Clinical Trial Results:
Immunogenicity and safety of the tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed (SP306) given intramuscularly compared to Diphtheria and Tetanus toxoids adsorbed (DT) given subcutaneously in Japanese adolescents 11 – 12 years of age
Summary
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EudraCT number |
2015-003950-41 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
05 Jul 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
18 Feb 2016
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First version publication date |
18 Feb 2016
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Other versions |
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 |
Td536 (EFC12579)
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02089347 | ||
WHO universal trial number (UTN) |
U1111-1124-7550 | ||
Sponsors
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Sponsor organisation name |
Sanofi K.K.
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Sponsor organisation address |
3-20-2, Nishi Shinjuku, Shinjuku-ku, Tokyo, Japan, 163-1488
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Public contact |
Medical Director, Sanofi K.K, +81 3 6301 3603, Toshiro.emori@sanofi.com
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Scientific contact |
Medical Director, Sanofi K.K, +81 3 6301 3603, Toshiro.emori@sanofi.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? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
05 Jul 2014
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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 |
05 Jul 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 |
To demonstrate the non-inferiority of SP306 versus DT (DT Biken 0.1 mL) vaccine in terms of diphtheria and tetanus booster response rate (proportion of subjects with booster responses) and seroprotection rate (percentage of subjects with antitoxin concentrations ≥0.1 IU/mL) at 28 days (window 28-35 days) after one injection in Japanese adolescents 11-12 years of age.
To evaluate the immune response of SP306 against the pertussis antigens (pertussis toxoid [PT] and filamentous hemagglutinin [FHA]) in terms of booster response rate (proportion of subjects with booster responses) at 28 days (window 28-35 days) after one injection in Japanese adolescents 11-12 years of age.
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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 was also available on site in case of any immediate allergic reactions.
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Background therapy |
Subjects were previously vaccinated with 4 doses of pediatric Diphtheria, Tetanus toxoid and acellular Pertussis vaccine adsorbed (DTaP). | ||
Evidence for comparator |
Not applicable | ||
Actual start date of recruitment |
01 Mar 2014
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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 |
Japan: 534
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Worldwide total number of subjects |
534
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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) |
0
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Children (2-11 years) |
418
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Adolescents (12-17 years) |
116
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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 |
The study subjects were enrolled from 01 March 2014 through 31 May 2014 at 21 clinic centers in Japan. | |||||||||||||||
Pre-assignment
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Screening details |
A total of 533 subjects who met all of the inclusion criteria - including having completed childhood vaccination against diphtheria, pertussis and tetanus (i.e., received 4 doses of Japanese-produced DTaP vaccine), and none of the exclusion criteria were randomized and vaccinated in this study. | |||||||||||||||
Period 1
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Period 1 title |
Overall trial (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, Assessor | |||||||||||||||
Blinding implementation details |
This was a modified double-blind study in which only the Investigator and limited, authorized, unblinded staff knew the group assignments since each vaccine had different dosing quantities and routes of administration. To maintain the blind, the vaccine was prepared and administered in separate rooms and the route of injection was not recorded. Subjects, parents, and safety assessors were blinded. In the event of emergencies, the code could be broken based on code-breaking procedures.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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SP306 Group | |||||||||||||||
Arm description |
Subjects received 1 dose of Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (SP306, Tdap5) vaccine intramuscularly. | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (SP306, Tdap5)
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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, intramuscular in the central region of deltoid, 1 injection on Day 0.
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Arm title
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DT Biken Group | |||||||||||||||
Arm description |
Subjects received 1 dose of Diphtheria Toxoid and Tetanus Toxoid Adsorbed (DT BIK®) vaccine. | |||||||||||||||
Arm type |
Active comparator | |||||||||||||||
Investigational medicinal product name |
Diphtheria Toxoid and Tetanus Toxoid Adsorbed (DT Biken)
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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 |
Subcutaneous use
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Dosage and administration details |
0.1 mL, subcutaneous in the central region of deltoid, 1 injection on Day 0.
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Baseline characteristics reporting groups
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Reporting group title |
SP306 Group
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Reporting group description |
Subjects received 1 dose of Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (SP306, Tdap5) vaccine intramuscularly. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
DT Biken Group
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Reporting group description |
Subjects received 1 dose of Diphtheria Toxoid and Tetanus Toxoid Adsorbed (DT BIK®) vaccine. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
SP306 Group
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Reporting group description |
Subjects received 1 dose of Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (SP306, Tdap5) vaccine intramuscularly. | ||
Reporting group title |
DT Biken Group
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Reporting group description |
Subjects received 1 dose of Diphtheria Toxoid and Tetanus Toxoid Adsorbed (DT BIK®) vaccine. |
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End point title |
Percentage of Subjects With Diphtheria and Tetanus Post-Vaccination Booster Response Following Vaccination with Either SP306 or DT BIK® Vaccine | ||||||||||||||||||
End point description |
Diphtheria booster response was defined as ≥4-fold rise in pre- to post-vaccination antitoxin concentration in a subject with a pre-vaccination antitoxin concentration ≤2.56 IU/mL or a ≥2-fold rise in a subject with a pre-vaccination antitoxin concentration >2.56 IU/mL. A tetanus booster response is defined as a ≥4-fold rise in pre- to post-vaccination antitoxin concentration in a subject with a pre-vaccination antitoxin concentration ≤2.7 IU/mL or a ≥2-fold rise in a subject with a pre-vaccination antitoxin concentration >2.7 IU/mL.
Diphtheria antitoxin concentration was assayed by the toxin neutralization test; Tetanus antitoxin concentration was assayed by the enzyme-linked immunosorbent assay (ELISA) method.
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End point type |
Primary
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End point timeframe |
Day 28 post-vaccination
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Statistical analysis title |
Diphtheria; Non-inferiority (SP306-DT Biken) | ||||||||||||||||||
Statistical analysis description |
Non-inferiority comparison of post-vaccination booster response rates between groups for diphtheria.
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Comparison groups |
SP306 Group v DT Biken Group
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Number of subjects included in analysis |
526
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | ||||||||||||||||||
Method |
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Parameter type |
% difference in booster response rates | ||||||||||||||||||
Point estimate |
1.42
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
-0.31 | ||||||||||||||||||
upper limit |
4.61 | ||||||||||||||||||
Notes [1] - Non-inferiority is supported by the data if the lower bound of the two-sided 95% confidence interval is greater than -10%. The 95% CI of the non-inferiority comparison was estimated by Wilson score method without continuity correction as described by Newcombe. The SP306 vaccine group was non-inferior to the DT Biken vaccine group. |
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Statistical analysis title |
Tetanus; Non-inferiority (SP306-DT Biken) | ||||||||||||||||||
Statistical analysis description |
Non-inferiority comparison of post-vaccination booster response rates between groups for tetanus.
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Comparison groups |
SP306 Group v DT Biken Group
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Number of subjects included in analysis |
526
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [2] | ||||||||||||||||||
Method |
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Parameter type |
% difference in booster response rates | ||||||||||||||||||
Point estimate |
6.25
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
3.32 | ||||||||||||||||||
upper limit |
10.84 | ||||||||||||||||||
Notes [2] - Non-inferiority is supported by the data if the lower bound of the two-sided 95% confidence interval is greater than -10%. The 95% CI of the non-inferiority comparison was estimated by Wilson score method without continuity correction as described by Newcombe. The SP306 vaccine group was non-inferior to the DT Biken vaccine group. |
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End point title |
Percentage of Subjects With Seroprotection to Diphtheria and Tetanus Antigens Post-Booster Vaccination With Either SP306 or DT BIK® Vaccine | ||||||||||||||||||
End point description |
Seroprotection was defined as the proportion of subjects at 28 days post-vaccination with diphtheria and tetanus antitoxin concentration ≥0.1 IU/mL.
Diphtheria antitoxin concentration was assayed by the toxin neutralization test; Tetanus antitoxin concentration was assayed by the enzyme-linked immunosorbent assay (ELISA) method.
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End point type |
Primary
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End point timeframe |
Day 28 post-vaccination
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Statistical analysis title |
Diphtheria; Non-inferiority (SP306-DT Biken) | ||||||||||||||||||
Statistical analysis description |
Non-inferiority comparison of post-vaccination seroprotection rates (≥0.1 IU/mL) between groups for diphtheria.
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Comparison groups |
SP306 Group v DT Biken Group
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Number of subjects included in analysis |
526
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [3] | ||||||||||||||||||
Method |
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Parameter type |
% difference in seroprotection rates | ||||||||||||||||||
Point estimate |
0.57
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
-0.61 | ||||||||||||||||||
upper limit |
3.15 | ||||||||||||||||||
Notes [3] - Non-inferiority is supported by the data if the lower bound of the two-sided 95% confidence interval is greater than -10%. The 95% CI of the non-inferiority comparison was estimated by Wilson score method without continuity correction as described by Newcombe. The SP306 vaccine group was non-inferior to the DT Biken vaccine group. |
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Statistical analysis title |
Tetanus; Non-inferiority (SP306-DT Biken) | ||||||||||||||||||
Statistical analysis description |
Non-inferiority comparison of post-vaccination seroprotection rates between groups for tetanus.
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Comparison groups |
SP306 Group v DT Biken Group
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Number of subjects included in analysis |
526
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [4] | ||||||||||||||||||
Method |
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Parameter type |
% difference in seroprotection rates | ||||||||||||||||||
Point estimate |
0
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
-1.09 | ||||||||||||||||||
upper limit |
2.14 | ||||||||||||||||||
Notes [4] - Non-inferiority is supported by the data if the lower bound of the two-sided 95% confidence interval is greater than -10%. The 95% CI of the non-inferiority comparison was estimated by Wilson score method without continuity correction as described by Newcombe. The SP306 vaccine group was non-inferior to the DT Biken vaccine group. |
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End point title |
Percentage of Subjects With Pertussis Booster Response Following Vaccination With Either SP306 or DT BIK® Vaccine [5] | ||||||||||||||||||
End point description |
Pertussis booster response was defined as a pre-vaccination antibody concentration less than the lower limit of quantitation (LLOQ) and a post-vaccination level ≥4X LLOQ; or a pre-vaccination antibody concentration ≥ LLOQ but <4X LLOQ and a 4-fold rise (i.e., post/pre-vaccination ≥4); or pre-vaccination antibody concentrations ≥4X LLOQ and a 2-fold rise (i.e., post/pre-vaccination ≥2).
Pertussis antitoxin concentration were assayed by the enzyme-linked immunosorbent assay (ELISA) method.
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End point type |
Primary
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End point timeframe |
Day 28 post-vaccination
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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: Descriptive analyses were performed based on the study groups and the study vaccine administered for this outcome. |
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects With Seroprotection to Diphtheria and Tetanus Antigens Before Vaccination With Either SP306 or DT BIK® Vaccine | ||||||||||||||||||
End point description |
Seroprotection was defined as the proportion of subjects with pre-vaccination with diphtheria and tetanus antitoxin concentration ≥ 0.1 IU/mL.
Diphtheria antitoxin concentration was assayed by the toxin neutralization test; Tetanus antitoxin concentration was assayed by the enzyme-linked immunosorbent assay (ELISA) method.
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End point type |
Secondary
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End point timeframe |
Day 0 (pre-vaccination)
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects With Seroprotection to Diphtheria and Tetanus Antigens Before and Following Vaccination With Either SP306 or DT BIK® Vaccine | ||||||||||||||||||||||||
End point description |
Seroprotection was defined as the proportion of subjects with diphtheria and tetanus antitoxin concentration level ≥ 0.01 IU/mL.
Diphtheria antitoxin concentration was assayed by the toxin neutralization test; Tetanus antitoxin concentration was assayed by the enzyme-linked immunosorbent assay (ELISA) method.
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End point type |
Secondary
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End point timeframe |
Day 0 (pre-vaccination) and Day 28 post-vaccination
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No statistical analyses for this end point |
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End point title |
Geometric Mean Concentration of Diphtheria and Tetanus Antibodies Before and Following Vaccination With Either SP306 or DT BIK® Vaccine | ||||||||||||||||||||||||
End point description |
Diphtheria antitoxin concentration was assayed by the toxin neutralization test; Tetanus antitoxin concentration was assayed by the enzyme-linked immunosorbent assay (ELISA) method.
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End point type |
Secondary
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End point timeframe |
Day 0 (pre-vaccination) and Day 28 post-vaccination
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects with Pertussis (Pertactin and Fimbriae Types 2 and 3) Booster Response Following Vaccination With Either SP306 or DT BIK® Vaccine | ||||||||||||||||||
End point description |
Pertussis booster response was defined as a pre-vaccination antibody concentration less than the lower limit of quantitation (LLOQ) and a post-vaccination level ≥4X LLOQ; or a pre-vaccination antibody concentration ≥ LLOQ but <4X LLOQ and a 4-fold rise (i.e., post/pre-vaccination ≥4); or pre-vaccination antibody concentrations ≥4X LLOQ and a 2-fold rise (i.e., post/pre-vaccination ≥2).
Pertussis antitoxin concentration were assayed by the enzyme-linked immunosorbent assay (ELISA) method.
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End point type |
Secondary
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End point timeframe |
Day 28 post-vaccination
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No statistical analyses for this end point |
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End point title |
Geometric Mean Concentration of Pertussis Antibodies Before and Following Vaccination With Either SP306 or DT BIK® Vaccine | ||||||||||||||||||||||||||||||||||||
End point description |
Pertussis antitoxin concentration levels were assayed by the enzyme-linked immunosorbent assay (ELISA) method.
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End point type |
Secondary
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End point timeframe |
Day 0 (pre-vaccination) and Day 28 post-vaccination
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects Reporting Solicited Injection-site and Systemic Reactions Following A Single Booster Dose of SP306 or DT BIK® Vaccine | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Solicited Injection-site: Pain, Erythema, Swelling; Solicited Systemic reactions: Fever (Temperature), Headache, Malaise, and Myalgia. Grade 3 Injection-site: Pain, Significant, prevents daily activity; Erythema and Swelling >100 mm. Grade 3 Systemic reactions: Fever, >39°C; Headache, Malaise, Myalgia, Significant, prevents daily activity.
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End point type |
Secondary
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End point timeframe |
Day 0 up to Day 7 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 event data were collected from Day 0 (post-vaccination) up to Day 28 post-vaccination.
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Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||
Dictionary version |
17.0
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Reporting groups
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Reporting group title |
SP306 Group
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Reporting group description |
Subjects received 1 dose of Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (SP306, Tdap5) vaccine intramuscularly. | |||||||||||||||||||||||||||||||||
Reporting group title |
DT Biken Group
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Reporting group description |
Subjects received 1 dose of Diphtheria Toxoid and Tetanus Toxoid Adsorbed (DT Biken) vaccine. | |||||||||||||||||||||||||||||||||
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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? No | |||
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 |