Clinical Trial Results:
A phase IV, open-label, multi-center follow-up study to determine the persistence of tick-borne encephalitis (TBE)-specific antibody responses among children and adolescents previously immunized against TBE.
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Summary
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EudraCT number |
2009-010145-31 |
Trial protocol |
DE |
Global end of trial date |
02 May 2011
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Results information
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Results version number |
v1(current) |
This version publication date |
11 May 2016
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First version publication date |
21 Feb 2015
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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 |
M48P3E1
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01106482 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Novartis Vaccines and Diagnostics
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Sponsor organisation address |
Via Fiorentina, 1, Siena, Italy, 53100
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Public contact |
Posting Director, Novartis Vaccines and Diagnostics, RegistryContactVaccinesUS@novartis.com
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Scientific contact |
Posting Director, Novartis Vaccines and Diagnostics, RegistryContactVaccinesUS@novartis.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 |
08 Jun 2012
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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 May 2011
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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 purpose of this study is to evaluate whether the first booster interval after primary vaccination with Encepur agains Tick borne encephalitis (TBE) can be prolonged from 3 years (current SPC recommendation) to 5 years.
Primary objectives:
1. To determine the proportion of study subjects with a TBE neutralizing titer ≥ 10 at 3, 4 and 5 years after completion of the primary immunization.
2. The kinetics of the TBE antibody response over time (at years 3, then 4, then 5) will also be assessed.
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Protection of trial subjects |
This clinical study was designed, implemented and reported in accordance with the ICH Harmonized Tripartite Guidelines for GCP, with applicable local regulations, including the European Directive 2001/20/EC, the US CFR Title 21, and the Japanese Ministry of Health, Labor, and Welfare, Novartis codes on the protection of human rights, and with the ethical principles laid down in the Declaration of Helsinki.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
08 May 2009
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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 |
Germany: 267
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Worldwide total number of subjects |
267
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EEA total number of subjects |
267
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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) |
201
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Adolescents (12-17 years) |
66
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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 |
Participants were enrolled from 10 studies center in Germany. | ||||||||||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
All enrolled participants were included in the trial. | ||||||||||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (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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Group 1 (TBE_C) | ||||||||||||||||||||||||||||||||||||||||
Arm description |
Participants who received Encepur® Children on days 0, 28, and 300 in the parent study M48P3 and had blood collected at approximately 3, 4 and 5 years after last vaccination in the primary immunization series. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Tick-borne encephalitis vaccine (inactivated, adsorbed for pediatric use)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Intramuscular use
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Dosage and administration details |
In this trial no IMP will be administered. This trial consists of 3 blood draws only.
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Arm title
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Group 2 (TBE_AC) | ||||||||||||||||||||||||||||||||||||||||
Arm description |
Participants who received Encepur® Children on days 0, 14, and 300 in the parent study M48P3 and had blood collected at approximately 3, 4 and 5 years after last vaccination in the primary immunization series. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
No intervention | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Arm title
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Group 3 (BAX_C) | ||||||||||||||||||||||||||||||||||||||||
Arm description |
Participants who received FSME-Immun® Junior on days 0 and 28 and Encepur® Children on day 300 in the parent study M48P3 and had blood collected at approximately 3 years after last vaccination in the primary immunization series. After the Year 3 interim analysis the participants were terminated from the study and received a recommendation for a booster injection. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
No intervention | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Arm title
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Group 4 (BAX_AC) | ||||||||||||||||||||||||||||||||||||||||
Arm description |
Participants who received FSME-Immun® Junior on days 0 and 14 and Encepur® Children on day 300 in the parent study M48P3 and had blood collected at approximately 3 years after last vaccination in the primary immunization series. After the Year 3 interim analysis the participants were terminated from the study and received a recommendation for a booster injection. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
No intervention | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Baseline characteristics reporting groups
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Reporting group title |
Group 1 (TBE_C)
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Reporting group description |
Participants who received Encepur® Children on days 0, 28, and 300 in the parent study M48P3 and had blood collected at approximately 3, 4 and 5 years after last vaccination in the primary immunization series. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group 2 (TBE_AC)
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Reporting group description |
Participants who received Encepur® Children on days 0, 14, and 300 in the parent study M48P3 and had blood collected at approximately 3, 4 and 5 years after last vaccination in the primary immunization series. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group 3 (BAX_C)
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Reporting group description |
Participants who received FSME-Immun® Junior on days 0 and 28 and Encepur® Children on day 300 in the parent study M48P3 and had blood collected at approximately 3 years after last vaccination in the primary immunization series. After the Year 3 interim analysis the participants were terminated from the study and received a recommendation for a booster injection. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group 4 (BAX_AC)
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Reporting group description |
Participants who received FSME-Immun® Junior on days 0 and 14 and Encepur® Children on day 300 in the parent study M48P3 and had blood collected at approximately 3 years after last vaccination in the primary immunization series. After the Year 3 interim analysis the participants were terminated from the study and received a recommendation for a booster injection. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Group 1 (TBE_C)
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Reporting group description |
Participants who received Encepur® Children on days 0, 28, and 300 in the parent study M48P3 and had blood collected at approximately 3, 4 and 5 years after last vaccination in the primary immunization series. | ||
Reporting group title |
Group 2 (TBE_AC)
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Reporting group description |
Participants who received Encepur® Children on days 0, 14, and 300 in the parent study M48P3 and had blood collected at approximately 3, 4 and 5 years after last vaccination in the primary immunization series. | ||
Reporting group title |
Group 3 (BAX_C)
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Reporting group description |
Participants who received FSME-Immun® Junior on days 0 and 28 and Encepur® Children on day 300 in the parent study M48P3 and had blood collected at approximately 3 years after last vaccination in the primary immunization series. After the Year 3 interim analysis the participants were terminated from the study and received a recommendation for a booster injection. | ||
Reporting group title |
Group 4 (BAX_AC)
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Reporting group description |
Participants who received FSME-Immun® Junior on days 0 and 14 and Encepur® Children on day 300 in the parent study M48P3 and had blood collected at approximately 3 years after last vaccination in the primary immunization series. After the Year 3 interim analysis the participants were terminated from the study and received a recommendation for a booster injection. | ||
Subject analysis set title |
All Enrolled Set
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All subjects who were enrolled irrespective of whether they have provided serum or not.
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Subject analysis set title |
Per Protocol Set (PPS)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
All subjects who were enrolled and who belonged to PPS of study M48P3, and had no major protocol violations as pre-specified in the Analysis Plan.
PPS was categorized in PPS-I and PPS-II:
Per Protocol Set - Version I, subjects boosted since end of study M48P3 excluded.
Per Protocol Set - Version II, subjects boosted since end of study M48P3 included.
Number of subjects reported refers to PPS-I.
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Subject analysis set title |
Full Analysis Set (FAS)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All subjects who were enrolled belonged to FAS of M48P3 study and who had at least one evaluable sample for the immunogenicity analysis. Subjects were analyzed according to the vaccines received in study M48P3.
FAS was categorized in FAS-I and FAS-II:
Full Analysis Set - Version I, subjects boosted since end of study M48P3 excluded.
Full Analysis Set - Version II, subjects boosted since end of study M48P3 included.
Number of subjects reported refers to FAS-I.
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End point title |
1. Percentages of Subjects with Antibody Titers ≥10 as Measured by NT (year 3) [1] | ||||||||||||||||||||||||||||||
End point description |
The proportion of study subjects with a TBE neutralizing titer (NT) ≥10 at 3 years after completion of the primary immunization were reported as percentages.
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End point type |
Primary
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End point timeframe |
3 years after vaccination
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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: No statistical analysis were performed for this end point. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
2. Percentages of Subjects with Antibody Titers ≥10 as Measured by NT (year 4 and 5) [2] [3] | ||||||||||||||||||||||||
End point description |
The proportion of study subjects with a TBE neutralizing titer (NT) ≥10 at 4 and 5 years after completion of the primary immunization were reported as percentages.
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End point type |
Primary
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End point timeframe |
4 and 5 years after vaccination
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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: No statistical analysis were performed for this end point. [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: No statistical analysis were performed for this end point. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
3. Percentages of Subjects with Antibody Titers ≥2 as Measured by NT (year 3) | ||||||||||||||||||||||||||||||
End point description |
The proportion of study subjects with a TBE neutralizing titer (NT) ≥2 at 3 years after completion of the primary immunization were reported as percentages.
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End point type |
Secondary
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End point timeframe |
3 years after vaccination
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
4. Percentages of Subjects with Antibody Titers ≥2 as Measured by NT (year 4 and 5) [4] | ||||||||||||||||||||||||
End point description |
The proportion of study subjects with a TBE neutralizing titer (NT) ≥2 at 4 and 5 years after completion of the primary immunization were reported as percentages.
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End point type |
Secondary
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End point timeframe |
4 and 5 years after vaccination
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| Notes [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: No statistical analysis were performed for this end point. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
5. Geometric Mean Concentration of Antibodies Measured by ELISA (year 3) | ||||||||||||||||||||||||||||||
End point description |
The levels of TBE-specific binding antibodies were measured by ELISA 3 years after completion of the primary immunization.
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End point type |
Secondary
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End point timeframe |
3 years after vaccination
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
6. Geometric Mean Concentration of Antibodies Measured by ELISA (year 4 and 5) [5] | ||||||||||||||||||||||||
End point description |
The levels of TBE-specific binding antibodies were measured by ELISA 4 and 5 years after completion of the primary immunization.
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End point type |
Secondary
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End point timeframe |
4 and 5 years after vaccination
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| Notes [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: No statistical analysis were performed for this end point. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
7. Percentages of Seropositive Subjects as Measured by ELISA (year 3) | ||||||||||||||||||||||||||||||
End point description |
The proportion of study seropositive subjects with a TBE-specific binding antibodies measured by ELISA 3 years after completion of the primary immunization were reported as percentages.
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End point type |
Secondary
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End point timeframe |
3 years after vaccination
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
8. Percentages of Seropositive Subjects as Measured by ELISA (year 4 and 5) [6] | ||||||||||||||||||||||||
End point description |
The proportion of study seropositive subjects with a TBE-specific binding antibodies measured by ELISA 4 and 5 years after completion of the primary immunization were reported as percentages.
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End point type |
Secondary
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End point timeframe |
4 and 5 years after vaccination
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| Notes [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: No statistical analysis were performed for this end point. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
from study start (8 MAY 2009) up to protocol amendment effective (9 FEB 2010)
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Adverse event reporting additional description |
First version of the protocol included safety data collection. As no vaccine was administered in the trial, protocol was amended (9 FEB 2010): all paragraphs on AE reporting were removed and safety data were not collected any longer.
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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 |
13.1
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Reporting groups
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Reporting group title |
Group 1 (TBE_C)
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Reporting group description |
- | ||||||||||||||||||||||||||||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: As no vaccine was administered in this study the adverse events were not collected. |
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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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15 Apr 2009 |
Amendment No. 1
On review of the protocol, ICF and the Assent form, the Ethics Committee of Bavaria, Germany issued comments which were in German. The Regional Physician translated these comments in English. Of the comments, only 2 as outlined below are relevant to the protocol, others will be implemented in the ICF and assent form.
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09 Feb 2010 |
Amendment No. 2
- As there was no vaccine administered in this study, there is no safety analysis. Therefore, all text referring to adverse events or serious adverse events was removed.
- The study protocol was revised to incorporate an analysis for antibody responses to the Neudoerfl antigen included in the FSME-Immun® Junior vaccine, which was one of the two study vaccines administered in the M48P3 parent study. The addition of this analysis broadened the understanding of immune responses in children to two different TBE vaccines over a long-term follow-up period.
- It was specified that relevant interim medical history at visit 8 and 9 should include any confirmed or suspected TBE exposure or a tick bite.
- The definition for the full analysis set (FAS) and per protocol set (PPS) for immunogenicity was clarified.
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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. | |||
| The 2 SAEs were collected because the initial version of the protocol included safety data collection. Given that no vaccine was administered in the trial, the protocol was revisited (Feb-2010) and safety data were not collected any longer. | |||
