Pivotal Study to Evaluate Safety and Immunogenicity of a Live-Attenuated Chikungunya Virus Vaccine Candidate in Adults

• ClinicalTrials.gov Identifier: NCT04546724
• Recruitment Status: Completed
• First Posted: September 14, 2020
• Results First Posted: July 25, 2022
• Last Update Posted: July 29, 2022
• Sponsor: Valneva Austria GmbH
• Information provided by (Responsible Party): Valneva Austria GmbH

Tracking Information

• First Submitted Date: September 4, 2020
• First Posted Date: September 14, 2020
• Results First Submitted Date: May 18, 2022
• Results First Posted Date: July 25, 2022
• Last Update Posted Date: July 29, 2022
• Actual Study Start Date: September 17, 2020
• Actual Primary Completion Date: May 19, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 28, 2022)

Number of Participants With a Seroprotective CHIKV Antibody Level for Baseline Negative Subjects 28 Days Post-vaccination [ Time Frame: on Day 29 after single vaccination ]

Seroprotection rate, based on a surrogate of protection agreed with FDA Assay used for analysis is based on µPRNT (Micro Plaque Reduction Neutralization Test). Participants at pre-selected sites were included, if they had available Day 1 and Day 29 samples and without major protocol deviations that could impact the immune response.

• Original Primary Outcome Measures (submitted: September 4, 2020): Proportion of subjects with a seroprotective CHIKV antibody level determined by µPRNT (Micro Plaque Reduction Neutralization Test) for baseline negative subjects 28 days post-vaccination. [ Time Frame: up to Day 29 after single vaccination ]

Current Secondary Outcome Measures (submitted: June 28, 2022)

• CHIKV-specific Neutralizing Antibody Titers [ Time Frame: Until Day 29 ]
  CHIKV-specific Neutralizing Antibody Titers on Day 8, and Day 29 Postvaccination as Determined by μPRNT ( (Micro Plaque Reduction Neutralization Test) Assay
• Number of Participants With Seroprotective CHIKV Antibody Level [ Time Frame: Until Day 29 ]
  Seroprotection rate, based on a surrogate of protection agreed with FDA Seroprotective CHIKV Antibody Level Defined as μPRNT (Micro Plaque Reduction Neutralization Test) for Baseline Negative Subjects
• Number of Participants With Seroconversion [ Time Frame: Until Day 29 ]
  Seroconversion was defined as CHIKV-specific neutralizing antibody titer of ≥ 20 based on µPRNT (Micro Plaque Reduction Neutralization Test) for baseline negative subjects
• Fold "Change" of CHIKV-specific Neutralizing Antibody Titers Compared to Baseline [ Time Frame: until Day 29 ]
  Fold Change of CHIKV-specific Neutralizing Antibody Titers Determined by μPRNT ( (Micro Plaque Reduction Neutralization Test) as compared to baseline calculation of fold change: Day 8/ Baseline and Day 29/ Baseline
• Number of Participants Reaching an X-fold Change in CHICKV-specific Neutralizing Antibody Titer Compared to Baseline [ Time Frame: until Day 29 ]
  Number of Participants Reaching an at Least 4-fold, 8-fold, 16-fold or 64-fold change of CHIKV-specific Neutralizing Antibody Titers Determined by μPRNT ( (Micro Plaque Reduction Neutralization Test) as compared to baseline
• Unsolicited AEs [ Time Frame: Until Day 29 ]
  Number of Participants with Unsolicited Adverse Events
• Solicited Injection Site AEs [ Time Frame: within 10 days post-vaccination ]
  Number of Participants with solicited injection site reactions
• Solicited Systemic AEs [ Time Frame: within 10 days post-vaccination ]
  Number of Participants with solicited systemic reactions
• Adverse Events [ Time Frame: until Day 29 ]
  Number of Participants with any Adverse Events
• Related Adverse Events [ Time Frame: until Day 29 ]
  Number of Participants with any related Adverse Events
• Serious Adverse Event [ Time Frame: until Day 29 ]
  Number of Participants with any Serious Adverse Events
• Related Serious Adverse Event [ Time Frame: until Day 29 ]
  Number of Participants with any Related Serious Adverse Events
• Adverse Event of Special Interest [ Time Frame: within 21 days post-vaccination ]
  Number of Participants with any Adverse Event of Special Interest AESI Definition: The following cluster of symptoms suggestive of CHIKV infection with or without remissions or exacerbations will receive particular consideration:

  1. Fever (≥38.0°C [100.4°F] measured orally) and
  2. Acute (poly)arthralgia/arthritis most frequently in the extremities (wrists, ankles, and phalanges, often symmetric), back pain and/or neurological symptoms (e.g. confusion, optic neuritis, meningoencephalitis, or polyneuropathy) and/or cardiac symptoms (e.g. myocarditis) or One or more of the following signs and symptoms: macular to maculopapular rash (sometimes with cutaneous pruritus [foot plant] and edema of the face and extremities), polyadenopathies; and
  3. Onset of symptoms 2 to 21 days after vaccination and
  4. Duration of event ≥3 days.
• Related Adverse Event of Special Interest [ Time Frame: within 21 days post-vaccination ]
  Number of Participants with any Related Adverse Event of Special Interest AESI Definition: The following cluster of symptoms suggestive of CHIKV infection with or without remissions or exacerbations will receive particular consideration:

  1. Fever (≥38.0°C [100.4°F] measured orally) and
  2. Acute (poly)arthralgia/arthritis most frequently in the extremities (wrists, ankles, and phalanges, often symmetric), back pain and/or neurological symptoms (e.g. confusion, optic neuritis, meningoencephalitis, or polyneuropathy) and/or cardiac symptoms (e.g. myocarditis) or One or more of the following signs and symptoms: macular to maculopapular rash (sometimes with cutaneous pruritus [foot plant] and edema of the face and extremities), polyadenopathies; and
  3. Onset of symptoms 2 to 21 days after vaccination and
  4. Duration of event ≥3 days.

Original Secondary Outcome Measures (submitted: September 4, 2020)

• Immune response as measured by CHIKV-specific neutralizing antibody titers on Day 8, Day 29, Day 85 and Month 6 post-vaccination as determined by µPRNT assay [ Time Frame: until Day 8, 85 and Month 6 ]
• Proportion of subjects with seroprotective CHIKV antibody levels as determined by µPRNT for baseline negative subjects [ Time Frame: until Day 8, 29, 85 and Month 6 ]
• Proportion of subjects with seroconversion at Day 29 and Month 6 as determined by µPRNT assay [ Time Frame: until Day 29 and Month 6 ]
• Fold increase of CHIKV-specific neutralizing antibody titers determined by µPRNT assay at Days 8, 29, 85 and Month 6 post-vaccination as compared to baseline [ Time Frame: until Day 8, 29, 85 and Month 6 ]
• Frequency and severity of unsolicited Adverse Events within 28 days post-vaccination [ Time Frame: until Day 29 ]
• Frequency and severity of solicited injection site and systemic reactions [ Time Frame: as recorded in the subject diaries ]
• Frequency and severity of any Adverse Event during the entire study period [ Time Frame: until Month 6 ]
• Frequency and severity of any Serious Adverse Event (SAE) during the entire study period [ Time Frame: until Month 6 ]
• Frequency and severity of any Adverse Event of Special Interest (AESI) [ Time Frame: until Month 6 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Pivotal Study to Evaluate Safety and Immunogenicity of a Live-Attenuated Chikungunya Virus Vaccine Candidate in Adults
• Official Title: A Multicenter, Randomized, Placebo-Controlled, Double-Blinded Pivotal Study To Evaluate Safety And Immunogenicity Of A Live-Attenuated Chikungunya Virus Vaccine Candidate In Adults Aged 18 Years And Above
• Brief Summary: This is a prospective, randomized, double-blinded, multicenter, pivotal clinical study evaluating the final dose of VLA1553 (1 x10E4 TCID50 per dose) in comparison to a placebo control. The final dose of VLA1553 or control will be administered as single immunization on Day 1. Overall, approximately 4,060 male and female subjects aged 18 years and above will be enrolled into the study.

Detailed Description

This is a prospective, double-blinded, multicenter, randomized, pivotal Phase 3 study comprising approximately 4,060 subjects aged 18 years or above randomized in a 3:1 ratio to the live-attenuated CHIKV vaccine candidate (VLA1553) or placebo. The final dose of lyophilized VLA1553 or placebo will be administered as a single intramuscular immunization. Subjects in this study will be stratified into two age strata of 18 to 64 years and 65 years of age or above. The primary objective of the study is to evaluate the immunogenicity and safety of the final dose of VLA1553 28 days following the single immunization. Immunogenicity evaluations in the immunogenicity subset will include the proportion of subjects with seroprotective neutralizing CHIKV antibody titers above a surrogate threshold indicative of protection. The surrogate of protection reasonably likely to predict clinical benefit has been established in non-human primate passive transfer studies using human sera from the Phase 1 study. Safety data collection and immunogenicity will continue to be assessed until Month 6

The first enrolled and randomized approximately 500 subjects will comprise the immunogenicity subset.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Prevention
• Condition: Chikungunya Virus Infection

Intervention

• Biological: VLA1553
  Single intramuscular vaccination on Day 1 with VLA1553, a lyophilized live-attenuated Chikungunya vaccine candidate; 1x10E4 TCID50 per dose
• Biological: Placebo
  Single intramuscular vaccination on Day 1 with Phosphate-Buffered Saline (PBS) as placebo

Study Arms

• Active Comparator: VLA1553
  Single intramuscular vaccination on Day 1 with VLA1553, a lyophilized live-attenuated Chikungunya vaccine candidate; 1x10E4 TCID50 per dose
  Intervention: Biological: VLA1553
• Placebo Comparator: Placebo
  Single intramuscular vaccination on Day 1 with Phosphate-Buffered Saline (PBS) as placebo
  Intervention: Biological: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 18, 2022): 4124
• Original Estimated Enrollment (submitted: September 4, 2020): 4060
• Actual Study Completion Date: October 15, 2021
• Actual Primary Completion Date: May 19, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. 18 years of age or above on the Day of screening
2. able to provide informed consent
3. generally healthy as determined by the Investigator's clinical judgement based on medical history, physical examination and screening laboratory tests

4. for women of childbearing potential:

   1. practiced an adequate method of contraception during 30 days before screening
   2. negative serum or urine pregnancy test at screening
   3. agrees to employ adequate birth control measures for the first three months post-vaccination (i.e. until Day 85).

Main Exclusion Criteria:

1. CHIKV infection in the past, including suspected CHIKV infection; is taking medication or other treatment for unresolved symptoms attributed to a previous CHIKV infection; or has participated in a clinical study involving an investigational CHIKV vaccine
2. acute or recent infection
3. Subject tests positive for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV);
4. live virus vaccine within 28 days or inactivated vaccine within 14 days prior to vaccination in this study or plans to receive a vaccine within 28 days or 14 days after vaccination, respectively
5. abnormal findings in any required study investigations (including medical history, physical examination, and clinical laboratory) considered clinically relevant by the Investigator which pose a risk for participation in the study
6. medical history of or currently has acute or progressive, unstable or uncontrolled clinical conditions that pose a risk for participation in the study
7. history of immune-mediated or clinically relevant arthritis / arthralgia
8. history of malignancy in the past 5 years other than squamous cell or basal cell skin cancer. If there has been surgical excision or treatment more than 5 years ago that is considered to have achieved a cure, the subject may be enrolled.
9. known or suspected defect of the immune system, such as subjects with congenital or acquired immunodeficiency, including infection with HIV, status post organ transplantation or immuno-suppressive therapy within 4 weeks prior to vaccination.
10. history of any vaccine related contraindicating event (e.g., anaphylaxis, allergy to components of the candidate vaccine, other known contraindications)
11. with clinical conditions representing a contraindication to intramuscular vaccination and blood draws
12. pregnant or lactating at the time of enrollment
13. Donation of blood, blood fractions or plasma within 30 days or received blood-derived products (e.g. plasma) within 90 days prior to vaccination in this study or plans to donate blood or use blood products until Day 180 of the study
14. rash, dermatological condition or tattoos that would, in the opinion of the Investigator, interfere with injection site reaction rating
15. known or suspected problem with alcohol or drug abuse as determined by the Investigator
16. any condition that, in the opinion of the Investigator, may compromise the subjects well-being, might interfere with evaluation of study endpoints, or would limit the subject's ability to complete the study;
17. committed to an institution (by virtue of an order issued either by the judicial or the administrative authorities)
18. Participation in another clinical study involving an investigational medicinal product (IMP) or device within 30 days prior to study enrollment or is scheduled to participate in another clinical study involving an IMP, or device during the course of this study
19. member of the team conducting the study or in a dependent relationship with one of the study team members. Dependent relationships include close relatives (i.e., children, partner/spouse, siblings, parents) as well as employees of the Investigator or site personnel conducting the study.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04546724
• Other Study ID Numbers: VLA1553-301
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Valneva Austria GmbH
• Original Responsible Party: Same as current
• Current Study Sponsor: Valneva Austria GmbH
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Chair: Valneva Clinical Development; Valneva Austria GmbH

• PRS Account: Valneva Austria GmbH
• Verification Date: July 2022