Phase 1-2, Randomized, Multi-Center, Double-Blind, Placebo-Controlled, Safety, Immunogenicity, and Efficacy Study in Healthy Adults of Intramuscular Norovirus Bivalent Virus-like Particle Vaccine in Experimental Human Norovirus GII.4 Disease
Overview
- Phase
- Phase 1
- Intervention
- Not specified
- Conditions
- Prevention From Norovirus Infection
- Sponsor
- Takeda
- Enrollment
- 132
- Locations
- 5
- Primary Endpoint
- Percentage of Participants Experiencing Solicited Local Adverse Events Within 7 Days Post-Dose 1
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief Summary
The purpose of this study is to determine whether the norovirus vaccine is effective in preventing acute gastroenteritis due to the experimental human Norovirus GII.4 challenge dose. The purpose is also to evaluate the safety of the vaccine and the immunogenicity of the vaccine.
Investigators
Eligibility Criteria
Inclusion Criteria
- •To be eligible to participate in this study, a subject must meet the following criteria:
- •Signed informed consent.
- •Age 18 to 50 years (e.g., not reached their 50th birthday).
- •Good general health as determined by a screening evaluation within 45 days of randomization.
- •Expressed interest, availability, and understanding to fulfill the study requirements including measures to prevent Norovirus contamination of the environment and spread of infection and illness to the community. The prospective subjects must pass (≥70 % correct answers) a written examination on all aspects of the study before enrollment.
- •Available to return for follow-up visits following discharge from the inpatient unit and able to deliver stool specimens to the investigative site promptly with no plan to move within the duration of the study.
- •Female subjects must be of non-childbearing potential, or if of childbearing potential (as determined by the investigator) must be practicing abstinence or using an effective licensed method of birth control (e.g. oral contraceptives; diaphragm or condom in combination with contraceptive jelly, cream, or foam; intrauterine contraceptive device, or Depo-Provera; skin patch; vaginal ring or cervical cap) for 30 days prior to vaccination and must agree to continue such precautions during the study and for 60 days after the Challenge visit. Male subjects must agree not to father a child from the day of vaccination until 60 days after the Challenge visit.
- •Have a serum antibody titer of ≤1:1600 to the GII.4 Norovirus challenge strain as measured by Immunoglobulin G (IgG) P Particle Enzyme-Linked Immunosorbent Assay (ELISA.)
- •Demonstrated to be H Type 1 secretor positive by Histoblood Group Antigen (HBGA) binding assay of their saliva test. \[This saliva test may be done at anytime prior to enrollment and does not need to be repeated.\]
- •Negative serology for hepatitis C antibody, Human Immune Deficiency Virus (HIV) antibody, hepatitis B surface antigen, and Rapid Plasma Reagin (RPR).
Exclusion Criteria
- •To be eligible to participate in this study, a subject must NOT meet any of the following criteria:
- •Living with or having daily contact with children age 5 years or less or a woman known to be pregnant. This includes significant contact at home, school, day-care, or equivalent facilities.
- •Nursing mother.
- •Living with or having daily contact with childcare workers.
- •Living with or having daily contact with elderly persons aged 70 years or more, or infirmed, diapered individuals, persons with disabilities or incontinent persons. This includes work or visits to nursing homes and day-care or equivalent facilities.
- •History of any gastroenteritis suggestive of Norovirus illness since screening serum antibody IgG P Particle ELISA testing was done.
- •History of any gastroenteritis within the past 2 weeks.
- •History of chronic functional dyspepsia, chronic gastroesophageal reflux disease, peptic ulcer disease, gastrointestinal hemorrhage, gall bladder disease, inflammatory bowel disease, irritable bowel syndrome, frequent diarrhea, chronic constipation, malabsorption, maldigestion, major Gastrointestinal (GI) surgery, or diverticulitis anytime during the subject's lifetime or any other chronic GI disorders that would interfere with interpretation of symptoms or evaluation during the study.
- •Routine use of medication other than oral contraceptive agents, anti-hypertensives, anti-depressants, vitamins and minerals. The use of any other medications should be discussed with the Sponsor and/or Central Safety Monitor (CSM).
- •History of any of the following medical illnesses:
Outcomes
Primary Outcomes
Percentage of Participants Experiencing Solicited Local Adverse Events Within 7 Days Post-Dose 1
Time Frame: Within 7 days post-dose 1
Local Adverse Events included local injection site reactions/symptoms: pain, tenderness, redness, and swelling.
Percentage of Participants Experiencing Solicited Systemic Adverse Events Within 7 Days Post-Dose 2
Time Frame: Within 7 days post-dose 2
Systemic signs or symptoms included: elevated fever, headache, fatigue, muscle aches, chills, joint aches and gastrointestinal symptoms of nausea, vomiting, diarrhea, abdominal cramps/pain.
Percentage of Participants With Viral AGE Clinical Illness and Fecal Virus Excretion Detected by RT-PCR OR 4-Fold Rise In Anti-GII.4 Norovirus P Particle Antibody Titer
Time Frame: Symptoms collected from Challenge dose (at least 28 days after dose 2) to discharge (at least 96 hours after challenge dose)
Viral AGE due to Norovirus GII.4 strain during the inpatient stay that meets clinical illness definition 1,2 or 3 and positive for infection as measured by fecal virus excretion detected by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) OR a 4-fold rise in Immunoglobulin G Enzyme-Linked Immunosorbent Assay (IgG ELISA) anti-GII.4 norovirus P particle antibody titer from pre-challenge (Within 2 weeks of Challenge Day 0) to post-challenge (Challenge Day 30). The clinical illness definitions are 1: diarrhea (defined as ≥ 3 loose or liquid stools OR \>400-600 grams of loose or liquid stools produced in any 24-hour period), 2: vomiting (defined as ≥ 2 vomiting episodes in any 24-hour period) or 3. One Vomiting episode plus any loose or liquid stool in any 24-hour period OR one vomiting episode plus at least 2 of the following 5 events: nausea, fever ≥99.7°F orally, abdominal cramps or pains, abdominal gurgling or bloating, or myalgia in any 24-hour period.
Percentage of Participants Experiencing Solicited Local Adverse Events Within 7 Days Post-Dose 2
Time Frame: Within 7 days post-dose 2
Local Adverse Events included local injection site reactions/symptoms: pain, tenderness, redness, and swelling.
Percentage of Participants Experiencing Solicited Systemic Adverse Events Within 7 Days Post-Dose 1
Time Frame: Within 7 days post-dose 1
Systemic signs or symptoms included: elevated daily oral temperature (fever), headache, fatigue, muscle aches, chills, joint aches and gastrointestinal symptoms of nausea, vomiting, diarrhea, abdominal cramps/pain.
Percentage of Participants With Serious Adverse Events (SAEs) 365 Days Following the Last Study Vaccination
Time Frame: 365 Days Following Dose 2 (Up to 393 days)
A SAE was any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.
Secondary Outcomes
- Percentage of Participants With GII.4 Seroresponse Rate (4-fold Rise) From Pre-challenge Day 0 to Post-Challenge Day 30(Pre Challenge to 30 Days Post Challenge)
- Pan-Ig ELISA - Anti-Norovirus GI.1 VLP Geometric Mean Titer (GMT)(Baseline, 28 days Post Dose 1 and 28 days Post Dose 2)
- Severity of Viral AGE Due to GII.4 Strain Assessed by Modified Vesikari Scoring System During the Inpatient Phase(Symptoms collected from Challenge dose (at least 28 days after dose 2) to discharge (at least 96 hours after challenge dose))
- Severity of Viral AGE Due to GII.4 Strain Assessed by Post-Challenge Symptom Collection During the Inpatient Phase(Symptoms collected from Challenge dose (at least 28 days after dose 2) to discharge (at least 96 hours after challenge dose))
- Pan-Ig ELISA - Anti-Norovirus GII.4 cVLP GMT(Baseline, 28 days post Dose 1 and 28 days post Dose 2)
- ELISA IgA- Anti-Norovirus GII.4 cVLP GMFR From Baseline(Baseline to 28 days post Dose 1 and 28 days post Dose 2)
- Percentage of Participant With ELISA IgA- Anti-Norovirus GII.4 cVLP Seroresponse From Baseline(Baseline to 28 days post Dose 1 and 28 days post Dose 2)
- Percentage of Participants With Unsolicited Non-Serious [i.e Other Than SAEs] Adverse Events (AEs)(Vaccination Stage: Initial vaccination until 28 days after second vaccination; or Challenge Stage: the day of challenge until 60 days after challenge)
- Percentage of Participants With 4-Fold Rise In Serum P-Particle Antibody Titer by ELISA or Detection of Norovirus GII.4 by RT-PCR in the Stool(Pre Challenge to 30 Days Post Challenge)
- Duration of Viral AGE Due to GII.4 Strain During the Inpatient Phase(Symptoms collected from Challenge dose (at least 28 days after dose 2) to discharge (at least 96 hours after challenge dose))
- Pan-Ig ELISA - Anti-Norovirus GI.1 VLP Geometric Mean Fold Rise (GMFR) From Baseline(Baseline to 28 days Post Dose 1 and 28 days Post Dose 2)
- Pan-Ig ELISA - Anti-Norovirus GII.4 cVLP GMFR From Baseline(Baseline to 28 days post Dose 1 and 28 days post Dose 2)
- ELISA Immunoglobulin A (IgA)- Anti-Norovirus GI.1 VLP Geometric Mean Fold Rise (GMFR) From Baseline(Baseline to 28 days Post Dose 1 and 28 days Post Dose 2)
- Percentage of Participants With Pan-Ig ELISA - Anti-Norovirus GI.1 VLP Seroresponse (4-fold Rise) From Baseline(Baseline, 28 days Post Dose 1 and 28 days Post Dose 2)
- Percentage of Participants With ELISA IgA- Anti-Norovirus GI.1 VLP Seroresponse (4-fold Rise) From Baseline(Baseline to 28 days Post Dose 1 and 28 days Post Dose 2)
- HBGA (PGM) - Anti-Norovirus GII.4 cVLP GMFR From Baseline(Baseline to 28 days post Dose 1 and 28 days post Dose 2)
- Percentage of Participants With GII.4 Norovirus Positive RT-PCR in the Stool During the Inpatient and /or Outpatient Phase(Pre Challenge to 30 Days Post Challenge)
- Percentage of Participants With Pan-Ig ELISA - Anti-Norovirus GII.4 cVLP Seroresponse From Baseline(Baseline to 28 days post Dose 1 and 28 days post Dose 2)
- ELISA IgA- Anti-Norovirus GI.1 VLP Geometric Mean Titer (GMT)(Baseline, 28 days Post Dose 1 and 28 days Post Dose 2)
- ELISA IgA- Anti-Norovirus GII.4 cVLP GMT(Baseline, 28 days post Dose 1 and 28 days post Dose 2)
- Percentage of Participants With HBGA (PGM) - Anti-Norovirus GI.1 VLP Seroresponse From Baseline(Baseline to 28 days post Dose 1 and 28 days post Dose 2)
- HBGA (PGM) - Anti-Norovirus GII.4 cVLP GMT(Baseline, 28 days post Dose 1 and 28 days post Dose 2)
- HBGA (PGM) - Anti-Norovirus GI.1 VLP GMFR From Baseline(Baseline to 28 days post Dose 1 and 28 days post Dose 2)
- HBGA (PGM) - Anti-Norovirus GI.1 VLP GMT(Baseline, 28 days post Dose 1 and 28 days post Dose 2)
- Percentage of Participants With HBGA (PGM) - Anti-Norovirus GII.4 cVLP Seroresponse From Baseline(Baseline to 28 days post Dose 1 and 28 days post Dose 2)