First-in-human Study of VE303 in Healthy Adult Volunteers

Study Overview
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Brief Summary
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This study was designed to evaluate safety and tolerability of a range of doses of VE303 in healthy adult volunteers. The study also evaluated pharmacokinetics of intestinal colonization by the VE303 strains and pharmacodynamics of recovery of the gut microbiota after administration of antibiotics followed by a course of VE303.

Detailed Description
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VE303 is a rationally-defined bacterial consortium candidate being developed for the prevention of recurrent C. difficile infection. VE303 consists of 8 types of clonal human commensal bacteria strains selected for their ability to provide colonization resistance to C. difficile and manufactured under GMP conditions.

Official Title
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A Phase 1a/1b, First-in-human, Open-label Study of Escalating Doses of VE303 in Healthy Adult Volunteers With or Without Vancomycin Pre-treatment to Evaluate Safety, Dosing, and Pharmacodynamics

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: VE303
* Drug: Oral Vancomycin


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Subjects who are judged to be in general good health Body mass index between 18.5 and 30 kg/m2 Women either of non-child bearing potential or using a highly effective form of contraception Men using a highly effective method of contraception Key Exclusion Criteria: Past or present clinically significant diseases that may affect the outcome of the study Taking any medications, herbal preparations, or natural substances, live bacteria products, or food that impacts or alter GI flora Use of proton pump inhibitors or other short or long acting antacid medications Taking or has received an investigation drug or treatment within 60 days of inpatient admission Known allergies to involved study drugs Chronic constipation or diarrhea History of or active IBD

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This Phase 1a/1b, first-in-human, open-label, single-center, dose-escalation study will evaluate the safety and microbiota changes induced by ingestion of VE303 following administration of oral vancomycin and VE303 administered without vancomycin pre-treatment in healthy adult subjects. Approximately 48 subjects are anticipated for enrollment, unless intermediate cohorts are required, in which case, up to an additional 18 subjects (for a total of approximately 66 subjects) may be enrolled.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Cohort 1 received oral vancomycin followed by a single dose of VE303. | Drug: VE303<br>* The VE303 Drug Product is a live biotherapeutic product (LBP) consisting of 8 clonal human commensal bacterial strains manufactured under GMP conditions.<br>Drug: Oral Vancomycin<br>* Vancomycin, when taken by mouth, is used to treat Clostridium difficile-associated diarrhea.<br>|
| Experimental: Cohort 2<br>Cohort 2 received oral vancomycin followed by a single day of 5 doses of VE303. | Drug: VE303<br>* The VE303 Drug Product is a live biotherapeutic product (LBP) consisting of 8 clonal human commensal bacterial strains manufactured under GMP conditions.<br>Drug: Oral Vancomycin<br>* Vancomycin, when taken by mouth, is used to treat Clostridium difficile-associated diarrhea.<br>|
| Experimental: Cohort 3<br>Cohort 3 received oral vancomycin followed by a single day of 10 doses of VE303. | Drug: VE303<br>* The VE303 Drug Product is a live biotherapeutic product (LBP) consisting of 8 clonal human commensal bacterial strains manufactured under GMP conditions.<br>Drug: Oral Vancomycin<br>* Vancomycin, when taken by mouth, is used to treat Clostridium difficile-associated diarrhea.<br>|
| Experimental: Cohort 4<br>Cohort 4 received oral vancomycin followed by 5 days of 10 doses daily of VE303. | Drug: VE303<br>* The VE303 Drug Product is a live biotherapeutic product (LBP) consisting of 8 clonal human commensal bacterial strains manufactured under GMP conditions.<br>Drug: Oral Vancomycin<br>* Vancomycin, when taken by mouth, is used to treat Clostridium difficile-associated diarrhea.<br>|
| Experimental: Cohort 5<br>Cohort 5 received oral vancomycin followed by 14 days of 10 capsules daily of VE303 | Drug: VE303<br>* The VE303 Drug Product is a live biotherapeutic product (LBP) consisting of 8 clonal human commensal bacterial strains manufactured under GMP conditions.<br>Drug: Oral Vancomycin<br>* Vancomycin, when taken by mouth, is used to treat Clostridium difficile-associated diarrhea.<br>|
| Experimental: Cohort 6<br>Cohort 6 received 21 days of 10 doses daily of VE303 | Drug: VE303<br>* The VE303 Drug Product is a live biotherapeutic product (LBP) consisting of 8 clonal human commensal bacterial strains manufactured under GMP conditions.<br>|
| Experimental: Cohort 7<br>Cohort 7 received oral vancomycin followed by 10 doses of VE303 daily for 2 days, followed by 2 doses of VE303 daily for 3 days | Drug: VE303<br>* The VE303 Drug Product is a live biotherapeutic product (LBP) consisting of 8 clonal human commensal bacterial strains manufactured under GMP conditions.<br>Drug: Oral Vancomycin<br>* Vancomycin, when taken by mouth, is used to treat Clostridium difficile-associated diarrhea.<br>|
| Experimental: Cohort 8<br>Cohort 8 received oral vancomycin followed by 10 doses of VE303 daily for 2 days, followed by 2 doses of VE303 daily for 3 days | Drug: VE303<br>* The VE303 Drug Product is a live biotherapeutic product (LBP) consisting of 8 clonal human commensal bacterial strains manufactured under GMP conditions.<br>Drug: Oral Vancomycin<br>* Vancomycin, when taken by mouth, is used to treat Clostridium difficile-associated diarrhea.<br>|
| Experimental: Cohort 9<br>Cohort 8 received oral vancomycin followed by 10 doses of VE303 daily for 2 days, followed by 2 doses of VE303 daily for 3 days | Drug: VE303<br>* The VE303 Drug Product is a live biotherapeutic product (LBP) consisting of 8 clonal human commensal bacterial strains manufactured under GMP conditions.<br>Drug: Oral Vancomycin<br>* Vancomycin, when taken by mouth, is used to treat Clostridium difficile-associated diarrhea.<br>|
| Placebo Comparator: Vancomycin only<br>This cohort only received oral vancomycin. | Drug: Oral Vancomycin<br>* Vancomycin, when taken by mouth, is used to treat Clostridium difficile-associated diarrhea.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of VE303 measured by incidence adverse events (AEs) | Measured in terms of incidence of AEs according to CTCAE V4.0 | 12 months post-dose | 
| Tolerability of VE303 using modified PROMIS questionnaire (v1.0) | Characterized the highest well tolerated dose regimen of VE303 using modified PROMIS questionnaire (v1.0) | 12 months post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the colonization of the intestinal microbiota with VE303 component bacteria | Measurement of VE303 strain colonization in stool samples was performed using a metagenomic sequencing-based bioinformatic approach. A strain-specific marker panel was employed to characterize the relative abundance of VE303 strains in the intestinal microbiota. | 12 months post-dose | 
| Evaluate the changes in the intestinal microbiota due to VE303 dosing. | Measurement of intestinal microbiota due to VE303 dosing was performed using metagenomic sequencing- and metabolomic analysis-based approaches. Thus, focusing on taxonomic and functional changes occurring in the gut. | 12 months post-dose | 
| Evaluate the metabolomic changes in stool due to VE303 dosing. | Quantified changes in pool of metabolite levels (bile acids and short-chain fatty acids) from stool samples | 12 months post-dose |