Dose-Confirmation, Immunogenicity and Safety Study of the Clostridium Difficile Vaccine Candidate VLA84 in Healthy Adults Aged 50 Years and Older. Phase II Study

Study Overview
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Brief Summary
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Phase 2, randomized, observer-blind, placebo-controlled, multi-centric study including 4 parallel study groups. 500 Subjects (thereof, 250 aged 50 - 64 years and 250 aged 65 years and older) will be randomized in a (3:3:3:1) ratio to receive either VLA84 75 µg w/o (without) Alum, VLA84 200 µg w/o Alum, VLA84 200 µg w/ (with) Alum (150 subjects each), or placebo (50 subjects), as i.m. (intramuscular) vaccinations into alternating arms, on Days 0, 7 and 28

Detailed Description
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This is a randomized, controlled, observer-blind Phase 2 study which aims to confirm the optimal dose and formulation of VLA84 in healthy adults aged ≥ 50 years of age. The study will be enrolled in two age strata, subjects aged 50 - 64 years and subjects aged 65 years and older, in a 1:1 ratio. 500 subjects (thereof, 250 aged 50 - 64 years and 250 aged 65 years and older) will be randomized in a 3:3:3:1 ratio to receive either VLA84 75 µg w/o Alum, VLA84 200 µg w/o Alum, VLA84 200 µg w/ Alum (150 subjects each), or placebo (50 subjects). Vaccinations consist of two i.m. injections administered in close proximity to each other in the deltoid region at Day 0, 7 and 28, starting with the non-dominant arm and alternating arms between the vaccination days. The study will investigate the immunogenicity and safety of VLA84 up to six months after the last vaccination, i.e. 210 days per subject. The study includes eight outpatient visits on days 0, 7, 14, 28, 35, 56, 120 and 210. Serum will be collected to assess humoral immunity at days 0, 7, 14, 28, 35, 56, 120 and 210. The study is OBSERVER blind. This means only pre-defined study staff will be unblinded, e.g., staff responsible for IMP accountability, preparation and administration, monitor responsible IMP accountability, or safety staff in case of safety reasons. All other persons involved in study conduct will remain blinded.

Official Title
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Dose Confirmation, Immunogenicity and Safety Study of the Clostridium Difficile Vaccine Candidate VLA84 in Healthy Adults Aged 50 Years and Older. Randomized, Controlled, Observer Blind Phase II Study

Conditions
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Clostridium Difficile

Intervention / Treatment
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* Biological: VLA84
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects aged ≥50 years of good general health, including subjects with pharmacologically controlled conditions like hypercholesterolemia, hypertension, or type 2 diabetes mellitus. Informed consent form has been signed and dated Exclusion Criteria: Subjects with any confirmed or suspected prior Clostridium difficile infection episode Previous vaccination against Clostridium difficile with any (investigational) vaccine or receipt of (investigational) monoclonal antibodies against Clostridium difficile toxins Use of any other investigational or non-registered medicinal product within 30 days prior to VLA84 vaccination at Visit 1 (Day 0) and throughout the entire study period. Active or passive vaccination four weeks before first vaccination at Visit 1 and during the entire study period, except for influenza (seasonal or pandemic) and pneumococcal vaccines which may be administered outside a 7-days interval before and after any trial vaccination Subject is pregnant, or lactating, or of childbearing potential (to be considered of non-childbearing potential, a female must be post-menopausal for at least 1 year or surgically sterile) Known thrombocytopenia, bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion or until Visit 4 (Day28), contraindicating i.m. vaccination as judged by the investigator Clinically relevant renal, hepatic, cardiac, pulmonary or central nervous disorders, as judged by the investigator. Subjects with hypercholesterolemia, hypertension, or type 2 diabetes mellitus requiring medication are allowed if disease is adequately controlled Receipt of blood or blood-derived products in the past 3 months or anticipation of such products during the study period Known congenital, hereditary or acquired immunodeficiency, including known infection with human immunodeficiency virus (HIV), administration of chronic (defined as longer than 14 days) immunosuppressants or other immune-modifying drugs within 30 days prior to VLA84 vaccination at Visit 1 (Day 0) and during the study until Visit 5 (Day 35). For corticosteroids this means prednisone or equivalent ≥ 0.05 mg/kg/day; topical and inhaled steroids are allowed. Periodic steroid injections, e.g., intra-articular, are not allowed within 30 days prior to first VLA84 vaccination at Visit 1 (Day 0) and until Visit 5 (Day 35) History of autoimmune disease, including Type I Diabetes mellitus. Subjects with vitiligo or thyroid disease taking thyroid hormone replacement are not excluded Any malignancy in the past 5 years. If treatment for cancer was successfully completed more than 5 years ago and the malignancy is considered to be cured, the subject may be enrolled Known hypersensitivity or allergic reactions to one of the components of the vaccine Inability or unwillingness to provide informed consent Persons who are committed to an institution (by virtue of an order issued either by the judicial or the administrative authorities) Persons who are in a dependent relationship with the sponsor, an investigator or other study team members, or the study center. Dependent relationships include close relatives and household members (i.e., children, partner/spouse, siblings, parents) as well as employees of the investigator or study center personnel

Ages Eligible for Study
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Minimum Age: 50 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: VLA84 75 mcg (microgram) w/o Alum<br>VLA84 75 mcg w/o Alum consists of 0.75 mL (milliliters) VLA84 w/o Alum and 0.75 mL Placebo Vaccination Days: 0, 7 and 28 each with two injections | Biological: VLA84<br>* a recombinant fusion protein consisting of truncated Clostridium difficile (C. difficile) Toxin A and Toxin B<br>Biological: Placebo<br>* phosphate buffered saline (PBS) solution<br>|
| Active Comparator: VLA84 200 mcg w/o Alum<br>VLA84 200 mcg w/o Alum consists of 2 injections each with 1.0 mL (milliliters) VLA84 w/o Alum Vaccination Days: 0, 7 and 28 each with two injections | Biological: VLA84<br>* a recombinant fusion protein consisting of truncated Clostridium difficile (C. difficile) Toxin A and Toxin B<br>|
| Active Comparator: VLA84 200 mcg with Alum<br>VLA84 200 mcg with Alum consists of 2 injections each with 1.0 mL (milliliters) VLA84 with Alum Vaccination Days: 0, 7 and 28 each with two injections | Biological: VLA84<br>* a recombinant fusion protein consisting of truncated Clostridium difficile (C. difficile) Toxin A and Toxin B<br>|
| Placebo Comparator: Placebo<br>Placebo consists of 2 injections each with 1.0 mL PBS (Phosphate Buffered Saline) Vaccination Days: 0, 7 and 28 each with two injections | Biological: Placebo<br>* phosphate buffered saline (PBS) solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Seroconversion Rate (SCR) on Day 56 | Seroconversion Rate (SCR), defined as percentage of subjects achieving a ≥4-fold increase in antibody titer from Day 0, for IgG against both Toxin A and Toxin B on Day 56; | Day 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SCR for IgG (Immunoglobulin G) Against Both Toxin A and Toxin B | Seroconversion Rate (SCR), defined as percentage of subjects achieving a ≥4-fold increase in antibody titer from Day 0, for IgG against both Toxin A and Toxin B on Day 14, 28, 35, 120 and 210; | Days 14, 28, 35, 120 and 210 | 
| Seroconversion Rate (SCR) for IgG Against Toxin A | Seroconversion Rate (SCR), defined as percentage of subjects achieving a ≥4-fold increase in antibody titer from Day 0, for IgG against Toxin A; | 14, 28, 35, 56, 120 and 210 | 
| Seroconversion Rate (SCR) for IgG Against Toxin B | Seroconversion Rate (SCR), defined as percentage of subjects achieving a ≥4-fold increase in antibody titer from Day 0, for IgG against Toxin B; | Days 14, 28, 35, 56, 120 and 210 | 
| Geometric Mean Titer (GMT) for IgG Against Toxin A | Geometric Mean Titer (GMT) for IgG against Toxin A as determined by ELISA on Days 0, 14, 28, 35, 56 (primary endpoint time point), 120 and 210; | Days 0, 14, 28, 35, 56, 120 and 210 | 
| Geometric Mean Titer (GMT) for IgG Against Toxin B | Geometric Mean Titer (GMT) for IgG against Toxin B as determined by ELISA on Days 0, 14, 28, 35, 56 (primary endpoint time point), 120 and 210; | Days 0, 14, 28, 35, 56, 120 and 210 | 
| GMT for Toxin A Neutralizing Antibodies | GMT for Toxin A neutralizing antibodies (TNA) as determined by Toxin Neutralization Assay on Days 0, 35, 56, 120* and 210 * TNA in sera from Day 120 were to be measured only if meaningful in view of the Day 56 and Day 210 results; in fact Day 120 TNA was not measured. | Days 0, 35, 56, 120 and 210 | 
| GMT for Toxin B Neutralizing Antibodies | GMT for Toxin B neutralizing antibodies (TNA) as determined by Toxin Neutralization Assay on Days 0, 35, 56, 120* and 210 * TNA in sera from Day 120 were to be measured only if meaningful in view of the Day 56 and Day 210 results; in fact Day 120 TNA was not measured. | Days 0, 35, 56, 120 and 210 | 
| SCR for IgG Against Toxin A, Against Toxin B and Against Both Toxin A and Toxin B Stratified by Age Group | Seroconversion Rate (SCR) for IgG against Toxin A, against Toxin B and against both Toxin A and Toxin B on Days 14, 28, 35, 56, 120 and 210, stratified by age group (subjects 50 - < 65 years and 65 years and older) | Days 14, 28, 35, 56, 120 and 210 | 
| GMT for IgG Against Toxin A and Against Toxin B Stratified by Age Group | GMT for IgG against Toxin A and against Toxin B on Days 0, 14, 28, 35, 56, 120 and 210, stratified by age group (subjects 50 - < 65 years and 65 years and older) | Days 0, 14, 28, 35, 56, 120, 210 | 
| GMTs for Toxin A Neutralizing Antibodies and for Toxin B Neutralizing Antibodies Stratified by Age Group | GMTs for Toxin A neutralizing antibodies and for Toxin B neutralizing antibodies as determined by Toxin Neutralization Assay on Days 0, 35, 56, 120* and 210, stratified by age group (subjects 50 - < 65 years and 65 years and older) * TNA in sera from Day 120 were to be measured only if meaningful in view of the Day 56 and Day 210 results; in fact Day 120 TNA was not measured. | Days 0, 35, 56, 120 and 210 | 
| Responder Rate (RR) for Neutralizing Antibodies Against Both Toxin A and Toxin B | Responder Rate (RR) (defined as percentage of subjects achieving a ≥4-fold increase in neutralizing antibody titer from Day 0) for neutralizing antibodies against both Toxin A and Toxin B on Days 35, 56, 120* and 210 * TNA in sera from Day 120 were to be measured only if meaningful in view of the Day 56 and Day 210 results; in fact Day 120 TNA was not measured. | Days 35, 56, 120, 210 | 
| Responder Rate (RR) for Toxin A Neutralizing Antibodies | Responder Rate (RR) (defined as percentage of subjects achieving a ≥4-fold increase in neutralizing antibody titer from Day 0) for neutralizing antibodies against Toxin A on Days 35, 56, 120* and 210 * TNA in sera from Day 120 were to be measured only if meaningful in view of the Day 56 and Day 210 results; in fact Day 120 TNA was not measured. | Days 35, 56, 120 and 210 | 
| Responder Rate (RR) for Toxin B Neutralizing Antibodies | Responder Rate (RR) (defined as percentage of subjects achieving a ≥4-fold increase in neutralizing antibody titer from Day 0) for neutralizing antibodies against Toxin B on Days 35, 56, 120* and 210 * TNA in sera from Day 120 were to be measured only if meaningful in view of the Day 56 and Day 210 results; in fact Day 120 TNA was not measured. | Days 35, 56, 120 and 210 | 
| Responder Rate (RR) for Neutralizing Antibodies Against Toxin A, Against Toxin B and Against Both Toxin A and Toxin B Stratified by Age Group | Responder Rate for neutralizing antibodies against Toxin A (RR Tox A), against Toxin B (RR Tox B) and against both Toxin A and Toxin B (RR Tox A and B) on Days 35, 56, 120* and 210, stratified by age group (subjects 50 - < 65 years and 65 years and older) * TNA in sera from Day 120 were to be measured only if meaningful in view of the Day 56 and Day 210 results; in fact Day 120 TNA was not measured. | Days 35, 56, 120 and 210 | 
| Rate of Study Participants With at Least One SAE (Serious Adverse Event) | percentage of study participants with at least one SAE starting up to Day 56 and up to Day 210 | Day 56 and Day 210 | 
| Rate of Study Participants With at Least One Related SAE | percentage of study participants with at least one related SAE starting up to Day 56 and up to Day 210 | Day 56 and Day 210 | 
| Rate of Study Participants With at Least One Unsolicited AEs (Adverse Event) | percentage of study participants with at least one unsolicited AE starting up to Day 56 and Day 210 (incl. clinically significant laboratory parameter changes) | Day 56 and Day 210 | 
| Rate of Study Participants With at Least One Related Unsolicited AE | percentage of study participants with at least one related unsolicited AE starting up to Day 56 and Day 210 (incl. clinically significant laboratory parameter changes) | Day 56 and Day 210 | 
| Rates of Study Participants With at Least One Solicited Local and Systemic AE | percentage of study participants with solicited local and systemic AE within 7 days after each and after any vaccination, collected via a subject diary with predefined terms | within 7 Days after each vaccination | 
| Rates of Study Participants With at Least One SAE, Related SAE, Unsolicited AE and Related Unsolicited AE Stratified by Age Group | percentage of study participants with at least one SAE, related SAE, unsolicited (unsol.) AE (incl. clinically significant laboratory parameter changes) and related unsolicited AE, starting up to Day 56 and Day 210, stratified by age group (subjects 50 - < 65 years and 65 years and older (65+)) | Day 56 and Day 210 | 
| Rates of Study Participants With at Least One Solicited Local and Systemic AE Within 7 Days After Each and Any Vaccination Stratified by Age Group | percentage of participants with solicited (sol.) local and systemic AEs within 7 days after each and after any vaccination (vacc.), collected via a subject diary with predefined terms, stratified by age group (subjects 50 - < 65 years and 65 years and older) | within 7 Days after each vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clostridium difficile, Valneva, Phase 2, Healthy adults