Effectiveness, Safety and Immunogenicity of GSK Biologicals' HPV Vaccine GSK580299 (Cervarix) Administered in Healthy Adolescents

Study Overview
=================
Brief Summary
-----------------
Genital infections with oncogenic human papillomaviruses (HPV) are common in both men and women. The most important disease associated with oncogenic HPV infection is cervical cancer, currently the second leading cause of cancer-related death among women globally. The current study is designed to evaluate the overall impact of HPV immunization in adolescents 12-15 years of age.

Official Title
-----------------
Evaluation of the Effectiveness of Two Vaccination Strategies Using GlaxoSmithKline Biologicals' HPV Vaccine GSK580299 (Cervarix) Administered in Healthy Adolescents

Conditions
-----------------
Infections, Papillomavirus

Intervention / Treatment
-----------------
* Biological: Cervarix
* Biological: Engerix-B


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Study participants who the investigator or delegate believes that they and/or their parents/legally acceptable representative can and will comply with the requirements of the protocol (e.g. completion of the diary cards, return for follow-up visits) should be enrolled in the study. A male or female between, and including, 12 and 15 years of age at the time of the first vaccination. A written informed assent must be obtained from all study participants prior to enrolment. In addition, a written informed consent must be obtained from the study participants' parent or legally acceptable representative. Note: As according to the Finnish law legal age of consent is 15 years, a written informed consent form can be obtained from study participants aged 15 years old and their parent(s)/legally acceptable representative(s) will receive a letter informing them of their child participation to the study. Healthy male and female study participants as established by medical history before entering into the study. If needed, a history-directed clinical examination will be performed by the investigator or delegate (e.g. study nurse). Study participants must not be pregnant. Absence of pregnancy should be verified (e.g. urine pregnancy test) as per investigator's or delegate's clinical judgement. If the study participant is female, she must be of non-childbearing potential, i.e. be abstinent, have a current tubal ligation, hysterectomy, ovariectomy or be post-menopausal or pre-menarcheal, or if she is of childbearing potential, she must use adequate contraception for 30 days prior to vaccination and continue for 2 months after completion of the vaccination series. Exclusion Criteria: Previous vaccination against HPV or Hepatitis B virus. History of allergic disease or reactions likely to be exacerbated by any component of the vaccines. Acute disease at the time of enrolment. (Acute disease is defined as the presence of a moderate or severe illness with or without fever. All vaccines can be administered to persons with a minor illness such as diarrhoea, mild upper respiratory infection with or without low-grade febrile illness, i.e. Oral temperature <37.5°C (99.5°F) / Axillary temperature <37.5°C (99.5°F) / Rectal temperature <38°C (100.4°F).) Pregnant or lactating female.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 15 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cervarix/Engerix-B A Group<br>The A group includes subjects from communities where 70% of male and female adolescents were to be vaccinated with Cervarix vaccine. To achieve a Cervarix vaccination coverage of 70%, a 9:1 ratio was used to allocate study participants to receive Cervarix vaccine versus control Engerix-B vaccine (meaning 90% of vaccinated subjects were randomized to Cervarix). Finally, subjects from A group were either vaccinated with Cervarix, Engerix-B (control vaccine), or not vaccinated (enrolled control without vaccination). Vaccines were administered intramuscularly in the deltoid region of the non-dominant arm according to a 0, 1, 6-month schedule. | Biological: Cervarix<br>* Intramuscular injection, 3 doses<br>Biological: Engerix-B<br>* Intramuscular injection, 3 doses<br>|
| Experimental: Cervarix/Engerix-B B Group<br>The B group includes subjects from communities where 70% of female adolescents were to be vaccinated with Cervarix vaccine. To achieve a Cervarix vaccination coverage of 70%, a 9:1 ratio was used to allocate female participants to receive Cervarix vaccine versus control Engerix-B vaccine (meaning 90% of vaccinated females were randomized to Cervarix). In this group, all male adolescents were to be vaccinated with Engerix-B control vaccine. Finally, subjects from B group were either vaccinated with Cervarix (females) or Engerix-B/not vaccinated (males and females). Vaccines were administered intramuscularly in the deltoid region of the non-dominant arm according to a 0, 1, 6-month schedule. | Biological: Cervarix<br>* Intramuscular injection, 3 doses<br>Biological: Engerix-B<br>* Intramuscular injection, 3 doses<br>|
| Active Comparator: Engerix-B Group<br>In this control group, all adolescents were to be vaccinated with Engerix-B control vaccine. Finally, subjects from this group were either vaccinated with Engerix-B or not vaccinated. The vaccine was administered intramuscularly in the deltoid region of the non-dominant arm according to a 0, 1, 6-month schedule. | Biological: Engerix-B<br>* Intramuscular injection, 3 doses<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Female Subjects With Overall Vaccine Effectiveness Against Genital Infection With Human Papilloma Virus (HPV)-16/18 Types in Cervarix/Engerix-B B Group Versus Engerix-B Group and in Cervarix/Engerix-B A Group Versus Engerix-B Group | The analysis of overall effectiveness of Cervarix vaccine against genital infection with HPV-16/18 types was based on stratified Mantel-Haenszel adjusted for clustering. The overall vaccine effectiveness was computed as 1- the prevalence odd ratio in all subjects from the investigated group (prevalence rate in all subjects from the investigated group/prevalence rate in all subjects from Engerix-B Group). | At the time of Visit 5 (i.e. at 18.5 years of age) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Female Subjects With Overall Vaccine Effectiveness Against Genital Infection With HPV-16/18 Types in Cervarix/Engerix-B A Group Versus Cervarix/Engerix-B B Group | The analysis of overall effectiveness of Cervarix vaccine against genital infection with HPV-16/18 types was based on stratified Mantel-Haenszel adjusted for clustering. The overall vaccine effectiveness was computed as 1- the prevalence odd ratio in all subjects from the investigated group (prevalence rate in all subjects from the Cervarix/Engerix-B A Group/prevalence rate in all subjects from Engerix-B Group). Note: As per Protocol and as the confirmatory objectives were not met, only exploratory interpretation could be performed for what concerns this secondary outcome measure. | At the time of Visit 5 (i.e. at 18.5 years of age) | 
| Number of Female Subjects With Overall Vaccine Effectiveness Against Genital Oncogenic Infection With Specific HPV Types | The analysis of overall effectiveness of Cervarix vaccine against genital infection with specific HPV types (16, 18, 31/45, 31/33/45, 31/33/45/51, 31/33/45/51/52, 31/33/35/39/45/51/52/56/58/59/66/68, 16/18/31/33/35/39/45/51/52/56/58/59/66/68, 6, 11, 6/11, 6/11/53/74) was based on stratified Mantel-Haenszel adjusted for clustering. The effectiveness was computed as 1- the prevalence odd ratio in all subjects from the investigated group (prevalence rate in all subjects from the investigated group/prevalence rate in all subjects from Engerix-B Group). | At the time of Visit 5 (i.e. at 18.5 years of age) | 
| Number of Female Subjects With Total Vaccine Effectiveness Against Oropharyngeal Infection With HPV-16/18 Types | The analysis of total effectiveness of Cervarix vaccine against oropharyngeal infection with HPV-16/18 types was based on stratified Mantel-Haenszel adjusted for clustering. The effectiveness was computed as 1- the prevalence odd ratio in Cervarix vaccinated subjects from the investigated group (prevalence rate in Cervarix vaccinated subjects from the investigated group/prevalence rate in all subjects from Engerix-B Group). | At the time of Visit 5 (i.e. at 18.5 years of age) | 
| Number of Female Subjects With Total Vaccine Effectiveness Against Oropharyngeal Oncogenic Infection With Specific HPV Types | The analysis of total effectiveness of Cervarix vaccine against oropharyngeal infection with specific HPV types (16, 18, 31/45, 31/33/45, 31/33/45/51, 31/33/45/51/52, 31/33/35/39/45/51/52/56/58/59/66/68, 16/18/31/33/35/39/45/51/52/56/58/59/66/68, 6, 11, 6/11, 6/11/53/74) was based on stratified Mantel-Haenszel adjusted for clustering. The effectiveness was computed as 1- the prevalence odd ratio in all Cervarix vaccinated subjects from the investigated group (prevalence rate in all Cervarix vaccinated subjects from the investigated group/prevalence rate in all subjects from Engerix-B Group). | At the time of Visit 5 (at 18.5 years of age) | 
| Number of Male Subjects Reporting Any and Grade 3 Solicited Local Symptoms, in a Subset of Subjects | Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling spreading beyond 50 millimeters (mm) of injection site. | During the 7-day post-vaccination period following each dose and across doses | 
| Number of Male Subjects Reporting Any, Grade 3 and Related to Vaccination Solicited General Symptoms, in a Subset of Subjects | Assessed solicited general symptoms were arthralgia, fatigue, fever [defined as axillary temperature equal to or above 37.5 degrees Celsius (°C)], gastrointestinal symptoms (including nausea, vomiting, diarrhoea and/or abdominal pain), headache, myalgia, rash and urticaria. Any = occurrence of the symptom regardless of intensity grade. Grade 3 symptom = symptom that prevented normal activity. Grade 3 fever = fever > 39.0 °C. Related = symptom assessed by the investigator as related to the vaccination. | During the 7-day post-vaccination period following each dose and across doses | 
| Number of Male Subjects Reporting Any, Grade 3 and Related to Vaccination Unsolicited Adverse Events (AEs), in a Subset of Subjects | An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and 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. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. Grade 3 AE = an AE which prevented normal, everyday activities. Related = AE assessed by the investigator as related to the vaccination. | Within the 30-day post-vaccination period | 
| Number of Male Subjects With Urticaria/Rash Within 30 Minutes After Each Vaccination Dose, in a Subset of Subjects | The number of subjects with urticaria/rash assessed within 30 minutes following each vaccine dose are reported. Confirmed urticaria/rash = subjects who reported urticaria/rash within the specified time frame. Not confirmed urticaria/rash = number of subjects who did not report urticaria/rash within the specified time frame. | Within 30 minutes following each vaccination dose | 
| Number of Male Subjects Reporting Medically Significant Conditions (MSCs), in a Subset of Subjects | MSCs are defined as AEs prompting emergency room or physician visits that are not (1) related to common diseases or (2) routine visits for physical examination or vaccination, or SAEs that are not related to common diseases. Common diseases include: upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections and injury. | From Dose 1 (at Day 0) until Month 12 | 
| Number of Male Subjects Reporting Any Serious Adverse Events (SAEs) and SAEs Causally Related to Vaccination, in a Subset of Subjects | Serious adverse events (SAEs) assessed include medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization or resulted in disability/incapacity. | From Dose 1 (at Day 0) until Month 12 | 
| Number of Subjects Reporting SAEs Assessed by the Investigator as Possibly Related to Vaccination | Serious adverse events (SAEs) assessed include medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization or resulted in disability/incapacity. | During the entire study period (from Day 0 up to Visit 5 [18.5 years of age] or up to the day before 19 years of age for subjects who did not attend Visit 5) | 
| Number of Subjects With New Onset of Autoimmune Diseases (NOADs), Retrieved From Care Register for Social Welfare and Health Care (HILMO) | NOADs include colitis ulcerative, juvenile arthritis, type 1 diabetes mellitus, coeliac disease and Chron's disease, Basedow's disease, erythema nodosum VIIth nerve paralysis and psoriasis. | During the entire study period (from day 0 up to Visit 5 [at 18.5 years of age] or up to the day before 19 years of age for subjects who did not attend Visit 5) | 
| Number of Subjects Reporting Pregnancies and Outcomes of Reported Pregnancies With Onset During the Study Period, Retrieved From Medical Birth Registry and HILMO | Pregnancies with onset during the study were classified by their outcome. Outcomes included live infant with no apparent congenital anomaly, elective termination with no apparent congenital anomaly, spontaneous abortion with no apparent congenital anomaly, ectopic pregnancy, stillbirth with no apparent congenital anomaly and molar pregnancy. Note: The analysis was performed based on the corrected demographical data. Please refer to the rationale provided in the Baseline characteristics section. | During the entire study period (from Day 0 up to Visit 5 [at 18.5 years of age] or up to the day before 19 years of age for subjects who did not attend Visit 5) | 
| Number of Subjects With HPV-16 and HPV-18 Antibody Concentrations Equal to or Above the Cut-off Values, by Gender, in a Subset of Subjects | The antibody concentrations against HPV-16 and HPV-18 were determined by Enzyme-linked immunosorbent assay (ELISA). The cut-off of the assay was 8 ELISA units per milliliter (EL.U/mL) for anti-HPV-16 and 7 EL.U/mL for anti-HPV-18 at Visits 1 and 4 and 19 EL.U/mL for HPV-16 and 18 EL.U/mL for HPV-18 at Visit 5. | At the time of Visit 1 (at Day 0), Visit 4 (at Month 7) and Visit 5 (at 18.5 years of age) | 
| Anti-HPV-16 and Anti-HPV-18 Antibody Concentrations, by Gender, in a Subset of Subjects | The antibody concentrations against HPV-16 and HPV-18 were determined by Enzyme-linked immunosorbent assay (ELISA). The cut-off of the assay was 8 ELISA units per milliliter (EL.U/mL) for anti-HPV-16 and 7 EL.U/mL for anti-HPV-18 at Visits 1 and 4 and 19 EL.U/mL for HPV-16 and 18 EL.U/mL for HPV-18 at Visit 5. | At the time of Visit 1 (Day 0), Visit 4 (at Month 7) and at the time of Visit 5 (18.5 years of age) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HPV vaccine, Healthy adolescents, Cervical cancer, Safety, Immunogenicity, Cervarix