Safety and Immunogenicity of GlaxoSmithKline Biologicals' HPV Vaccine 580299 (Cervarix) in HIV Infected Females

Study Overview
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Brief Summary
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Infection with human papillomavirus (HPV) has been clearly established as the central cause of cervical cancer. The current study is designed to evaluate the safety and immunogenicity of GlaxoSmithKline Biologicals' HPV vaccine 580299 in HIV infected adult females living in the Republic of South Africa. The study is double blinded, randomized for HIV positive subjects and open for HIV negative subjects. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

Official Title
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Evaluation of the Safety and Immunogenicity of GlaxoSmithKline Biologicals' HPV Vaccine 580299 (Cervarix) in Adult Human Immunodeficiency Virus (HIV) Infected Female Subjects

Conditions
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Infections, Papillomavirus

Intervention / Treatment
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* Biological: Cervarix
* Biological: Placebo Control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who the investigator believes that they can and will comply with the requirements of the protocol A female between, and including, 18 and 25 years of age at the time of the first vaccination. Written, signed or thumb-printed informed consent obtained from the subject prior to enrolment. Subjects willing to undergo HIV Voluntary Counseling and Testing (VCT) and willing to be informed of their HIV status. Subjects willing to provide place of residence and be visited at home. HIV seropositive subjects: Subjects must be HIV seropositive according to WHO case definition Subjects with WHO Clinical Stage 1 HIV-associated disease Subjects currently on antiretroviral therapy (ART) must be compliant to ART and have undetectable viral load HIV seronegative subjects: Subjects confirmed as HIV seronegative at the screening visit are eligible to participate in the HIV-/HPV group of the study. Non-virgin subjects must have a normal colposcopy at the screening visit. Non-virgin subjects must have a normal cervical cytology (Pap smear) or no greater than atypical squamous cells of undetermined significance (ASC-US) at the screening visit. All subjects must have a negative urine pregnancy test at the screening visit and at visit 1 (Day 0). Subjects must be of non-childbearing potential or, if of childbearing potential, must be abstinent or have used adequate contraceptive precautions for 30 days prior to vaccination, have a negative pregnancy test and must agree to continue such precautions for two months after completion of the vaccination series. Subjects must have had no more than 6 life-time sexual partners prior to enrolment. Subjects must have one single intact cervix Exclusion Criteria: Active tuberculosis (TB) Current TB prophylaxis or therapy. Anemia at the screening visit. increased creatinine at the screening visit. Increased hepatic enzym (ALT) at the screening visit Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine within 30 days preceding the first dose of study vaccine/control, or planned use during the entire study period (up to Month 12). Chronic administration of immunosuppressants or other immune-modifying drugs within 6 months prior to the first vaccine dose. Administration of a vaccine not foreseen by the study protocol within 30 days before the first dose of study vaccine/control. Enrolment will be postponed until the subject is outside the specified window. Planned administration of a vaccine not foreseen by the study protocol within 30 days before or 30 days after (i.e., Days 0-29) any dose of study vaccine. Previous vaccination against HPV, or planned administration of any HPV vaccine other than that foreseen by the study protocol during the study period (Month 0 to Month 12). previous administration of components of the investigational vaccine Cancer or autoimmune disease under treatment. Hypersensitivity to latex. History of allergic disease or reactions likely to be exacerbated by any component of the vaccine/control. Acute disease at the time of enrolment. Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory testing performed at the screening visit. History of any neurological disorders or seizures. Pregnant or breastfeeding female. A subject planning to become pregnant, likely to become pregnant (as determined by the investigator) or planning to discontinue contraceptive precautions during the study period, up to two months after the last vaccine dose. Concurrently participating in another clinical study, at any time during the study period (up to Month 12), in which the subject has been or will be exposed to an investigational or a non-investigational product (pharmaceutical product or device). Any medically diagnosed or suspected immunodeficient condition (other than HIV for HIV seropositive subjects), based on medical history, physical examination and/or laboratory tests results. Administration of immunoglobulins and/or any blood products within the three months preceding the first dose of study vaccine/control or planned administration during the study period. Enrolment will be postponed until the subject is outside the specified window. Administration of trimethoprim/sulphamethoxazole within 7 days before the first dose of study vaccine/control, or planned administration of trimethoprim/sulphamethoxazole within 7 days after the first dose of study vaccine/control. Current drugs or alcohol abuse.

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HIV+/Cervarix Group<br>Human immunodeficiency virus positive (HIV+) female subjects who received 3 doses of Cervarix vaccine administrated by intramuscular injection into the deltoid region of the non-dominant arm, according to a 0, 1, 6-month schedule. | Biological: Cervarix<br>* Intramuscular injection, 3 doses<br>|
| Active Comparator: HIV+/Aluminium Hydroxide Group<br>Human immunodeficiency virus positive (HIV+) female subjects who received 3 doses of control Aluminium Hydroxide [Al(OH)3], administrated by intramuscular injection into the deltoid region of the non-dominant arm according to a 0, 1, 6-month schedule. | Biological: Placebo Control<br>* Intramuscular injection, 3 doses<br>|
| Experimental: HIV-/Cervarix Group<br>Human immunodeficiency virus negative (HIV-) subjects who received 3 doses of Cervarix vaccine administrated by intramuscular injection into the deltoid region of the non-dominant arm according to a 0, 1, 6-month schedule. | Biological: Cervarix<br>* Intramuscular injection, 3 doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Reporting Any and Grade 3 Solicited Local Symptoms | Solicited local symptoms assessed were pain and swelling. Any = occurrence of any solicited local regardless of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 swelling = swelling spreading beyond 50 millimeters (mm) of injection site. Solicited local symptoms were assessed as related to the study vaccination. | Within 7 days after each dose and across doses | 
| Number of Subjects Reporting Any, Severe (Grade 3) and Related Solicited General Symptoms | Solicited general symptoms assessed were arthralgia, fatigue, fever [defined as axillary temperature equal to or above (≥) 37.5 degrees Celsius (°C)], gastrointestinal, headache, myalgia, rash and urticaria. Any = occurrence of any solicited general symptom regardless of their intensity grade or relationship. Grade 3 Symptom = symptom that prevented normal activity. Grade 3 Urticaria = Urticaria distributed on at least 4 body areas. Related = symptom assessed by the investigator as causally related to the vaccination. | Within 7 days after each dose and across doses | 
| Number of Subjects Reporting Any, Grade 3 and Related Unsolicited Symptoms | 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 30 days after any vaccination | 
| Number of Subjects With Medically Significant Conditions (MSCs) From Day 0 up to Month 7 | Medically significant conditions (MSCs) were collected regardless of causal relationship to vaccination and intensity. Medically significant conditions were defined as adverse events (AEs) prompting emergency room or physician visits that were not (1) related to common diseases or (2) routine visits for physical examination or vaccination, or serious adverse events (SAEs) that were not related to common diseases. Common diseases include upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervico-vaginal yeast infections, menstrual cycle abnormalities and injury. | From Day 0 up to Month 7 | 
| Number of Subjects Reporting Serious Adverse Events (SAEs) From Day 0 up to Month 7 | SAEs assessed include medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity or a congenital anomaly/birth defect in the offspring of a study subject. | From Day 0 up to Month 7 | 
| Number of Subjects With Pregnancies and Outcomes of Reported Pregnancies From Day 0 up to Month 7 | The subjects with confirmed pregnancies were followed up to determine the outcomes of the reported pregnancies. The outcome of the reported pregnancy was a live infant with no apparent congenital anomaly. | From Day 0 up to Month 7 | 
| Number of Subjects Reporting SAEs From Day 0 up to Month 12 | SAEs assessed include medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity or a congenital anomaly/birth defect in the offspring of a study subject. | From Day 0 up to Month 12 | 
| Number of Subjects With MSCs From Day 0 up to Month 12 | MSCs were collected regardless of causal relationship to vaccination and intensity. Medically significant conditions were defined as adverse events (AEs) prompting emergency room or physician visits that were not (1) related to common diseases or (2) routine visits for physical examination or vaccination, or serious adverse events (SAEs) that were not related to common diseases. Common diseases include upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervico-vaginal yeast infections, menstrual cycle abnormalities and injury. | From Day 0 up to Month 12 | 
| Number of Subjects With Pregnancies and Outcomes of Reported Pregnancies From Day 0 up to Month 12 | The subjects with confirmed pregnancies were followed up to determine the outcomes of the reported pregnancies. The outcome of the reported pregnancy was a live infant with no apparent congenital anomaly. | From Day 0 up to Month 12 | 
| Number of Subjects Reporting Clinically Relevant Abnormalities in Red Blood Cells and Platelets Parameters at Day 7 and at Months 1, 2, 4, 6 and 7 | Haematological laboratory parameters assessed were red blood cells (RBC) and platelets (PLA). For each parameter and by pre-vaccination status, it was assessed whether the post-vaccination values of the parameter were above, below or in the normal range (missing values are also indicated). | At Day 7 and at Months 1, 2, 4, 6 and 7 | 
| Number of Subjects Reporting Clinically Relevant Abnormalities in White Blood Cells and Neutrophils Parameters at Day 7 and Months 1, 2, 4, 6 and 7 | Haematological laboratory parameters assessed were white blood cells (WBC) and neutrophils (NEU). For each parameter and by pre-vaccination status, it was assessed whether the post-vaccination values of the parameter were above, below or in the normal range (missing values are also indicated). | At Day 7 and Months 1, 2, 4, 6 and 7 | 
| Number of Subjects Reporting Clinically Relevant Abnormalities in Lymphocytes and Monocytes Parameters at Day 7 and Months 1, 2, 4, 6 and 7 | Haematological laboratory parameters assessed were lymphocytes (LYM) and monocytes (MON). For each parameter and by pre-vaccination status, it was assessed whether the post-vaccination values of the parameter were above, below or in the normal range (missing values are also indicated). | At Day 7 and at Months 1, 2, 4, 6 and 7 | 
| Number of Subjects Reporting Clinically Relevant Abnormalities in Haemoglobin and Haematocrit Parameters at Day 7 and Months 1, 2, 4, 6 and 7 | Haematological laboratory parameters assessed were haemoglobin (Hgb) and haematocrit (Hct). For each parameter and by pre-vaccination status, it was assessed whether the post-vaccination values of the parameter were above, below or in the normal range (missing values are also indicated). | At Day 7 and Months 1, 2, 4, 6 and 7 | 
| Number of Subjects With Clinically Relevant Abnormalities in Eosinophils, Basophils and Creatinine Parameters at Day 7 and Months 1, 2, 4, 6 and 7 | Haematological and biochemical laboratory parameters assessed were eosinophils (EOS), basophils (BAS) and creatinine (CREA). For each parameter and by pre-vaccination status, it was assessed whether the post-vaccination values of the parameter were above, below or in the normal range (missing values are also indicated). | At Day 7 and at Months 1, 2, 4, 6 and 7 | 
| Number of Subjects With Clinically Relevant Abnormalities in Alanine Aminotransferase Parameter at Day 7 and Months 1, 2, 4, 6 and 7 | Biochemical laboratory parameter assessed was alanine aminotransferase (ALAT). By pre-vaccination status, it was assessed whether the post-vaccination values of the parameter were above, below or in the normal range (missing values are also indicated). | At Day 7 and Months 1, 2, 4, 6 and 7 | 
| Number of Subjects Reporting Clinically Relevant Abnormalities in Neutrophils, Platelets, Red Blood Cells and White Blood Cells at Month 10 and Month 12 | Haematological laboratory parameters assessed were neutrophils (NEU), platelets (PLA), red blood cells (RBC) and white blood cells (WBC). For each parameter and by pre-vaccination status, it was assessed whether the post-vaccination values of the parameter were above, below or in the normal range (missing values are also indicated). | At Month 10 and Month 12 | 
| Number of Subjects With Clinically Relevant Abnormalities in Alanine Aminotransferase, Basophils, Creatinine, Eosinophils, Haematocrit, Haemoglobin, Lymphocytes and Monocytes Parameters at Month 10 and Month 12 | Haematological and biochemical laboratory parameters assessed were alanine aminotransferase (ALAT), basophils (BAS), creatinine (CREA), eosinophils (EOS), haematocrit (Hct), haemoglobin (Hgb), lymphocytes (LYM) and monocytes (MON). For each parameter and by pre-vaccination status, it was assessed whether the post-vaccination values of the parameter were above, below or in the normal range (missing values are also indicated). | At Month 10 and Month 12 | 
| Number of Cluster of Differention 4 (CD4+) Cells Per Cubic Millimeter in All HIV+ Subjects at Pre-vaccination (Day 0) and Months 1, 2, 4, 6 and 7 | The number of CD4+ cells per cubic millimeter (mm^3) in all HIV+ subjects at pre-vaccination (Day 0) and Months 1, 2, 4, 6 and 7 is reported. | At pre-vaccination (Day 0) and Months 1, 2, 4, 6 and 7 | 
| Number of CD4+ Cells Per Cubic Millimeter in All HIV+ Subjects at Month 10 and Month 12 | The number of CD4+ cells per cubic millimeter (mm^3) in all HIV+ subjects at Month 10 and Month 12 is reported. | At Month 10 and Month 12 | 
| HIV Viral Load in All HIV+ Subjects at Pre-vaccination (Day 0) and Months 1, 2, 4, 6 and 7 | The viral load was calculated by estimating the amount of virus in blood samples and it was given in number of Ribonucleic acid copies per milliliter (in log10) [RNA copies/mL (in log10)]. | At pre-vaccination (Day 0) and Months 1, 2, 4, 6 and 7 | 
| HIV Viral Load in All HIV+ Subjects at Month 10 and Month 12 | The viral load was calculated by estimating the amount of virus in blood samples and was given in number of RNA copies/mL (in log 10). | At Month 10 and Month 12 | 
| Number of Subjects in Each World Health Organisation (WHO) HIV Clinical Stage by CD4+ Cell Count Category at Baseline in All HIV+ Subjects at Months 1, 2, 4, 6 and 7 | CD4+ cell count categories, at baseline, assessed were (i) below (<) 200 CD4+ cells per cubic millimeter (mm^3), (ii) between 200 and 500 CD4+ cells/mm^3 and (iii) above 500 CD4+ cells/mm^3. WHO classification of HIV-associated clinical disease: 1 = Asymptomatic HIV-associated symptoms = WHO clinical stage 1; 2 = Mild HIV-associated symptoms = WHO clinical stage 2; 3 = Advanced HIV-associated symptoms = WHO clinical stage 3; 4 = Severe HIV-associated symptoms = WHO clinical stage 4. | At Months 1, 2, 4, 6 and 7 | 
| Number of Subjects in Each World Health Organisation (WHO) HIV Clinical Stage by CD4+ Cell Count Category at Baseline in All HIV+ Subjects at Month 10 and Month 12 | CD4+ cell count categories, at baseline, assessed were: (i) below (<) 200 CD4+ cells per cubic millimeter (mm^3), (ii) between 200 and 500 CD4+ cells/mm^3 and (iii) above (>) 500 CD4+ cells/mm^3. WHO classification of HIV-associated clinical disease: 1 = Asymptomatic HIV-associated symptoms = WHO clinical stage 1; 2 = Mild HIV-associated symptoms = WHO clinical stage 2; 3 = Advanced HIV-associated symptoms = WHO clinical stage 3; 4 = Severe HIV-associated symptoms = WHO clinical stage 4. | At Month 10 and Month 12 | 
| Number of Seroconverted Subjects for HPV-16 and HPV-18 Antibodies at Pre-vaccination (Day 0) and Months 2 and 7 | Seroconversion is defined as the appearance of anti-HPV-16 and/or anti-HPV-18 antibodies (anti-HPV-16 titers ≥ 8 EL.U/mL and anti-HPV-18 titers ≥ 7 EL.U/mL) in the serum of subjects seronegative before vaccination. A seronegative subject is a subject whose antibody titers are below the cut-off value. Due to the high proportion of initially seropositive subjects in the study population, seroconversion rates were considered for all subjects in the According-to-Protocol (ATP) cohort for immunogenicity regardless of baseline serostatus. | At pre-vaccination (Day 0) and Months 2 and 7 | 
| Number of Seroconverted Subjects for HPV-16 and HPV-18 Antibodies at Month 12 | Seroconversion is defined as the appearance of anti-HPV-16 and/or anti-HPV-18 antibodies (anti-HPV-16 titers ≥ 8 ELISA units per milliliter (EL.U/mL) and anti-HPV-18 titers ≥ 7 EL.U/mL) in the serum of subjects seronegative before vaccination. A seronegative subject is a subject whose antibody titers are below the cut-off value. Due to the high proportion of initially seropositive subjects in the study population, seroconversion rates were considered for all subjects in the ATP cohort for immunogenicity regardless of baseline serostatus. | At Month 12 | 
| Concentrations for HPV-16 and HPV-18 Antibodies at Pre-vaccination (Day 0) and Months 2 and 7 | Concentrations are expressed as geometric mean antibody concentrations (GMCs) and are given in EL.U/mL. The antibody concentrations against HPV-16 and HPV-18 were determined by Enzyme-linked immunosorbent assay (ELISA). The cut-off values of the assay are 8 EL.U/mL for anti-HPV-16 and 7 EL.U/mL for anti-HPV-18. | At pre-vaccination (Day 0) and Months 2 and 7 | 
| Concentrations for HPV-16 and HPV-18 Antibodies at Month 12 | Concentrations are expressed as geometric mean antibody concentrations (GMCs) and are given in EL.U/mL. The antibody concentrations against HPV-16 and HPV-18 were determined by Enzyme-linked immunosorbent assay (ELISA). The cut-off values of the assay are 8 EL.U/mL for anti-HPV-16 and 7 EL.U/mL for anti-HPV-18. | At Month 12 | 
| Cell Mediated Immune (CMI) Response (B-cell Responses) Related to HPV 16/18 Virus-like Particles (VLPs) Measured by Flow Cytometry at Day 0 | The CMI response is expressed by the number of subjects with B-cell response to VLP-16 and VLP-18 above (>) 0 as measured by Flow cytometry. | At pre-vaccination (Day 0) | 
| CMI B-cell Responses Related to HPV 16/18 Virus-like Particles (VLPs) Measured by Flow Cytometry at Month 2 | The CMI response is expressed by the number of subjects with B-cell response to VLP-16 and VLP-18 above (>) 0 as measured by Flow cytometry. | At Month 2 | 
| CMI B-cell Responses Related to HPV 16/18 Virus-like Particles (VLPs) Measured by Flow Cytometry at Month 7 | The CMI response is expressed by the number of subjects with B-cell response to VLP-16 and VLP-18 above (>) 0 as measured by Flow cytometry. | At Month 7 | 
| CMI B-cell Responses Related to HPV 16/18 Virus-like Particles (VLPs) Measured by Flow Cytometry at Month 12 | The CMI response is expressed by the number of subjects with B-cell response to VLP-16 and VLP-18 above (>) 0 as measured by Flow cytometry. | At Month 12 | 
| CMI Response (T-cell Responses) Related to HPV-16 and HPV-18 Measured by Intracellular Cytokine Staining (ICS) | The CMI response is the measure of the cytokines production [i.e. Cluster of Differentiation 40 Ligand (CD40L), Interferon gamma (IFN-γ), interleukin-2 (IL-2) and tumor necrosis factor alpha (TNF-α)] by HPV-antigen specific T lymphocytes and measured by Intracellular Cytokine Staining (ICS) assay. The results were expressed as a frequency of positive CD4 or CD8 T-cell producing at least 1 cytokine within the CD4 or CD8 T-cell sub-population. All doubles = T cell expressing at least 2 cytokines. | At pre-vaccination (Day 0) and at Months 2, 7 and 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HPV, Human papillomavirus (HPV) vaccine, Human Immunodeficiency Virus (HIV), Cervical cancer, Papillomavirus