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

Study Overview
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Brief Summary
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RATIONALE: Chemoprevention is the use of certain drugs to keep cancer form forming, growing, or coming back. Vaccines may help the body build an effective immune response against human papillomavirus and may be effective in preventing cervical intraepithelial neoplasia or cervical cancer. It is not yet known whether human papillomavirus vaccine is more effective than hepatitis A vaccine in preventing cervical intraepithelial neoplasia or cervical cancer. PURPOSE: This randomized phase III trial is studying human papillomavirus vaccine to see how well it works compared to hepatitis A vaccine in preventing cervical intraepithelial neoplasia or cervical cancer in younger healthy participants.

Detailed Description
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OBJECTIVES: Primary •Demonstrate the efficacy of the candidate vaccine, human papillomavirus 16/18 (HPV 16/18) L1 virus-like particle (VLP)/AS04 vaccine compared with control in preventing grade 2 or 3 cervical intraepithelial neoplasia, adenocarcinoma in situ of the cervix, or invasive cervical cancer (CIN2+) associated with HPV 16 or HPV 18 cervical infection in younger healthy participants who are negative for HPV DNA by polymerase chain reaction (PCR) for the corresponding HPV type at months 0 and 6. Secondary Determine the duration of protection against HPV 16 or HPV 18 cervical infection in participants treated with the HPV 16/18 L1 VLP/AS04 vaccine. Determine the safety of this vaccine in these participants, regardless of their initial HPV 16/18 DNA status. Evaluate the efficacy of the candidate vaccine, HPV 16/18 L1 VLP/AS04 vaccine compared with control in preventing CIN2+ associated with any oncogenic HPV type cervical infection in participants who are negative for HPV DNA by PCR for the corresponding HPV type at months 0 and 6. Compare the efficacy of the candidate vaccine with control in preventing CIN2+ associated with HPV 16 or HPV 18 cervical infection, detected within the lesional component of the cervical tissue specimen by PCR, in participants who are negative for HPV DNA by PCR for the corresponding HPV type at months 0 and 6 and by enzyme-linked immunosorbent assay (ELISA) at month 0. Compare the efficacy of the candidate vaccine with control in preventing persistent HPV 16 or HPV 18 cervical infection in these participants. Determine the immunogenicity of HPV 16/18 L1 VLP/AS04 vaccine by ELISA and V5/J4 monoclonal antibody inhibition enzyme immunoassay in the first 600 participants randomized to receive HPV 16/18 L1 VLP/AS04 vaccine. OUTLINE: This is a randomized, controlled, double-blind, parallel-group study. Participants are randomized to 1 of 2 treatment arms. Arm I: Participants receive human papillomavirus 16/18 L1 virus-like particle/AS04 vaccine intramuscularly (IM) once in months 0, 1, and 6. Arm II: Participants receive hepatitis A vaccine (Havrix®) IM once in months 0, 1, and 6. After completion of study treatment, participants are followed at 6 months and then at least annually for 3 years. PROJECTED ACCRUAL: Approximately 7,500 participants will be accrued for this study.

Official Title
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A Double-Blind, Controlled, Randomized, Phase III Study of the Efficacy of an HPV16/18 VLP Vaccine in the Prevention of Advanced Cervical Intraepithelial Neoplasia (CIN2, CIN3, Adenocarcinoma In Situ [AIS] and Invasive Cervical Cancer) Associated With HPV 16 or HPV 18 Cervical Infection in Healthy Young Adult Women in Costa Rica.

Conditions
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Cervical Cancer, Precancerous Condition

Intervention / Treatment
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* Biological: human papillomavirus 16/18 L1 virus-like particle/AS04 vaccine
* Biological: hepatitis A inactivated virus vaccine


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: •Healthy participants Deemed to be in good general health by history and physical examination •Resident of Guanacaste Province of Costa Rica and surrounding areas Must remain a resident for ≥ 6 months after the first study vaccination PATIENT CHARACTERISTICS: Age 18 to 25 Performance status •Not specified Life expectancy •Not specified Hematopoietic •Not specified Hepatic No history of chronic hepatitis requiring treatment No acute or chronic clinically significant hepatic function abnormality by physical examination or laboratory findings No known history of hepatitis A infection Renal No history of kidney disease requiring treatment No acute or chronic clinically significant kidney function abnormality by physical examination or laboratory findings Cardiovascular No acute or chronic clinically significant cardiovascular function abnormality by physical examination or laboratory findings Pulmonary No acute or chronic clinically significant pulmonary function abnormality by physical examination or laboratory findings Immunology No history of allergic disease No history of autoimmune disorder requiring treatment No history of allergic reaction (e.g., difficulty breathing) to any vaccine No suspected allergy or reaction likely to be exacerbated by a component of the study vaccines (e.g., 2-phenoxyethanol or neomycin) No hypersensitivity to latex No diagnosis or suspicion of any immunodeficient condition by medical history or physical examination Other Not pregnant or nursing ◦No delivery within the past 3 months Negative pregnancy test Fertile patients must use effective contraception for 30 days before, during, and for 60 days after completion of study treatment Able to speak or understand Spanish Mentally competent Able to undergo pelvic exam (i.e., no heavy bleeding [menstruation or otherwise] or heavy vaginal discharge) No history of cancer requiring treatment No history of diabetes requiring treatment No history of other chronic conditions requiring treatment No acute or chronic clinically significant neurologic function abnormality by physical examination or laboratory findings No other acute disease No fever ≥ 37.5º C PRIOR CONCURRENT THERAPY: Biologic therapy More than 6 months since prior chronic administration (i.e., > 14 days) of immune-modulating drugs More than 90 days since prior immunoglobulins More than 30 days since prior and no other concurrent investigational or non-registered vaccines More than 30 days since prior registered vaccines More than 8 days since prior routine meningococcal, hepatitis B, influenza, or diphtheria/tetanus vaccine No prior vaccination against hepatitis A No prior vaccination against human papillomavirus No prior monophosphoryl lipid A or AS04 adjuvant Chemotherapy •Not specified Endocrine therapy More than 6 months since prior chronic administration (i.e., > 14 days) of corticosteroids (e.g., ≥ 0.5 mg/kg/day of prednisone or equivalent) Concurrent inhaled or topical steroids allowed Radiotherapy •Not specified Surgery •No prior hysterectomy Other More than 6 months since prior chronic administration (i.e., > 14 days) of immunosuppressants More than 30 days since prior and no other concurrent investigational or non-registered drugs

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 25 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cervarix Group<br>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. | Biological: human papillomavirus 16/18 L1 virus-like particle/AS04 vaccine<br>* Three doses of Cervarix vaccine administered on a 0, 1, 6-month schedule<br>|
| Active Comparator: Havrix Group<br>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. | Biological: hepatitis A inactivated virus vaccine<br>* Three doses of Havrix vaccine administered on a 0, 1, 6-month schedule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Histopathologically Confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Cases Associated With HPV16 and/or HPV18 Infection Detected in the Preceding Cervical Cytology Specimen. | CIN2+ was defined as CIN grade 2 (CIN2), CIN grade 3 (CIN3), adenocarcinoma in situ (AIS) or invasive cervical cancer. Preceding cervical cytology means the last cervical cytology specimen collected before the histopathology specimen was obtained. Subjects were human papillomavirus (HPV) deoxyribonucleic acid (DNA) negative (DNA-) by polymerase chain reaction (PCR) at Month 0 and Month 6 for the corresponding HPV-type. | From Month 6 up to Month 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Cervical Infection With HPV16 or HPV18. | Subjects were human papillomavirus (HPV) deoxyribonucleic acid (DNA) negative (DNA-) (by PCR) at Month 0 and Month 6 for the corresponding HPV-type | From Month 6 up to Month 48 | 
| Number of Histopathologically Confirmed CIN2+ Cases Associated With Infection by Any Oncogenic HPV Type | Oncogenic HPV types included HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68 detected by polymerase chain reaction (PRC) in the preceding cervical cytology specimen. Note: The assay did not distinguish between HPV types 68 and 73. CIN2+ was defined as CIN grade 2 (CIN2), CIN grade 3 (CIN3), adenocarcinoma in situ (AIS) or invasive cervical cancer Subjects were human papillomavirus (HPV) deoxyribonucleic acid (DNA) negative (DNA-) (by PCR) at Month 0 and Month 6 for the corresponding HPV-type | From Month 6 up to Month 48 | 
| Number of Persistent Infection (12-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18 Cases | 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. | From Month 6 up to Month 48 | 
| Geometric Mean Titers (GMTs) for HPV-16 Antibody in the Immunogenicity Subcohort. | Titers were assessed for the 600 subjects enrolled into the immunogenicity subcohort by Enzyme linked immunosorbent assay (ELISA) and expressed as geometric mean titers (GMTs). Seronegative subjects = antibody concentration below 8 ELISA Units per millilitre (EL.U/mL) prior to vaccination. Seropositive subjects=antibody concentration equal to or above 8 EL.U/mL prior to vaccination. Immunogenicity subcohort = subset of 600 subjects from the 2 groups of the ATP cohort: subjects attended 1 extra clinic visit approximately 1 month (30 to 60 days) after the last dose was administered (Month 7) | Before vaccination and at Month 1, 6, 7, 12, 18, 24, 30, 36, 42 and 48 | 
| Geometric Mean Titers (GMTs) for HPV-18 Antibody in the Immunogenicity Subcohort | Titers were assessed for the 600 subjects enrolled into the immunogenicity subcohortby Enzyme linked immunosorbent assay (ELISA) and expressed as geometric mean titers (GMTs). Seronegative (Sero-) subjects=antibody concentration below 7 EL.U/mL prior to vaccination. Seropositive (Sero+) subjects=antibody concentration equal to or above 7 EL.U/mL prior to vaccination. Immunogenicity subcohort=subset of 600 subjects from the 2 groups of the ATP cohort: subjects attended 1 extra clinic visit approximately 1 month (30 to 60 days) after the last dose was administered (Month 7). | Before vaccination and at Month 1, 6, 7, 12, 18, 24, 30, 36, 42 and 48 | 
| HPV-16 Geometric Mean Titers (GMTs) (V5 Monoclonal Antibody Inhibition Test) | Titers were assessed for the 600 subjects enrolled into the immunogenicity subcohort by Inhibition Enzyme Immunoassay (EIA) and expressed as geometric mean antibody titers (GMTs). Seronegative (Sero-) subjects=antibody concentration below 41 EL.U/mL prior to vaccination. Seropositive (Sero+) subjects=antibody concentration equal to or above 41 EL.U/mL prior to vaccination. Immunogenicity subcohort=subset of 600 subjects from the 2 groups of the ATP cohort: subjects attended 1 extra clinic visit approximately 1 month (30 to 60 days) after the last dose was administered (Month 7). | Before vaccination and at Month 1, 6, 7, 12, 18, 24, 30, 36, 42 and 48 | 
| HPV-18 Geometric Mean Titers (GMTs) (J4 Monoclonal Antibody Inhibition Test) | Titers were assessed for the 600 subjects enrolled into the immunogenicity subcohort by Inhibition Enzyme Immunoassay (EIA) and expressed as geometric mean antibody titers (GMTs). Seronegative (Sero-) subjects=antibody concentration below 110 EL.U/mL prior to vaccination. Seropositive (Sero+) subjects=antibody concentration equal to or above 110 EL.U/mL prior to vaccination. Immunogenicity subcohort=subset of 600 subjects from the 2 groups of the ATP cohort: subjects attended 1 extra clinic visit approximately 1 month (30 to 60 days) after the last dose was administered (Month 7). | Before vaccination and at Month 1, 6, 7, 12, 18, 24, 30, 36, 42 and 48 | 
| Number of Subjects Reporting Any and Grade 3 Solicited Local Symptoms. | Solicited local symptoms assessed were pain, redness and swelling. Any was defined as any solicited local symptom reported irrespective of intensity. Grade 3 pain was defined as pain that prevented normal everyday activities as assessed by inability to attend work or school and which necessitated the administration of corrective therapy. Grade 3 redness and swelling was defined as redness/swelling above 50 millimeter (mm). | Within 60 minutes after vaccination | 
| Number of Subjects Reporting Any and Grade 3 Solicited General Symptoms. | Solicited general symptoms assessed were arthralgia, fatigue, gastrointestinal, headache, myalgia, rash, urticaria and fever (Fever = oral temperature equal to or above (≥) 37.5 degrees Celsius (°C)). Any = any solicited general symptom reported irrespective of intensity and relationship to vaccination. Grade 3 symptoms = symptoms that prevented normal everyday activities as assessed by inability to attend work or school and which necessitated the administration of corrective therapy.Grade 3 urticaria = urticaria distributed on at least 4 body areas. Grade 3 fever = oral temperature > 39.0°C. | Within 60 minutes after vaccination | 
| Number of Subjects Reporting Any and Grade 3 Solicited Local Symptoms on a 10% Random Subset of Participants. | Solicited local symptoms assessed were pain, redness and swelling. Any was defined as any solicited local symptom reported irrespective of intensity. Grade 3 pain was defined as pain that prevented normal everyday activities as assessed by inability to attend work or school and which necessitated the administration of corrective therapy. Grade 3 redness and swelling was defined as redness/swelling above 50 millimeter (mm). | From Day 3 to Day 6 after vaccination | 
| Number of Subjects Reporting Any and Grade 3 Solicited General Symptoms on a 10% Random Subset of Participants. | Solicited general symptoms assessed were arthralgia, fatigue, gastrointestinal, headache, myalgia, rash, urticaria and fever (Fever = oral temperature equal to or above (≥) 37.5 degrees Celsius (°C)). Any = any solicited general symptom reported irrespective of intensity and relationship to vaccination. Grade 3 symptoms = symptoms that prevented normal everyday activities as assessed by inability to attend work or school and which necessitated the administration of corrective therapy.Grade 3 urticaria = urticaria distributed on at least 4 body areas. Grade 3 fever = oral temperature > 39.0°C. | From Day 3 to Day 6 after vaccination | 
| Number of Subjects Reporting Serious Adverse Events (SAEs). | SAEs assessed include medical occurrences that results in death, are life threatening, require hospitalization or prolongation of hospitalization, results in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subjects. | During the entire study period (From Month 0 up to Month 48). | 
| Number of Subjects Reporting Unsolicited Adverse Events (AEs). | An unsolicited adverse event is any adverse event (i.e. any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product) reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. | During the entire study period (From Month 0 up to Month 48). | 
| Number of Subjects With All Possible Pregnancy Outcomes | The range of possible pregnancy outcomes was: Pregnancy loss, Pregnancy resolved alive, and Unresolved pregnancy. | During the entire study period (From Month 0 up to Month 48). | 
| Number of Cervical Infection With HPV16 or HPV18. | Subjects were human papillomavirus (HPV) deoxyribonucleic acid (DNA) negative (DNA-) (by PCR) at Month 0 and Month 6 for the corresponding HPV-type | During the first year of follow-up period | 
| Number of Cervical Infection With HPV16 or HPV18. | Subjects were human papillomavirus (HPV) deoxyribonucleic acid (DNA) negative (DNA-) (by PCR) at Month 0 and Month 6 for the corresponding HPV-type | During the second year of follow-up period | 
| Number of Cervical Infection With HPV16 or HPV18. | Subjects were human papillomavirus (HPV) deoxyribonucleic acid (DNA) negative (DNA-) (by PCR) at Month 0 and Month 6 for the corresponding HPV-type | During the third year of follow-up period | 
| Number of Cervical Infection With HPV16 or HPV18. | Subjects were human papillomavirus (HPV) deoxyribonucleic acid (DNA) negative (DNA-) (by PCR) at Month 0 and Month 6 for the corresponding HPV-type | From the fourth year follow-up period | 
| Number of Subjects Reporting Unsolicited Adverse Events (AEs). | An unsolicited adverse event is any adverse event (i.e. any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product) reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. | within 30 days (Days 0-29) after vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cervical intraepithelial neoplasia grade 2, cervical cancer, cervical intraepithelial neoplasia grade 3