Clinical Trial Results:
A Phase II, Randomized, Observer-Blind, Multi-Center, Study to Evaluate Safety, Tolerability and Immunogenicity of an Adjuvanted Cell Culture-Derived H5N1 Subunit Influenza Virus Vaccine at Two Different Formulations in Healthy Pediatric Subjects.
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Summary
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EudraCT number |
2021-004813-37 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
16 Jun 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
09 Jul 2022
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First version publication date |
09 Jul 2022
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
V89_11
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01776554 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Seqirus Inc. formerly Novartis Vaccines and Diagnostics Inc. Inc.
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Sponsor organisation address |
475 Green Oaks Parkway, Holly Springs, North Carolina, United States, 27540
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Public contact |
Clinical Study Disclosure Desk, Seqirus Inc. formerly Novartis Vaccines and Diagnostics Inc., Seqirus.ClinicalTrials@seqirus.com
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Scientific contact |
Clinical Study Disclosure Desk, Seqirus Inc. formerly Novartis Vaccines and Diagnostics Inc., Seqirus.ClinicalTrials@seqirus.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-002869-PIP01-21 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
03 Dec 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
16 Jun 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
16 Jun 2014
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Primary Immunogenicity Objective:
To select the vaccine (low dose or high dose aH5N1c) to be tested in Phase III based on achievement of CBER criteria 3 weeks after the second vaccine administration as measured by strain-specific hemagglutination inhibition (HI) assays.
Primary Safety Objective:
To evaluate the safety and tolerability of low dose and high dose aH5N1c vaccine in Subjects 6 months to 17 years of age.
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Protection of trial subjects |
This clinical study was designed, implemented, and reported in accordance with the ICH Harmonised Tripartite Guidelines for Good Clinical Practice, applicable local regulations, and the ethical principles laid down in the Declaration of Helsinki. Only subjects who met all of the eligibility criteria were enrolled and vaccinated in the study. Potential subjects with allergy to any component of the vaccine or a history of serious vaccine reactions were not included in the study. Vaccinations were performed by trained, qualified healthcare professionals. After vaccination, subjects remained under medical supervision and were monitored for any immediate post-vaccination reactions for at least 30 minutes.
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Background therapy |
None | ||
Evidence for comparator |
No comparator | ||
Actual start date of recruitment |
31 Jan 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 182
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Country: Number of subjects enrolled |
Thailand: 480
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Worldwide total number of subjects |
662
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
126
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Children (2-11 years) |
409
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Adolescents (12-17 years) |
127
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
This study was conducted at 10 centers in the United States and 2 centers in Thailand. | ||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 662 subjects were enrolled in the study, of whom 658 subjects received study vaccine. | ||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Period 1 (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Assessor, Carer | ||||||||||||||||||||||||||||||
Blinding implementation details |
The study was an observer-blind study. Vaccine administration was shielded from the subject’s parent(s)/Legally Acceptable Representative(s) and blinded study personnel.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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aH5N1c low dose | ||||||||||||||||||||||||||||||
Arm description |
Enrolled subjects who were randomized and received 0.25mL of aH5N1c vaccine containing 3.75µg HA_0.125mL MF59 (low dose) | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Adjuvanted cell culture-derived H5N1 subunit influenza virus vaccine
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Investigational medicinal product code |
aH5N1c
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Other name |
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Pharmaceutical forms |
Suspension for injection in pre-filled syringe
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Routes of administration |
Intramuscular use
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Dosage and administration details |
Each subject randomized to the low dose arm received a 0.25 mL (low dose) IM dose of aH5N1c on Day 1 and Day 22.
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Arm title
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aH5N1c high dose | ||||||||||||||||||||||||||||||
Arm description |
Enrolled subjects who were randomized and received 0.5mL of aH5N1c vaccine containing 7.5µg HA_0.25mL MF59 (high dose) | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Adjuvanted cell culture-derived H5N1 subunit influenza virus vaccine
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Investigational medicinal product code |
aH5N1c
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Other name |
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Pharmaceutical forms |
Suspension for injection in pre-filled syringe
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Routes of administration |
Intramuscular use
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Dosage and administration details |
Each subject randomized to the high dose arm received a 0.5 mL (high dose) IM dose of aH5N1c on Day 1 and Day 22.
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Baseline characteristics reporting groups
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Reporting group title |
aH5N1c low dose
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Reporting group description |
Enrolled subjects who were randomized and received 0.25mL of aH5N1c vaccine containing 3.75µg HA_0.125mL MF59 (low dose) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
aH5N1c high dose
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Reporting group description |
Enrolled subjects who were randomized and received 0.5mL of aH5N1c vaccine containing 7.5µg HA_0.25mL MF59 (high dose) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
aH5N1c low dose
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Reporting group description |
Enrolled subjects who were randomized and received 0.25mL of aH5N1c vaccine containing 3.75µg HA_0.125mL MF59 (low dose) | ||
Reporting group title |
aH5N1c high dose
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Reporting group description |
Enrolled subjects who were randomized and received 0.5mL of aH5N1c vaccine containing 7.5µg HA_0.25mL MF59 (high dose) | ||
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End point title |
Primary Immunogenicity: Percentage of subjects achieving seroconversion against A/H5N1 strain [1] | |||||||||||||||
End point description |
Immunogenicity was measured in terms of the percentages of subjects achieving seroconversion or significant increase in HI titer against the vaccine strain, three weeks after receiving two injections of low dose or high dose of aH5N1c vaccine according to the CBER criteria.
Seroconversion is defined as the percentages of subjects with a prevaccination HI titer <10, a postvaccination titer ≥40; or in subjects with prevaccination HI titer ≥10, and a minimum four-fold rise in postvaccination HI antibody titer.
CBER criterion is met if the lower limit of the two-sided 95% CI for the percentages of subjects achieving seroconversion for HI antibody titer meets or exceeds 40%.
Dataset used: FAS
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End point type |
Primary
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End point timeframe |
End point timeframe: Three weeks after 2nd vaccination (Day 43).
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: There is no formal statistical analysis between group comparison. Only individual treatment arm seroconversion compared with CBER criteria. |
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End point title |
Primary Immunogenicity: Percentage of subjects achieving hemagglutination inhibition titers ≥1:40 against A/H5N1 strain [2] | |||||||||||||||
End point description |
The optimal aH5N1c vaccine formulation was evaluated in terms of percentages of subjects achieving HI titers ≥1:40 against homologous A/H5N1 strain, three weeks after second vaccination with either low dose or high dose of aH5N1c vaccine, according to the Center for Biologics Evaluation and Research (CBER) criterion.
As there is no CBER criteria defined for children, immunogenicity was evaluated using CBER criterion applicable for adults (18-64 years).
CBER criterion is met if the lower limit of the two-sided 95% confidence interval (CI) for the percentages of subjects achieving HI titer ≥1:40 meets or exceeds 70%.
Dataset used: FAS
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End point type |
Primary
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End point timeframe |
End point timeframe: Three weeks after 2nd vaccination (Day 43).
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: There is no formal statistical analysis between group comparison. Only individual treatment arm hemagglutination inhibition titers ≥1:40 compared with CBER criteria. |
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Primary Safety: Number of subjects (6 month to <6 years) reporting solicited local and systemic AEs, after each dose and any vaccination [3] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Safety was assessed using the number of subjects who reported solicited local and systemic adverse events following vaccination with either low or high dose of aH5N1c vaccine.
Dataset used: Analysis was done on the safety dataset, i.e. the subjects in the exposed population who provided postvaccination safety data.
Grades of AE: Grade 0 (< 25 mm), any (10-25mm [Grade 1], 26-50 mm [Grade 2], >50 mm [Grade 3])
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End point type |
Primary
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End point timeframe |
From Day 1 through Day 7 after each vaccination
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: There is no statistical null hypothesis associated with the safety objective, which was analyzed descriptively. All safety analyses were done by vaccine group and by age group. |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Primary Safety: Number of subjects (≥6 years to 17 years) reporting solicited local and systemic AEs, after any vaccination [4] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Safety was assessed using the number of subjects who reported solicited local and systemic adverse events following vaccination with either low or high dose of aH5N1c vaccine.
Dataset used: Analysis was done on the safety dataset, i.e. the subjects in the exposed population who provided postvaccination safety data.
Grade of AE: Grade 0 (< 25 mm), any (10-25mm [Grade 1], 26-50 mm [Grade 2], >50 mm [Grade 3])
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End point type |
Primary
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End point timeframe |
From Day 1 through Day 7 after each vaccination
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| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: There is no statistical null hypothesis associated with the safety objective, which was analyzed descriptively. All safety analyses were done by vaccine group and by age group. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Primary Safety: Number of subjects reporting unsolicited AEs after any vaccination [5] | ||||||||||||||||||||||||||||||||||||
End point description |
Safety was assessed using the number of subjects who reported any unsolicited adverse events, adverse events possibly or probably related to study vaccine, serious adverse events (SAEs), new onset of chronic diseases (NOCDs), medically attended AEs, AEs of special interest (AESIs), AEs leading to withdrawal from study following vaccination with either low or high dose of aH5N1c vaccine.
Dataset used: Analysis was done on the safety dataset, i.e. the subjects in the exposed population who provided postvaccination safety data.
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End point type |
Primary
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End point timeframe |
Any unsolicited AEs - day 1 through day 22 after any vaccination; SAEs, NOCDs, medically attended AEs, AESIs, AEs leading to study withdrawal- day 1 to day 387.
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: There is no statistical null hypothesis associated with the safety objective, which was analyzed descriptively. All safety analyses were done by vaccine group and by age group. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
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End point title |
Secondary Immunogenicity: Geometric Mean HI Titers and Geometric Mean Ratios Against A/H5N1 Strain Following 2-Dose Vaccination Schedule Of Either Low Dose Or High Dose AH5N1c Vaccine | |||||||||||||||||||||||||||||||||
End point description |
Immunogenicity was measured as the geometric mean HI titers (GMT) and geometric mean ratio (GMR). The ratio of postvaccination to prevaccination HI GMTs, 3 weeks after first vaccination, 3 weeks after second vaccination and 12 months after second vaccination with either low dose or high dose of aH5N1c.
The criterion is met according to the European Committee for Medicinal Products for Human Use (CHMP) criteria if the geometric mean increase GMR (day 43/day 1) in HI antibody titer is >2.5.
As no CHMP criteria are established for the pediatric population, criteria given for subjects 18-60 years of age were applied.
Dataset used: FAS
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End point type |
Secondary
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End point timeframe |
End point timeframe: Day 1, Day 22, Day 43, and Day 387
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||
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End point title |
Secondary Immunogenicity: The Percentages Of Subjects Achieving Seroconversion Against A/H5N1 Strain | |||||||||||||||||||||
End point description |
Immunogenicity was assessed in terms of percentages of subjects achieving seroconversion in HI titers, 3 weeks after first vaccination, 3 weeks after second vaccination and 12 months after second vaccination of either low dose or high dose aH5N1c vaccine according to the CHMP criterion.
Seroconversion is defined as the percentages of subjects with a prevaccination HI titer <10, a postvaccination titer ≥40; or in subjects with prevaccination HI titer ≥10, and a minimum four-fold rise in postvaccination HI antibody titer.
The criterion is met according to the European (CHMP) guideline if the percentage of subjects achieving seroconversion (at day 43) is >40%.
Dataset used: FAS
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End point type |
Secondary
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End point timeframe |
End point timeframe: Day 22, Day 43, and Day 387
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
Secondary Immunogenicity: Percentages Of Subjects With HI Titers ≥1:40 Against A/H5N1 Strain | ||||||||||||||||||||||||
End point description |
Immunogenicity was assessed in terms of percentage of subjects achieving HI titers ≥1:40, 3 weeks after first vaccination, 3 weeks after second vaccination and 12 months after second vaccination of either low dose or high dose of aH5N1c according to the CHMP criterion.
European Licensure (CHMP) criterion is met if the percentage of subjects achieving (at day 43) HI titers ≥40 is >70%.
Dataset used: FAS
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End point type |
Secondary
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End point timeframe |
End point timeframe: Day 1, Day 22, Day 43, and Day 387
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
SAEs: Day 1 to end of study (Day 1 to Day 387)
Nonserious Unsolicited AEs: Day 1 to Day 43
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Adverse event reporting additional description |
Nonserious Unsolicited Aes and SAEs were reported
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
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Reporting groups
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Reporting group title |
High dose aH5N1c
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Reporting group description |
Randomised subjects who received high dose aH5N1c and had any assessment of unsolicited AEs | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Low dose aH5N1c
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Reporting group description |
Randomised subjects who received low dose aH5N1c and had any assessment of unsolicited AEs | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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04 Aug 2011 |
Version 1.0 to Version 2.0
The main reasons for the protocol amendment were the following:
1. Increased the duration of the follow-up period from 6 months to 12 months after third (booster) vaccination, for total trial participation for each subject of approximately 24 months, instead of 18 months.
2. Inclusion of a separate section for clarification on criteria that would necessitate a delay to enrollment.
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29 Mar 2012 |
Version 2.0 to Version 3.0
The main reasons for the protocol amendment were the following:
1. Planned day 387 analysis was not to be performed. Analyses were planned for day 43 data and at trial completion only.
2. Planned analyses (include reference to safety profile): clarification that the vaccine formulation to be tested in phase 3 was to be the lowest antigen/adjuvant formulation able to achieve all CBER criteria 3 weeks after 2 doses as measured by strain specific HI assays and with an acceptable safety profile.
3. Exclusion criterion 21 added: Individuals diagnosed with any disorders in growth such as failure to thrive or short stature were not eligible for the trial.
4. Appendix A: List of AESI based on list provided by CBER on 9 December 2011.
5. Subgroup analysis, comparing the antibody response in subjects who had received a seasonal influenza vaccine in the past year compared to those who had not had been added, as per CBER request.
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09 Nov 2012 |
Between protocol versions 3 and 5, following were collective major changes:
1. Exploratory objective ‘A’ amended to extend to all heterologous influenza strains, not only H5N1.
2. New exploratory objective was added “For each aH5N1c vaccine (low dose or high dose), to evaluate the antibody responses against heterologous and homologous influenza strain(s) as measured by MN assay.
3. Subjects with a recent history of Guillain-Barré disease (instead of those with current Guillain-Barré disease) were excluded. Exclusion criterion 6 adapted accordingly.
4. Revision of age subgroup ages from: 6 to 35 months, 3 to 8 years and 9 to 17 years TO: 6 to <36 months, 3 to <9 years and 9 to <18 years.
5. Criteria for delay of vaccination and for repeat vaccination added.
6. Change of solicited AEs that were to be collected (deletion of injection site swelling, persistent crying, vomiting diarrhea, and chills and addition of ecchymosis, loss of appetite and malaise) and the ages across which they were to be collected
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17 Apr 2013 |
Version 5.0 to Version 6.0
The main reasons for the protocol amendment were the following:
1. The majority of the changes reflected the removal of the booster dose at day 366 and subsequent safety follow-up.
2. Clarifications to exclusion criteria (including the specification of any diagnosis on the AESI list in Appendix A of clinical study protocol as a chronic disease under Exclusion #3).
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31 Oct 2013 |
Version 6.0 to Version 7.0
The main reasons for the protocol amendment were the following:
1. Further documentation of the acceptable time interval to obtain the ICF prior to the first vaccine administration.
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None | |||
