the fecal microbiome at week 24.
Time frame: 24 weeks
Population: Enrolled subjects who provided stool samples for analysis at week 24.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| VE303 High Dose | VE303 Strains Detected | 3.25 Number of VE303 strains detected | Standard Deviation 2.807 |
| VE303 Low Dose | VE303 Strains Detected | 1.62 Number of VE303 strains detected | Standard Deviation 1.962 |
| Placebo | VE303 Strains Detected | 0.36 Number of VE303 strains detected | Standard Deviation 0.633 |
Other Pre-specified
CDI Recurrence Week 12
Percentage of participants with toxin-positive, laboratory-confirmed, or clinically diagnosed and treated CDI recurrence before or at Week 12 (i.e., 12 weeks after the first dose of study treatment).
Time frame: 12 Weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| VE303 High Dose | CDI Recurrence Week 12 | C. difficile recurrences (laboratory-confirmed) | 4 Participants |
| VE303 High Dose | CDI Recurrence Week 12 | C. difficile recurrences (toxin-positive) | 4 Participants |
| VE303 High Dose | CDI Recurrence Week 12 | C. difficile recurrences (laboratory-confirmed, or clinically diagnosed and treated) | 4 Participants |
| VE303 Low Dose | CDI Recurrence Week 12 | C. difficile recurrences (laboratory-confirmed) | 10 Participants |
| VE303 Low Dose | CDI Recurrence Week 12 | C. difficile recurrences (toxin-positive) | 9 Participants |
| VE303 Low Dose | CDI Recurrence Week 12 | C. difficile recurrences (laboratory-confirmed, or clinically diagnosed and treated) | 10 Participants |
| Placebo | CDI Recurrence Week 12 | C. difficile recurrences (toxin-positive) | 5 Participants |
| Placebo | CDI Recurrence Week 12 | C. difficile recurrences (laboratory-confirmed, or clinically diagnosed and treated) | 10 Participants |
| Placebo | CDI Recurrence Week 12 | C. difficile recurrences (laboratory-confirmed) | 8 Participants |
Other Pre-specified
CDI Recurrence Week 24
Percentage of participants with toxin-positive, laboratory-confirmed, or clinically diagnosed and treated CDI recurrence before or at Week 24 (i.e., 24 weeks after the first dose of study treatment).
Time frame: 24 Weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| VE303 High Dose | CDI Recurrence Week 24 | C. difficile recurrences (laboratory-confirmed) | 5 Participants |
| VE303 High Dose | CDI Recurrence Week 24 | C. difficile recurrences (toxin-positive) | 4 Participants |
| VE303 High Dose | CDI Recurrence Week 24 | C. difficile recurrences (laboratory-confirmed or clinically diagnosed and treated) | 5 Participants |
| VE303 Low Dose | CDI Recurrence Week 24 | C. difficile recurrences (laboratory-confirmed) | 11 Participants |
| VE303 Low Dose | CDI Recurrence Week 24 | C. difficile recurrences (toxin-positive) | 9 Participants |
| VE303 Low Dose | CDI Recurrence Week 24 | C. difficile recurrences (laboratory-confirmed or clinically diagnosed and treated) | 11 Participants |
| Placebo | CDI Recurrence Week 24 | C. difficile recurrences (toxin-positive) | 5 Participants |
| Placebo | CDI Recurrence Week 24 | C. difficile recurrences (laboratory-confirmed or clinically diagnosed and treated) | 10 Participants |
| Placebo | CDI Recurrence Week 24 | C. difficile recurrences (laboratory-confirmed) | 8 Participants |
Other Pre-specified
CDI Recurrence Week 4
Percentage of participants with toxin-positive, laboratory-confirmed, or clinically diagnosed and treated CDI recurrence before or at Week 4 (i.e., 4 weeks after the first dose of study treatment).
Time frame: 4 Weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| VE303 High Dose | CDI Recurrence Week 4 | C. difficile recurrences (laboratory-confirmed) | 4 Participants |
| VE303 High Dose | CDI Recurrence Week 4 | C. difficile recurrences (toxin-positive) | 4 Participants |
| VE303 High Dose | CDI Recurrence Week 4 | C. difficile recurrences (laboratory-confirmed, or clinically diagnosed and treated) | 4 Participants |
| VE303 Low Dose | CDI Recurrence Week 4 | C. difficile recurrences (laboratory-confirmed) | 10 Participants |
| VE303 Low Dose | CDI Recurrence Week 4 | C. difficile recurrences (toxin-positive) | 9 Participants |
| VE303 Low Dose | CDI Recurrence Week 4 | C. difficile recurrences (laboratory-confirmed, or clinically diagnosed and treated) | 10 Participants |
| Placebo | CDI Recurrence Week 4 | C. difficile recurrences (toxin-positive) | 2 Participants |
| Placebo | CDI Recurrence Week 4 | C. difficile recurrences (laboratory-confirmed, or clinically diagnosed and treated) | 6 Participants |
| Placebo | CDI Recurrence Week 4 | C. difficile recurrences (laboratory-confirmed) | 5 Participants |
Other Pre-specified
Changes in the Fecal Metabolomic Profile, Including Short-chain Fatty Acids and Bile Acids.
Changes in the fecal metabolomic profile, including short-chain fatty acids and bile acids for the duration of the study.
Time frame: 31 Months 1 Week
Other Pre-specified
Determine the Recommended VE303 Phase 3 Dose Regimen(s).
Determine the recommended VE303 phase 3 dose regimen(s) based on safety and efficacy, as indicated by the CDI recurrence rate for the duration of the study.
Time frame: 31 Months 1 Week
Other Pre-specified
Microbiota Diversity
Characterize the fecal microbiome Shannon Diversity at week 24.
Time frame: 24 weeks
Other Pre-specified
Taxonomic Composition
Characterize Taxonomic Composition
Time frame: 31 Months, 1 Week