A Study of Safety, Reactogenicity and Immunogenicity of HRV Vaccine in HIV Infected Infants in South Africa

Study Overview
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Brief Summary
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The aim of this study is to evaluate the reactogenicity, safety and immunogenicity of GSK Biologicals' human rotavirus (HRV) vaccine given concomitantly with routine vaccines including OPV in HIV positive infants. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

Detailed Description
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HIV infected infants as determined prior to study entry (screening) and asymptomatic or mildly symptomatic (WHO stages I and II) of disease will be enrolled. The study will have two groups: Group HRV and Group Placebo. Three-dose immunisation will be administered at approximately 6, 10, and 14 weeks of age. Routine EPI (Expanded Program on Immunisation) vaccinations will be administered concomitantly with the study vaccines. At the time of first dose, subjects will be aged 6 to 10 weeks. This study will evaluate safety, reactogenicity and immunogenicity of the HRV vaccine relative to the placebo.

Official Title
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A Phase II, Double-blind, Randomized, Placebo-controlled Study to Assess the Safety, Reactogenicity and Immunogenicity of Three Doses of GlaxoSmithKline (GSK) Biologicals' Oral Live Attenuated Human Rotavirus (HRV) Vaccine

Conditions
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Infections, Rotavirus

Intervention / Treatment
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* Biological: Rotarix
* Biological: Placebo
* Biological: Tritanrix-HB+Hib
* Biological: Polio Sabin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who the investigator believes that their parents/guardians can and will comply with the requirements of the protocol should be enrolled in the study. A male or female between, and including 6 and 10 weeks of age at the time of the first vaccination. Written informed consent obtained from the parents or guardians of the subject Documented HIV status of the subject as confirmed by PCR. HIV asymptomatic and HIV mildly symptomatic; Stages I and II disease according to WHO's most recent classification for HIV stages in infants and children. Born after a gestation period of 36 to 42 weeks. Exclusion Criteria: Use of any investigational or non-registered drug or vaccine other than the study vaccine(s) within 30 days preceding the first dose of study vaccine, or planned use during the study period. Previous routine vaccination except OPV, BCG and HBV vaccination at birth Any clinically significant history of chronic gastrointestinal disease including any uncorrected congenital malformation of the GI tract or other serious medical condition as determined by the investigator. History of allergic disease or reaction likely to be exacerbated by any component of the vaccine. Acute disease at time of enrolment. Gastroenteritis within 7 days preceding the study vaccine administration. Previous confirmed occurrence of RV gastroenteritis. Other conditions which in the opinion of the investigator may potentially interfere with interpretation of study outcomes. HIV moderately and severely symptomatic: stages III and IV according to WHO's recent classification. Administration of immunoglobulins and/or blood products since birth or planned administration during the study period.

Ages Eligible for Study
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Minimum Age: 6 Weeks
Maximum Age: 10 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rotarix Group<br>Subjects received 3 doses of Rotarix vaccine co-administered with routine Tritanrix HepB Hib and Polio Sabin vaccines. | Biological: Rotarix<br>* Oral vaccination<br>Biological: Tritanrix-HB+Hib<br>* Concomitant routine vaccination, IM administration<br>Biological: Polio Sabin<br>* Oral administration, concomitant routine vaccination<br>|
| Placebo Comparator: Placebo Group<br>Subjects received 3 doses of placebo co-administered with routine Tritanrix HepB Hib and Polio Sabin vaccines. | Biological: Placebo<br>* Oral administration<br>Biological: Tritanrix-HB+Hib<br>* Concomitant routine vaccination, IM administration<br>Biological: Polio Sabin<br>* Oral administration, concomitant routine vaccination<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Reporting Grade 2 or Grade 3 Fever, Vomiting or Diarrhea | Symptoms reported in the table include: Fever: temperature (axillary route) > 38.0 degree Celsius (°C); Diarrhea: ≥ 4 looser than normal stools/day; Vomiting: ≥ 2 episodes of vomiting/day. | Within the 15-day solicited follow-up period after any dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Reporting Any Unsolicited Symptoms | An unsolicited symptom was any spontaneously reported untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. | Within 30 days after any dose | 
| Number of Subjects Reporting Any Serious Adverse Events | A serious adverse event (SAE) is any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect in the offspring of a study subject, or may evolve into one of the outcomes listed above. | Until 2 months after dose 3 (for subjects RV negative at Day 42 post-dose 3) or until end of RV shedding (for subjects who shed RV at Day 42 post-dose 3) | 
| Number of Subjects Reporting Each Type of Solicited Symptom | Solicited symptoms included Cough, Diarrhea (3 or more looser than normal stools/day), Fever (axillary temperature ≥ 37.5°C), Irritability, Loss of appetite, and Vomiting. | Within the 15-day solicited follow-up period after each dose | 
| The Number of Subjects With no Evidence of Immunosuppression and Moderate/ Severe Suppression, Based on CD4+ Absolute Cell Count and CD4+ Percent | Severe suppression: CD4+ cells/microliter (μl) < 750 and CD4+ percent < 15 percent (%); No evidence of suppression: CD4+ cells/μl ≥ 1500 and CD4+ percent ≥ 25%; Moderate suppression = all other CD4+ cell count and CD4+ % combinations. | At the screening visit and 2 months after dose 3 (Visit 4) | 
| Human Immunodeficiency Virus (HIV) Viral Load | The HIV viral load was expressed as mean and standard deviation of the base-10 logarithm of HIV-1 ribonucleic acid (RNA) copies per milliliter (mL). | At the screening visit and 2 months after dose 3 | 
| Number of Subjects Who Seroconverted Against Rotavirus | A subject with anti-rotavirus Immunoglobulin (IgA) antibody concentration < 20 units/milliliter (U/mL) before vaccination and ≥ 20 U/mL after vaccination is considered as seroconverted. | Two months after dose 3 | 
| Number of Subjects With Vaccine Take | Vaccine take: appearance of serum IgA to rotavirus at a concentration of ≥ 20 U/ml or rotavirus shedding in any stool sample collected from the Screening Visit to 2 months after dose 3 for subjects initially negative for rotavirus. | Two months after dose 3 | 
| Serum Rotavirus Immunoglobulin A (IgA) Antibody Concentrations | Concentrations are given as geometric mean concentrations (GMC) for anti-rotavirus IgA antibodies. | Two months after dose 3 | 
| Number of Subjects With Anti-polyribosyl Ribitol Phosphate (PRP) Antibody Concentrations More Than or Equal to the Cut-off Value | Cut-off values for anti-PRP antibody concentrations were ≥ 0.15 and ≥ 1.0 microgram/milliliter (µg/mL). | Two months after dose 3 | 
| Geometric Mean Concentration for Anti-PRP Antibodies | Anti-PRP antibody concentrations are presented as geometric mean concentrations, expressed in microgram/milliliter (μg/mL). | Two months after dose 3 | 
| Number of Subjects With Anti-diphtheria and Anti-tetanus Toxoids Antibody Concentrations More Than or Equal to the Cut-off Value | The cut-off value was ≥ 0.1 International Units/milliliter (IU/mL). | Two months after dose 3 | 
| Geometric Mean Concentration for Anti-diphtheria and Anti-tetanus Toxoids Antibodies | Anti-diphteria and anti-tetanus toxoids antibody concentrations are presented as geometric mean concentrations, expressed in international units/milliliter (IU/mL). | Two months after dose 3 | 
| Number of Subjects With Anti-hepatitis B (HBs) Antibody Concentrations More Than or Equal to the Cut-off Value | The cut-off value was ≥ 10 milli international units/milliliter (mIU/mL). | Two months after dose 3 | 
| Geometric Mean Concentration for Anti-HBs Antibodies | Anti-HBs antibody concentrations are presented as geometric mean concentrations, expressed in milli international units/milliliter (mIU/mL). | Two months after dose 3 | 
| Number of Subjects With Anti-Bordetella Pertussis (BPT) Antibody Concentrations More Than or Equal to the Cut-off Value | The cut-off value was ≥ 15 Enzyme Linked Immunosorbent Assay Unit/milliliter (EL.U/mL). | Two months after dose 3 | 
| Geometric Mean Concentration for Anti-BPT Antibodies | Anti-BPT antibody concentrations are presented as geometric mean concentrations, expressed in ELISA units/milliliter (EL.U/mL). | Two months after dose 3 | 
| Number of Subjects With Anti-polio Types 1, 2 and 3 Antibody Titers More Than or Equal to the Cut-off Value | The cut-off value was ≥ 1:8. The lowest dilution at which serum samples were tested was 1:8, from which a test was considered positive. | Two months after dose 3 | 
| Geometric Mean Titer for Anti-polio Types 1, 2 and 3 Antibodies. | Anti-polio types 1, 2 and 3 antibody titers are presented as geometric mean titers. | Two months after dose 3 | 
| Rotavirus Antigen Excretion in Stool Samples | Number of subjects with rotavirus detected by Enzyme Linked Immunosorbent Assay (ELISA) in stool samples collected from Dose 1 until study end. | At day of each vaccination and at planned days following each vaccine dose until 2 months after dose 3 or until end of RV shedding | 
| Rotavirus in Diarrheal Stool Samples | Number of subjects reporting at least one rotavirus (vaccine strain or wild type rotavirus) gastroenteritis episode. | From Dose 1 until 2 months after dose 3 or until end of RV shedding | 
| Rotavirus Vaccine Strain Identification | Number of gastroenteritis (GE) episodes classified by rotavirus vaccine strain/serotype. Unknown: These samples were typed post hoc and found G1P8 vaccine type for one subject in HRV group, G3P8 and G2P4 for subjects in placebo group. | From dose 1 until 2 months after dose 3 or until end of RV shedding | 
| Enteric Pathogens Identification | Number of subjects reporting gastroenteritis (GE) episodes classified by enteric pathogen tests results. | From Dose 1 until 2 months after dose 3 or until end of RV shedding | 
| Number of Subjects With the RV in Stool Samples | Number of subjects with presence of RV in stool samples (shedding) collected at pre-determined time points by RV type (Yes, No, Mixed type = G1V+G1WT+G2+G3+P4+P8V+P8WT and results not available [NA]). | From Dose 1 until post Dose 3 |