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

Valneva Austria GmbH500 enrolled

Overview

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

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

QUADRUPLE

Enrollment

Eligibility

Sex: ALLMin age: 50 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Locations (10)

Optimal Research LLC

Huntsville, Alabama, United States

eStudy Site, Chula Vista

Chula Vista, California, United States

eStudy Site, La Mesa

La Mesa, California, United States

eStudy Site, Oceanside

Oceanside, California, United States

Optimal Research LLC

Melbourne, Florida, United States

Optimal Research LLC

Peoria, Illinois, United States

Optimal Research LLC

Mishawaka, Indiana, United States

Berliner Zentrum für Reise- und Tropenmedizin

Berlin, Germany

KFGN Klinische Forschung Hannover- Mitte GmbH

Hanover, Germany

Klinik und Poliklinik für Innere Medizin der Universität Rostock

Rostock, Germany

Outcomes

Primary Outcomes

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;

Time frame: Day 56

Secondary Outcomes

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;

Time frame: 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;

Time frame: 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;

Time frame: 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;

Time frame: 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;

Time frame: 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.

Time frame: 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.

Time frame: 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)

Time frame: 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)

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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