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Trial record 68 of 58417 for:    Placebo

A Phase 4, Placebo-Controlled, Randomized Study to Evaluate the Immunogenicity and Safety of HPV and Tdap When Administered With MenACWY in Adolescents

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ClinicalTrials.gov Identifier: NCT01424644
Recruitment Status : Completed
First Posted : August 29, 2011
Results First Posted : February 14, 2014
Last Update Posted : February 14, 2014
Sponsor:
Collaborator:
Novartis Vaccines
Information provided by (Responsible Party):
Novartis

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Prevention
Condition Meningococcal Meningitis
Interventions Biological: Placebo + Combined Tetanus, Reduced Diphtheria Toxoid, Acellular Pertussis Vaccine + Quadrivalent Human Papillomavirus Vaccine
Biological: MenACWY-CRM Conjugate Vaccine + Combined Tetanus, Reduced Diphtheria Toxoid, Acellular Pertussis Vaccine + Quadrivalent Human Papillomavirus Vaccine
Enrollment 801
Recruitment Details Subjects were enrolled in two countries (US and Italy).
Pre-assignment Details All enrolled subjects were included in the trial.
Arm/Group Title MenACWY-CRM+Tdap+HPV Placebo+Tdap+HPV
Hide Arm/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. 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.
Period Title: Overall Study
Started 402 399
Completed 369 372
Not Completed 33 27
Reason Not Completed
Adverse Event             2             0
Withdrawal by Subject             9             12
Lost to Follow-up             16             12
Protocol Violation             4             3
Administrative Reason             1             0
Unable to Classify             1             0
Arm/Group Title MenACWY-CRM+Tdap+HPV Placebo+Tdap+HPV Total
Hide Arm/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. 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. Total of all reporting groups
Overall Number of Baseline Participants 402 399 801
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 402 participants 399 participants 801 participants
11.9  (1.7) 11.8  (1.5) 11.9  (1.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 402 participants 399 participants 801 participants
Female
169
  42.0%
155
  38.8%
324
  40.4%
Male
233
  58.0%
244
  61.2%
477
  59.6%
1.Primary Outcome
Title Percentages of Subjects With Anti-diphtheria and Anti-tetanus Antibody Concentrations ≥ 0.1 IU/mL When Tdap is Administered Concomitantly With HPV and MenACWY-CRM Vaccine Compared to Tdap Given Concomitantly With HPV and Placebo
Hide Description The percentages of subjects with anti-diphtheria and anti-tetanus antibody concentrations ≥ 0.1 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.
Time Frame 1 month post Tdap vaccination.
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was done on the Tdap per-protocol population, i.e., all subjects who received all the relevant doses of vaccine correctly, and provided serology results at one month postvaccination, and had no major protocol violation as defined prior to unblinding.
Arm/Group Title MenACWY-CRM+Tdap+HPV Placebo+Tdap+HPV
Hide Arm/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.
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.
Overall Number of Participants Analyzed 376 382
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentages of subjects
Day 1 (diphtheria) (N=375, 380)
5
(3 to 8)
3
(2 to 5)
One month post dose (diphtheria)
95
(93 to 97)
82
(78 to 86)
Day 1 (tetanus ) (N=375, 380)
28
(24 to 33)
28
(23 to 32)
One month post dose (tetanus )
99
(97 to 100)
98
(97 to 99)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection MenACWY-CRM+Tdap+HPV, Placebo+Tdap+HPV
Comments 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
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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 [(MenACWY-CRM+Tdap+HPV) minus (Placebo+Tdap + HPV)] was greater than -10%, at 1 month after Tdap vaccination
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Miettinen and Nurminen
Comments [Not Specified]
Method of Estimation Estimation Parameter Vaccine group difference
Estimated Value 13
Confidence Interval (2-Sided) 95%
9 to 17
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection MenACWY-CRM+Tdap+HPV, Placebo+Tdap+HPV
Comments 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.
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Miettinen and Nurminen
Comments [Not Specified]
Method of Estimation Estimation Parameter Vaccine group difference
Estimated Value 0
Confidence Interval (2-Sided) 95%
-2 to 2
Estimation Comments [Not Specified]
2.Primary Outcome
Title 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
Hide Description The geometric mean concentrations (GMCs) of antibodies against pertussis antigens (PT, FHA and 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.
Time Frame 1 month post Tdap vaccination.
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was done on the Tdap per-protocol population.
Arm/Group Title MenACWY-CRM+Tdap+HPV Placebo+Tdap+HPV
Hide Arm/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.
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.
Overall Number of Participants Analyzed 376 382
Geometric Mean (95% Confidence Interval)
Unit of Measure: EU/mL
PT (Day 1) (N= 375, 380)
4.77
(4.11 to 5.53)
4.16
(3.59 to 4.82)
PT(One month post dose)
44
(40 to 48)
44
(40 to 48)
FHA (Day 1) (N= 375, 380)
24
(21 to 27)
21
(18 to 23)
FHA (One month post dose)
202
(187 to 218)
240
(222 to 259)
PRN (Day 1) (N= 375, 380)
20
(18 to 23)
21
(18 to 24)
PRN (One month post dose)
330
(300 to 363)
403
(367 to 443)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection MenACWY-CRM+Tdap+HPV, Placebo+Tdap+HPV
Comments 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.
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Vaccine group ratio-Geometric mean conc
Estimated Value 1.01
Confidence Interval (2-Sided) 95%
0.89 to 1.14
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection MenACWY-CRM+Tdap+HPV, Placebo+Tdap+HPV
Comments 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.
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Vaccine group ratio- Geometric mean conc
Estimated Value 0.84
Confidence Interval (2-Sided) 95%
0.76 to 0.93
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection MenACWY-CRM+Tdap+HPV, Placebo+Tdap+HPV
Comments 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.
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Vaccine group ratio-Geometric mean conc
Estimated Value 0.82
Confidence Interval (2-Sided) 95%
0.72 to 0.93
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Geometric Mean hSBA Titers Against N. Meningitidis Serogroups A,C,W and Y at 1 Month After Men ACWY Vaccination.
Hide Description The immunogenicity was assessed in terms of geometric mean hSBA titers of MenACWY when administered concomitantly with Tdap and HPV at 1 month after 1 dose of MenACWY vaccination.
Time Frame 1 month post MenACWY-CRM vaccination.
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was done on the MenACWY per-protocol population - all subjects who received all the relevant doses of vaccine correctly, and provided evaluable serum samples at baseline and one month postvaccination for at least one serogroup, and had no major protocol violation as defined prior to unblinding.
Arm/Group Title MenACWY-CRM+Tdap+HPV Placebo+Tdap+HPV
Hide Arm/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.
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.
Overall Number of Participants Analyzed 371 99
Geometric Mean (95% Confidence Interval)
Unit of Measure: Titers
Men A
35
(29 to 42)
2.13
(1.97 to 2.31)
Men C (N=370, 97)
59
(48 to 73)
3.92
(3.3 to 4.66)
Men W (N=369, 96)
61
(53 to 69)
12
(9.26 to 17)
Men Y (N=369, 97)
48
(40 to 58)
3.54
(2.9 to 4.31)
4.Secondary Outcome
Title 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
Hide 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.
Time Frame Day 1-7 after any vaccination.
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was done on solicited safety Set - All subjects in the exposed population who provided solicited AEs.
Arm/Group Title MenACWY-CRM+Tdap+HPV Placebo+Tdap+HPV
Hide Arm/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.
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.
Overall Number of Participants Analyzed 389 385
Measure Type: Number
Unit of Measure: Subjects
Local 209 164
Injection site pain 158 134
Injection site erythema 65 25
Injection site induration 61 37
Systemic 205 179
Chills 60 50
Nausea 54 39
Malaise 57 44
Myalgia 115 101
Arthralgia 35 43
Headache 113 95
Rash 4 7
Fever ≥ 38°C 9 8
Other 88 80
Stayed home due to reaction 25 33
Analgesic / Antipyretic medication used 74 65
5.Secondary Outcome
Title 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
Hide 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 AE and another subject prior to study vaccination on day 1.

Time Frame Throughout the study (Day 1 to Day 211).
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was done on overall safety population - All subjects in the exposed population who provided postvaccination and post-baseline safety data.
Arm/Group Title MenACWY-CRM+Tdap+HPV Placebo+Tdap+HPV
Hide Arm/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.
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.
Overall Number of Participants Analyzed 396 397
Measure Type: Number
Unit of Measure: Subjects
Any AEs 201 197
At least possibly related AEs 17 14
Serious AEs 4 3
AEs leading to Premature Withdrawal 2 0
Time Frame From day 1 through day 211.
Adverse Event Reporting Description

Serious adverse events (SAEs) were collected from Day 1 through Day 211.

Note: Among 801 subjects in the enrolled population (reported in the participant flow module), 793 subjects were exposed to the study vaccines.

 
Arm/Group Title MenACWY-CRM+Tdap+HPV Placebo+Tdap+HPV
Hide Arm/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. 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.
All-Cause Mortality
MenACWY-CRM+Tdap+HPV Placebo+Tdap+HPV
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
MenACWY-CRM+Tdap+HPV Placebo+Tdap+HPV
Affected / at Risk (%) Affected / at Risk (%)
Total   4/396 (1.01%)   3/397 (0.76%) 
Endocrine disorders     
Hypothyroidism * 1  1/396 (0.25%)  0/397 (0.00%) 
Gastrointestinal disorders     
Abdominal adhesions * 1  1/396 (0.25%)  0/397 (0.00%) 
Small intestinal obstruction * 1  1/396 (0.25%)  0/397 (0.00%) 
Infections and infestations     
Peritonsillar abscess * 1  0/396 (0.00%)  1/397 (0.25%) 
Injury, poisoning and procedural complications     
Accidental overdose * 1  0/396 (0.00%)  1/397 (0.25%) 
Metabolism and nutrition disorders     
Type 1 Diabetes mellitus * 1  1/396 (0.25%)  0/397 (0.00%) 
Psychiatric disorders     
Affective disorder * 1  0/396 (0.00%)  1/397 (0.25%) 
Aggression * 1  1/396 (0.25%)  0/397 (0.00%) 
Renal and urinary disorders     
Haematuria * 1  1/396 (0.25%)  0/397 (0.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (Unspecified)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
MenACWY-CRM+Tdap+HPV Placebo+Tdap+HPV
Affected / at Risk (%) Affected / at Risk (%)
Total   288/396 (72.73%)   248/397 (62.47%) 
Gastrointestinal disorders     
Nausea  1  59/396 (14.90%)  42/397 (10.58%) 
General disorders     
Chills  1  65/396 (16.41%)  50/397 (12.59%) 
Injection site erythema  1  79/396 (19.95%)  30/397 (7.56%) 
Injection site induration  1  69/396 (17.42%)  43/397 (10.83%) 
Injection site pain  1  193/396 (48.74%)  165/397 (41.56%) 
Malaise  1  59/396 (14.90%)  45/397 (11.34%) 
Infections and infestations     
Pharyngitis * 1  22/396 (5.56%)  21/397 (5.29%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  40/396 (10.10%)  47/397 (11.84%) 
Myalgia  1  117/396 (29.55%)  109/397 (27.46%) 
Nervous system disorders     
Headache  1  128/396 (32.32%)  105/397 (26.45%) 
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (Unspecified)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Posting Director
Organization: Novartis Vaccines and Diagnostics
Responsible Party: Novartis
ClinicalTrials.gov Identifier: NCT01424644     History of Changes
Other Study ID Numbers: V59_40
2011-000476-34 ( EudraCT Number )
First Submitted: August 23, 2011
First Posted: August 29, 2011
Results First Submitted: November 20, 2013
Results First Posted: February 14, 2014
Last Update Posted: February 14, 2014