Clinical Trial Results:
A Phase IV, Placebo-Controlled, Randomized Study to Evaluate the Immunogenicity and Safety of a Combined Tetanus, Reduced Diphtheria Toxoid, Acellular Pertussis Vaccine (Tdap, Boostrix®) and Quadrivalent Human Papillomavirus [Types 6, 11, 16, 18]Recombinant Vaccine (Gardasil®) in Healthy Adolescents when Administered with MenACWY Conjugate Vaccine
Due to a system error, the data reported in v1 is not correct and has been removed from public view.
Summary
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EudraCT number |
2011-000476-34 |
Trial protocol |
IT |
Global end of trial date |
20 Dec 2012
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Results information
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Results version number |
v2(current) |
This version publication date |
15 Jun 2016
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First version publication date |
12 Apr 2015
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Other versions |
v1 (removed from public view) |
Version creation reason |
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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 |
V59_40
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01424644 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Novartis Vaccines and Diagnostics s.r.l
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Sponsor organisation address |
Via Fiorentina, 1, Siena, Italy, 53100
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Public contact |
CR&D Southern Europe, Novartis Vaccines and Diagnostic, +39 0577 249226, noemi.giglioli@novartis.com
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Scientific contact |
CR&D Southern Europe, Novartis Vaccines and Diagnostic, +39 0577 249226, noemi.giglioli@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 |
15 Oct 2013
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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 |
20 Dec 2012
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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 |
Immunogenicity Objectives:
Co-primary 1. To demonstrate that the immune response of Tdap given concomitantly with MenACWY-CRM and HPV vaccine is non inferior to the response of Tdap vaccine when given with placebo and HPV when measured at 1 month after 1 dose of Tdap. 2. To demonstrate that the immune response of HPV vaccine given concomitantly with MenACWY and Tdap is non-inferior to the response when HPV is given with placebo and Tdap when measured at 1 month after the third dose of HPV vaccination. Safety objectives: - To describe the safety profile of Tdap + HPV + MenACWY versus Tdap + HPV + placebo
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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 Code of Federal Regulations Title 21, 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 |
26 Sep 2011
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 554
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Country: Number of subjects enrolled |
Italy: 247
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Worldwide total number of subjects |
801
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EEA total number of subjects |
247
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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) |
498
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Adolescents (12-17 years) |
284
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Adults (18-64 years) |
19
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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 20 centers located in Italy and USA. | ||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
All subjects enrolled were included in the trial. | ||||||||||||||||||||||||||||||
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 |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | ||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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MenACWY-CRM+Tdap+HPV | ||||||||||||||||||||||||||||||
Arm description |
Subjects received one dose of Tdap, MenACWY-CRM, and HPV concomitantly on day 1. A second and third dose of HPV was administered at 2 and 6 months, respectively, after the first dose. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Meningococcal (groups A, C, W, and Y) oligosaccharide diphtheria CRM-197 conjugate vaccine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder and solution for solution for injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
After reconstitution, one dose (0.5 ml) of MenACWY injectable solution was administered by IM.
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Investigational medicinal product name |
Tdap vaccine
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Investigational medicinal product code |
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Other name |
(GSK Boostrix vaccine)
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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 |
One dose (0.5 ml) of Tdap was administered by IM.
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Investigational medicinal product name |
HPV vaccine
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Investigational medicinal product code |
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Other name |
(Merck & Co. Gardasil vaccine)
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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 |
One dose (0.5 ml) of HPV was administered by IM on day 1, month 2 and 6 months after the first dose.
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Arm title
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Placebo+Tdap+HPV | ||||||||||||||||||||||||||||||
Arm description |
Subjects received one dose of Tdap, placebo, and HPV concomitantly on day 1. A second and third dose of HPV was administered at 2 and 6 months, respectively, after the first dose. | ||||||||||||||||||||||||||||||
Arm type |
Placebo Comparator | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Tdap vaccine
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Investigational medicinal product code |
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Other name |
(GSK Boostrix vaccine)
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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 |
One dose (0.5 ml) of Tdap was administered by IM.
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Investigational medicinal product name |
HPV vaccine
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Investigational medicinal product code |
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Other name |
(Merck & Co. Gardasil vaccine)
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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 |
One dose (0.5 ml) of HPV was administered by IM on day 1, month 2 and 6 months after the first dose.
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Investigational medicinal product name |
Placebo (NaCl 0.9%)
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
One 0.5 ml dose of saline placebo was administered by IM injection.
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Baseline characteristics reporting groups
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Reporting group title |
MenACWY-CRM+Tdap+HPV
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Reporting group description |
Subjects received one dose of Tdap, MenACWY-CRM, and HPV concomitantly on day 1. A second and third dose of HPV was administered at 2 and 6 months, respectively, after the first dose. | ||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo+Tdap+HPV
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Reporting group description |
Subjects received one dose of Tdap, placebo, and HPV concomitantly on day 1. A second and third dose of HPV was administered at 2 and 6 months, respectively, after the first dose. | ||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
MenACWY-CRM+Tdap+HPV
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Reporting group description |
Subjects received one dose of Tdap, MenACWY-CRM, and HPV concomitantly on day 1. A second and third dose of HPV was administered at 2 and 6 months, respectively, after the first dose. | ||
Reporting group title |
Placebo+Tdap+HPV
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Reporting group description |
Subjects received one dose of Tdap, placebo, and HPV concomitantly on day 1. A second and third dose of HPV was administered at 2 and 6 months, respectively, after the first dose. | ||
Subject analysis set title |
All Enrolled Population
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The enrolled population contained all subjects enrolled and randomized in the study, ie, all subjects who had data in panel DEMOG. These were subjects who signed informed consent, were enrolled into the study and were randomized. This population was used for the analysis of demographics and all subject listings.
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Subject analysis set title |
Exposed Population
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All subjects in the enrolled population who received a study vaccination.
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Subject analysis set title |
MITT Population -Tdap
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
The MITT population included all subjects in the enrolled population who received all the relevant doses of vaccine, and provided at least 1 evaluable serum sample after baseline. For purposes of analysis of this population, subjects were to be included in the group they were assigned to during randomization.
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Subject analysis set title |
MITT Population- MenACWY
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
The MITT population included all subjects in the enrolled population who received all the relevant doses of vaccine, and provided at least 1 evaluable serum sample after baseline. For purposes of analysis of this population, subjects were to be included in the group they were assigned to during randomization.
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Subject analysis set title |
Per Protocol (PP) Population - Tdap
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The PP population included all subjects in the MITT immunogenicity population who: ▫ correctly received all the relevant doses of vaccine; ▫ provided evaluable serum samples at the relevant time points; and ▫ had no major protocol deviation as defined prior to study unblinding.
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Subject analysis set title |
Safety Population
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All subjects who had received at least 1 study vaccine and had postbaseline safety data were included in the safety analysis.
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Subject analysis set title |
Per Protocol (PP) Population- MenACWY
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The PP population included all subjects in the MITT immunogenicity population who: ▫ correctly received all the relevant doses of vaccine; ▫ provided evaluable serum samples at the relevant time points; and ▫ had no major protocol deviation as defined prior to study unblinding.
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End point title |
1. Percentages of Subjects With Anti-diphtheria and Anti-tetanus Antibody Concentrations ≥ 1.0 IU/mL When Tdap is Administered Concomitantly With HPV and MenACWY-CRM Vaccine Compared to Tdap Given Concomitantly With HPV and Placebo | ||||||||||||||||||||||||
End point description |
The percentages of subjects with anti-diphtheria and anti-tetanus antibody concentrations ≥ 1.0 IU/mL (as measured by ELISA) following concomitant administration of Tdap with HPV and MenACWY-CRM vaccine as compared to concomitant administration of Tdap with HPV and placebo.
Analysis was done on the Tdap per protocol population, i.e., all subjects who received all the relevant doses of vaccine correctly, and provided evaluable serum samples at the relevant time points, and had no major protocol violation as defined prior to unblinding.
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End point type |
Primary
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End point timeframe |
1 month post Tdap vaccination
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||||||
Statistical analysis description |
Non-inferiority of anti-diphtheria immune response following concomitant administration of Tdap with HPV and MenACWY-CRM as compared to concomitant administration of Tdap with HPV and placebo
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Comparison groups |
MenACWY-CRM+Tdap+HPV v Placebo+Tdap+HPV
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Number of subjects included in analysis |
758
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | ||||||||||||||||||||||||
Method |
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Parameter type |
Vaccine group difference | ||||||||||||||||||||||||
Point estimate |
13
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||
sides |
2-sided
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lower limit |
9 | ||||||||||||||||||||||||
upper limit |
17 | ||||||||||||||||||||||||
Notes [1] - The immune response to diphtheria toxin for the MenACWY-CRM+Tdap+HPV group was considered non-inferior to that of the Placebo+Tdap+HPV group if the lower limit of the two-sided 95% CI of the difference in seroprotection rates [(MenACWYCRM+ Tdap+HPV) minus (Placebo+Tdap + HPV)] was greater than -10%, at 1 month after Tdap vaccination |
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Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||||||||
Statistical analysis description |
Non-inferiority of anti-tetanus immune response following concomitant administration of Tdap with HPV and MenACWY-CRM as compared to concomitant administration of Tdap with HPV and placebo.
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Comparison groups |
MenACWY-CRM+Tdap+HPV v Placebo+Tdap+HPV
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Number of subjects included in analysis |
758
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [2] | ||||||||||||||||||||||||
Method |
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Parameter type |
Vaccine group difference | ||||||||||||||||||||||||
Point estimate |
0
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||
sides |
2-sided
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lower limit |
-2 | ||||||||||||||||||||||||
upper limit |
2 | ||||||||||||||||||||||||
Notes [2] - The immune response to tetanus toxin for the MenACWY-CRM+Tdap+HPV group was considered non-inferior to that of Placebo+Tdap+HPV group if the lower limit of the two-sided 95% CI of the difference in seroprotection rates [(MenACWY-CRM+ Tdap+HPV) minus (Placebo+Tdap + HPV)] was greater than -10%, at 1 month after Tdap vaccination. |
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End point title |
2. Geometric Mean Concentrations of Antibodies Against Pertussis Antigens After Concomitant Administration of Tdap With HPV and MenACWY-CRM Compared to Concomitant Administration of Tdap With HPV and Placebo | ||||||||||||||||||||||||||||||
End point description |
The geometric mean concentrations (GMCs) of antibodies against pertussis antigens (Pertussis Toxin (PT), Filamentous Hemagglutinin (FHA) and Pertactin (PRN), as measured by ELISA, following concomitant administration of Tdap with HPV and MenACWY-CRM as compared to concomitant administration of Tdap with HPV and placebo.
Analysis was done on the Tdap per protocol population, i.e., all subjects who received all the relevant doses of vaccine correctly, and provided evaluable serum samples at the relevant time points, and had no major protocol violation as defined prior to unblinding.
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End point type |
Primary
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End point timeframe |
1 month post Tdap vaccination
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||||||||||||
Statistical analysis description |
Non-inferiority of anti-PT immune response following concomitant administration of Tdap with HPV and MenACWY-CRM as compared to concomitant administration of Tdap with HPV and placebo.
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Comparison groups |
MenACWY-CRM+Tdap+HPV v Placebo+Tdap+HPV
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Number of subjects included in analysis |
758
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [3] | ||||||||||||||||||||||||||||||
Method |
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Parameter type |
Vaccine group ratio of GMCs | ||||||||||||||||||||||||||||||
Point estimate |
1.01
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
0.89 | ||||||||||||||||||||||||||||||
upper limit |
1.14 | ||||||||||||||||||||||||||||||
Notes [3] - The immune response to PT antigen for the MenACWY-CRM+Tdap+HPV group was considered non-inferior to that of the Placebo+Tdap+HPV group if the lower limit of the two-sided 95% CI of the ratio of the GMCs of the MenACWY-CRM +Tdap+HPV group to the Placebo+Tdap + HPV group was greater than 0.5, at 1 month after Tdap vaccination. |
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Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||||||||||||||
Statistical analysis description |
Non-inferiority of anti-FHA immune response following concomitant administration of Tdap with HPV and MenACWY-CRM as compared to concomitant administration of Tdap with HPV and placebo.
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Comparison groups |
MenACWY-CRM+Tdap+HPV v Placebo+Tdap+HPV
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Number of subjects included in analysis |
758
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [4] | ||||||||||||||||||||||||||||||
Method |
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Parameter type |
Vaccine group ratio of GMCs | ||||||||||||||||||||||||||||||
Point estimate |
0.84
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
0.76 | ||||||||||||||||||||||||||||||
upper limit |
0.93 | ||||||||||||||||||||||||||||||
Notes [4] - The immune response to FHA antigen for the MenACWY-CRM+Tdap+HPV group was considered non-inferior to that of Placebo+Tdap+HPV group if the lower limit of the 95% CI of the difference [(MenACWY-CRM +Tdap+HPV) minus (Placebo+Tdap + HPV)] was greater than 0.5, at 1 month after Tdap vaccination. |
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Statistical analysis title |
Statistical Analysis 3 | ||||||||||||||||||||||||||||||
Statistical analysis description |
Non-inferiority of anti-PRN immune response following concomitant administration of Tdap with HPV and MenACWY-CRM as compared to concomitant administration of Tdap with HPV and placebo.
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Comparison groups |
MenACWY-CRM+Tdap+HPV v Placebo+Tdap+HPV
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Number of subjects included in analysis |
758
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [5] | ||||||||||||||||||||||||||||||
Method |
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Parameter type |
Vaccine group ratio of GMCs | ||||||||||||||||||||||||||||||
Point estimate |
0.82
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
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lower limit |
0.72 | ||||||||||||||||||||||||||||||
upper limit |
0.93 | ||||||||||||||||||||||||||||||
Notes [5] - The immune response to PRN antigen for the MenACWY-CRM+Tdap+HPV group was considered non-inferior to that of Placebo+Tdap+HPV group if the lower limit of the 95% CI of the difference [(MenACWY-CRM+Tdap+HPV) minus (Placebo+Tdap + HPV)] was greater than 0.5, at 1 month after vaccination. |
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End point title |
3. Geometric Mean of Human Serum Bactericidal Assay (hSBA) Titers Against N. meningitidis when MenACWY-CRM is Concomitantly Administered With Tdap and HPV | ||||||||||||||||||||||||
End point description |
The Geometric Mean of hSBA Titers Against N meningitidis Serogroups A, C, W, and Y were determined at 1 Month After MenACWY or Placebo Vaccination.
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End point type |
Secondary
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End point timeframe |
1 month post MenACWY-CRM vaccination or Placebo Vaccination
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No statistical analyses for this end point |
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End point title |
4. Number of Subjects With Solicited Local and Systemic Adverse Events When Tdap and HPV Are Concomitantly Administered With MenACWY-CRM Compared to When Tdap and HPV Are Concomitantly Administered With Placebo | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The number of subjects reporting solicited local and systemic reactions following concomitant administration of MenACWY-CRM vaccine, Tdap and HPV vaccine as compared to concomitant administration of placebo with Tdap and HPV.
Analysis was done on the safety population.
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End point type |
Secondary
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End point timeframe |
Day 1-7 after any vaccination
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No statistical analyses for this end point |
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End point title |
5. Number of Subjects With Unsolicited Adverse Events When Tdap and HPV Are Concomitantly Administered With MenACWY-CRM Compared to When Tdap and HPV Are Concomitantly Administered With Placebo | |||||||||||||||||||||
End point description |
The number of subjects reporting any unsolicited adverse reactions (AEs) when Tdap and HPV are concomitantly administered with MenACWY-CRM as compared to when Tdap and HPV vaccine are concomitantly administered with placebo.
Note: A total of 2 MenACWY-CRM+Tdap+HPV subjects reported AEs leading to premature withdrawal - one subject due to treatment emergent AEs and another subject prior to study vaccination on day 1.
Analysis was done on the safety population.
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End point type |
Secondary
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End point timeframe |
Throughout the study (Day 1 to Day 211)
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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 |
From day 1 through day 211
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Adverse event reporting additional description |
Serious adverse events (SAEs) were collected from Day 1 through Day 211.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.1
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Reporting groups
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Reporting group title |
MenACWY-CRM+Tdap+HPV
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Reporting group description |
Subjects received one dose of Tdap, MenACWY-CRM, and HPV concomitantly on day 1. A second and third dose of HPV was administered at 2 and 6 months, respectively, after the first dose. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo+Tdap+HPV
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Reporting group description |
Subjects received one dose of Tdap, placebo, and HPV concomitantly on day 1. A second and third dose of HPV was administered at 2 and 6 months, respectively, after the first dose. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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14 Feb 2011 |
Amendment No. 1. The amendment included clarifications and revisions primarily related to operational aspects of the protocol. |
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19 Jul 2011 |
Amendment No. 2. The rationale for the amendment was the requirement to switch from MenACWY prefilled syringe and vial presentation to a vial-vial presentation, as well as to require that all female subjects have a negative urine pregnancy test before enrollment, instead of only female subjects of child bearing potential. |
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20 Dec 2012 |
Amendment No. 3. The third amendment dated 20 JUN 2013, was due to delays associated with testing of immune response to HPV types at an external laboratory. The protocol was revised to include a stepwise analysis for the 2 coprimary objectives as follows. A final analysis including all safety data and immunogenicity data for the first primary and secondary objectives would be conducted on cleaned data. The results of this analysis would be presented in the clinical study report, including individual listings and unblinded data. The immunogenicity analysis for the second primary objective (assessment of immune response against HPV antigens) would be performed as soon as serological results become available. The HPV results would be presented in an addendum to the clinical study report. This change was communicated to and accepted by regulatory authorities in the US and Italy. |
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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 |