Safety and Immunogenicity of Norovirus GI.1/GII.4 Bivalent Virus-Like Particle (VLP) Vaccine in Children

Norovirus Clinical Trial

Official title:

A Phase II, Randomized, Double-Blind, Dosage, Safety and Immunogenicity Trial of Intramuscular Norovirus GI.1/GII.4 Bivalent Virus-Like Particle Vaccine Combined With Aluminum Hydroxide Adjuvant in Children, Toddlers, and Infants

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02153112
• Other study ID #: NOR-202
• Secondary ID: 2014-000778-20U1
• Status: Completed
• Phase: Phase 2
• Start date: June 23, 2015
• Est. completion date: June 20, 2018

Study information

• Verified date: December 2018
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to select the optimal formulation of the norovirus vaccine from different concentrations of virus-like particles (VLP) combined with aluminum hydroxide for further development in children.

Description:

The vaccine being tested in this study is called norovirus GI.1/GII.4 bivalent virus-like particle (VLP) vaccine with aluminum hydroxide. The norovirus vaccine is being tested to assess different formulations of the vaccine that will then be further developed. This study will look at the number of antibodies to norovirus formed in children, toddlers and infants who are administered different formulations of the norovirus vaccine.

The study enrolled 840 patients. Participants will be randomly assigned (by chance) to one of ten treatment groups—which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need).

All participants in Cohort 1 will be vaccinated on Day 1 and Day 29 of the study, and all participants in Cohort 2 will be vaccinated on Day 1, Day 56, and Day 112. All treatment groups in Cohort 1 will receive either one dose of the norovirus vaccine, or two doses. One treatment group in Cohort 2 will receive 2 doses of the norovirus vaccine, and the other group will receive 3. In order to keep the treatment undisclosed to the participant and the doctor in Cohort 1, those randomized to the one-dose groups will receive the norovirus vaccine on Day 1, followed by a dose of placebo vaccine on Day 29. In order to keep the treatment arms undisclosed to the participant and the doctor in Cohort 2, those randomized to the two-dose groups will receive the norovirus vaccine on Day 1 and Day 56, followed by a dose of placebo vaccine on Day 112. Placebo vaccine is saline solution. Participants will be asked to record any symptoms that may be related to the vaccine or the injection site in a diary card for 7 days after each vaccination.

This multi-center trial will be conducted in Finland, Panama, and Colombia. The overall time to participate in this study is up to 210 days for participants in Cohort 1 and up to 293 Days for participants in Cohort 2. Participants in Cohort 1 will make 6 visits to the clinic, and participants in Cohort 2 will make 10 visits to the clinic.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 840
• Est. completion date: June 20, 2018
• Est. primary completion date: June 20, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 6 Weeks to 8 Years

Eligibility

Inclusion Criteria:

1. Male and female participants aged between 6 weeks and less than 9 years at the time of enrollment.

2. Are in good health at the time of entry into the trial as determined by medical history, physical examination (including vital signs) and clinical judgment of the investigator.

3. Participants legally authorized representative (LAR) signs and dates a written, informed consent form (ICF) and any required privacy authorization prior to the initiation of any trial procedures, after the nature of the trial has been explained according to local regulatory requirements. An assent will also be obtained according to age-appropriate country-specific regulations.

4. Participants who can comply with trial procedures and are available for the duration of the trial.

Exclusion Criteria:

1. Participants with a clinically significant active infection (as assessed by the investigator) or body temperature 38.0°C (100.4°F) or higher within 3 days of the intended date of vaccination.

2. Have received antipyretic/analgesic medications within 24 hours prior to the intended vaccine administration.

3. Known hypersensitivity or allergy to investigational vaccine (including excipients of the investigational vaccines).

4. Participants with behavioral or cognitive impairment or psychiatric disease that, in the opinion of the investigator, may interfere with the ability to participate in the trial.

5. Has a history of any progressive or severe neurologic disorder, seizure disorder, or neuroinflammatory disease (eg, Guillain-Barre´ syndrome).

6. Known or suspected impairment/alteration of immune function, including the following:

1. Children <18 months of age with history of repeated episodes of acute otitis media (AOM) in the first 6 months of life (AOM defined as a bulging tympanic membrane) and not to be confused with otitis media with effusion (OME).

2. Chronic use of oral steroids (equivalent to 20 mg/day prednisone for =12 weeks/=2 mg/kg body weight/day for =2 weeks) within 60 days prior to Day 1 (use of inhaled, intranasal, or topical corticosteroids is allowed).

3. Receipt of parenteral steroids (equivalent to 20 mg/day prednisone =12 weeks/=2 mg/kg body weight/day for =2 weeks) within 60 days prior to Day 1.

4. Receipt of immunostimulants within 60 days prior to Day 1.

5. Receipt of parenteral, epidural, or intra-articular immunoglobulin preparation, blood products, and/or plasma derivatives within 3 months prior to Day 1 or planned during the full length of the trial.

6. Receipt of immunosuppressive therapy within 6 months prior to Day 1.

7. Human immunodeficiency virus (HIV) infection or HIV-related disease.

8. Chronic Hepatitis B or C infection.

9. Heritable immunodeficiency.

7. Abnormalities of splenic or thymic function.

8. Has a known bleeding diathesis or any condition that may be associated with a prolonged bleeding time.

9. Has any serious chronic or progressive disease according to judgment of the investigator (e.g., neoplasm, insulin dependent diabetes, cardiac, renal, or hepatic disease).

10. Is participating in any clinical trial with another investigational product 30 days prior to first trial visit or intent to participate in another clinical trial at any time during the conduct of this trial.

11. Has received any other vaccines within 14 days (for inactivated vaccines) or 28 days (for live vaccines) prior to enrollment in this trial.

12. Are first degree relatives of individuals involved in trial conduct.

13. Has a history of autoimmune disease.

Related Conditions & MeSH terms

• Norovirus

Intervention

Biological:
• GI.1/GII.4 (15/15)
Norovirus GI.1/GII.4 (15 µg/15 µg) bivalent VLP vaccine combined with 500 µg aluminum hydroxide for IM injection
• GI.1/GII.4 (15/50)
Norovirus GI.1/GII.4 (15 µg/50 µg) bivalent VLP vaccine combined with 500 µg aluminum hydroxide for IM injection
• GI.1/GII.4 (50/50)
Norovirus GI.1/GII.4 (50 µg/50 µg) bivalent VLP vaccine combined with 500 µg aluminum hydroxide for IM injection
• GI.1/GII.4 (50/150)
Norovirus GI.1/GII.4 (50 µg/150 µg) bivalent VLP vaccine combined with 500 µg aluminum hydroxide for IM injection

Drug:
• Placebo
Placebo saline solution

Locations

Country	Name	City	State
Colombia	Centro de Estudios em Infectologia Pediatrica SAS	Cali	San Fernando
Finland	Espoon Rokotetutkimusklinikka	Espoo
Finland	Etela-Helsingin Rokotetutkimusklinikka	Helsinki
Finland	Ita-Helsingin Rokotetutkimusklinikka	Helsinki
Finland	Jarvenpaan Rokotetutkimusklinikka	Jarvenpaan
Finland	Oulun Rokotetutkimusklinikka	Oulu
Finland	Porin Rokotetutkimusklinikka	Pori
Finland	Seinajoen Rokotetutkimusklinikka	Seinajoki
Finland	Tampere Vaccine Research Clinic	Tampere
Finland	Turun Rokotetutkimusklinikka	Turku
Panama	CEVAXIN Plaza Carolina - Ciudad de Panama	Ciudad de Panama
Panama	CEVAXIN	Panama

Sponsors (1)

Lead Sponsor	Collaborator
Takeda

Countries where clinical trial is conducted

Colombia,  Finland,  Panama, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With a Seroresponse (Pan-Ig ELISA) in Cohort 1	Seroresponse was defined as 4-fold rise or greater at Day 57 in serum anti-norovirus antibody titers for both GI.1 virus-Like particle (VLP) and GII.4 VLP as measured by pan immunoglobulin (Pan-Ig) enzyme-linked immunosorbent assay (ELISA).	Day 57
Primary	Percentage of Participants With a Seroresponse (Pan-Ig ELISA) in Cohort 2	Seroresponse was defined as 4-fold rise or greater at Day 140 in serum anti-norovirus antibody titers for both GI.1 virus-Like particle (VLP) and GII.4 VLP as measured by pan immunoglobulin (Pan-Ig) enzyme-linked immunosorbent assay (ELISA).	Day 140
Primary	Percentage of Participants With Solicited Local (Injection Site) Adverse Events (AEs) (Diary-Recorded) Following Either Vaccination on Day 1	Solicited local AEs at injection site are defined as: pain, erythema, induration, and swelling that occur on the vaccination day through Day 7 after each vaccination.	Day 1 after either of the vaccination given on Days 1, 29, 56 or 112
Primary	Percentage of Participants With Solicited Local (Injection Site) Adverse Events (AEs) (Diary-Recorded) Following Either Vaccination on Day 2	Solicited local AEs at injection site are defined as: pain, erythema, induration, and swelling that occur on the vaccination day through Day 7 after each vaccination.	Day 1 after either of the vaccination given on Days 1, 29, 56 or 112
Primary	Percentage of Participants With Solicited Local (Injection Site) Adverse Events (AEs) (Diary-Recorded) Following Either Vaccination on Day 3	Solicited local AEs at injection site are defined as: pain, erythema, induration, and swelling that occur on the vaccination day through Day 7 after each vaccination.	Day 3 after either of the vaccination given on Days 1, 29, 56 or 112
Primary	Percentage of Participants With Solicited Local (Injection Site) Adverse Events (AEs) (Diary-Recorded) Following Either Vaccination on Day 4	Solicited local AEs at injection site are defined as: pain, erythema, induration, and swelling that occur on the vaccination day through Day 7 after each vaccination.	Day 4 after either of the vaccination given on Days 1, 29, 56 or 112
Primary	Percentage of Participants With Solicited Local (Injection Site) Adverse Events (AEs) (Diary-Recorded) Following Either Vaccination on Day 5	Solicited local AEs at injection site are defined as: pain, erythema, induration, and swelling that occur on the vaccination day through Day 7 after each vaccination.	Day 5 after either of the vaccination given on Days 1, 29, 56 or 112
Primary	Percentage of Participants With Solicited Local (Injection Site) Adverse Events (AEs) (Diary-Recorded) Following Either Vaccination on Day 6	Solicited local AEs at injection site are defined as: pain, erythema, induration, and swelling that occur on the vaccination day through Day 7 after each vaccination.	Day 6 after either of the vaccination given on Days 1, 29, 56 or 112
Primary	Percentage of Participants With Solicited Local (Injection Site) Adverse Events (AEs) (Diary-Recorded) Following Either Vaccination on Day 7	Solicited local AEs at injection site are defined as: pain, erythema, induration, and swelling that occur on the vaccination day through Day 7 after each vaccination.	Day 7 after either of the vaccination given on Days 1, 29, 56 or 112
Primary	Percentage of Participants With Solicited Systemic Adverse Events (AEs) (Diary-Recorded) Following Either Vaccination	Systemic AEs are defined as headache, fatigue, myalgia, arthralgia, vomiting (number per day/intensity), and diarrhea (number per day/consistency) for children aged 4 to <9 years; and irritability/fussiness, drowsiness, loss of appetite, vomiting (number per day/intensity), and diarrhea (number per day/consistency) for children aged 6 weeks to <4 years on the day of vaccination and daily through Day 7 after each vaccination.	Days 1 through 7 after each vaccination given on Days 1, 29, 56 or 112
Primary	Body Temperature Through Day 7 Following Either Vaccination	Body temperature measurement was performed using the thermometer provided by the site through Day 7 after each vaccination. The highest body temperature observed each day was recorded on the Diary Card. Body temperature is categorized as 1) Any (temperature 38°C or higher), 2) 38°C - <38.5°C, 3) 38.5°C - <39°C, 4) 39°C - <39.5°C, 5) 39.5°C - <40°C, 6) 40°C or higher. Number of participants with the particular body temperature is reported within the pre-defined categories.	Post-vaccination approximately 30 minutes and 6 hours later, then daily through Day 7 after each vaccination given on Days 1, 29, 56 or 112
Primary	Percentage of Participants With at Least One Unsolicited AE Following Either Vaccination Dose	Unsolicited AEs are any local or systemic AEs, as defined by this study, that are not solicited.	Unsolicited AEs were collected within 28 days of all vaccinations (Day 1 to 57 for Cohort 1 and Day 1 to 140 for Cohort 2)
Primary	Percentage of Participants With Serious Adverse Events (SAEs)	A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria.	Cohort 1: Day 1 up to Day 210; Cohort 2: Day 1 up to Day 293
Secondary	Percentage of Participants With a Seroresponse for GI.1 Virus-Like Particle (VLP) (Pan-Ig ELISA)	Seroresponse was defined as 4-fold rise or greater in serum anti-norovirus antibody titers for GI.1 virus-Like particle (VLP) as measured by pan immunoglobulin (Pan-Ig) enzyme-linked immunosorbent assay (ELISA).	Cohort 1: Day 57; Cohort 2: Day 140
Secondary	Percentage of Participants With a Seroresponse for GII.4 Virus-Like Particle (VLP) (Pan-Ig ELISA)	Seroresponse was defined as 4-fold rise or greater in serum anti-norovirus antibody titers for GII.4 virus-Like particle (VLP) as measured by pan immunoglobulin (Pan-Ig) enzyme-linked immunosorbent assay (ELISA).	Cohort 1: Day 57; Cohort 2: Day 140
Secondary	Geometric Mean Titer (GMT) of GI.1 VLP Antibody Titers (Pan-Ig ELISA)	Geometric mean titer (GMT) of anti-norovirus GI.1 VLP antibody titers as measured by pan-Ig ELISA.	Cohort 1: Day 57; Cohort 2: Day 140
Secondary	Geometric Mean Titer (GMT) of GII.4 VLP Antibody Titers (Pan-Ig ELISA)	Geometric mean titer (GMT) of anti-norovirus GII.4 VLP antibody titers as measured by pan-Ig ELISA.	Cohort 1: Day 57; Cohort 2: Day 140
Secondary	Geometric Mean Fold Rise (GMFR) of GI.1 VLP Antibody Titers (Pan-Ig ELISA)	Geometric mean fold rise (GMFR) of anti-norovirus GI.1 VLP antibody titers as measured by pan-Ig ELISA. The fold rise was calculated as the ratio of the post-vaccination titer level to the pre-vaccination titer level.	Cohort 1: Day 57; Cohort 2: Day 140
Secondary	Geometric Mean Fold Rise (GMFR) of GII.4 VLP Antibody Titers (Pan-Ig ELISA)	Geometric mean fold rise (GMFR) of anti-norovirus GII.4 VLP antibody titers as measured by pan-Ig ELISA. The fold rise was calculated as the ratio of the post-vaccination titer level to the pre-vaccination titer level.	Cohort 1: Day 57; Cohort 2: Day 140
Secondary	Percentage of Participants With a 4-Fold Rise or Greater in Serum Antibody Titers for GI.1 VLP and GII.4 VLP (HBGA)	Percentage of participants with a 4-fold rise or greater in serum anti-norovirus antibody titers for both GI.1 VLP and GII.4 VLP as measured by histoblood group antigen (HBGA) binding assay.	Cohort 1: Day 57; Cohort 2: Day 140
Secondary	Percentage of Participants With a 4-Fold Rise or Greater in Serum GI.1 VLP Antibody Titers (HBGA)	The percentage of participants with a 4-fold rise or greater in serum anti-norovirus antibody titers for GI.1 virus-like particle (VLP) as measured by HBGA binding assay.	Cohort 1: Day 57; Cohort 2: Day 140
Secondary	Percentage of Participants With a 4-Fold Rise or Greater in Serum GII.4 VLP Antibody Titers (HBGA)	The percentage of participants with a 4-fold rise or greater in serum anti-norovirus antibody titers for GII.4 virus-like particle (VLP) as measured by HBGA binding assay.	Cohort 1: Day 57; Cohort 2: Day 140
Secondary	Blocking Titers 50 (BT50) of Anti-Norovirus GI.1 VLP Antibody Titers (HBGA)	Blocking titers 50 (BT50) of anti-norovirus GI.1 VLP antibody titers as measured by HBGA binding assay.	Cohort 1: Day 57; Cohort 2: Day 140
Secondary	Blocking Titers 50 (BT50) of Anti-Norovirus GII.4 VLP Antibody Titers (HBGA)	Blocking titers 50 (BT50) of anti-norovirus GII.4 VLP antibody titers as measured by HBGA binding assay.	Cohort 1: Day 57; Cohort 2: Day 140
Secondary	Geometric Mean Fold Rise (GMFR) of GI.1 VLP Antibody Titers (HBGA)	Geometric mean fold rise (GMFR) of anti-norovirus GI.1 VLP antibody titers as measured by pan-Ig ELISA. The fold rise was calculated as the ratio of the post-vaccination titer level to the pre-vaccination titer level.	Cohort 1: Day 57; Cohort 2: Day 140
Secondary	Geometric Mean Fold Rise (GMFR) of GII.4 VLP Antibody Titers (HBGA)	Geometric mean fold rise (GMFR) of anti-norovirus GII.4 VLP antibody titers as measured by pan-Ig ELISA. The fold rise was calculated as the ratio of the post-vaccination titer level to the pre-vaccination titer level.	Cohort 1: Day 57; Cohort 2: Day 140
Secondary	Percentage of Participants With Any Adverse Event (AE) Leading to Withdrawal From the Study	Withdrawal due to an AE will occur if the participant experiences an AE that requires early termination because continued participation imposes an unacceptable risk to the participant's health or the participant is unwilling to continue because of the AE.	Cohort 1: Day 1 up to Day 210; Cohort 2: Day 1 up to Day 293