Human Papilloma Virus (HPV) Vaccine Efficacy Trial Against Cervical Pre-cancer in Young Adults With GlaxoSmithKline (GSK) Biologicals HPV-16/18

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00122681
First received: July 20, 2005
Last updated: February 29, 2016
Last verified: April 2015
Results First Received: November 30, 2009  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Prevention
Condition: Infections, Papillomavirus
Interventions: Biological: Cervarix™
Biological: Havrix™-based investigational formulation

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Of the 18729 subjects enrolled in the study, 64 subjects were not vaccinated. Within the 18665 subjects vaccinated, 21 subjects from 1 center were excluded from all analyses because of potential data discrepancies identified at this center. As a result, a total of 18644 subjects are reported as started in the participant flow.

Reporting Groups
  Description
Havrix Group Subjects received 3 doses of GSK Biologicals' hepatitis A vaccine [HAV] (Havrix™-based investigational formulation) at Months 0, 1 and 6.
Cervarix Group Subjects received 3 doses of Cervarix™ (GSK Biologicals' human papillomavirus [HPV] vaccine) at Months 0, 1 and 6.

Participant Flow:   Overall Study
    Havrix Group     Cervarix Group  
STARTED     9325     9319  
COMPLETED     7811     7798  
NOT COMPLETED     1514     1521  
Adverse Event                 20                 16  
Lost to Follow-up                 1080                 1097  
Protocol Violation                 7                 10  
Withdrawal by Subject                 257                 251  
Personal reasons                 150                 147  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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Reporting Groups
  Description
Havrix Group Subjects received 3 doses of GSK Biologicals' hepatitis A vaccine [HAV] (Havrix™-based investigational formulation) at Months 0, 1 and 6.
Cervarix Group Subjects received 3 doses of Cervarix™ (GSK Biologicals' human papillomavirus [HPV] vaccine) at Months 0, 1 and 6.
Total Total of all reporting groups

Baseline Measures
    Havrix Group     Cervarix Group     Total  
Number of Participants  
[units: participants]
  9325     9319     18644  
Age  
[units: years]
Mean (Standard Deviation)
  20.0  (3.12)     20.0  (3.10)     20.0  (3.11)  
Gender  
[units: subjects]
     
Female     9325     9319     18644  
Male     0     0     0  



  Outcome Measures
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1.  Primary:   Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With HPV-16 and/or -18 Cervical Infection in Subjects HPV DNA Negative and Seronegative at Baseline or Overall (Any Serostatus at Baseline)   [ Time Frame: Up to the moment when 36 cases of CIN2+ lesions associated with HPV-16 or HPV-18 infection had been detected, including at least 15 cases of CIN2+ associated with HPV-18 infection. Mean follow-up was 34.9 months post-dose 3 ]
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Measure Type Primary
Measure Title Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With HPV-16 and/or -18 Cervical Infection in Subjects HPV DNA Negative and Seronegative at Baseline or Overall (Any Serostatus at Baseline)
Measure Description

CIN2+ was defined as CIN grades 2 and 3, endocervical adenocarcinoma in situ (AIS) and invasive cervical cancer.

Detection was done in:

  1. DNA- and sero-: subjects HPV deoxyribonucleic acid (DNA) negative (DNA-) at Month 0 and Month 6 for the corresponding HPV-type and seronegative (sero-) for HPV-16 and/or HPV-18 by Enzyme-linked Immunosorbent Assay (ELISA) at baseline (Month 0).
  2. Overall: subjects DNA- at Month 0 and Month 6 for the corresponding HPV-type and regardless of initial serostatus at baseline.
Time Frame Up to the moment when 36 cases of CIN2+ lesions associated with HPV-16 or HPV-18 infection had been detected, including at least 15 cases of CIN2+ associated with HPV-18 infection. Mean follow-up was 34.9 months post-dose 3  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Analysis was performed on the According-to-Protocol (ATP) cohort for efficacy, which included all evaluable subjects who had received 3 doses of study vaccine, who had a normal or low-grade cytology (i.e. negative or Atypical Squamous Cells of Undetermined Significance (ASC-US) or Low-grade Squamous Intraepithelial Lesion (LSIL)) at Month 0.

Reporting Groups
  Description
Havrix Group Subjects received 3 doses of GSK Biologicals' hepatitis A vaccine [HAV] (Havrix™-based investigational formulation) at Months 0, 1 and 6.
Cervarix Group Subjects received 3 doses of Cervarix™ (GSK Biologicals' human papillomavirus [HPV] vaccine) at Months 0, 1 and 6.

Measured Values
    Havrix Group     Cervarix Group  
Number of Participants Analyzed  
[units: participants]
  7767     7814  
Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With HPV-16 and/or -18 Cervical Infection in Subjects HPV DNA Negative and Seronegative at Baseline or Overall (Any Serostatus at Baseline)  
[units: subjects]
   
HPV-16/18, DNA- & sero- subjects (n= 7312, 7344)     56     4  
HPV-16, DNA- & sero- subjects (n= 6165, 6303)     46     2  
HPV-18, DNA- & sero- subjects (n= 6746, 6794)     15     2  
HPV-16/18, overall (n= 7767, 7814)     65     6  
HPV-16, overall (n= 7276, 7372)     54     4  
HPV-18, overall (n= 7583, 7645)     16     2  


Statistical Analysis 1 for Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With HPV-16 and/or -18 Cervical Infection in Subjects HPV DNA Negative and Seronegative at Baseline or Overall (Any Serostatus at Baseline)
Groups [1] All groups
1-Rate Ratio [2] 92.9
95% Confidence Interval 79.9 to 98.3
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Vaccine efficacy against CIN2+ associated with HPV-16 or HPV-18 (by PCR) in HPV DNA negative and seronegative subjects at baseline, using conditional exact method. The VE was defined as follows: VE = 1-Rate Ratio (RR), where RR = incidence rate in HPV Group (vaccine)/ incidence rate in HAV Group (control); Incidence rate = n/T(per 100); n= number of subjects reporting at least one event in each group and T(years) = sum of follow-up period (censored at the first occurrence of an event) expressed.
[2] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With HPV-16 and/or -18 Cervical Infection in Subjects HPV DNA Negative and Seronegative at Baseline or Overall (Any Serostatus at Baseline)
Groups [1] All groups
1-Rate Ratio [2] 95.7
95% Confidence Interval 82.9 to 99.6
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Vaccine efficacy against CIN2+ associated with HPV-16 (by PCR) in HPV DNA negative and seronegative subjects at baseline, using conditional exact method. The VE was defined as follows: VE = 1-Rate Ratio (RR), where RR = incidence rate in HPV Group (vaccine)/ incidence rate in HAV Group (control); Incidence rate = n/T(per 100); n= number of subjects reporting at least one event in each group and T(years) = sum of follow-up period (censored at the first occurrence of an event) expressed.
[2] Other relevant estimation information:
  No text entered.

Statistical Analysis 3 for Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With HPV-16 and/or -18 Cervical Infection in Subjects HPV DNA Negative and Seronegative at Baseline or Overall (Any Serostatus at Baseline)
Groups [1] All groups
1-Rate Ratio [2] 86.7
95% Confidence Interval 39.7 to 98.7
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Vaccine efficacy against CIN2+ associated with HPV-18 (by PCR) in HPV DNA negative and seronegative subjects at baseline, using conditional exact method. The VE was defined as follows: VE = 1-Rate Ratio (RR), where RR = incidence rate in HPV Group (vaccine)/ incidence rate in HAV Group (control); Incidence rate = n/T(per 100); n= number of subjects reporting at least one event in each group and T(years) = sum of follow-up period (censored at the first occurrence of an event) expressed.
[2] Other relevant estimation information:
  No text entered.

Statistical Analysis 4 for Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With HPV-16 and/or -18 Cervical Infection in Subjects HPV DNA Negative and Seronegative at Baseline or Overall (Any Serostatus at Baseline)
Groups [1] All groups
1-Rate Ratio [2] 90.8
95% Confidence Interval 78.1 to 96.9
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Vaccine efficacy against CIN2+ for HPV-16 or HPV-18 (by PCR) in HPV DNA negative subjects at baseline, regardless of initial serostatus, using conditional exact method. The VE was defined as follows: VE = 1-Rate Ratio (RR), where RR = incidence rate in HPV Group (vaccine)/ incidence rate in HAV Group (control); Incidence rate = n/T(per 100); n= number of subjects reporting at least one event in each group and T(years) = sum of follow-up period (censored at the first occurrence of an event).
[2] Other relevant estimation information:
  No text entered.

Statistical Analysis 5 for Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With HPV-16 and/or -18 Cervical Infection in Subjects HPV DNA Negative and Seronegative at Baseline or Overall (Any Serostatus at Baseline)
Groups [1] All groups
1-Rate Ratio [2] 92.7
95% Confidence Interval 79.3 to 98.2
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Vaccine efficacy against CIN2+ for HPV-16 (by PCR) in HPV DNA negative subjects at baseline, regardless of initial serostatus, using conditional exact method. The VE was defined as follows: VE = 1-Rate Ratio (RR), where RR = incidence rate in HPV Group (vaccine)/ incidence rate in HAV Group (control); Incidence rate = n/T(per 100); n= number of subjects reporting at least one event in each group and T(years) = sum of follow-up period (censored at the first occurrence of an event).
[2] Other relevant estimation information:
  No text entered.

Statistical Analysis 6 for Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With HPV-16 and/or -18 Cervical Infection in Subjects HPV DNA Negative and Seronegative at Baseline or Overall (Any Serostatus at Baseline)
Groups [1] All groups
1-Rate Ratio [2] 87.6
95% Confidence Interval 44.1 to 98.8
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Vaccine efficacy against CIN2+ for HPV-18 (by PCR) in HPV DNA negative subjects at baseline, regardless of initial serostatus, using conditional exact method. The VE was defined as follows: VE = 1-Rate Ratio (RR), where RR = incidence rate in HPV Group (vaccine)/ incidence rate in HAV Group (control); Incidence rate = n/T(per 100); n= number of subjects reporting at least one event in each group and T(years) = sum of follow-up period (censored at the first occurrence of an event).
[2] Other relevant estimation information:
  No text entered.



2.  Primary:   Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With HPV-16 and/or -18 Cervical Infection in Subjects HPV DNA Negative and Seronegative at Baseline or Overall (Any Serostatus at Baseline)   [ Time Frame: at Month 48 ]

3.  Secondary:   Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 or HPV-18 Detected Within the Lesional Component of the Cervical Tissue Specimen   [ Time Frame: Up to the moment when 36 cases of CIN2+ lesions associated with HPV-16 or HPV-18 infection had been detected, including at least 15 cases of CIN2+ associated with HPV-18 infection. Mean follow-up was 34.9 months post dose 3 ]

4.  Secondary:   Number of Subjects Reporting Solicited Local and General Symptoms   [ Time Frame: Within 7 days after any vaccination ]

5.  Secondary:   Number of Subjects Reporting Unsolicited Adverse Events   [ Time Frame: Within 30 days after any vaccination ]

6.  Secondary:   Number of Subjects Reporting Serious Adverse Events (SAEs)   [ Time Frame: Throughout the entire study period (Month 0 to Month 48) ]

7.  Secondary:   Number of Subjects Reporting New Onset of Chronic Disease (NOCDs)   [ Time Frame: Throughout the entire study (Month 0 to 48) ]

8.  Secondary:   Number of Subjects Reporting Medically Significant Conditions   [ Time Frame: Throughout entire study period (Month 0 to Month 48) ]

9.  Secondary:   Number of Subjects With Outcome of Pregnancies, Overall and Stratified by Initial (Month 0) HPV-16/18 DNA Status and According to HPV-16 or -18 Serostatus   [ Time Frame: Throughout the entire study period (Month 0 to Month 48) ]

10.  Secondary:   Number of Subjects With Persistent Infection (6-month Definition) With HPV-16 or HPV-18   [ Time Frame: Up to the moment when 36 cases of CIN2+ lesions associated with HPV-16 or HPV-18 infection had been detected, including at least 15 cases of CIN2+ associated with HPV-18 infection. Mean follow-up was 34.9 months post dose 3 ]

11.  Secondary:   Number of Subjects With Persistent Infection (6-month Definition) With HPV-16 or HPV-18   [ Time Frame: at Month 48 ]

12.  Secondary:   Number of Subjects With Persistent Infection (6-month Definition) With Oncogenic HPV Types   [ Time Frame: Up to the moment when 36 cases of CIN2+ lesions associated with HPV-16 or HPV-18 infection had been detected, including at least 15 cases of CIN2+ associated with HPV-18 infection. Mean follow-up was 34.9 months post dose 3 ]

13.  Secondary:   Number of Subjects With Persistent Infection (6-month Definition) With Oncogenic HPV Types   [ Time Frame: at Month 48 ]

14.  Secondary:   Number of Subjects With Histopathologically-confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With HPV-16 or HPV-18 Detected Within the Lesional Component of the Cervical Tissue Specimen   [ Time Frame: at Month 48 ]

15.  Secondary:   Number of Subjects Reporting Persistent Infection (12-month Definition) With HPV-16 or HPV-18   [ Time Frame: Up to the moment when 36 cases of CIN2+ lesions associated with HPV-16 or HPV-18 infection had been detected, including at least 15 cases of CIN2+ associated with HPV-18 infection. Mean follow-up was 34.9 months post dose 3 ]

16.  Secondary:   Number of Subjects Reporting Persistent Infection (12-month Definition) With HPV-16 or HPV-18   [ Time Frame: at Month 48 ]

17.  Secondary:   Number of Subjects With Histopathologically Confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With Oncogenic HPV Types Detected Within the Lesional Component of the Cervical Tissue Specimen   [ Time Frame: Up to the moment when 36 cases of CIN2+ lesions associated with HPV-16 or HPV-18 infection had been detected, including at least 15 cases of CIN2+ associated with HPV-18 infection. Mean follow-up was 34.9 months post dose 3 ]

18.  Secondary:   Number of Subjects With Histopathologically Confirmed Cervical Intraepithelial Neoplasia (CIN)1+ Associated With Oncogenic HPV Types Detected Within the Lesional Component of the Cervical Tissue Specimen   [ Time Frame: at Month 48 ]

19.  Secondary:   Number of Subjects With Histopathologically Confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With Oncogenic HPV Types Detected Within the Lesional Component of the Cervical Tissue Specimen   [ Time Frame: Up to the moment when 36 cases of CIN2+ lesions associated with HPV-16 or HPV-18 infection had been detected, including at least 15 cases of CIN2+ associated with HPV-18 infection. Mean follow-up was 34.9 months post dose 3 ]

20.  Secondary:   Number of Subjects With Histopathologically Confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Associated With Oncogenic HPV Types Detected Within the Lesional Component of the Cervical Tissue Specimen   [ Time Frame: at Month 48 ]

21.  Secondary:   Number of Seropositive Subjects for Anti-HPV-16 and Anti-HPV-18 Antibody Titers by ELISA in the Immunogenicity Subset, According to Initial (Month 0) HPV-16 or HPV-18 Serostatus   [ Time Frame: At Months 6, 7, 12, 24, 36 & 48 ]

22.  Secondary:   Anti-HPV-16 and Anti-HPV-18 ELISA Titers in the Immunogenicity Subset   [ Time Frame: At Months 6, 7, 12, 24, 36 and 48 ]

23.  Secondary:   HPV-16 and HPV-18 Seroconversion (V5/J4 Monoclonal Inhibition Test)   [ Time Frame: Month 0, 7, 12 and 24 ]

24.  Secondary:   HPV-16 and HPV-18 Geometric Mean Titers (GMT) (V5/J4 Monoclonal Inhibition Test)   [ Time Frame: Month 0, 7, 12, 24 ]

25.  Secondary:   Number of Subjects Seropositive for Anti-HPV-16 and Anti-HPV-18 Antibodies Using Pseudovirion Based Neutralizing Assay (PBNA)   [ Time Frame: At Month 0, 7, 12, 24, 36 and 48 ]

26.  Secondary:   Titers for Anti-HPV-16 and Anti-HPV-18 Antibodies Using Pseudovirion Based Neutralizing Assay (PBNA)   [ Time Frame: At month 0, 7, 12, 24, 36 and 48 ]

27.  Secondary:   Geometric Mean Titers of Anti-HPV-16 in Subjects Without and With 6-month Persistent Infection   [ Time Frame: At Month 7 ]

28.  Secondary:   Number of Seroconverted Subjects for Anti-HPV-16 Without and With 6-month Persistent Infection   [ Time Frame: At Month 7 ]

29.  Secondary:   Geometric Mean Titers of Anti-HPV-16 in Subjects Without and With 12-month Persistent Infection   [ Time Frame: At Month 7 ]

30.  Secondary:   Number of Seroconverted Subjects for Anti-HPV-16 Without and With 12-month Persistent Infection   [ Time Frame: At Month 7 ]

31.  Secondary:   Geometric Mean Titers of Anti-HPV-18 in Subjects Without and With 6-month Persistent Infection   [ Time Frame: At Month 7 ]

32.  Secondary:   Number of Seroconverted Subjects for Anti-HPV-18 Without and With 6-month Persistent Infection   [ Time Frame: At Month 7 ]

33.  Secondary:   Geometric Mean Titers of Anti-HPV-18 in Subjects Without and With 12-month Persistent Infection   [ Time Frame: At Month 7 ]

34.  Secondary:   Number of Seroconverted Subjects for Anti-HPV-18 Without and With 12-month Persistent Infection   [ Time Frame: At Month 7 ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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