Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of VE303 for Recurrent Clostridioides difficile Infection Prevention in Adults
- Trial ID
- 2022-502972-22-00
- Protocol
- VE303-003
- Sponsor
- Vedanta Biosciences Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **Clostridioides difficile infection** (CDI) recurrence rate at Week 8 in participants treated with VE303 versus placebo. This is clinically relevant as CDI is a significant cause of morbidity, and reducing recurrence rates can improve patient outcomes and reduce healthcare burdens.
Secondary objectives include:
- Assessing the safety profile in participants treated with VE303 versus placebo.
- Comparing the CDI recurrence rate at Weeks 12 and 24 in participants treated with VE303 versus placebo.
- Evaluating VE303 bacterial strain detection, relative abundance, and duration in participants treated with VE303 versus placebo.
- Measuring health-related quality of life and daily CDI symptoms in participants treated with VE303 versus placebo.
- Describing the association of VE303 strain colonization with efficacy in participants treated with VE303 versus placebo.
Participants
The clinical trial involves a total of **264 participants** diagnosed with **Clostridioides difficile infection** (CDI). The study population includes both male and female subjects, with an age range starting from 12 years, where adolescents are permitted, and extending to individuals aged 75 years and older. Participants were selected based on a laboratory-confirmed qualifying episode of CDI, with specific criteria for recurrence or high-risk populations. The trial includes individuals with varying health statuses, including those with kidney dysfunction, a history of proton pump inhibitor use, prior CDI episodes, immunosuppression, or those who have undergone organ transplantation. The study population is characterized by a diverse range of ages and health conditions, reflecting a vulnerable population. Participants are required to have completed a course of standard-of-care antibiotic therapy and must be clinically stable at the time of randomization. The trial does not specify particular lifestyle considerations such as diet or physical activity. The selection process ensures that participants are able and willing to comply with study procedures, including the ability to swallow oral capsules and provide necessary samples and data.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled** Phase 3 study aimed at evaluating the efficacy of VE303 in preventing recurrent **Clostridioides difficile infection** (CDI). The trial will compare the CDI recurrence rate at Week 8 between participants treated with VE303 and those receiving a placebo. The study will involve participants aged 12 years and older, with specific inclusion criteria based on age and risk factors for CDI recurrence. The trial is expected to commence recruitment on September 12, 2024, and conclude by September 25, 2027.
Participants will be involved in the study for a maximum of 24 weeks, with the primary endpoint being the proportion of participants with laboratory-confirmed CDI recurrence through Week 8. Secondary endpoints include the incidence and severity of treatment-emergent adverse events, CDI recurrence through Week 12 and Week 24, and the relationship between VE303 strain colonization and CDI recurrence rate. The study will also assess changes in quality of life scores and symptom severity from baseline.
The trial will consist of several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the principal inclusion criteria. Participants will then be randomized to receive either VE303 or placebo capsules, which are visually identical and contain microcrystalline cellulose. The study drug will be administered orally, with a maximum daily dose of 3 capsules and a total treatment period of 14 days. Follow-up visits will occur at Weeks 8, 12, and 24 to monitor CDI recurrence and adverse events. The end-of-study visit will assess the final outcomes and collect any remaining data.
Participants may be terminated early from the study if they experience severe adverse events, fail to comply with study procedures, or withdraw consent. The trial will ensure that all participants provide written informed consent, with additional provisions for minors and those unable to consent independently. The study aims to provide robust data on the efficacy and safety of VE303 in preventing CDI recurrence, contributing to improved management strategies for this condition.
Treatment
The clinical trial involves the administration of **VE303**, an experimental medication formulated as a **capsule**. VE303 is composed of a consortium of live bacterial strains, specifically selected for their potential therapeutic effects. The active substances include various strains of **Clostridia** and **Bacilli**, such as Clostridia, Cluster XIVa, Strain Relative Clostridium_Q Symbiosum, and Bacilli, Cluster XVII, Strain Relative Clostridium_AQ Innocuum, among others. These strains are structurally diverse and are provided in a live form. The medication is administered orally, with a maximum daily dose of three capsules, and a total maximum dose of 42 capsules over a treatment period of 14 days. The primary objective of the trial is to evaluate the efficacy of VE303 in preventing the recurrence of **Clostridioides difficile infection** (CDI) by comparing the recurrence rate at Week 8 between participants treated with VE303 and those receiving a placebo.
The study also includes a **placebo** control, which consists of capsules containing microcrystalline cellulose. These placebo capsules are visually identical to the VE303 capsules and are indistinguishable in appearance. Importantly, the placebo capsules do not contain any bacterial strains or formulation buffer used in the VE303 drug product. The use of a placebo is critical for maintaining the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. This design allows for an unbiased comparison of the treatment effects of VE303 against the placebo, thereby providing robust data on the efficacy of the experimental medication.
Efficacy
Efficacy in this clinical trial will be assessed by evaluating the **Clostridioides difficile** infection (CDI) recurrence rate at Week 8 in participants treated with VE303 compared to those receiving a placebo. The primary endpoint is the proportion of participants with laboratory-confirmed CDI recurrence through Week 8. Secondary endpoints include the incidence and severity of treatment-emergent adverse events (TEAEs), treatment-related TEAEs, serious adverse events (SAEs), medically attended adverse events (MAAEs), and adverse events of special interest (AESIs) through Weeks 8 and 24. Additionally, the proportion of participants with laboratory-confirmed CDI recurrence will be assessed through Weeks 12 and 24.
Further secondary endpoints involve the fecal VE303 bacterial strain colonization abundance and duration, changes from baseline in the Cdiff32 score, EQ-5D score, utility index, EQ VAS score, and CDI-DaySyms daily symptoms score. The relationship between VE303 strain colonization and CDI recurrence rate and time to recurrence will also be analyzed. These efficacy parameters will be measured and collected at specified timepoints, including Weeks 8, 12, and 24, using validated laboratory tests and patient-reported outcomes. The analysis will focus on comparing the outcomes between the VE303 and placebo groups to determine the efficacy of VE303 in preventing recurrent CDI.
Inclusion and Exclusion Criteria
Inclusion Criteria
- For enrollment in Stage 1 (rCDI population): Age ≥ 12 years where enrollment of adolescents is permitted, and age ≥ 18 years of age or older in other countries, 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): Age ≥ 75 years with a laboratory-confirmed qualifying episode of CDI or Age ≥ 12 years to 74 years where enrollment of adolescents is permitted, and age 18 to 74 in other countries, 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 m2at 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 Has undergone solid organ or hematopoietic stem cell transplantation
- For enrollment in either Stage 1 or Stage 2: 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 results), as performed at either a local laboratory or the central laboratory d. Diarrhea considered unlikely to have another etiology
- For enrollment in either Stage 1 or Stage 2: Prior to receiving study medication, the participant should: a. Receive and complete a course of SoC antibiotic therapy for at least 10 days, up to a maximum of 28 days (The choice of SoC agent is at the physician’s discretion. To ensure that adequate antibiotic levels are maintained in the gut to allow for subsequent VE303 strain colonization: i. Vancomycin must be administered at a dosing frequency of at least twice daily. ii. Fidaxomicin must be administered at a dosing frequency of at least once daily. 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.
- For enrollment in either Stage 1 or Stage 2: 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. Sexual abstinence is defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method are not acceptable methods of contraception.
- For enrollment in either Stage 1 or Stage 2: 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 2 days after completion of antibiotic dosing
- For enrollment in either Stage 1 or Stage 2: Recovered from any complications of severe or fulminant CDI and be clinically stable by the time of randomization
- For enrollment in either Stage 1 or Stage 2: 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)
- For enrollment in either Stage 1 or Stage 2: 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.
- Inclusion Criteria for the VE303 Safety Cohort: Inclusion criteria will be identical to the aforementioned Stage 1 population.
Exclusion Criteria
- for Double-Blind Treatment (1-18) :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
- Receipt of bezlotoxumab during the course of SoC antibiotic treatment for the qualifying CDI episode
- Use of antidiarrheal drugs (eg, loperamide, diphenoxylate) within 3 days prior to the planned first dose of study drug
- Anticipated administration of oral or parenteral antibacterial therapy for a non-CDI indication after randomization through week 24 (end of study).
- Receipt of chemotherapy or other antineoplastic treatment with known GI adverse effects within 2 months prior to randomization
- Receipt of any investigational drug or investigational vaccine within 30 days prior to randomization
- Current or immediate potential for mechanical ventilation or vasopressors for hemodynamic support
- Life expectancy of < 3 months
- 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
- White blood cell count > 15.0 × 109 cells/L within 7 days prior to randomization
- Pregnant or breastfeeding
- Known hypersensitivity/allergy/intolerance to any ingredient in the VE303 study formulation.
- Infectious diarrhea other than CDI (including bacterial, viral, or parasitic etiology) identified with the qualifying CDI episode
- 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 well-being of the participant.
- Known or suspected toxic megacolon or small bowel ileus at the time of randomization
- 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
- Contraindication to oral/enteral therapy (eg, severe reflux, severe nausea/vomiting, or ileus) at the time of randomization
- Absolute neutrophil count (ANC) of < 0.5 ×10^9 cells/L on 2 consecutive occasions within 7 days prior to randomization, or sustained ANC < 1.0 × 109 cells/L
- Exclusion Criteria for the VE303 Safety Cohort: Participants must be excluded from the study except where noted if any of the criteria are met. Exclusion criteria will be identical to the aforementioned Stage 1 population for points 1,2,3,5,7,9,10,11,12,13,14,15,16,17,18 excluding criterion: 6 and 8 as NA , and different for criterion: 4. GI tract fistulas .
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Recruiting | 12 Sept 2024 | 5 |
 Bulgaria | Recruiting | 12 Sept 2024 | 20 |
 Czechia | Not Recruiting | 12 Sept 2024 | 8 |
 Denmark | Recruiting | 12 Sept 2024 | 12 |
 France | Recruiting | 12 Sept 2024 | 10 |
 Germany | Recruiting | 12 Sept 2024 | 10 |
 Hungary | Recruiting | 12 Sept 2024 | 10 |
 Ireland | Not Recruiting | 12 Sept 2024 | 3 |
 Italy | Recruiting | 12 Sept 2024 | 14 |
 The Netherlands | Recruiting | 12 Sept 2024 | — |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Placebo capsules containing microcrystalline cellulose, visually identical to and not discernible from VE303 capsules. Placebo capsules do not contain any bacterial strains or formulation buffer used in the VE303 drug product. | Placebo | N/A | — | — | — | N/A |