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Genital Diseases

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Vaccines

Immunologic Factors

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.

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.

Three doses of Cervarix vaccine administered on a 0, 1, 6-month schedule

human papillomavirus 16/18 L1 virus-like particle/AS04 vaccine

Three doses of Havrix vaccine administered on a 0, 1, 6-month schedule

hepatitis A inactivated virus vaccine

GSK Clinical Trials

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.

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.

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

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.

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.

Subjects were human papillomavirus (HPV) deoxyribonucleic acid (DNA) negative (DNA-) (by PCR) at Month 0 and Month 6 for the corresponding 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

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.

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)

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).

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).

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).

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).

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.

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.

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.

The range of possible pregnancy outcomes was: Pregnancy loss, Pregnancy resolved alive, and Unresolved pregnancy.

GlaxoSmithKline

For this study, the Total Number (#) of Participants Affected by Other (non-serious) Adverse Events (AEs) was analyzed separately for expected AEs and for unexpected AEs. A consolidated analysis of all expected and unexpected AEs was not technically possible to be performed and the relevant data are no longer available. Therefore, the Total #Participants Affected in Other Adverse Events Table is currently populated by the highest value of #Participants affected within other AE's table.

Cervarix Group

Havrix Group

Total

Years

Age, Continuous

Sex: Female, Male

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.

GSK Response Center

HPV16 Associated CIN2+ (N=2464;2452)

HPV18 Associated CIN2+ (N=2567; 2593)

HPV16 and/or 18 Associated CIN2+ (N=2635;2677)

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).

Number of Histopathologically Confirmed Cervical Intraepithelial Neoplasia (CIN)2+ Cases Associated With HPV16 and/or HPV18 Infection Detected in the Preceding Cervical Cytology Specimen.

HPV16 Cervical Infection (N=2464;2452)

HPV18 Cervical Infection (N=2567;2593)

HPV16 and/or 18 Cervical Infection (N=2635;2677)

Number of Cervical Infection With HPV16 or HPV18.

HPV18 Associated CIN2+ (N=2567,2593)

HPV31 Associated CIN2+ (N=2525;2546)

HPV33 Associated CIN2+ (N=2596;2645)

HPV35 Associated CIN2+ (N=2593;2631)

HPV39 Associated CIN2+ (N=2528;2581)

HPV45 Associated CIN2+ (N=2573;2622)

HPV51 Associated CIN2+ (N=2453;2539)

HPV52 Associated CIN2+ (N=2456;2505)

HPV56 Associated CIN2+ (N=2524;2564)

HPV58 Associated CIN2+ (N=2551;2595)

HPV59 Associated CIN2+ (N=2576;2637)

HPV68 and/or 73 Associated CIN2+ (N=2519;2576)

Non 16/18 Onco HPV Associated CIN2+ (N=2643;2697)

Any Oncogenic HPV Associated CIN2+ (N=2643;2697)

Number of Histopathologically Confirmed CIN2+ Cases Associated With Infection by Any Oncogenic HPV Type

Persistent HPV16 Infection (N=2464,2452)

Persistent HPV18 Infection (N=2567;2593)

Persistent HPV16 and/or 18 Infection (N=2635;2677)

Number of Persistent Infection (12-month Definition) With Human Papillomavirus (HPV)-16 or HPV-18 Cases

HPV-16 [before vaccination] (N=194;156)

HPV-16 [at Month 1] (N=196,157)

HPV-16 [at Month 6] (N=195,156)

HPV-16 [at Month 7] (N=195,157)

HPV-16 [at Month 12] (N=182,146)

HPV-16 [at Month 18] (N=25,17)

HPV-16 [at Month 24] (N=175,137)

HPV-16 [at Month 30] (N=19,15)

HPV-16 [at Month 36] (N=163,132)

HPV-16 [at Month 42] (N=22,18)

HPV-16 [at Month 48] (N=172,131)

The ATP cohort for immunogenicity included subjects who received 3 doses of vaccine, who were HPV DNA- for the corresponding type at enrollment and during the 48-month follow-up period, who did not have a biopsy or treatment during the vaccination phase (prior to the Month 6) and for whom immunogenicity results were available.

Geometric Mean Titers (GMTs) for HPV-16 Antibody in the Immunogenicity Subcohort.

HPV-18 [before vaccination] (N=200;173)

HPV-18 [at Month 1] (N=203;170)

HPV-18 [at Month 6] (N=203;175)

HPV-18 [at Month 7] (N=202;175)

HPV-18 [at Month 12] (N=190;166)

HPV-18 [at Month 18] (N=28;20)

HPV-18 [at Month 24] (N=178;150)

HPV-18 [at Month 30] (N=17;19)

HPV-18 [at Month 36] (N=168;145)

HPV-18 [at Month 42] (N=25;19)

HPV-18 [at Month 48] (N=179;149)

Geometric Mean Titers (GMTs) for HPV-18 Antibody in the Immunogenicity Subcohort

HPV-16 [before vaccination] (N=196;158)

HPV-16 [at Month 1] (N=182;155)

HPV-16 [at Month 6] (N=189;156)

HPV-16 [at Month 7] (N=193;158)

HPV-16 [at Month 12] (N=175;146)

HPV-16 [at Month 18] (N=24;17)

HPV-16 [at Month 24] (N=169;138)

HPV-16 [at Month 30] (N=18;15)

HPV-16 [at Month 36] (N=162;132)

HPV-16 [at Month 42] (N=22;18)

HPV-16 [at Month 48] (N=168;133)

HPV-16 Geometric Mean Titers (GMTs) (V5 Monoclonal Antibody Inhibition Test)

HPV-18 [before vaccination] (N=203;176)

HPV-18 [at Month 1] (N=197;173)

HPV-18 [at Month 6] (N=195;175)

HPV-18 [at Month 7] (N=198;176)

HPV-18 [at Month 12] (N=182;166)

HPV-18 [at Month 24] (N=170;154)

HPV-18 [at Month 36] (N=167;145)

HPV-18 [at Month 48 (N=179;150)

HPV-18 Geometric Mean Titers (GMTs) (J4 Monoclonal Antibody Inhibition Test)

Any pain

Grade 3 pain

Any redness

Grade 3 redness > 50 mm

Any swelling

Grade 3 swelling > 50 mm

The Total Vaccinated cohort included all vaccinated subjects with at least 1 vaccine administration documented.

Number of Subjects Reporting Any and Grade 3 Solicited Local Symptoms.

Any fatigue

Grade 3 fatigue

Any myalgia

Grade 3 myalgia

Any arthralgia

Grade 3 arthralgia

Any gastrointestinal

Grade 3 gastrointestinal

Any headache

Grade 3 headache

Any rash

Grade 3 rash

Any urticaria

Grade 3 urticaria

Fever (oral) >= 37.5°C

Fever (oral) > 39.0°C

Number of Subjects Reporting Any and Grade 3 Solicited General Symptoms.

Grade 3 redness

Grade 3 swelling

Number of Subjects Reporting Any and Grade 3 Solicited Local Symptoms on a 10% Random Subset of Participants.

Number of Subjects Reporting Any and Grade 3 Solicited General Symptoms on a 10% Random Subset of Participants.

Number of Subjects Reporting Serious Adverse Events (SAEs).

Number of Subjects Reporting Unsolicited Adverse Events (AEs).

Pregnancy loss

Pregnancy resolved alive

Unresolved pregnancy

The analysis was performed on the Total Vaccinated Cohort, on all pregnant subjects.

Spots Global Cancer Trial Database for hepatitis a inactivated virus vaccine