VE303-003

To compare the CDI recurrence rate at week 8 in participants treated with VE303 versus placebo

Double-Blind, Placebo-Controlled Study: 

• To assess the safety profile in participants treated with VE303 versus placebo,
• To compare the CDI recurrence rate at Weeks 12 and 24 in participants treated with VE303 versus placebo,
• To assess VE303 bacterial strain detection, relative abundance, and duration in participants treated with VE303 versus placebo,
• To measure health-related quality of life and daily CDI symptoms in participants treated with VE303 versus placebo,
• To describe the association of VE303 strain colonization with efficacy in participants treated with VE303 versus placebo,

Exploratory:

• To assess the fecal metabolite profile, and identify associations with efficacy in participants treated with VE303 versus placebo
• To assess the fecal microbiota diversity and taxonomic composition, and identify associations with efficacy in participants treated with VE303 versus placebo,
• To measure changes in CDI- associated immune biomarkers in participants treated with VE303 versus placebo,
• To quantify the CDI-related healthcare resource utilization in participants treated with VE303 versus placebo,
• To assess work productivity and activity in participants treated with VE303 versus placebo.

Open-Label Treatment:

• To assess the safety profile in participants who receive open-label VE303 following an on-study CDI recurrence,
• To assess the CDI recurrence rate at Week 8 in participants treated with open-label VE303 following an on-study CDI recurrence,
• To assess VE303 component bacterial strain detection, relative abundance, and duration in participants who receive open-label VE303 following an on-study CDI recurrence,

Exploratory:

• To explore the fecal metabolite profile in participants who receive open-label VE303 following an on- study CDI recurrence,
• To explore the fecal microbiota diversity and taxonomic composition in participants who receive open-label VE303 following an on-study CDI recurrence,
• To explore if VE303 strain colonization is associated with efficacy in participants who receive open-label VE303 following an on- study CDI recurrence,
• To measure changes in CDI- associated immune biomarkers in participants who receive open-label VE303 following an on-study CDI recurrence.

Participants will be eligible for inclusion if they meet all of the following criteria:

For enrollment in Stage 1 (rCDI population):

1. Age ≥ 12 years with a laboratory-confirmed qualifying episode of CDI and at least one prior occurrence of CDI within the last 6 months

For enrollment in Stage 2 (pCDI-hr population):

2. Age ≥ 75 years with a laboratory-confirmed qualifying episode of CDI or

3. Age ≥ 12 years with a laboratory-confirmed qualifying episode of CDI and at least two of the following risk factors:
– Age ≥ 65 years
– Kidney dysfunction, defined as estimated creatinine clearance
< 60mL/min/1.73 m2 at the time of the qualifying CDI episode
– History of regular use of a proton pump inhibitor (PPI) within the past 2 months and expectation of continued use of PPIs throughout the study
– History of a prior CDI episode between 6 and 12 months prior to enrollment
– Immunosuppression due to an underlying disease or its treatment (see Appendix 3)
– Has undergone solid organ or hematopoietic stem cell transplantation

For enrollment in either Stage 1 or Stage 2:

4. The qualifying episode of CDI must meet all the following criteria:
a. New onset of ≥ 3 unformed bowel movements (ie, Types 5 to 7 on the Bristol stool scale) within 24 hours for at least 2 consecutive days
b. CDI symptoms started within 4 weeks prior to the initiation of SoC antibiotic therapy for CDI
c. Stool sample collected before (or no later than 72 hours after) initiation of SoC antibiotic therapy that was positive in a CDI laboratory test, defined as EIA for toxin A/B and GDH (with PCR reflex testing for discordant GDH/EIA toxin results), as performed at either a local laboratory or the central laboratory
d. Diarrhea considered unlikely to have another etiology

5. Prior to receiving study medication, the participant should:
a. Receive and complete a course of SoC antibiotics for at least 10 days, up to a maximum of 21 days (Note: choice of SoC agent is at the physician’s discretion and antibiotic tapering is not allowed)
b. Meet the criterion for a successful clinical response, defined as symptomatic control of the qualifying CDI episode, ie, < 3 loose/unformed bowel movements per 24 hours for at least 2 consecutive days

6. Persons of childbearing potential must have a negative pregnancy test and must agree to either use a highly effective, acceptable form of birth control (highly effective contraception is defined as a method that can achieve a failure rate of less than 1% per year when used consistently and correctly, eg, established hormonal birth control plus a barrier method, hormonal methods of contraception when associated with inhibition of ovulation, including implants, injectables, combined oral contraceptives, some intrauterine devices), remain sexually abstinent during the study period and up to 3 months after the last dose of study drug, or be exclusively with female and/or vasectomized partner(s) who have had medical confirmation of surgical success

7. Able to receive the first dose of study drug on the last planned day of SoC antibiotic administration for a qualifying CDI episode, or no later than 1 day after completion of antibiotic dosing

8. Recovered from any complications of severe or fulminant CDI and be clinically stable by the time of randomization

9. Able and willing to follow study assessments (eg, able to swallow oral capsules, comply with study visits and procedures, provide blood and stool samples, complete questionnaires)

10. Able and willing to provide written informed consent/assent prior to initiation of any study-specific procedure or study drug administration and aware of the potential risks and benefits of study enrollment and study drug administration. When appropriate, informed consent may be provided by a legally-authorized representative (LAR). For participants younger than the age of majority (18 years of age in most geographies), the consent should be signed or co-signed by the participant’s legal guardian and a child-specific assent form may be used, consistent with local regulations and practices.

Exclusion Criteria (for both Stage 1 and Stage 2):

Participants must be excluded from the study except where noted if any of the following criteria are met:

1. History of chronic diarrhea (defined as ≥ 3 loose stools per day lasting for at least 4
weeks) within 3 months prior to randomization that is not related to CDI

2. Laboratory-confirmed infectious diarrhea other than CDI (including bacterial, viral, or parasitic etiology) within 30 days prior to randomization

3. Known or suspected toxic megacolon or small bowel ileus at the time of randomization

4. History of confirmed celiac disease, inflammatory bowel disease, microscopic colitis, short gut, gastrointestinal (GI) tract fistulas, or a recent episode (within 6 months of screening) of intestinal ischemia or ischemic colitis

5. Contraindication to oral/enteral therapy (eg, severe reflux, severe nausea/vomiting, or ileus) at the time of randomization

6. White blood cell count > 15.0 × 109 cells/L at the time of randomization

7. Absolute neutrophil count (ANC) of < 0.5 ×109 cells/L on 2 consecutive occasions within 7 days prior to randomization, or sustained ANC < 1.0 × 109 cells/L

8. Use of probiotics within 2 weeks prior to randomization (Note: consumption of food- based probiotics such as yogurt, kombucha, and kefir is permissible)

9. Receipt of bezlotoxumab during the course of SoC antibiotic treatment for the qualifying CDI episode

10. Receipt of SER-109/VOWST™, RBX2660/REBYOTA®, or any other approved or investigational genetically modified live bacterial, fungal, viral, or bacteriophage isolates, fecal-derived live bacterial isolates, or other LBPs for CDI-associated diarrhea, including fecal microbiota transplantation, within 6 months prior to randomization

11. Use of antidiarrheal drugs (eg, loperamide, diphenoxylate) within 3 days prior to the planned first dose of study drug

12. Anticipated administration of oral or parenteral antibacterial therapy for a non-CDI indication after randomization through week 24 (end of study).

13. History of malignancy and receipt of chemotherapy or other treatments with known GI adverse effects within 2 months prior to randomization

14. Receipt of any investigational drug or investigational vaccine within 30 days prior to randomization

15. Current or immediate potential for mechanical ventilation or vasopressors for hemodynamic support

16. Life expectancy of < 3 months

17. Major GI surgery (eg, significant bowel resection or diversion) within 3 months prior to randomization, current ileostomy, or history of total colectomy. Participants with a history of appendectomy, cholecystectomy, or gastric restrictive procedures, such as banding, may be permitted upon discussion with the Medical Monitor if surgery was at least 1 month prior to randomization and the participant has fully recovered

18. Pregnant or breastfeeding

19. Known hypersensitivity/allergy/intolerance to any ingredient in the VE303 study formulation (sucrose, histidine, yeast extract, cysteine, sodium metabisulfite, microcrystalline cellulose, simethicone, and magnesium stearate.)

20. Clinically significant or poorly controlled medical or surgical condition not mentioned in the above criteria that, in the Investigator’s opinion, could interfere with the administration of study drug, interpretation of study’s safety or efficacy data, or compromise the safety or wellbeing of the participant.

This is a randomized, double-blind, placebo-controlled Phase 3 study to evaluate the efficacy, safety, and microbiota changes following administration of VE303 compared with placebo in preventing CDI recurrence following completion of a course of SoC antibiotics in participants with Rcdi and participants with Pcdi-hr. The study populations will be enrolled in a staggered manner, with 2 distinct study stages: Stage 1 will enroll participants with Rcdi; once 50% of the total Rcdi population has reached Week 8, an interim analysis (IA) will be conducted to assess efficacy and safety (without stopping rules) and act as a trigger for beginning enrollment in Stage
2. Participants with Pcdi-hr will be enrolled only if the DMC declares that safety and efficacy in the Rcdi population is acceptable. The trigger to start Stage 2 will be based on a minimal threshold of efficacy for Stage 1.