Vaccine To Prevent Cervical Intraepithelial Neoplasia or Cervical Cancer in Younger Healthy Participants

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00128661
First received: August 8, 2005
Last updated: May 24, 2012
Last verified: May 2012
Results First Received: December 15, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator, Outcomes Assessor);   Primary Purpose: Prevention
Conditions: Cervical Cancer
Precancerous Condition
Interventions: Biological: human papillomavirus 16/18 L1 virus-like particle/AS04 vaccine
Biological: hepatitis A inactivated virus vaccine

  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
Solicited symptoms were collected for 3730 and 3740 subjects instead of the 3727 and 3739 subjects who were randomized in the study in the Cervarix and the Havrix groups, respectively. These 4 sujects received both vaccines and were included in the denominator of both arm based on the actual vaccine type administered.

Reporting Groups
  Description
Cervarix Group Subjects received 3 doses of Cervarix vaccine at study Months 0, 1 and 6. All the vaccine doses were administered intramuscularly in the deltoid region of the non-dominant arm.
Havrix Group Subjects received 3 doses of Havrix vaccine at study Months 0, 1 and 6. All the vaccine doses were administered intramuscularly in the deltoid region of the non-dominant arm.

Participant Flow:   Overall Study
    Cervarix Group     Havrix Group  
STARTED     3727     3739  
COMPLETED     3453     3481  
NOT COMPLETED     274     258  
Adverse Event                 14                 11  
Lost to Follow-up                 10                 7  
Withdrawal by Subject                 243                 232  
Unspecified                 7                 8  



  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.
No text entered.

Reporting Groups
  Description
Cervarix Group Subjects received 3 doses of Cervarix vaccine at study Months 0, 1 and 6. All the vaccine doses were administered intramuscularly in the deltoid region of the non-dominant arm.
Havrix Group Subjects received 3 doses of Havrix vaccine at study Months 0, 1 and 6. All the vaccine doses were administered intramuscularly in the deltoid region of the non-dominant arm.
Total Total of all reporting groups

Baseline Measures
    Cervarix Group     Havrix Group     Total  
Number of Participants  
[units: participants]
  3727     3739     7466  
Age  
[units: Years]
Mean ± Standard Deviation
     
Years     21.1  ± 2.3     21.1  ± 2.3     21.1  ± 2.3  
Gender  
[units: Subjects]
     
Female     3727     3739     7466  
Male     0     0     0  



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Number of Histopathologically Confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Cases Associated With HPV16 and/or HPV18 Infection Detected in the Preceding Cervical Cytology Specimen.   [ Time Frame: From Month 6 up to Month 48 ]

2.  Secondary:   Number of Cervical Infection With HPV16 or HPV18.   [ Time Frame: From Month 6 up to Month 48 ]

3.  Secondary:   Number of Histopathologically Confirmed CIN2+ Cases Associated With Infection by Any Oncogenic HPV Type   [ Time Frame: From Month 6 up to Month 48 ]

4.  Secondary:   Number of Persistent Infection (12-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18 Cases   [ Time Frame: From Month 6 up to Month 48 ]
  Hide Outcome Measure 4

Measure Type Secondary
Measure Title Number of Persistent Infection (12-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18 Cases
Measure Description

Persistent incident HPV-16 and /or HPV-18 cervical infection had to fulfil the following criteria: first detection after the 6-month visit, 2 same type HPV positive (by PCR) test results 10+ months apart, and no intervening HPV negative tests for the corresponding type.

Persistent HPV16 or HPV18 cervical infection = detection of the same HPV type by polymerase chain reaction (PCR) in cervical samples from all consecutive evaluations over approximately 12 months.

Subjects were HPV deoxyribonucleic acid (DNA) negative (DNA-) at Month 0 and Month 6 for the corresponding HPV-type.

Time Frame From Month 6 up to Month 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 According-To-Protocol (ATP) cohort for efficacy included subjects with efficacy data available, who received 3 doses of vaccine, who were HPV DNA- for the corresponding type at enrollment and at the time of administration of the 3rd dose (Month 6) and who did not have a biopsy or treatment during the vaccination phase (prior to the Month 6).

Reporting Groups
  Description
Cervarix Group Subjects received 3 doses of Cervarix vaccine at study Months 0, 1 and 6. All the vaccine doses were administered intramuscularly in the deltoid region of the non-dominant arm.
Havrix Group Subjects received 3 doses of Havrix vaccine at study Months 0, 1 and 6. All the vaccine doses were administered intramuscularly in the deltoid region of the non-dominant arm.

Measured Values
    Cervarix Group     Havrix Group  
Number of Participants Analyzed  
[units: participants]
  2635     2677  
Number of Persistent Infection (12-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18 Cases  
[units: Events]
   
Persistent HPV16 Infection (N=2464,2452)     10     71  
Persistent HPV18 Infection (N=2567;2593)     0     37  
Persistent HPV16 and/or 18 Infection (N=2635;2677)     10     104  

No statistical analysis provided for Number of Persistent Infection (12-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18 Cases



5.  Secondary:   Geometric Mean Titers (GMTs) for HPV-16 Antibody in the Immunogenicity Subcohort.   [ Time Frame: Before vaccination and at Month 1, 6, 7, 12, 18, 24, 30, 36, 42 and 48 ]

6.  Secondary:   Geometric Mean Titers (GMTs) for HPV-18 Antibody in the Immunogenicity Subcohort   [ Time Frame: Before vaccination and at Month 1, 6, 7, 12, 18, 24, 30, 36, 42 and 48 ]

7.  Secondary:   HPV-16 Geometric Mean Titers (GMTs) (V5 Monoclonal Antibody Inhibition Test)   [ Time Frame: Before vaccination and at Month 1, 6, 7, 12, 18, 24, 30, 36, 42 and 48 ]

8.  Secondary:   HPV-18 Geometric Mean Titers (GMTs) (J4 Monoclonal Antibody Inhibition Test)   [ Time Frame: Before vaccination and at Month 1, 6, 7, 12, 18, 24, 30, 36, 42 and 48 ]

9.  Secondary:   Number of Subjects Reporting Any and Grade 3 Solicited Local Symptoms.   [ Time Frame: Within 60 minutes after vaccination ]

10.  Secondary:   Number of Subjects Reporting Any and Grade 3 Solicited General Symptoms.   [ Time Frame: Within 60 minutes after vaccination ]

11.  Secondary:   Number of Subjects Reporting Any and Grade 3 Solicited Local Symptoms on a 10% Random Subset of Participants.   [ Time Frame: From Day 3 to Day 6 after vaccination ]

12.  Secondary:   Number of Subjects Reporting Any and Grade 3 Solicited General Symptoms on a 10% Random Subset of Participants.   [ Time Frame: From Day 3 to Day 6 after vaccination ]

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

14.  Secondary:   Number of Subjects Reporting Unsolicited Adverse Events (AEs).   [ Time Frame: During the entire study period (From Month 0 up to Month 48). ]

15.  Secondary:   Number of Subjects With All Possible Pregnancy Outcomes   [ Time Frame: During the entire study period (From Month 0 up to Month 48). ]

16.  Secondary:   Number of Cervical Infection With HPV16 or HPV18.   [ Time Frame: During the first year of follow-up period ]

17.  Secondary:   Number of Cervical Infection With HPV16 or HPV18.   [ Time Frame: During the second year of follow-up period ]

18.  Secondary:   Number of Cervical Infection With HPV16 or HPV18.   [ Time Frame: During the third year of follow-up period ]

19.  Secondary:   Number of Cervical Infection With HPV16 or HPV18.   [ Time Frame: From the fourth year follow-up period ]

20.  Secondary:   Number of Subjects Reporting Unsolicited Adverse Events (AEs).   [ Time Frame: within 30 days (Days 0-29) after vaccination ]


  Serious Adverse Events
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Time Frame Solicited AEs: within 60 minutes after vaccination for all subjects; From Day 3 to Day 6 post-vaccination in the subset. SAEs: From Month 0 up to Month 48. Unsolicited AEs: From Month 0 up to Month 48 and Within 30 days (Days 0-29) after vaccination
Additional Description Solicited AEs were collected and tabulated for all subjects and for a 10% random subset of participants.

Reporting Groups
  Description
Cervarix Group Subjects received 3 doses of Cervarix vaccine at study Months 0, 1 and 6. All the vaccine doses were administered intramuscularly in the deltoid region of the non-dominant arm.
Havrix Group Subjects received 3 doses of Havrix vaccine at study Months 0, 1 and 6. All the vaccine doses were administered intramuscularly in the deltoid region of the non-dominant arm.

Serious Adverse Events
    Cervarix Group     Havrix Group  
Total, serious adverse events      
# participants affected / at risk     912/3727 (24.47%)     891/3739 (23.83%)  
Blood and lymphatic system disorders      
Anaemia of pregnancy *    
# participants affected / at risk     24/3727 (0.64%)     22/3739 (0.59%)  
Lymphadenitis *    
# participants affected / at risk     2/3727 (0.05%)     1/3739 (0.03%)  
Blood disorder *    
# participants affected / at risk     1/3727 (0.03%)     1/3739 (0.03%)  
Anaemia *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Anaemia haemolytic autoimmune *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Haemorrhagic anaemia *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Haemorrhagic disorder *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Thrombocytopenia *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Cardiac disorders      
Cardiovascular disorder *    
# participants affected / at risk     5/3727 (0.13%)     0/3739 (0.00%)  
Acute myocardial infarction *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Congestive cardiomyopathy *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Congenital, familial and genetic disorders      
Congenital flat feet *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Multiple congenital abnormalities *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Endocrine disorders      
Hyperthyroidism *    
# participants affected / at risk     2/3727 (0.05%)     1/3739 (0.03%)  
Eye disorders      
Eye degenerative disorder *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Retinal disorder *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Strabismus *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Ulcerative keratitis *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Gastrointestinal disorders      
Gastrointestinal disorder *    
# participants affected / at risk     9/3727 (0.24%)     9/3739 (0.24%)  
Pancreatitis acute *    
# participants affected / at risk     6/3727 (0.16%)     5/3739 (0.13%)  
Abdominal pain *    
# participants affected / at risk     6/3727 (0.16%)     3/3739 (0.08%)  
Irritable bowel syndrome *    
# participants affected / at risk     1/3727 (0.03%)     4/3739 (0.11%)  
Colitis ulcerative *    
# participants affected / at risk     2/3727 (0.05%)     1/3739 (0.03%)  
Appendix disorder *    
# participants affected / at risk     2/3727 (0.05%)     0/3739 (0.00%)  
Constipation *    
# participants affected / at risk     1/3727 (0.03%)     1/3739 (0.03%)  
Gastrointestinal inflammation *    
# participants affected / at risk     1/3727 (0.03%)     1/3739 (0.03%)  
Abdominal mass *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Abdominal pain lower *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Abdominal pain upper *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Crohn’s disease *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Duodenal ulcer haemorrhage *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Femoral hernia *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Gastritis *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Gastrointestinal haemorrhage *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Ileus paralytic *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Intestinal obstruction *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Pancreatitis chronic *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Peritoneal adhesions *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Peritoneal disorder *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Tooth ankylosis *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Tooth development disorder *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Tooth malformation *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
General disorders      
Pyrexia *    
# participants affected / at risk     5/3727 (0.13%)     1/3739 (0.03%)  
Eye complication associated with device *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Gait disturbance *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Hepatobiliary disorders      
Cholecystitis *    
# participants affected / at risk     26/3727 (0.70%)     19/3739 (0.51%)  
Cholelithiasis *    
# participants affected / at risk     22/3727 (0.59%)     9/3739 (0.24%)  
Liver disorder *    
# participants affected / at risk     0/3727 (0.00%)     3/3739 (0.08%)  
Bile duct stone *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Biliary cirrhosis *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Biliary tract disorder *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Immune system disorders      
Anaphylactic shock *    
# participants affected / at risk     0/3727 (0.00%)     2/3739 (0.05%)  
Rhesus incompatibility *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Infections and infestations      
Dengue fever *    
# participants affected / at risk     38/3727 (1.02%)     48/3739 (1.28%)  
Urinary tract infection *    
# participants affected / at risk     25/3727 (0.67%)     24/3739 (0.64%)  
Appendicitis *    
# participants affected / at risk     17/3727 (0.46%)     18/3739 (0.48%)  
Postoperative wound infection *    
# participants affected / at risk     12/3727 (0.32%)     12/3739 (0.32%)  
Postpartum sepsis *    
# participants affected / at risk     12/3727 (0.32%)     8/3739 (0.21%)  
Subcutaneous abscess *    
# participants affected / at risk     5/3727 (0.13%)     5/3739 (0.13%)  
Infectious peritonitis *    
# participants affected / at risk     6/3727 (0.16%)     2/3739 (0.05%)  
Pelvic inflammatory disease *    
# participants affected / at risk     3/3727 (0.08%)     3/3739 (0.08%)  
Cellulitis *    
# participants affected / at risk     1/3727 (0.03%)     4/3739 (0.11%)  
Salpingitis *    
# participants affected / at risk     3/3727 (0.08%)     2/3739 (0.05%)  
Staphylococcal infection *    
# participants affected / at risk     3/3727 (0.08%)     2/3739 (0.05%)  
Bronchopneumonia *    
# participants affected / at risk     1/3727 (0.03%)     3/3739 (0.08%)  
Viral infection *    
# participants affected / at risk     1/3727 (0.03%)     3/3739 (0.08%)  
Amniotic cavity infection *    
# participants affected / at risk     1/3727 (0.03%)     2/3739 (0.05%)  
Bartholin’s abscess *    
# participants affected / at risk     2/3727 (0.05%)     1/3739 (0.03%)  
Bronchitis *    
# participants affected / at risk     2/3727 (0.05%)     1/3739 (0.03%)  
Sexually transmitted disease *    
# participants affected / at risk     1/3727 (0.03%)     2/3739 (0.05%)  
HIV infection *    
# participants affected / at risk     1/3727 (0.03%)     1/3739 (0.03%)  
Otitis externa *    
# participants affected / at risk     2/3727 (0.05%)     0/3739 (0.00%)  
Parametritis *    
# participants affected / at risk     1/3727 (0.03%)     1/3739 (0.03%)  
Pneumonia *    
# participants affected / at risk     2/3727 (0.05%)     0/3739 (0.00%)  
Tooth abscess *    
# participants affected / at risk     2/3727 (0.05%)     0/3739 (0.00%)  
Vaginal infection *    
# participants affected / at risk     1/3727 (0.03%)     1/3739 (0.03%)  
Anal abscess *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Breast abscess *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Candida sepsis *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Chronic sinusitis *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Genital herpes *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Genitourinary tract infection *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Malaria *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Mastitis postpartum *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Meningitis viral *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Otitis media *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Pilonidal cyst *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Pneumonia viral *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Post procedural infection *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Pyoderma *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Skin infection *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Syphilis *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Varicella *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Vulval abscess *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Injury, poisoning and procedural complications      
Multiple injuries *    
# participants affected / at risk     3/3727 (0.08%)     10/3739 (0.27%)  
Injury *    
# participants affected / at risk     2/3727 (0.05%)     5/3739 (0.13%)  
Postoperative wound complication *    
# participants affected / at risk     4/3727 (0.11%)     3/3739 (0.08%)  
Concussion *    
# participants affected / at risk     2/3727 (0.05%)     3/3739 (0.08%)  
Lower limb fracture *    
# participants affected / at risk     2/3727 (0.05%)     2/3739 (0.05%)  
Open wound *    
# participants affected / at risk     3/3727 (0.08%)     1/3739 (0.03%)  
Humerus fracture *    
# participants affected / at risk     3/3727 (0.08%)     0/3739 (0.00%)  
Toxicity to various agents *    
# participants affected / at risk     2/3727 (0.05%)     1/3739 (0.03%)  
Lumbar vertebral fracture *    
# participants affected / at risk     1/3727 (0.03%)     1/3739 (0.03%)  
Multiple fractures *    
# participants affected / at risk     2/3727 (0.05%)     0/3739 (0.00%)  
Post procedural complication *    
# participants affected / at risk     0/3727 (0.00%)     2/3739 (0.05%)  
Road traffic accident *    
# participants affected / at risk     1/3727 (0.03%)     1/3739 (0.03%)  
Thermal burn *    
# participants affected / at risk     2/3727 (0.05%)     0/3739 (0.00%)  
Ulna fracture *    
# participants affected / at risk     1/3727 (0.03%)     1/3739 (0.03%)  
Venom poisoning *    
# participants affected / at risk     0/3727 (0.00%)     2/3739 (0.05%)  
Chemical poisoning *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Contusion *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Facial bones fracture *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Femoral neck fracture *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Foot fracture *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Foreign body *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Jaw fracture *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Muscle injury *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Muscle strain *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Radius fracture *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Tendon injury *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Tibia fracture *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Investigations      
Medical observation *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Metabolism and nutrition disorders      
Gestational diabetes *    
# participants affected / at risk     5/3727 (0.13%)     6/3739 (0.16%)  
Type 2 diabetes mellitus *    
# participants affected / at risk     3/3727 (0.08%)     1/3739 (0.03%)  
Diabetic ketoacidosis *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Hypokalaemia *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Musculoskeletal and connective tissue disorders      
Rheumatoid arthritis *    
# participants affected / at risk     1/3727 (0.03%)     1/3739 (0.03%)  
Systemic lupus erythematosus *    
# participants affected / at risk     2/3727 (0.05%)     0/3739 (0.00%)  
Back pain *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Intervertebral disc displacement *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Musculoskeletal pain *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Myalgia *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Tenosynovitis *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)      
Benign ovarian tumour *    
# participants affected / at risk     11/3727 (0.30%)     7/3739 (0.19%)  
Thyroid cancer *    
# participants affected / at risk     1/3727 (0.03%)     3/3739 (0.08%)  
Ovarian cancer *    
# participants affected / at risk     2/3727 (0.05%)     1/3739 (0.03%)  
Uterine leiomyoma *    
# participants affected / at risk     2/3727 (0.05%)     1/3739 (0.03%)  
Benign hydatidiform mole *    
# participants affected / at risk     1/3727 (0.03%)     1/3739 (0.03%)  
Colon neoplasm *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Nasal sinus cancer *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Non-Hodgkin’s lymphoma *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Placental neoplasm *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Vulval neoplasm *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Nervous system disorders      
Migraine *    
# participants affected / at risk     2/3727 (0.05%)     1/3739 (0.03%)  
Convulsion *    
# participants affected / at risk     1/3727 (0.03%)     1/3739 (0.03%)  
Nervous system disorder *    
# participants affected / at risk     0/3727 (0.00%)     2/3739 (0.05%)  
Tension headache *    
# participants affected / at risk     1/3727 (0.03%)     1/3739 (0.03%)  
Autonomic nervous system imbalance *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Complicated migraine *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Epilepsy *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Headache *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Hydrocephalus *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Intracranial hypotension *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Vascular headache *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Pregnancy, puerperium and perinatal conditions      
Abortion spontaneous incomplete *    
# participants affected / at risk     134/3727 (3.60%)     108/3739 (2.89%)  
False labour *    
# participants affected / at risk     66/3727 (1.77%)     88/3739 (2.35%)  
Abortion spontaneous complete *    
# participants affected / at risk     64/3727 (1.72%)     64/3739 (1.71%)  
Abortion missed *    
# participants affected / at risk     59/3727 (1.58%)     63/3739 (1.68%)  
Foetal distress syndrome *    
# participants affected / at risk     57/3727 (1.53%)     64/3739 (1.71%)  
Uterine hypotonus *    
# participants affected / at risk     54/3727 (1.45%)     54/3739 (1.44%)  
Gestational hypertension *    
# participants affected / at risk     39/3727 (1.05%)     53/3739 (1.42%)  
Abortion threatened *    
# participants affected / at risk     42/3727 (1.13%)     37/3739 (0.99%)  
Cephalo-pelvic disproportion *    
# participants affected / at risk     33/3727 (0.89%)     45/3739 (1.20%)  
Breech presentation *    
# participants affected / at risk     40/3727 (1.07%)     33/3739 (0.88%)  
Pre-eclampsia *    
# participants affected / at risk     18/3727 (0.48%)     23/3739 (0.62%)  
Failed induction of labour *    
# participants affected / at risk     19/3727 (0.51%)     20/3739 (0.53%)  
Complication of pregnancy *    
# participants affected / at risk     18/3727 (0.48%)     19/3739 (0.51%)  
Intra-uterine death *    
# participants affected / at risk     16/3727 (0.43%)     18/3739 (0.48%)  
Foetal growth restriction *    
# participants affected / at risk     18/3727 (0.48%)     14/3739 (0.37%)  
Premature rupture of membranes *    
# participants affected / at risk     11/3727 (0.30%)     19/3739 (0.51%)  
Obstructed labour *    
# participants affected / at risk     13/3727 (0.35%)     15/3739 (0.40%)  
Abnormal product of conception *    
# participants affected / at risk     14/3727 (0.38%)     11/3739 (0.29%)  
Ectopic pregnancy *    
# participants affected / at risk     9/3727 (0.24%)     14/3739 (0.37%)  
Postpartum haemorrhage *    
# participants affected / at risk     13/3727 (0.35%)     7/3739 (0.19%)  
Oligohydramnios *    
# participants affected / at risk     11/3727 (0.30%)     8/3739 (0.21%)  
Premature separation of placenta *    
# participants affected / at risk     5/3727 (0.13%)     10/3739 (0.27%)  
Hyperemesis gravidarum *    
# participants affected / at risk     6/3727 (0.16%)     8/3739 (0.21%)  
Multiple pregnancy *    
# participants affected / at risk     8/3727 (0.21%)     2/3739 (0.05%)  
Placenta praevia haemorrhage *    
# participants affected / at risk     6/3727 (0.16%)     4/3739 (0.11%)  
Foetal disorder *    
# participants affected / at risk     7/3727 (0.19%)     2/3739 (0.05%)  
Large for dates baby *    
# participants affected / at risk     4/3727 (0.11%)     4/3739 (0.11%)  
Premature delivery *    
# participants affected / at risk     5/3727 (0.13%)     2/3739 (0.05%)  
Premature labour *    
# participants affected / at risk     2/3727 (0.05%)     4/3739 (0.11%)  
Transverse presentation *    
# participants affected / at risk     3/3727 (0.08%)     3/3739 (0.08%)  
Abortion incomplete *    
# participants affected / at risk     4/3727 (0.11%)     1/3739 (0.03%)  
Umbilical cord abnormality *    
# participants affected / at risk     3/3727 (0.08%)     2/3739 (0.05%)  
Eclampsia *    
# participants affected / at risk     1/3727 (0.03%)     3/3739 (0.08%)  
Retained placenta or membranes *    
# participants affected / at risk     4/3727 (0.11%)     0/3739 (0.00%)  
Abortion complicated *    
# participants affected / at risk     3/3727 (0.08%)     0/3739 (0.00%)  
Foetal malpresentation *    
# participants affected / at risk     0/3727 (0.00%)     3/3739 (0.08%)  
Placenta praevia *    
# participants affected / at risk     2/3727 (0.05%)     1/3739 (0.03%)  
Polyhydramnios *    
# participants affected / at risk     1/3727 (0.03%)     1/3739 (0.03%)  
Traumatic delivery *    
# participants affected / at risk     1/3727 (0.03%)     1/3739 (0.03%)  
Umbilical cord prolapse *    
# participants affected / at risk     2/3727 (0.05%)     0/3739 (0.00%)  
Abortion incomplete complicated *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Abortion spontaneous incomplete complicated *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Foetal malposition *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Intrapartum haemorrhage *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Pelvic haematoma obstetric *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Placental disorder *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Post abortion haemorrhage *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Postpartum disorder *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Previous caesarean section *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Prolonged labour *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Prolonged pregnancy *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Twin pregnancy *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Uterine inversion *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Psychiatric disorders      
Intentional self-injury *    
# participants affected / at risk     20/3727 (0.54%)     17/3739 (0.45%)  
Depression *    
# participants affected / at risk     5/3727 (0.13%)     3/3739 (0.08%)  
Mental disorder *    
# participants affected / at risk     5/3727 (0.13%)     3/3739 (0.08%)  
Post-traumatic stress disorder *    
# participants affected / at risk     1/3727 (0.03%)     1/3739 (0.03%)  
Acute psychosis *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Drug dependence *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Emotional disorder *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Psychotic disorder *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Renal and urinary disorders      
Calculus urinary *    
# participants affected / at risk     1/3727 (0.03%)     2/3739 (0.05%)  
Tubulointerstitial nephritis *    
# participants affected / at risk     2/3727 (0.05%)     1/3739 (0.03%)  
Nephrolithiasis *    
# participants affected / at risk     2/3727 (0.05%)     0/3739 (0.00%)  
Proteinuria *    
# participants affected / at risk     2/3727 (0.05%)     0/3739 (0.00%)  
Calculus ureteric *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Haematuria *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Reproductive system and breast disorders      
Ovarian cyst *    
# participants affected / at risk     5/3727 (0.13%)     6/3739 (0.16%)  
Uterine haemorrhage *    
# participants affected / at risk     5/3727 (0.13%)     5/3739 (0.13%)  
Menometrorrhagia *    
# participants affected / at risk     5/3727 (0.13%)     2/3739 (0.05%)  
Vaginal haemorrhage *    
# participants affected / at risk     3/3727 (0.08%)     4/3739 (0.11%)  
Breast inflammation *    
# participants affected / at risk     2/3727 (0.05%)     2/3739 (0.05%)  
Endometriosis *    
# participants affected / at risk     2/3727 (0.05%)     2/3739 (0.05%)  
Pelvic pain *    
# participants affected / at risk     1/3727 (0.03%)     3/3739 (0.08%)  
Perineal pain *    
# participants affected / at risk     1/3727 (0.03%)     3/3739 (0.08%)  
Genital disorder female *    
# participants affected / at risk     1/3727 (0.03%)     2/3739 (0.05%)  
Menstruation irregular *    
# participants affected / at risk     1/3727 (0.03%)     2/3739 (0.05%)  
Bartholin’s cyst *    
# participants affected / at risk     1/3727 (0.03%)     1/3739 (0.03%)  
Cervix disorder *    
# participants affected / at risk     2/3727 (0.05%)     0/3739 (0.00%)  
Uterine polyp *    
# participants affected / at risk     1/3727 (0.03%)     1/3739 (0.03%)  
Amenorrhoea *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Breast disorder *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Breast enlargement *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Cervical dysplasia *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Haematocolpos *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Haematosalpinx *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Ovarian torsion *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Ovulation pain *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Polycystic ovaries *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Polymenorrhagia *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Respiratory, thoracic and mediastinal disorders      
Respiratory disorder *    
# participants affected / at risk     5/3727 (0.13%)     2/3739 (0.05%)  
Asthma *    
# participants affected / at risk     2/3727 (0.05%)     0/3739 (0.00%)  
Status asthmaticus *    
# participants affected / at risk     2/3727 (0.05%)     0/3739 (0.00%)  
Bronchitis chronic *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Dyspnoea *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Neonatal respiratory failure *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Pleural effusion *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Skin and subcutaneous tissue disorders      
Urticaria *    
# participants affected / at risk     0/3727 (0.00%)     2/3739 (0.05%)  
Granuloma skin *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Skin disorder *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Toxic skin eruption *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Social circumstances      
Physical assault *    
# participants affected / at risk     3/3727 (0.08%)     0/3739 (0.00%)  
Sexual abuse *    
# participants affected / at risk     1/3727 (0.03%)     0/3739 (0.00%)  
Surgical and medical procedures      
Caesarean section *    
# participants affected / at risk     56/3727 (1.50%)     59/3739 (1.58%)  
Therapeutic procedure *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Vascular disorders      
Hypertension *    
# participants affected / at risk     5/3727 (0.13%)     6/3739 (0.16%)  
Essential hypertension *    
# participants affected / at risk     4/3727 (0.11%)     1/3739 (0.03%)  
Circulatory collapse *    
# participants affected / at risk     2/3727 (0.05%)     1/3739 (0.03%)  
Phlebitis *    
# participants affected / at risk     0/3727 (0.00%)     2/3739 (0.05%)  
Varicose vein *    
# participants affected / at risk     0/3727 (0.00%)     2/3739 (0.05%)  
Embolism venous *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
Varicophlebitis *    
# participants affected / at risk     0/3727 (0.00%)     1/3739 (0.03%)  
* Events were collected by non-systematic assessment




  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

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
The following analysis "occurence of histopathologically confirmed CIN2+ cases associated with HPV16 or HPV18 infection was not performed, in accordance with the Statistical Analysis Plan submitted to the FDA.


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