A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of VE303 for Prevention of Recurrent Clostridioides difficile Infection: The RestoratiVE303 Study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Vedanta Biosciences Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

Trial duration

31 Oct 2024 → ongoing

Decision date (initial)

2024-10-11

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2022-502972-22-00

ClinicalTrials.gov

NCT06237452

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Others, Safety

To compare the Clostridioides difficile infection (CDI) recurrence rate at Week 8 in participants treated with VE303 versus placebo.

Secondary objectives 5

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

Conditions and MedDRA coding

Clostridioides difficile infection.

Study design 5 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-003601-PIP01-24

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 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
2. 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
3. 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
4. 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.
5. 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.
6. 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
7. 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
8. 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)
9. 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.
10. Inclusion Criteria for the VE303 Safety Cohort: Inclusion criteria will be identical to the aforementioned Stage 1 population.

Exclusion criteria 19

1. 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
2. Receipt of bezlotoxumab during the course of SoC antibiotic treatment for the qualifying CDI episode
3. Use of antidiarrheal drugs (eg, loperamide, diphenoxylate) within 3 days prior to the planned first dose of study drug
4. Anticipated administration of oral or parenteral antibacterial therapy for a non-CDI indication after randomization through week 24 (end of study).
5. Receipt of chemotherapy or other antineoplastic treatment with known GI adverse effects within 2 months prior to randomization
6. Receipt of any investigational drug or investigational vaccine within 30 days prior to randomization
7. Current or immediate potential for mechanical ventilation or vasopressors for hemodynamic support
8. Life expectancy of < 3 months
9. 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
10. White blood cell count > 15.0 × 109 cells/L within 7 days prior to randomization
11. Pregnant or breastfeeding
12. Known hypersensitivity/allergy/intolerance to any ingredient in the VE303 study formulation.
13. Infectious diarrhea other than CDI (including bacterial, viral, or parasitic etiology) identified with the qualifying CDI episode
14. 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.
15. Known or suspected toxic megacolon or small bowel ileus at the time of randomization
16. 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
17. Contraindication to oral/enteral therapy (eg, severe reflux, severe nausea/vomiting, or ileus) at the time of randomization
18. 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
19. 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 .

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Proportion of participants with central laboratory confirmed CDI recurrence through Week 8

Secondary endpoints 5

1. 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 week 8 and 248 (primary safety endpoint) and week 24
2. Proportion of participants with central laboratory confirmed CDI recurrence through Week 12 and Week 24
3. Fecal VE303 bacterial strain colonization detection, abundance and duration
4. Change from baseline in the the short-chain fatty acids (Cdiff32) score Change from baseline in EQ-5D score, utility index, and EuroQol Visual Analogue Scale ( EQ VAS ) score Change from baseline in CDI-Daily Symptoms ( CDI-DaySyms) daily symptoms score
5. Relationship between of VE303 strain colonization and CDI recurrence rate and time to recurrence.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Vedanta Biosciences Inc.

Sponsor organisation

Vedanta Biosciences Inc.

Address

19 Blackstone Street

City

Cambridge

Postcode

02139-3709

Country

United States

Scientific contact point

Organisation

Vedanta Biosciences Inc.

Contact name

Dr. Steven Shiff

Public contact point

Organisation

Vedanta Biosciences Inc.

Contact name

Mary Garfield

Third parties 1

Locations

14 EU/EEA countries · 75 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 265 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications