Clinical trial NCT01609257: Norovirus Bivalent-Vaccine Efficacy Study
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Prevention From Norovirus Infection
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2012-05-31
Enrollment: 132
Sex: ALL
Minimum age (years): 18
Maximum age (years): 49
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.


Eligibility criteria: Inclusion Criteria:

To be eligible to participate in this study, a subject must meet the following criteria:

1. Signed informed consent.
2. Age 18 to 50 years (e.g., not reached their 50th birthday).
3. Good general health as determined by a screening evaluation within 45 days of randomization.
4. 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.
5. 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.
6. 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.
7. 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.)
8. Demonstrated to be H Type 1 secretor positive by Histoblood Group Antigen (HBGA) binding assay of their saliva test. \[This saliva test may be done at anytime prior to enrollment and does not need to be repeated.\]
9. Negative serology for hepatitis C antibody, Human Immune Deficiency Virus (HIV) antibody, hepatitis B surface antigen, and Rapid Plasma Reagin (RPR).
10. Agrees not to participate in another clinical trial with an investigational product for the duration of the study (12 months after the last dose of study vaccine or placebo i.e. 393 days).

Exclusion Criteria:

To be eligible to participate in this study, a subject must NOT meet any of the following criteria:

1. 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.
2. Nursing mother.
3. Living with or having daily contact with childcare workers.
4. 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.
5. History of any gastroenteritis suggestive of Norovirus illness since screening serum antibody IgG P Particle ELISA testing was done.
6. History of any gastroenteritis within the past 2 weeks.
7. 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.
8. 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).
9. History of any of the following medical illnesses:

   * Immunosuppression (disease or treatments that may affect immune system function)
   * Diabetes (including gestational diabetes during the pregnancy that required treatment other than dietary).
   * Cancer (malignancy other than a resolved or excised skin lesion).
   * Heart disease (hospitalization for a heart attack, arrhythmia, or syncope)
   * Unconsciousness (other than a single brief "concussion")
   * Seizures (other than febrile seizures as a child \<5 years old)
   * Asthma requiring treatment with inhaler or medication in the past 2 years.
   * Neuro-inflammatory disease
   * Autoimmune disease
   * Eating disorder
   * Chronic headaches associated with vomiting
   * Chronic vomiting syndrome
10. Any current illness requiring daily medication other than vitamins, minerals, birth control, anti-hypertensives or anti-depressants. The use of any other medications should be discussed with the Sponsor and/or CSM.
11. Allergies or hypersensitivity to any component of the vaccine or challenge virus.
12. Any clinically significant abnormality detected on physical examination, including:

    * Murmur (other than a functional, ie normal, murmur)
    * Focal neurological abnormality
    * Hepatosplenomegaly
    * Lymphadenopathy
    * Jaundice
13. Hypertension defined as BP \> 150/90 mm Hg on two separate measurements. Chronic stable well-controlled hypertension on medications is allowed.
14. History of 3 or more hospitalizations for invasive bacterial infections (pneumonia, meningitis), acute or chronic dermatitis (e.g. eczema, seborrhea, psoriasis) or collagen vascular disease (e.g. Systemic Lupus Erythematosus (SLE) or dermatomyositis).
15. Presence of serious chronic illness.
16. Positive stool/fecal culture for bacterial pathogens (salmonella, campylobacter, E. coli 0157:H7, yersinia, or shigella) or positive stool/fecal screen for ova and parasites.
17. Employment in the food service industry, such as restaurants or cafeteria facilities. Specifically, this will include persons whose employment requires food processing in the 4 weeks following challenge.
18. Health-care workers with patient contact expected in the 4 weeks following challenge.
19. Expected contact (through employment or at home) with immunocompromised persons (HIV-positive, receiving immunosuppressive medications such as oral steroids or anti-neoplastic agents) in the 4 weeks following challenge.
20. Employment as an airline flight attendant scheduled to work in the 4 weeks following challenge.
21. Persons planning on taking a cruise in the 4 weeks following challenge.
22. Persons who plan to be living in a confined environment (e.g. ship, camp, or dormitory) within 4 weeks following challenge.
23. Persons who have consumed or plan to consume raw shellfish (e.g. oysters) from screening through post challenge Day 30.
24. Any of the following lab abnormalities (per the site local laboratory):

    * Absolute neutrophil count (ANC) outside the normal range
    * Total White Blood Cell Count (WBC) outside the normal range
    * Hemoglobin or hematocrit outside the normal range
    * Platelet count outside the normal range
    * Electrolytes \[Sodium (Na), Potassium (K), Chloride (Cl), Carbon dioxide (CO2)\], Blood Urea Nitrogen (BUN) and/or creatinine outside the normal range
    * Screening glucose \> upper limit of normal (ULN). Fasting glucose is not required
    * Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), alkaline phosphatase, bilirubin (total and indirect), or Gamma Glutamyl Transferase (GGT) outside the upper limit of the normal range
    * Screening urinalysis with a value higher than "trace" positive for urine protein or urine glucose, or urine Red Blood Cells (RBCs) (≥3; other than women during menses).

    All of the above labs may be repeated if outside the normal limits. If repeated and continue outside site normal ranges, may enroll if determined by the Principal Investigator (PI) to be not clinically significant and discussed with the Sponsor and/or CSM.
25. For women of child bearing potential, positive serum pregnancy test within 14 days or positive urine pregnancy test within one day of randomization.
26. Temperature \> 100.4°F orally, or symptoms of an acute self-limited illness such as an upper respiratory infection within 3 days of administering either dose of Norovirus Bivalent VLP vaccine or placebo control or the challenge product.
27. Resting heart rate \>100 beats per minute or \<55 beats per minute, respiratory rate ≥ 20 breaths per minute. If heart rate \<55 beat per minute and the investigator determines that this is not clinically significant and heart rate increases \> 55 beats per minute on moderate exercise, subject will not be excluded. Vital signs may be repeated.
28. Clinically abnormal screening electrocardiogram (ECG) defined as pathologic Q waves and significant ST-T wave changes; criteria for left ventricular hypertrophy; and any non-sinus rhythm excluding isolated premature atrial contractions.
29. Previous participation in a study of experimental norovirus infection or norovirus vaccine.
30. Study site personnel or their family members
31. Significant history of psychiatric hospitalization, alcohol abuse, or illicit drug use.
32. Receipt of a licensed live vaccine within 28 days or a licensed inactivated vaccine within 14 days of administration of either dose of vaccine or placebo or the challenge product.
33. Completion of an investigational vaccine or drug study within 7 days of randomization.
34. Receipt of systemic corticosteroids for greater than 7 days within the past six months.
35. Regular use of laxatives or anti-motility agents.
36. Receipt of blood or blood products within the past six months.
37. Subjects who are unwilling or unable to cease smoking from entry to the inpatient facility until discharge from the inpatient facility.
38. Other condition that in the clinical judgment of the investigator would jeopardize the safety or rights of a subject participating in the trial, would render the subject unable to comply with the protocol, or would interfere with the evaluation of the Vaccination stage or the evaluation of the Challenge stage.

Challenge Stage Exclusion Criteria

The following additional exclusion criteria must not be met prior to admission to the inpatient unit for Challenge:

1. Use of antibiotics within the 7 days prior to entry into the inpatient challenge facility.
2. Use of any H-2 receptor antagonists (e.g. Tagamet, Zantac, and Pepcid), proton pump inhibitors (e.g. Prilosec, Protonix, and Prevacid), or prescription acid suppression medication or over the counter antacids within 72 hours of the challenge.
3. Use of prescription or Over the Counter (OTC) medications containing acetaminophen, aspirin, ibuprofen, and/or other non-steroidal anti-inflammatory drugs within 48 hours prior to challenge.

Primary outcomes:
measure: 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
timeFrame: Symptoms collected from Challenge dose (at least 28 days after dose 2) to discharge (at least 96 hours after challenge dose)
measure: Percentage of Participants Experiencing Solicited Local Adverse Events Within 7 Days Post-Dose 1
timeFrame: Within 7 days post-dose 1
measure: Percentage of Participants Experiencing Solicited Local Adverse Events Within 7 Days Post-Dose 2
timeFrame: Within 7 days post-dose 2
measure: Percentage of Participants Experiencing Solicited Systemic Adverse Events Within 7 Days Post-Dose 1
timeFrame: Within 7 days post-dose 1
measure: Percentage of Participants Experiencing Solicited Systemic Adverse Events Within 7 Days Post-Dose 2
timeFrame: Within 7 days post-dose 2
measure: Percentage of Participants With Serious Adverse Events (SAEs) 365 Days Following the Last Study Vaccination
timeFrame: 365 Days Following Dose 2 (Up to 393 days)
Secondary outcomes:
measure: 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
timeFrame: Pre Challenge to 30 Days Post Challenge
measure: Severity of Viral AGE Due to GII.4 Strain Assessed by Modified Vesikari Scoring System During the Inpatient Phase
timeFrame: Symptoms collected from Challenge dose (at least 28 days after dose 2) to discharge (at least 96 hours after challenge dose)
measure: Severity of Viral AGE Due to GII.4 Strain Assessed by Post-Challenge Symptom Collection During the Inpatient Phase
timeFrame: Symptoms collected from Challenge dose (at least 28 days after dose 2) to discharge (at least 96 hours after challenge dose)
measure: Duration of Viral AGE Due to GII.4 Strain During the Inpatient Phase
timeFrame: Symptoms collected from Challenge dose (at least 28 days after dose 2) to discharge (at least 96 hours after challenge dose)
measure: Percentage of Participants With GII.4 Norovirus Positive RT-PCR in the Stool During the Inpatient and /or Outpatient Phase
timeFrame: Pre Challenge to 30 Days Post Challenge
measure: Percentage of Participants With GII.4 Seroresponse Rate (4-fold Rise) From Pre-challenge Day 0 to Post-Challenge Day 30
timeFrame: Pre Challenge to 30 Days Post Challenge
measure: Pan-Ig ELISA - Anti-Norovirus GI.1 VLP Geometric Mean Fold Rise (GMFR) From Baseline
timeFrame: Baseline to 28 days Post Dose 1 and 28 days Post Dose 2
measure: Percentage of Participants With Pan-Ig ELISA - Anti-Norovirus GI.1 VLP Seroresponse (4-fold Rise) From Baseline
timeFrame: Baseline, 28 days Post Dose 1 and 28 days Post Dose 2
measure: Pan-Ig ELISA - Anti-Norovirus GI.1 VLP Geometric Mean Titer (GMT)
timeFrame: Baseline, 28 days Post Dose 1 and 28 days Post Dose 2
measure: Pan-Ig ELISA - Anti-Norovirus GII.4 cVLP GMFR From Baseline
timeFrame: Baseline to 28 days post Dose 1 and 28 days post Dose 2
measure: Percentage of Participants With Pan-Ig ELISA - Anti-Norovirus GII.4 cVLP Seroresponse From Baseline
timeFrame: Baseline to 28 days post Dose 1 and 28 days post Dose 2
measure: Pan-Ig ELISA - Anti-Norovirus GII.4 cVLP GMT
timeFrame: Baseline, 28 days post Dose 1 and 28 days post Dose 2
measure: ELISA Immunoglobulin A (IgA)- Anti-Norovirus GI.1 VLP Geometric Mean Fold Rise (GMFR) From Baseline
timeFrame: Baseline to 28 days Post Dose 1 and 28 days Post Dose 2
measure: Percentage of Participants With ELISA IgA- Anti-Norovirus GI.1 VLP Seroresponse (4-fold Rise) From Baseline
timeFrame: Baseline to 28 days Post Dose 1 and 28 days Post Dose 2
measure: ELISA IgA- Anti-Norovirus GI.1 VLP Geometric Mean Titer (GMT)
timeFrame: Baseline, 28 days Post Dose 1 and 28 days Post Dose 2
measure: ELISA IgA- Anti-Norovirus GII.4 cVLP GMFR From Baseline
timeFrame: Baseline to 28 days post Dose 1 and 28 days post Dose 2
measure: Percentage of Participant With ELISA IgA- Anti-Norovirus GII.4 cVLP Seroresponse From Baseline
timeFrame: Baseline to 28 days post Dose 1 and 28 days post Dose 2
measure: ELISA IgA- Anti-Norovirus GII.4 cVLP GMT
timeFrame: Baseline, 28 days post Dose 1 and 28 days post Dose 2
measure: HBGA (PGM) - Anti-Norovirus GI.1 VLP GMFR From Baseline
timeFrame: Baseline to 28 days post Dose 1 and 28 days post Dose 2
measure: Percentage of Participants With HBGA (PGM) - Anti-Norovirus GI.1 VLP Seroresponse From Baseline
timeFrame: Baseline to 28 days post Dose 1 and 28 days post Dose 2
measure: HBGA (PGM) - Anti-Norovirus GI.1 VLP GMT
timeFrame: Baseline, 28 days post Dose 1 and 28 days post Dose 2
measure: HBGA (PGM) - Anti-Norovirus GII.4 cVLP GMFR From Baseline
timeFrame: Baseline to 28 days post Dose 1 and 28 days post Dose 2
measure: Percentage of Participants With HBGA (PGM) - Anti-Norovirus GII.4 cVLP Seroresponse From Baseline
timeFrame: Baseline to 28 days post Dose 1 and 28 days post Dose 2
measure: HBGA (PGM) - Anti-Norovirus GII.4 cVLP GMT
timeFrame: Baseline, 28 days post Dose 1 and 28 days post Dose 2
measure: Percentage of Participants With Unsolicited Non-Serious [i.e Other Than SAEs] Adverse Events (AEs)
timeFrame: Vaccination Stage: Initial vaccination until 28 days after second vaccination; or Challenge Stage: the day of challenge until 60 days after challenge
Other outcomes:
measure: Correlation of GII.4 Serum HBGA Antibodies Prior to Challenge Associated With Protection From GII.4 Illness
timeFrame: Pre Challenge to Day 30 Post Challenge
measure: Correlation of GII.4 Serum HGBA Antibodies Prior to Challenge Associated With Protection From GII.4 Infection
timeFrame: Pre Challenge to Day 30 Post Challenge
Locations:
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Baltimore
country: United States
facility: SNBL
state: Maryland
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Childrens Hospital Medical Center
state: Ohio
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
Study officials:
affiliation: Cincinatti Children's Hospital
name: David Bernstein, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: SNBL Clinical Pharmacology Center
name: Mohamed S Al-Ibrahim, MB, ChB
role: PRINCIPAL_INVESTIGATOR
affiliation: Baylor College of Medicine
name: David Y Graham, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital Medical Center, Cincinnati
name: Robert L Atmar, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory University
name: G. Marshall Lyon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Rochester
name: John J Treanor, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bernstein DI, Atmar RL, Lyon GM, Treanor JJ, Chen WH, Jiang X, Vinje J, Gregoricus N, Frenck RW Jr, Moe CL, Al-Ibrahim MS, Barrett J, Ferreira J, Estes MK, Graham DY, Goodwin R, Borkowski A, Clemens R, Mendelman PM. Norovirus vaccine against experimental human GII.4 virus illness: a challenge study in healthy adults. J Infect Dis. 2015 Mar 15;211(6):870-8. doi: 10.1093/infdis/jiu497. Epub 2014 Sep 9.
citation: Atmar RL, Bernstein DI, Lyon GM, Treanor JJ, Al-Ibrahim MS, Graham DY, Vinje J, Jiang X, Gregoricus N, Frenck RW, Moe CL, Chen WH, Ferreira J, Barrett J, Opekun AR, Estes MK, Borkowski A, Baehner F, Goodwin R, Edmonds A, Mendelman PM. Serological Correlates of Protection against a GII.4 Norovirus. Clin Vaccine Immunol. 2015 Aug;22(8):923-9. doi: 10.1128/CVI.00196-15. Epub 2015 Jun 3.
citation: Sundararajan A, Sangster MY, Frey S, Atmar RL, Chen WH, Ferreira J, Bargatze R, Mendelman PM, Treanor JJ, Topham DJ. Robust mucosal-homing antibody-secreting B cell responses induced by intramuscular administration of adjuvanted bivalent human norovirus-like particle vaccine. Vaccine. 2015 Jan 15;33(4):568-76. doi: 10.1016/j.vaccine.2014.09.073. Epub 2014 Nov 22.