Clinical Trial Results:
A phase II, open label trial to describe immune and transcriptional responses to MF59 adjuvanted trivalent influenza vaccine (ATIV) in 13-24 month healthy children and adults 18-65 years
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Summary
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EudraCT number |
2015-001648-12 |
Trial protocol |
GB |
Global end of trial date |
24 Sep 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
16 Nov 2019
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First version publication date |
16 Nov 2019
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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 |
OVG2015/02
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02529904 | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
University of Oxford. Clinical Trials and Research Governance Team (CTRG).
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Sponsor organisation address |
Joint Research Office 1st floor, Boundary Brook House Churchill Drive, Headington, Oxford, United Kingdom, OX3 7GB
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Public contact |
Professor Andrew J Pollard, Oxford Vaccine Group, 0044 1865 611400, andrew.pollard@paediatrics.ox.ac.uk
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Scientific contact |
Professor Andrew J Pollard, Oxford Vaccine Group, 0044 1865 611400, andrew.pollard@paediatrics.ox.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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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 |
15 Mar 2019
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
24 Sep 2018
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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 |
The principal research objective of this study was to identify the specific ‘immune response’ genes which are activated by the ATIV vaccine and to correlate them to the immune response (level of antibodies - these are specific proteins against a virus which are part of the immune response) which occur when these genes are ‘switched on’ (this is also called gene expression). We were interested in assessing the difference between the response in children (aged 13-24 months) compared to adults (aged 18 -65 years).
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Protection of trial subjects |
Ethical, Legal and Management Protection: Every effort was made to ensure that participants, parents or guardians giving informed consent were able to understand fully the nature of the study including the risks,burdens, benefits and implications that taking part would have. The study involved the vaccination and the collection of blood samples that would not normally be part of routine care. In order to minimise any discomfort, local anaesthetic cream was offered to numb children's skin prior to the sample being collected.
The members of the study team undertaking vaccination and venepuncture had specific training and experience. With the participant/parent/guardians agreement two attempts at blood sampling were made and if unsuccessful a further visit was arranged by the study team.
Strict inclusion and exclusion criteria applied to the enrolment of each study participant.
The study complied with the Data Protection Act which requires data to be anonymised as soon as it is practical to do so ensuring that the participant's anonymity was maintained throughout the trial.
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Background therapy |
Not applicable. | ||
Evidence for comparator |
The study aimed to assess early gene transcriptional responses to priming and boosting with ATIV in children aged 13-24 months and adults aged 18 - 65 years, and to establish correlations with HAI titers. This study adds to the initial ADITEC Flu pilot study conducted in 2012 (EudraCT Number: 2012-002443-26, Ethics Ref: OxREC C 12/SC/0407); a phase 2, randomised, open label study, also demonstrated increased immunogenicity and a relatively similar reactogenicity profile following ATIV immunisation compared to TIV. This current study adds to the initial study by collecting immunogenicity and gene expression data following the first ATIV dose (the initial study only collected blood samples for gene analysis post-second ATIV dose) and directly comparing child to adult data by enrolling both child and adult cohorts. Children received 2 doses (0.25ml) approximately 2 weeks apart and adults received a single dose (0.5ml) of the Fluad vaccine (MF59 Adjuvanted trivalent influenza vaccine (MF59ATIV)) by intramuscular injection. | ||
Actual start date of recruitment |
05 Oct 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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 Kingdom: 120
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Worldwide total number of subjects |
120
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EEA total number of subjects |
120
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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) |
90
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
30
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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 |
Recruitment started on the 5th of October 2015. Screening visits started on the 3rd November 2015. Recruitment was completed on the 22nd February 2016. Eligible participants were identified within the Thames Valley area of England (UK) using a variety of recruitment methods including posters, leaflets, website and mail outs. | |||||||||||||||
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Pre-assignment
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Screening details |
Full inclusion/exclusion criteria assessed by the study doctor.Screening assessment included: physical examination, medical history, concomitant medication, temperature measurement, demographics. | |||||||||||||||
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Period 1
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Period 1 title |
Study Duration (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Children aged 13 to 24 months of age | |||||||||||||||
Arm description |
Children received 2 half doses of the vaccine (0.25ml) at V1 (Day 0) and V4 (Day 28) | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
FLUAD
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Investigational medicinal product code |
J07BB02
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Other name |
FLUAD (Influenza Vaccine, Adjuvanted)
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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 |
Children received a 0.25 ml dose administered at visit 1 and visit 4, intramuscularly into the upper lateral aspect of either thigh muscle using a 0.6 x 25 mm 23 gauge needle.
Adults received a 0.5ml administered at visit 1 intramuscularly into the deltoid area of either arm using a 25mm 23 gauge needle.
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Arm title
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Adults aged 18 to 65 years of age | |||||||||||||||
Arm description |
Adults received a single full dose of the vaccine (0.5ml) at V1 (Day 0) | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
FLUAD
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Investigational medicinal product code |
J07BB02
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Other name |
FLUAD (Influenza Vaccine, Adjuvanted)
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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 |
Children received a 0.25 ml dose administered at visit 1 and visit 4, intramuscularly into the upper lateral aspect of either thigh muscle using a 0.6 x 25 mm 23 gauge needle.
Adults received a 0.5ml administered at visit 1 intramuscularly into the deltoid area of either arm using a 25mm 23 gauge needle.
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Baseline characteristics reporting groups
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Reporting group title |
Study Duration
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Reporting group description |
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Subject analysis sets
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Subject analysis set title |
Group 1 (aged 13 - 24 months)
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Children 13-24 months of age.
Baseline Visit (Day -7 to Day 0) = Blood sample for HAI, innate responses and transcriptomics, V1 (Day 0) = ATIV dose 1, V2 (Day 1) = Blood sample for innate responses and transcriptomics, V4 (Day 28) = ATIV dose 2, V7 (Day 56) = blood sample for HAI
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Subject analysis set title |
Group 2 (aged 13 - 24 months)
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Children 13-24 months of age.
V1 (Day 0) = ATIV dose 1, V3 (Day 21 to Day 28) = Blood sample for HAI, innate responses and transcriptomics, V4 (Day 28) = ATIV dose 2, V5 (Day 29) = blood sample for innate response and transcriptomics, V7 (Day 56) = blood sample for HAI
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Subject analysis set title |
Group 3 (aged 13 - 24 months)
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Children 13-24 months of age.
V1 (Day 0) = ATIV dose 1, V4 (Day 28) = Blood sample for HAI, innate responses and transcriptomics and ATIV dose 2, V6 (Day 31) = blood sample for innate response and transcriptomics, V7 (Day 56) = blood sample for HAI
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Subject analysis set title |
Group 4 (aged 18 - 65 years)
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Adults 18-65 years of age.
Baseline Visit (Day -7 to Day 0) = Blood sample for HAI, V1 (Day 0) = ATIV, V2 (Day 1) = blood sample for innate responses and transcriptomics, V3 (Day 3) = blood sample for innate responses and transcriptomics, V4 (Day 28) = blood sample for HAI
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End points reporting groups
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Reporting group title |
Children aged 13 to 24 months of age
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Reporting group description |
Children received 2 half doses of the vaccine (0.25ml) at V1 (Day 0) and V4 (Day 28) | ||
Reporting group title |
Adults aged 18 to 65 years of age
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Reporting group description |
Adults received a single full dose of the vaccine (0.5ml) at V1 (Day 0) | ||
Subject analysis set title |
Group 1 (aged 13 - 24 months)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Children 13-24 months of age.
Baseline Visit (Day -7 to Day 0) = Blood sample for HAI, innate responses and transcriptomics, V1 (Day 0) = ATIV dose 1, V2 (Day 1) = Blood sample for innate responses and transcriptomics, V4 (Day 28) = ATIV dose 2, V7 (Day 56) = blood sample for HAI
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Subject analysis set title |
Group 2 (aged 13 - 24 months)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Children 13-24 months of age.
V1 (Day 0) = ATIV dose 1, V3 (Day 21 to Day 28) = Blood sample for HAI, innate responses and transcriptomics, V4 (Day 28) = ATIV dose 2, V5 (Day 29) = blood sample for innate response and transcriptomics, V7 (Day 56) = blood sample for HAI
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Subject analysis set title |
Group 3 (aged 13 - 24 months)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Children 13-24 months of age.
V1 (Day 0) = ATIV dose 1, V4 (Day 28) = Blood sample for HAI, innate responses and transcriptomics and ATIV dose 2, V6 (Day 31) = blood sample for innate response and transcriptomics, V7 (Day 56) = blood sample for HAI
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Subject analysis set title |
Group 4 (aged 18 - 65 years)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Adults 18-65 years of age.
Baseline Visit (Day -7 to Day 0) = Blood sample for HAI, V1 (Day 0) = ATIV, V2 (Day 1) = blood sample for innate responses and transcriptomics, V3 (Day 3) = blood sample for innate responses and transcriptomics, V4 (Day 28) = blood sample for HAI
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End point title |
Gene Expression [1] | ||||||||||||||||||||
End point description |
Differential gene expression following ATIV at baseline and days 1 (children and adults) and 3 (adults only) post initial immunization and at baseline and days 1 and 3 post boost immunization (children only).
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End point type |
Primary
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End point timeframe |
Endpoint 1: Differential gene expression following ATIV at baseline and days 1 (children and adults) and 3 (adults only) post initial immunization and at baseline and days 1 and 3 post boost immunization (children only).
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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: The statistics will be descriptive and will be included in the trial publication. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
HAI Titres [2] | ||||||||||||||||||||
End point description |
HAI titers (for strains influenza A H1N1,influenza A H3N2 and influenza B) ≥ defined thresholds (1:40, 1:110 and 1:620), the HAI geometric mean titers (GMT) and the mean geometric fold rise in HAI titers from baseline to day 28 (adults and children) and to day 56 (children only).
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End point type |
Primary
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End point timeframe |
Group 1 = Baseline (Day -7 to Day 0) and V7 (Day 56)
Group 2 = V3 (Day 21 to Day 28) and V7 (Day 56)
Group 3 = V4 (Day 28) and V7 (Day 56)
Group 4 = Baseline (Day -7 to 0) and V4 (Day 28)
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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: The statistics will be descriptive and will be included in the trial publication. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Innate Immune Cells | ||||||||||||||||||||
End point description |
Analysis of the frequency and activation of granulocytes, monocytes, and dendritic cells as measured in the peripheral whole blood at the following time points: baseline, day 1 and day 28 (children and adults), and also day 3 (adults only) post initial immunization and at day 1 and 3 post-boost immunization (children only).
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End point type |
Secondary
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End point timeframe |
Group 1 = Baseline (Day -7 to Day 0) and V2 (Day 1)
Group 2 = V3 (Day 21 to Day 28) and V5 (Day 29)
Group 3 = V4 (Day 28) and V6 (Day 31)
Group 4 = Baseline (Day -7 to 0), V2 (Day 1) and V3 (Day 3)
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Immunogenicity of ATIV | ||||||||||||||||||||
End point description |
The percentage of participants with HAI titers (for strains influenza A H1N1, influenza A H3N2 and influenza B) ≥ defined thresholds (1:40, 1:110 and 1:620), the HAI geometric mean titers (GMT) and the mean geometric fold rise in HAI titers from baseline to day 28 (adults and children) and to day 56 (children only).
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End point type |
Secondary
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End point timeframe |
Group 1 = Baseline (Day -7 to Day 0) and V2 (Day 1)
Group 2 = V3 (Day 21 to Day 28) and V5 (Day 29)
Group 3 = V4 (Day 28) and V6 (Day 31)
Group 4 = Baseline (Day -7 to 0), V2 (Day 1) and V3 (Day 3)
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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 |
Adverse event reporting in this study were reported from the point of first study intervention. The time frame for adverse event reporting was from the baseline visit or 2 days prior to V1 when the electronic diary (ediary) entries commenced.
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Adverse event reporting additional description |
All AEs occurring on the day of vaccine administration and three days following, and all AEs resulting in withdrawal from the study occurring within 1 month after vaccination, whether or not attributed to study medication, will be reported on the CRF/source document. AEs will be divided up into solicited and unsolicited reactions.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
Protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
3.0
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Reporting groups
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Reporting group title |
Systemic Local AE's: redness and swelling
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Reporting group description |
Redness and swelling will be measured and recorded in the eDiary. They will be categorised as absent, mild, moderate and severe based on the size of affected area. A ruler will be given to the parent/participant with instructions for measuring any redness or swelling at the injection site. The parent/participant will be asked to measure the largest diameter of a local reaction and record this in the eDiary. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Systemic Local AE's: Tenderness
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Reporting group description |
The parent/participant will be asked to assess and record in the eDiary whether tenderness is present at the injection site and grade it based on the degree to which the tenderness affects movement of the limb and routine daily activities. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Solicited Systemic AE's: Temperature
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Reporting group description |
Temperature will be measured by the parent/participant and recorded from day of immunisation until three days post-vaccination. A digital thermometer will be provided by the study team at the screening visit. Temperature will be considered as fever if equal to or greater than 38.0°C. In the event of fever, the highest value measured throughout each day should be recorded in the eDiary. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Solicited Systemic AE's: Systemic AE's
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Reporting group description |
Systemic AEs for children include: reduced feeding, reduced activity, irritability, vomiting or diarrhoea. For adults, systemic AEs include: headache, nausea/vomiting, malaise, myalgia and arthralgia. The severity of these solicited systemic AEs will be graded as follows: 0 if none, 1 if mild symptoms, 2 if moderate symptoms and 3 if severe symptoms. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Unsolicited AE's
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Reporting group description |
Unsolicited AEs are any adverse events that are not pre-listed in the eDiary but may be reported in the eDiary in the three days following vaccination (in addition to day of vaccine administration) by the parent/participant or through interview. The following information will be recorded for medically significant, unsolicited AEs: description, date of onset and end date, severity, assessment of relatedness to study medication, other suspect drug or device and action taken. It will be left to the investigator’s clinical judgment whether or not an AE is of sufficient severity to require the participant’s removal from treatment. A participant’s parents/participant may also voluntarily withdraw from treatment due to what he or she perceives as an intolerable AE. The severity of events will be assessed on the following scale: 1 = mild, 2 = moderate, 3 = severe. The relationship of AEs to the study medication will be assessed. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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02 Oct 2015 |
The addition of Thames Valley General Practitioner (GP) surgeries for study recruitment purposes. |
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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 reported | |||
