Clinical Trial Results:
Immunogenicity of the Inactivated, Split-Virion Influenza Vaccine Administered by the Intradermal Route in Comparison with Intramuscular Vaccination with Vaxigrip® in Adults.
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Summary
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EudraCT number |
2005-002401-23 |
Trial protocol |
DE BE |
Global end of trial date |
02 Jul 2008
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Results information
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Results version number |
v1(current) |
This version publication date |
05 Feb 2016
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First version publication date |
27 Sep 2014
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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 |
GID15
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00258934 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Sanofi Pasteur SA
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Sponsor organisation address |
1541, Avenue Marcel Mérieux, Marcy L’Etoile, France, 69280
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Public contact |
Director,
Clinical Development, Sanofi Pasteur, SA, 33 4 37 37 58 50 , Stephanie.pepin@sanofipasteur.com
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Scientific contact |
Director,
Clinical Development, Sanofi Pasteur, SA, 33 4 37 37 58 50 , Stephanie.pepin@sanofipasteur.com
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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 |
21 Jul 2008
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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 |
02 Jul 2008
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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 |
To demonstrate that the vaccine administered by the intradermal (ID) route with the new Becton Dickinson (BD) ID system (pre-filled ID system allowing a better ergonomic use) is at least as immunogenic as the administration of the vaccine by the intramuscular (IM) route after the first vaccination.
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Protection of trial subjects |
Only subjects that met all the study inclusion and none of the exclusion criteria were randomized and vaccinated in the study. Vaccinations were performed by qualified and trained study personnel. Subjects with allergy to any of the vaccine components were not vaccinated. After vaccination, subjects were also kept under clinical observation for 30 minutes to ensure their safety. Appropriate medical equipment were also available on site in case of any immediate allergic reactions.
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Background therapy |
Not applicable. | ||
Evidence for comparator |
Same vaccine with a different route of administration. An earlier study in 2002, GID01 conducted in 300 Lithuanian adult subjects assessed three dosages (3 µg, 6 µg, and 9 µg of each HA per strain) administered with an intradermal (ID) system, one dosage (3 µg of each HA per strain) administered with a classic ID syringe, and, as a reference, Vaxigrip® IM (containing 15 µg of each HA per strain), showed that the trivalent inactivated split-virion influenza vaccine induced a similar immune response as measured by geometric mean of titers (GMTs), when administered by the IM route or the ID route. | ||
Actual start date of recruitment |
19 Sep 2005
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Efficacy, Safety | ||
Long term follow-up duration |
3 Years | ||
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 |
Belgium: 750
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Country: Number of subjects enrolled |
Germany: 150
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Country: Number of subjects enrolled |
Switzerland: 78
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Worldwide total number of subjects |
978
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EEA total number of subjects |
900
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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) |
0
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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) |
978
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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 |
Study subjects were enrolled and vaccinated from 19 September 2005 to 21 November 2005, at 4 clinical centers in Belgium, Germany and Switzerland. They got a second vaccination (Year 1) from 20 September 2006 to 31 October 2006, and a third vaccination (Year 2) from 24 September 2007 to 07 November 2007. | |||||||||
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Pre-assignment
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Screening details |
A total of 978 subjects who met all the inclusion, but none of the exclusion criteria were enrolled and vaccinated in the study. | |||||||||
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Period 1
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Period 1 title |
Overall (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | |||||||||
Blinding implementation details |
Not applicable
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Intradermal Vaccination Group | |||||||||
Arm description |
Subjects received 9 µg dose influenza vaccine by the intradermal route on Day 0 (first vaccination) | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Intradermal Influenza Vaccine
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Investigational medicinal product code |
333
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Other name |
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Pharmaceutical forms |
Suspension for injection
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Routes of administration |
Intradermal use
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Dosage and administration details |
0.1 mL (9 µg) single annual dose, intradermal into the upper arm (deltoid area)
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Arm title
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Intramuscular Vaccine Group | |||||||||
Arm description |
Subjects received 15 µg dose influenza vaccine by the intramuscular route on Day 0 (first vaccination) | |||||||||
Arm type |
Active comparator | |||||||||
Investigational medicinal product name |
Intradermal Influenza Vaccine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Suspension for injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
0.5 mL (15 µg) single annual dose, intramuscular into the upper arm (deltoid area)
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Baseline characteristics reporting groups
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Reporting group title |
Intradermal Vaccination Group
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Reporting group description |
Subjects received 9 µg dose influenza vaccine by the intradermal route on Day 0 (first vaccination) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Intramuscular Vaccine Group
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Reporting group description |
Subjects received 15 µg dose influenza vaccine by the intramuscular route on Day 0 (first vaccination) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Intradermal Vaccination Group
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Reporting group description |
Subjects received 9 µg dose influenza vaccine by the intradermal route on Day 0 (first vaccination) | ||
Reporting group title |
Intramuscular Vaccine Group
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Reporting group description |
Subjects received 15 µg dose influenza vaccine by the intramuscular route on Day 0 (first vaccination) | ||
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End point title |
Geometric Mean Titers of Antibodies to Influenza Antigens Before and After either Intradermal or Intramuscular Influenza vaccination | ||||||||||||||||||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Day 0 (pre-vaccination) and 21 days Post-vaccination
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Statistical analysis title |
Non-inferiority test of ID Group for A/H1N1 Strain | ||||||||||||||||||||||||||||||
Statistical analysis description |
For each strain, the primary parameter was the difference of the log10 transformation of post-vaccination geometric mean of titer between the compared vaccine groups. For each strain, the hypotheses tested were as follows:
H0: log10(GMTID)-log10(GMTIM) ≤ -0.176 which is equivalent to GMTIM / GMTID ≥ 1.5
H1: log10(GMTID)-log10(GMTIM) > -0.176 which is equivalent to GMTIM / GMTID < 1.5
The ID group was considered as non-inferior to the IM group if the hypothesis H0 was rejected for each strain
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Comparison groups |
Intradermal Vaccination Group v Intramuscular Vaccine Group
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Number of subjects included in analysis |
760
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | ||||||||||||||||||||||||||||||
Method |
2-Sided Confidence Interval | ||||||||||||||||||||||||||||||
Parameter type |
Median difference (final values) | ||||||||||||||||||||||||||||||
Point estimate |
0.098
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
0.006 | ||||||||||||||||||||||||||||||
upper limit |
0.189 | ||||||||||||||||||||||||||||||
| Notes [1] - The ID group was considered as non-inferior to the IM group if the hypothesis H0 was rejected for each strain. |
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Statistical analysis title |
Non-inferiority test of ID Group for A/H3N2 Strain | ||||||||||||||||||||||||||||||
Statistical analysis description |
For each strain, the primary parameter was the difference of the log10 transformation of post-vaccination geometric mean of titer between the compared vaccine groups. For each strain, the hypotheses tested were as follows:
H0: log10(GMTID)-log10(GMTIM) ≤ -0.176 which is equivalent to GMTIM / GMTID ≥ 1.5
H1: log10(GMTID)-log10(GMTIM) > -0.176 which is equivalent to GMTIM / GMTID < 1.5
The ID group was considered as non-inferior to the IM group if the hypothesis H0 was rejected for each strain
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Comparison groups |
Intradermal Vaccination Group v Intramuscular Vaccine Group
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Number of subjects included in analysis |
760
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [2] | ||||||||||||||||||||||||||||||
Method |
2-Sided Confidence Interval | ||||||||||||||||||||||||||||||
Parameter type |
Median difference (final values) | ||||||||||||||||||||||||||||||
Point estimate |
0.162
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
0.087 | ||||||||||||||||||||||||||||||
upper limit |
0.236 | ||||||||||||||||||||||||||||||
| Notes [2] - The ID group was considered as non-inferior to the IM group if the hypothesis H0 was rejected for each strain. |
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Statistical analysis title |
Non-inferiority test of ID Group for B Strain | ||||||||||||||||||||||||||||||
Statistical analysis description |
For each strain, the primary parameter was the difference of the log10 transformation of post-vaccination geometric mean of titer between the compared vaccine groups. For each strain, the hypotheses tested were as follows:
H0: log10(GMTID)-log10(GMTIM) ≤ -0.176 which is equivalent to GMTIM / GMTID ≥ 1.5
H1: log10(GMTID)-log10(GMTIM) > -0.176 which is equivalent to GMTIM / GMTID < 1.5
The ID group was considered as non-inferior to the IM group if the hypothesis H0 was rejected for each strain
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Comparison groups |
Intradermal Vaccination Group v Intramuscular Vaccine Group
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Number of subjects included in analysis |
760
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [3] | ||||||||||||||||||||||||||||||
Method |
2-Sided Confidence Interval | ||||||||||||||||||||||||||||||
Parameter type |
Median difference (final values) | ||||||||||||||||||||||||||||||
Point estimate |
0.067
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
-0.003 | ||||||||||||||||||||||||||||||
upper limit |
0.136 | ||||||||||||||||||||||||||||||
| Notes [3] - The ID group was considered as non-inferior to the IM group if the hypothesis H0 was rejected for each strain. |
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End point title |
Percentage of Subjects with Seroprotection Against Influenza Antigens Before and After First Vaccination with either Intradermal or Intramucular Influenza Vaccine | ||||||||||||||||||||||||||||||
End point description |
Influenza virus antibodies were measured by the hemagglutination inhibition (HI) technique. Seroprotection was defined as an antibody titer of ≥40 1/dilution.
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End point type |
Secondary
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End point timeframe |
Day 0 (pre-vaccination) snd 21 Days Post-vaccination (First vaccination)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Percentage of Subjects with Seroconversion or Significant Increase in Influenza Antibodies Post-vaccination with either an Intradermal or Intramucular Influenza Vaccine | |||||||||||||||||||||
End point description |
Influenza antibodies were measured using the hemagglutination inhibition (HI) technique. Seroconversion was defined as a pre-vaccination titer <10 (1/dil): post-injection titer ≥40 (1/dil) on Day 21; Significant increase was defined as a pre-vaccination titer ≥10 (1/dil): ≥4-fold increase from pre- to post-injection titer on Day 21.
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End point type |
Secondary
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End point timeframe |
21 Days post-vaccination
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
Number of Subjects Experiencing at Least one Reaction Listed in the EMEA Note for Guidance Within 3 days After First Vaccination with Either an Intradermal or Intramuscular Influenza Vaccine | ||||||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Within 3 Days post-vaccination (First vaccination)
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Number of Subjects Reporting Solicited Reactions Within 7 Days After First Vaccination with Either an Intradermal or Intramuscular Influenza Vaccine | ||||||||||||||||||||||||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Day 0 to Day 7 Post First Vaccination
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||
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End point title |
Number of Subjects Experiencing at Least one Reaction Listed in the EMEA Note for Guidance Within 3 days After Second Vaccination with Either an Intradermal or Intramuscular Influenza Vaccine | ||||||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Within 3 Days post-second injection
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Number of Subjects Reporting Solicited Reactions Within 7 Days After Second Vaccination with Either an Intradermal or Intramuscular Influenza Vaccine | ||||||||||||||||||||||||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Day 0 up to Day 7 post-second vaccination
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||
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End point title |
Number of Subjects Experiencing at Least One Reaction Listed in the EMEA Note for Guidance Within 3 days After Third Vaccination with Either an Intradermal or Intramuscular Influenza Vaccine | ||||||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Within 3 Days After Third Vaccination
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Antibody Persistence to Influenza Antigens Before and 21 Days, 3, 6 and 12 Months Post-vaccination with Either Intradermal or an Intramuscular Influenza Vaccine | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Influenza antibodies were measured using the hemagglutination inhibition (HI) technique. Antibody persistence was defined as seroprotection, antibody titer ≥40 (1/dilution) at each defined timepoints.
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End point type |
Other pre-specified
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End point timeframe |
Day 0 (pre-vaccination) and 21 Days, 3, 6 and 12 months post-vaccination
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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 events data were collected from Day 0 after Dose 1 through up to 6 months after the last dose
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Assessment type |
Non-systematic | |||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||
Dictionary version |
7.0
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Reporting groups
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Reporting group title |
Intradermal Vaccination Group
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Reporting group description |
Subjects received 9 µg influenza vaccine by the intradermal route on Day 0 (first vaccination) | |||||||||||||||||||||
Reporting group title |
Intramuscular Vaccine Group
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Reporting group description |
Subjects received 0.5 mL (15 µg) dose by the intramuscular route | |||||||||||||||||||||
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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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17 Aug 2005 |
The use of paper CRF instead of electronic CRF; Ealuation of immunogenicity in a subset of subjects following the second and third vaccinations; Definition of Serum storage and shipping temperature. |
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16 Mar 2006 |
The replacement of a Principal Investigator in Germany, was submitted to the German IEC only. |
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23 May 2006 |
Information on the vaccine formulation to be administered for the second vaccination (2006-2007 Northern Hemisphere) and planned the assessment of the comfort vaccination using a Verbal Rating Scale (VRS) and a Patient-Reported Outcome questionnaire: the Vaccination Comfort Questionnaire (VCQ).
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19 Jun 2006 |
Before the second vaccination a modification of the immunogenicity analysis. |
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13 Sep 2006 |
A replacement of a Principal Investigator in Belgium was submitted to the Belgium IEC only.
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10 Nov 2006 |
A replacement of a Principal Investigator in Belgium was submitted to the Belgium IEC only.
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24 May 2007 |
Information on the vaccine formulation to be administered for the third vaccination (2007-2008 Northern Hemisphere) was provided along with notice of the change of Center Name from "MDS Pharma Germany GmbH" to "Momentum Pharma Service GmbH” and the an update to the process of documenting local reactions at the injection site; the sample preparation process, and the VCQ form and the SAEs reporting process.
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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. | |||
| Not applicable. | |||
