Clinical trial NCT01168401: Bivalent Norovirus Vaccine Study
Official title: Phase 1, Randomized Controlled Dose Escalation, Safety and Immunogenicity Study of Intramuscular Norovirus GI.1/GII.4 Bivalent Virus-Like Particle (VLP) Vaccine Adjuvanted With Monophosphoryl Lipid A (MPL) and Aluminum Hydroxide [Al(OH)3] in Adults
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Gastroenteritis
Keywords: Vaccine, norovirus, acute gastroenteritis
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2010-07-23
Enrollment: 102
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Randomized, multi-site, dose-escalation study of the safety and immunogenicity of four dosage levels of Intramuscular (IM) Norovirus Bivalent VLP Vaccine adjuvanted with MPL and Al(OH)3 compared to controls. Participants will receive two doses, by IM injection, 28 days apart.

The hypotheses for this study are:

* The incidence of adverse events after vaccination with IM Norovirus Bivalent VLP Vaccine will be similar to the incidence of adverse events after other IM vaccines including CERVARIX® which contains MPL and Al(OH)3.
* Two doses of IM Norovirus Bivalent VLP Vaccine will be more immunogenic than one dose.
* The post-vaccination serum antibody responses, the number of antibody secreting cells (ASC), including homing markers, and memory B-cell responses directed against norovirus antigens will be increased after IM Norovirus Bivalent VLP Vaccine compared to controls.


Eligibility criteria: Inclusion Criteria:

Participants must meet all of the inclusion criteria listed below:

1. Signed written informed consent.
2. Age:

   * Cohort A: 18-49 years, inclusive
   * Cohort B: 50-64 years, inclusive
   * Cohort C: 65-85 years, inclusive
   * Cohort D: 18-49 years, inclusive
3. Health Status:

   * Cohort A and D: In good health as determined by a screening evaluation that includes vital signs, medical history, and physical exam within 45 days before administration of IM Norovirus Bivalent VLP Vaccine or control.
   * Cohorts B and C: In good health as determined by a screening evaluation that includes vital signs, medical history, and physical exam within 45 days before administration of IM Norovirus Bivalent VLP Vaccine or control. Any existing medical diagnoses or conditions must be stable based on medical history and targeted physical examination. A stable medical condition is defined as: (A) Clinically acceptable health outcomes for the specific condition over the prior 6 months and (B) No change in prescription medication(s), dose, or frequency over the prior 3 months. Acceptable changes in medications are: a change of health care provider or insurance company or that is made for financial reasons as long as the medications are in the same class and/or a change due to improvement in a disease outcome.
4. Expressed interest and availability to fulfill the study requirements.
5. Female participants must be of non-childbearing potential (surgically sterile or post-menopausal for greater than or equal to \[\>=\] 12 months), or if of childbearing potential (as determined by the investigator) must be practicing abstinence or using an effective licensed method of birth control (example 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 for at least 60 days after the last vaccination. A woman is eligible if she is monogamous with a male who has had a vasectomy. Male participants must agree not to father a child for at least 60 days after the last vaccination and to practice abstinence or use an effective method of birth control as noted above.
6. Agrees not to participate in another clinical trial with an investigational product for the entire duration of the study one year after the last study dose that is 393 days.
7. Agrees to storage of unused clinical specimens for an indefinite period of time for future norovirus research or research on other gastrointestinal pathogens.

Exclusion Criteria:

Participants who meet any of the exclusion criteria at baseline will be excluded from study participation. The exclusion criteria are:

1. History of any of the following medical illnesses:

   * Diabetes
   * Cancer (malignancy other than resolved/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 less than \[\<\] 5 years old)
   * Recurrent infections (more than 3 hospitalizations for invasive bacterial infections such as pneumonia or meningitis)
   * Any condition associated with immunodeficiency or participants taking immunosuppressant medication
   * Neuroinflamatory or auto-immune disease
2. Any current illness requiring daily medication other than the following:

   * Cohort A and D: Vitamins, birth control, anti-hypertensive medication, antihistamines or anti-depressant medication. The Principal Investigator (PI) should consult with the Central Safety Monitor and/or the sponsor for any clarification of medications allowable.
   * Cohorts B and C: Vitamins, birth control, anti-hypertensive medication, antihistamines or anti-depressant medication or any current illness requiring daily medication other than as noted above in inclusion criteria 3. The PI should consult with the Central Safety Monitor and/or the sponsor for any clarification of medications allowable.
3. Allergies or hypersensitivity to any component of the vaccine including MPL and Al(OH)3 adjuvants.
4. Any clinically significant abnormality detected on physical examination, including:

   * Murmur (other than a functional murmur)
   * Focal neurological abnormality
   * Hepatosplenomegaly
   * Lymphadenopathy
   * Jaundice
5. Hypertension (Blood Pressure \[BP\] greater than \[\>\] 140/90 millimeter of mercury \[mm Hg\] on two separate days)
6. Any lab abnormality (per the site local laboratory), as listed below:

   * Absolute Neutrophil Count (ANC) outside the normal range (may be repeated if outside this limit)
   * Total white blood cells (WBC) outside the normal range (may be repeated if outside this limit)
   * Hemoglobin outside the normal range (may be repeated if outside this limit)
   * Platelet count outside the normal range (may be repeated if outside this limit)
   * Blood urea nitrogen (BUN) \> upper limit of normal (ULN) (may be repeated if outside this limit)
   * Creatinine \> ULN (may be repeated if outside this limit)
   * Glucose (fasting or random) outside the normal range (may be repeated if outside this limit)
   * Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) \> ULN (may be repeated if outside this limit)
7. Positive serology for hepatitis C or Human Immunodeficiency Virus (HIV) antibody or hepatitis B surface antigen.
8. For women of child bearing potential, positive serum pregnancy test within 14 days and urine pregnancy test within 24 hours of administering either dose of IM Norovirus Bivalent VLP Vaccine or control.
9. Nursing mother.
10. Temperature \>100.4 degree Fahrenheit (F) or symptoms of an acute self-limited illness such as an upper respiratory infection or gastroenteritis within 3 days of administration of IM Norovirus Bivalent VLP Vaccine or control.
11. Previous participation in a Norovirus vaccine or challenge study.
12. Study site personnel or their family members.
13. Significant history of psychiatric hospitalization, alcohol abuse, or illicit drug use in the prior 5 years.
14. Completion of an investigational vaccine or drug study within 28 days before administration of IM Norovirus Bivalent VLP Vaccine or control.
15. Have a history of receiving immunoglobulin or other blood product within the 3 months prior to vaccination in this study.
16. Other condition that in the clinical judgment of the investigator would jeopardize the safety or rights of a participant participating in the trial, would render the participant unable to comply with the protocol or would interfere with the evaluation of the vaccine.

Primary outcomes:
measure: Number of Participants With Solicited Local Adverse Events (AEs) Post Dose 1
timeFrame: Day 0 up to Day 7
measure: Number of Participants With Solicited Local AEs Post Dose 2
timeFrame: Day 28 up to Day 35
measure: Number of Participants With Solicited Systemic AEs Post Dose 1
timeFrame: Day 0 up to Day 7
measure: Number of Participants With Solicited Systemic AEs Post Dose 2
timeFrame: Day 28 up to Day 35
measure: Number of Participants With Unsolicited AEs Post Dose 1
timeFrame: Baseline up to Day 28 (Pre-dose 2)
measure: Number of Participants With Unsolicited AEs Post Dose 2
timeFrame: Day 28 up to Day 56 (Post dose 2)
measure: Number of Participants With Clinically Significant Change From Baseline in Markedly Abnormal Laboratory Values
timeFrame: Baseline up to Day 35
measure: Number of Participants With Serious Adverse Events (SAEs), Onset of Significant New Medical Conditions, Including Adverse Events of Special Interest (AESI)
timeFrame: Baseline up to 365 Days after post dose 2 (Day 393)
Secondary outcomes:
measure: Geometric Mean Titer (GMT) of Serum Anti-norovirus GI.1 and GII.4 VLP Ig (Immunoglobulin) A
timeFrame: First (I) run: predose 1 and 7, 21, 28 days postdose (PD)1, and 7 and 28 days PD2; second (II) run: predose 1 and 28, 152 and 365 days PD2 (up to Day 393)
measure: GMT of Serum Anti-norovirus GI.1 and GII.4 VLP IgG
timeFrame: I run: predose 1 and 7, 21, 28 days PD1, and 7 and 28 days PD2; II run: predose 1 and 28, 152 and 365 days PD2 (up to Day 393)
measure: GMT of Serum Anti-norovirus GI.1 and GII.4 VLP IgM
timeFrame: I run: predose 1 and 7, 21, 28 days PD1, and 7 and 28 days PD2; II run: predose 1 and 28, 152 and 365 days PD2 (up to Day 393)
measure: Geometric Mean Fold Rise (GMFR) of Serum Anti-norovirus GI.1 and GII.4 VLP IgA as Compared to Baseline
timeFrame: I run: 7, 21, 28 days PD1, 7 and 28 days PD2; II run: 28, 152 and 365 days PD2 (up to Day 393)
measure: GMFR of Serum Anti-norovirus GI.1 and GII.4 VLP IgG as Compared to Baseline
timeFrame: I run: 7, 21, 28 days PD1, 7 and 28 days PD2; II run: 28, 152 and 365 days PD2 (up to Day 393)
measure: GMFR of Serum Anti-norovirus GI.1 and GII.4 VLP IgM as Compared to Baseline
timeFrame: I run: 7, 21, 28 days PD1, 7 and 28 days PD2; II run: 28, 152 and 365 days PD2 (up to Day 393)
measure: Percentage of Participants With Seroresponse for Serum Anti-norovirus GI.1 and GII.4 VLP IgA
timeFrame: I run: 7, 21, 28 days PD1, 7 and 28 days PD2; II run: 28, 152 and 365 days PD2 (up to Day 393)
measure: Percentage of Participants With Seroresponse for Serum Anti-norovirus GI.1 and GII.4 VLP IgG
timeFrame: I run: 7, 21, 28 days PD1, 7 and 28 days PD2; II run: 28, 152 and 365 days PD2 (up to Day 393)
measure: Percentage of Participants With Seroresponse for Serum Anti-norovirus GI.1 and GII.4 VLP IgM
timeFrame: I run: 7, 21, 28 days PD1, 7 and 28 days PD2; II run: 28, 152 and 365 days PD2 (up to Day 393)
measure: GMT of Anti-norovirus GI.1 and GII.4 VLP IgA, IgG, and IgM Combined Using Pan-Ig Enzyme-Linked Immunosorbent Assay (ELISA)
timeFrame: I run: predose 1, 7, 21, 28 days PD1, 7 and 28 days PD2; II run: predose 1, 28, 152 and 365 days PD2 (up to Day 393)
measure: GMFR of Anti-norovirus GI.1 and GII.4 VLP IgA, IgG, and IgM Combined Using Pan-Ig ELISA as Compared to Baseline
timeFrame: I run: 7, 21, 28 days PD1, 7 and 28 days PD2; II run: 28, 152 and 365 days PD2 (up to Day 393)
measure: Percentage of Participants With Seroresponse (4-Fold Rise) of Anti-norovirus GI.1 and GII.4 VLP IgA, IgG, and IgM Combined Using Pan-Ig ELISA
timeFrame: I run: 7, 21, 28 days PD1, 7 and 28 days PD2; II run: 28, 152 and 365 days PD2 (up to Day 393)
Other outcomes:
Locations:
city: Silver Springs
country: United States
facility: Navy Medical Research Center
state: Maryland
city: Saint Louis
country: United States
facility: Saint Louis University
state: Missouri
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
Study officials:
References:
citation: Ramani S, Neill FH, Ferreira J, Treanor JJ, Frey SE, Topham DJ, Goodwin RR, Borkowski A, Baehner F, Mendelman PM, Estes MK, Atmar RL. B-Cell Responses to Intramuscular Administration of a Bivalent Virus-Like Particle Human Norovirus Vaccine. Clin Vaccine Immunol. 2017 May 5;24(5):e00571-16. doi: 10.1128/CVI.00571-16. Print 2017 May.
citation: Lindesmith LC, Ferris MT, Mullan CW, Ferreira J, Debbink K, Swanstrom J, Richardson C, Goodwin RR, Baehner F, Mendelman PM, Bargatze RF, Baric RS. Broad blockade antibody responses in human volunteers after immunization with a multivalent norovirus VLP candidate vaccine: immunological analyses from a phase I clinical trial. PLoS Med. 2015 Mar 24;12(3):e1001807. doi: 10.1371/journal.pmed.1001807. eCollection 2015 Mar.
citation: Treanor JJ, Atmar RL, Frey SE, Gormley R, Chen WH, Ferreira J, Goodwin R, Borkowski A, Clemens R, Mendelman PM. A novel intramuscular bivalent norovirus virus-like particle vaccine candidate--reactogenicity, safety, and immunogenicity in a phase 1 trial in healthy adults. J Infect Dis. 2014 Dec 1;210(11):1763-71. doi: 10.1093/infdis/jiu337. Epub 2014 Jun 20.