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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
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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 
Overall Participants Analyzed 
[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 ]

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 ]
  Hide Outcome Measure 21

Measure Type Secondary
Measure Title 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
Measure Description

Cut-off values assessed for seropositivity include 8 enzyme-linked immunosorbent assay units per milliliter (EL.U/mL) for anti-HPV-16 antibodies and 7 EL.U/mL for anti-HPV-18 antibodies.

Results are presented for the total group and stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus by ELISA - seronegative (sero-) or seropositive (sero+)

Time Frame At Months 6, 7, 12, 24, 36 & 48  
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.
The analyses were performed on the ATP cohort for immunogenicity on evaluable subjects for whom immunogenicity data were available.

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 
Participants Analyzed 
[Units: Participants]
 898   1036 
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 
[Units: Subjects]
   
HPV-16, sero-, pre-vaccination (n= 750, 872)   0   0 
HPV-16, sero-, Month 6 (n= 738, 865)   41   864 
HPV-16, sero-, Month 7 (n= 740, 865)   34   861 
HPV-16, sero-, Month 12 (n= 719, 839)   30   837 
HPV-16, sero-, Month 24 (n= 672, 797)   33   796 
HPV-16, sero-, Month 36 (n= 664, 784)   35   784 
HPV-16, sero-, Month 48 (n= 603, 746)   47   746 
HPV-16, sero+, pre-vaccination (n= 147, 164)   147   164 
HPV-16, sero+, Month 6 (n= 139, 162)   119   161 
HPV-16, sero+, Month 7 (n= 139, 163)   106   162 
HPV-16, sero+, Month 12 (n= 134, 154)   101   154 
HPV-16, sero+, Month 24 (n= 138, 146)   96   146 
HPV-16, sero+, Month 36 (n= 127, 142)   88   142 
HPV-16, sero+, Month 48 (n= 118, 145)   85   145 
HPV-16, total, pre-vaccination (n= 897, 1036)   147   164 
HPV-16, total, Month 6 (n= 877, 1027)   160   1025 
HPV-16, total, Month 7 (n= 879, 1028)   140   1023 
HPV-16, total, Month 12 (n= 853, 993)   131   991 
HPV-16, total, Month 24 (n= 810, 943)   129   942 
HPV-16, total, Month 36 (n= 791, 926)   123   926 
HPV-16, total, Month 48 (n= 721, 891)   132   891 
HPV-18, sero-, pre-vaccination (n= 790,939)   0   0 
HPV-18, sero-, Month 6 (n= 771, 930)   29   927 
HPV-18, sero-, Month 7 (n= 772, 930)   32   925 
HPV-18, sero-, Month 12 (n= 748, 901)   36   901 
HPV-18, sero-, Month 24 (n= 698, 854)   37   853 
HPV-18, sero-, Month 36 (n= 691, 841)   31   841 
HPV-18, sero-, Month 48 (n= 633, 806)   32   804 
HPV-18, sero+, pre-vaccination (n= 108, 97)   108   97 
HPV-18, sero+, Month 6 (n= 105, 97)   90   96 
HPV-18, sero+, Month 7 (n= 105, 97)   90   97 
HPV-18, sero+, Month 12 (n= 106, 92)   89   92 
HPV-18, sero+, Month 24 (n= 102, 89)   84   89 
HPV-18, sero+, Month 36 (n= 98, 86)   73   86 
HPV-18, sero+, Month 48 (n= 91, 86)   70   86 
HPV-18, total, pre-vaccination (n= 898, 1036)   108   97 
HPV-18, total, Month 6 (n= 876, 1027)   119   1023 
HPV-18, total, Month 7 (n= 877, 1027)   122   1022 
HPV-18, total, Month 12 (n= 854, 993)   125   993 
HPV-18, total, Month 24 (n= 800, 943)   121   942 
HPV-18, total, Month 36 (n= 789, 927)   104   927 
HPV-18, total, Month 48 (n= 724, 892)   102   890 

No statistical analysis provided for 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



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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