A Study to Understand the Safety and Effects of New Formulations of a Clostridioides Difficile Vaccine Shot That Will be Given to Healthy Adults

Study Overview
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Brief Summary
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An antibody is a substance your body makes to fight off infection. This study will explore the safety and antibody response of a vaccine to prevent severe diarrhea caused by a germ called Clostridoides difficile (C. diff). Three new formulations of the C. diff vaccine will be used in this study, in addition to a C. diff vaccine formulation that has been studied in previous clinical trials. The purpose of this study is to understand if giving the new C. diff vaccine formulations helps people make as many antibodies as giving the previously studied C. diff vaccine formulation. The study is divided into 2 phases. Phase 1 will evaluate 3 new formulations of the C. diff vaccine and 2 dosing schedules spread out over 2 months or 6 months. The Phase 1 portion of the study is seeking participants: who are healthy adults of 65 to 84 years of age who have not had a C. diff infection before who have not received a C. diff vaccine or C. diff monoclonal antibody therapy before. All participants in Phase 1 will receive study injections with active vaccine or placebo at each vaccination visit, depending on the vaccine group to which they are assigned. A placebo does not contain any active ingredients. Participants in Phase 1 will attend at least 9 study visits and will take part in the study for approximately 18 months. Based on the results of Phase 1, 1 or 2 of the new C. diff vaccine formulations will be chosen for further study in Phase 2. Phase 2 will evaluate the safety and effects of the new C. diff vaccine formulation(s) chosen in Phase 1. The Phase 2 portion of the study is seeking participants: who are healthy adults of 50 to 84 years of age who have not had a C. diff infection before who have not received a C. diff vaccine or C. diff monoclonal antibody therapy before. All Phase 2 participants will receive active C. diff vaccine at each vaccination visit. Participants in Phase 2 will attend at least 9 study visits and will take part in the study for approximately 4.5 years.

Official Title
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A Phase 1 Randomized and Phase 2 Study to Evaluate the Safety, Tolerability, Immunogenicity, and Immunopersistence of a Clostridioides Difficile Vaccine Administered in a 2-Dose Regimen With Novel Adjuvants in Healthy Adults

Conditions
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Clostridoides Difficile Associated Disease

Intervention / Treatment
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* Biological: C. difficile vaccine (previously studied formulation)
* Biological: C. difficile vaccine formulation 1
* Biological: C. difficile vaccine formulation 2
* Biological: C. difficile vaccine formulation 3
* Other: Saline Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Each phase of the study will enroll participants in different age categories: Phase 1: Participants ≥65 to <85 years of age; Phase 2: Participants ≥50 to <85 years of age. Healthy participants as determined by medical history, clinical assessment, and the judgment of the investigator. Participants who are willing and able to comply with all scheduled visits, investigational plan, laboratory tests, lifestyle considerations, and other study procedures. Capable of giving personally signed informed consent, which includes compliance with the requirements and restrictions listed in the ICD and in this protocol. Exclusion Criteria: Pregnant or breastfeeding female participants; fertile male participants and WOCBP who are unwilling or unable to use an effective method of contraception from the signing of informed consent until at least 28 days after the last dose of study intervention. Serious chronic disorder, including history of metastatic malignancy, severe COPD requiring supplemental oxygen, end-stage renal disease with or without dialysis, cirrhosis of the liver, clinically unstable cardiac disease, or any other disorder that, in the investigator's opinion, would make the participant inappropriate for entry into the study. Any contraindication to vaccination or vaccine components, including previous hypersensitivity or anaphylactic reaction to any vaccine or vaccine-related components. Prior episode of CDI, confirmed by either laboratory test or diagnosis of pseudomembranous colitis at colonoscopy, at surgery, or histopathologically. Any bleeding disorder or anticoagulant therapy that would contraindicate intramuscular injection. Known or suspected immunodeficiency or other conditions associated with immunosuppression, including, but not limited to, leukocyte, lymphocyte, or immunoglobulin class/subclass deficiencies or abnormalities, generalized malignancy, HIV infection, leukemia, lymphoma, or organ or bone marrow transplant. Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study. Previous receipt of an investigational C difficile vaccine or C difficile mAb therapy. Receipt of blood product or immunoglobulin within 6 months before enrollment. Currently receives treatment with immunosuppressive therapy, including cytotoxic agents or systemic corticosteroids, or planned receipt throughout the study. Participants may not be enrolled if corticosteroids were administered within 28 days before study intervention administration. Participation in other studies involving investigational drugs, investigational vaccines, or investigational devices within 28 days prior to study entry through 12 months after the last dose of study intervention. Phase 1 only: Any screening hematology and/or blood chemistry laboratory value that meets the definition of a ≥ Grade 1 abnormality. Investigator site staff directly involved in the conduct of the study and their family members, site staff otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 84 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: C. difficile vaccine formulation 1, 2-month schedule (Phase 1)<br>Novel vaccine formulation 1 | Biological: C. difficile vaccine formulation 1<br>* C. difficile vaccine formulation 1 given as an intramuscular injection<br>Other: Saline Placebo<br>* 0.9% sodium chloride solution given as an intramuscular injection<br>|
| Experimental: C. difficile vaccine formulation 2, 2-month schedule (Phase 1)<br>Novel vaccine formulation 2 | Biological: C. difficile vaccine formulation 2<br>* C. difficile vaccine formulation 2 given as an intramuscular injection<br>Other: Saline Placebo<br>* 0.9% sodium chloride solution given as an intramuscular injection<br>|
| Experimental: C. difficile vaccine formulation 3, 2-month schedule (Phase 1)<br>Novel vaccine formulation 3 | Biological: C. difficile vaccine formulation 3<br>* C. difficile vaccine formulation 3 given as an intramuscular injection<br>Other: Saline Placebo<br>* 0.9% sodium chloride solution given as an intramuscular injection<br>|
| Experimental: C. difficile vaccine formulation 1, 6-month schedule (Phase 1)<br>Novel vaccine formulation 1 | Biological: C. difficile vaccine formulation 1<br>* C. difficile vaccine formulation 1 given as an intramuscular injection<br>Other: Saline Placebo<br>* 0.9% sodium chloride solution given as an intramuscular injection<br>|
| Experimental: C. difficile vaccine formulation 2, 6-month schedule (Phase 1)<br>Novel vaccine formulation 2 | Biological: C. difficile vaccine formulation 2<br>* C. difficile vaccine formulation 2 given as an intramuscular injection<br>Other: Saline Placebo<br>* 0.9% sodium chloride solution given as an intramuscular injection<br>|
| Experimental: C. difficile vaccine formulation 3, 6-month schedule (Phase 1)<br>Novel vaccine formulation 3 | Biological: C. difficile vaccine formulation 3<br>* C. difficile vaccine formulation 3 given as an intramuscular injection<br>Other: Saline Placebo<br>* 0.9% sodium chloride solution given as an intramuscular injection<br>|
| Active Comparator: C. difficile vaccine (previously studied formulation) (Phase 1)<br>Previously studied C. difficile vaccine formulation | Biological: C. difficile vaccine (previously studied formulation)<br>* Toxoid based Clostridioides difficile vaccine (previously studied formulation) given as an intramuscular injection<br>Other: Saline Placebo<br>* 0.9% sodium chloride solution given as an intramuscular injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Percentage of participants reporting local reactions | Injection site pain, redness, and swelling as self-reported in electronic diaries | For 7 days after each vaccination (through Month 6) | 
| Phase 1: Percentage of participants reporting systemic events | Vomiting, diarrhea, headache, fatigue, new or worsening muscle pain, new or worsening joint pain, and fever, as self-reported in electronic diaries | For 7 days after each vaccination (through Month 6) | 
| Phase 1: Percentage of participants reporting adverse events | As elicited by investigational site staff | From Dose 1 (Day 1) through 1 month after the last dose (Month 7) | 
| Phase 1: Percentage of participants reporting serious adverse events | As elicited by investigational site staff | From Dose 1 (Day 1) through 6 months after the last dose (Month 12) | 
| Phase 1: Percentage of participants reporting medically attended adverse events | As elicited by investigational site staff | From Dose 1 (Day 1) through 6 months after the last dose (Month 12) | 
| Phase 1: Percentage of participants with abnormal hematology and chemistry laboratory values | As measured at the central laboratory | 1 week after Dose 1 (Day 7) and 1 month after each dose (through Month 7) | 
| Phase 2: Percentage of participants reporting local reactions | Injection site pain, redness, and swelling as self-reported in electronic diaries | For 7 days after each vaccination (through Month 6) | 
| Phase 2: Percentage of participants reporting systemic events | Vomiting, diarrhea, headache, fatigue, new or worsening muscle pain, new or worsening joint pain, and fever, as self-reported in electronic diaries | For 7 days after each vaccination (through Month 6) | 
| Phase 2: Percentage of participants reporting adverse events | As elicited by investigational site staff | From Dose 1 (Day 1) through 1 month after each dose (Month 7) | 
| Phase 2: Percentage of participants reporting serious adverse events | As elicited by investigational site staff | From Dose 1 (Day 1) through 6 months after the last dose (Month 12) | 
| Phase 2: Percentage of participants reporting medically attended adverse events | As elicited by investigational site staff | From Dose 1 (Day 1) through 6 months after the last dose (Month 12) | 
| Phase 2: Geometric mean concentration (GMC) of C. difficile toxin A- and toxin B-specific neutralizing antibodies | As measured at the central laboratory | 1 month after the last dose (Month 7) | 
| Phase 2: Geometric mean fold-rise (GMFR) of C. difficile toxin A- and toxin B-specific neutralizing antibody concentrations | As measured at the central laboratory | From before Dose 1 (Day 1) to 1 month after the last dose (Month 7) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Percentage of participants reporting serious adverse events | As elicited by investigational site | From 6 month (Month 12) through 12 months after the last dose (Month 18) | 
| Phase 1: Percentage of participants reporting medically attended adverse events | As elicited by investigational site | From 6 month (Month 12) through 12 months after the last dose (Month 18) | 
| Phase 1: Geometric mean concentration (GMC) of C. difficile toxin A- and toxin B-specific neutralizing antibodies | As measured at the central laboratory | 1 month after each dose (through Month 7) and 6 months after the first and last dose (Months 6 and 12) | 
| Phase 1: Geometric mean fold-rise (GMFR) of C. difficile toxin A- and toxin B-specific neutralizing antibody concentrations | As measured at the central laboratory | From before Dose 1 (Day 1) to 1 month after each dose (through Month 7) | 
| Phase 2: Percentage of participants reporting serious adverse events | As elicited by investigational site | From 6 month (Month 12) through 12 months after the last dose (Month 18) | 
| Phase 2: Percentage of participants reporting medically attended adverse events | As elicited by investigational site | From 6 month (Month 12) through 12 months after the last dose (Month 18) | 
| Phase 2: Geometric mean concentration (GMC) of C. difficile toxin A- and toxin B-specific neutralizing antibodies | As measured at the central laboratory | 1 month after Dose 1 (Month 1) and 6 months after the last dose (Month 12) | 
| Phase 2: Geometric mean fold-rise (GMFR) of C. difficile toxin A- and toxin B-specific neutralizing antibody concentrations | As measured at the central laboratory | From before Dose 1 (Day 1) to 1 month after Dose 1 (Month 1) and 6 months after the last dose (Month 12) | 
| Phase 2: The percentage of participants with a greater than or equal to 4-fold rise in C. difficile toxin A- and toxin B-specific neutralizing antibody concentrations | As measured at the central laboratory | From before Dose 1 (Day 1) to 1 month after the last dose (Month 7) | 
| Phase 2: Geometric mean concentration (GMC) of C. difficile toxin A- and toxin B-specific neutralizing antibodies | As measured at the central laboratory | 1, 2, 3, and 4 years after the last dose (Years 1, 2, 3, and 4) | 
| Phase 2: Geometric mean fold-rise (GMFR) of C. difficile toxin A- and toxin B-specific neutralizing antibody concentrations | As measured at the central laboratory | From before Dose 1 (Day 1) to 1, 2, 3, and 4 years after the last dose (Years 1, 2, 3, and 4) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clostridioides difficile, Clostridium difficile, C. diff, vaccine