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

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

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

Study Overview

• Status: Completed
• Conditions: Clostridium Difficile
• Intervention / Treatment: Biological: VLA84; Biological: Placebo

Detailed Description

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
• Enrollment (Actual): 500
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 10117
    • Berliner Zentrum für Reise- und Tropenmedizin
  • Hannover, Germany, 30159
    • KFGN Klinische Forschung Hannover- Mitte GmbH
  • Rostock, Germany, 18057
    • Klinik und Poliklinik für Innere Medizin der Universität Rostock
• United States
  • Alabama
    • Huntsville, Alabama, United States, 35802
      • Optimal Research LLC
  • California
    • Chula Vista, California, United States, 91911
      • eStudy Site, Chula Vista
    • La Mesa, California, United States, 91942
      • eStudy Site, La Mesa
    • Oceanside, California, United States, 92056
      • eStudy Site, Oceanside
  • Florida
    • Melbourne, Florida, United States, 32934
      • Optimal Research LLC
  • Illinois
    • Peoria, Illinois, United States, 61614
      • Optimal Research LLC
  • Indiana
    • Mishawaka, Indiana, United States, 46545
      • Optimal Research LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: VLA84 75 mcg (microgram) w/o Alum; 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; a recombinant fusion protein consisting of truncated Clostridium difficile (C. difficile) Toxin A and Toxin B; Biological: Placebo; phosphate buffered saline (PBS) solution
ACTIVE_COMPARATOR: VLA84 200 mcg w/o Alum; 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; a recombinant fusion protein consisting of truncated Clostridium difficile (C. difficile) Toxin A and Toxin B
ACTIVE_COMPARATOR: VLA84 200 mcg with Alum; 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; a recombinant fusion protein consisting of truncated Clostridium difficile (C. difficile) Toxin A and Toxin B
PLACEBO_COMPARATOR: Placebo; 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; phosphate buffered saline (PBS) solution

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Valneva Austria GmbH

Study record dates

Study Major Dates

• Study Start: December 1, 2014
• Primary Completion (ACTUAL): May 1, 2015
• Study Completion (ACTUAL): October 1, 2015

Study Registration Dates

• First Submitted: December 9, 2014
• First Submitted That Met QC Criteria: December 12, 2014
• First Posted (ESTIMATE): December 15, 2014

Study Record Updates

• Last Update Posted (ACTUAL): June 8, 2017
• Last Update Submitted That Met QC Criteria: April 25, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: Clostridium difficile; Healthy adults; Phase 2; Valneva
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Clostridium Infections
• Other Study ID Numbers: VLA84-201