Vaccine Efficacy Against Rotavirus Diarrhea; Vaccine Given With Routine Childhood Vaccinations in Healthy African Infants

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to determine if the GSK Biologicals' human rotavirus (HRV) vaccine (pooled HRV groups) given concomitantly with routine expanded program on immunisation (EPI) vaccinations can prevent severe rotavirus gastroenteritis (≥11 on the 20-point Vesikari scoring system [Ruuska, 1990]) caused by the circulating wild-type RV strains during the period from 2 weeks after the last dose of HRV vaccine or placebo until Visit 5. The primary objective will be reached if the lower limit of the 95% confidence interval (CI) on vaccine efficacy is >0%. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.

Detailed Description
-----------------
The study will have three groups: Rotarix 3-Dose Group, Rotarix 2-Dose Group and Placebo Group. Three-dose immunisation will be administered in healthy infants at approximately 6, 10, and 14 weeks of age. Routine EPI vaccinations will be administered concomitantly with the study vaccines. This study will also evaluate immunogenicity and safety relative to the placebo.

Official Title
-----------------
Multi-Center Study to Assess the Efficacy, Safety and Immunogenicity of 2 or 3 Doses of GSK Biologicals' Oral Live Attenuated Human Rotavirus (HRV) Vaccine Given Concomitantly With Routine EPI Vaccinations in Healthy Infants

Conditions
-----------------
Infections, Rotavirus

Intervention / Treatment
-----------------
* Biological: Rotarix™
* Biological: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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 child between, and including, 5 and 10 weeks of age at the time of the first study vaccination. Written informed consent obtained from the parent or guardian of the subject who is of legal age Healthy subjects as established by medical history and clinical examination before entering into the study. In South Africa, birth weight > 2000 grams or if weight unknown, gestation period > 36 weeks. Exclusion Criteria: Use of any investigational or non-registered product (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. Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational product Planned administration of a vaccine not foreseen by the study protocol within 14 days before each dose of study vaccine(s) and ending 14 days after. Chronic administration (defined as more than 14 days) of immunosuppressants since birth. History of use of experimental rotavirus vaccine. Previous routine vaccination except Bacille Calmette-Guérin (BCG), hepatitis B virus (HBV) and oral poliovirus (OPV) vaccination at birth Any clinically significant history of chronic gastrointestinal disease including any uncorrected congenital malformation of the gastrointestinal tract, intussusception or other medical condition determined to be serious by the investigator. Any confirmed or suspected immunosuppressive or immunodeficient condition based on medical history and physical examination History of allergic disease or reaction likely to be exacerbated by any component of the vaccine. Acute disease at the time of enrolment. Gastroenteritis within 7 days preceding the first study vaccine administration Previous confirmed occurrence of rotavirus gastroenteritis (RV GE). A family history of congenital or hereditary immunodeficiency. Administration of immunoglobulins and/or blood products since birth or planned administration during the study period. History of any neurologic disorders or seizures. Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory screening tests.

Ages Eligible for Study
-----------------
Minimum Age: 5 Weeks
Maximum Age: 10 Weeks

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rotarix 3-Dose Group<br>Subjects received 3 doses of Rotarix™ vaccine given concomitantly with routine EPI vaccines. | Biological: Rotarix™<br>* Two or Three doses, oral administration<br>* Other names: GSK Biologicals' HRV vaccine;|
| Experimental: Rotarix 2-Dose Group<br>Subjects received 1 dose of placebo followed by 2 doses of Rotarix™ vaccine given concomitantly with routine EPI vaccines. | Biological: Rotarix™<br>* Two or Three doses, oral administration<br>* Other names: GSK Biologicals' HRV vaccine;Biological: Placebo<br>* One or three doses, oral administration.<br>|
| Placebo Comparator: Placebo Group<br>Subjects received 3 doses of placebo given concomitantly with routine EPI vaccines. | Biological: Placebo<br>* One or three doses, oral administration.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Severe Rotavirus Gastroenteritis (RV GE) Caused by the Circulating Wild-type Rotavirus Strain | Number of subjects presenting with three or more looser than normal stools or watery stools within a day, occurring after administration of dose 1 of study vaccine in which rotavirus other than vaccine strain was identified in a stool sample with a score ≥ 11 on the 20-point Vesikari scoring system. | From 2 weeks after the last vaccine or placebo dose up to 1 year of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Severe Rotavirus Gastroenteritis Caused by the Circulating Wild-type Rotavirus Strain, Classified by Rotavirus Type | Number of subjects presenting with three or more looser than normal stools within a day, occurring after administration of dose 1 of study vaccine in which rotavirus other than vaccine strain was identified in a stool sample with a score ≥ 11 on the 20-point Vesikari scoring system. Rotavirus types were G1 wild type (WT) and non-G1. | From 2 weeks after the last vaccine or placebo dose up to 1 year of age | 
| Number of Subjects Reporting Any Rotavirus Gastroenteritis Caused by the Circulating Wild-type Rotavirus Strain | Number of subjects presenting with three or more looser than normal stools or watery stools within a day, occurring after administration of dose 1 of study vaccine in which rotavirus other than vaccine strain was identified in a stool sample. | From 2 weeks after the last vaccine or placebo dose up to 1 year of age | 
| Number of Subjects With Severe Rotavirus Gastroenteritis Caused by the Circulating Wild-type Rotavirus Strain | Number of subjects presenting with three or more looser than normal stools or watery stools within a day, occurring after administration of dose 1 of study vaccine in which rotavirus other than vaccine strain was identified in a stool sample with a score ≥ 11 on the 20-point Vesikari scoring system. | From the first vaccine or placebo dose up to 1 year of age | 
| In South Africa, Number of Subjects With Severe Rotavirus Gastroenteritis Caused by the Circulating Wild-type Rotavirus Strain | Number of subjects presenting with three or more looser than normal stools or watery stools within a day, occurring after administration of dose 1 of study vaccine in which rotavirus other than vaccine strain was identified in a stool sample with a score ≥ 11 on the 20-point Vesikari scoring system. | From 2 weeks after the third dose of vaccine or placebo up to 1 year of age | 
| Number of Subjects Reporting Severe Gastroenteritis of Any Cause | Number of subjects with gastroenteritis (three or more looser than normal stools or watery stools within a day) that scored ≥ 11 on the 20-point Vesikari scoring system. | From 2 weeks after the last vaccine or placebo dose up to 1 year of age | 
| Number of Subjects Hospitalized and/or With Supervised Re-hydration Therapy Due to Rotavirus Gastroenteritis (RV GE) Caused by the Circulating Wild-type Rotavirus Strain | RV GE caused by the circulating wild-type rotavirus strain: three or more looser than normal stools or watery stools within a day, occurring after administration of dose 1 of study vaccine in which rotavirus other than vaccine strain was identified in a stool sample collected as soon as possible after the symptoms begin. | From 2 weeks after the last vaccine or placebo dose up to 1 year of age | 
| For Subjects in Cohort 2 South Africa and the Cohort in Malawi: Number of Subjects With Severe Rotavirus Gastroenteritis (RV GE) Caused by the Circulating Wild-type Rotavirus Strains | Number of subjects presenting with three or more looser than normal stools or watery stools within a day, occurring after administration of dose 1 of study vaccine in which rotavirus other than vaccine strain was identified in a stool sample with a score ≥ 11 on the 20-point Vesikari scoring system. | During the period from 2 weeks after the last dose of vaccine or placebo until study end | 
| For Subjects in Cohort 2 South Africa and the Cohort in Malawi: Number of Subjects With Severe Rotavirus Gastroenteritis (RV GE) Caused by the Circulating Wild-type Rotavirus Strains | Number of subjects presenting with three or more looser than normal stools or watery stools within a day, occurring after administration of dose 1 of study vaccine in which rotavirus other than vaccine strain was identified in a stool sample with a score ≥ 11 on the 20-point Vesikari scoring system. | During the period from 1 year of age to study end | 
| For Subjects in Cohort 2 South Africa and the Cohort in Malawi: Number of Subjects Hospitalized and/or With Supervised Re-hydration Therapy Due to Rotavirus Gastroenteritis (RV GE) Episode Caused by the Circulating Wild-type RV Strains | RV GE caused by the circulating wild-type rotavirus strain: three or more looser than normal stools or watery stools within a day, occurring after administration of dose 1 of study vaccine in which rotavirus other than vaccine strain was identified in a stool sample collected as soon as possible after the symptoms begin. | During the period from 2 weeks after the last dose of vaccine or placebo until study end | 
| For Subjects in Cohort 2 South Africa and the Cohort in Malawi: Number of Subjects Hospitalized and/or With Supervised Re-hydration Therapy Due to Rotavirus Gastroenteritis (RV GE) Episode Caused by the Circulating Wild-type RV Strains | RV GE caused by the circulating wild-type rotavirus strain: three or more looser than normal stools or watery stools within a day, occurring after administration of dose 1 of study vaccine in which rotavirus other than vaccine strain was identified in a stool sample collected as soon as possible after the symptoms begin. | During the period from 1 year of age to study end | 
| For Subjects in Cohort 2 South Africa and the Cohort in Malawi: Number of Subjects With Severe Rotavirus Gastroenteritis Caused by the Circulating Wild-type Rotavirus Strains, Classified by Rotavirus Type | Number of subjects presenting with three or more looser than normal stools or watery stools within a day, occurring after administration of dose 1 of study vaccine in which rotavirus other than vaccine strain was identified in a stool sample with a score ≥ 11 on the 20-point Vesikari scoring system. Rotavirus types were G1 wild type (WT) and non-G1. | During the period from 2 weeks after the last dose of vaccine or placebo until study end | 
| For Subjects in Cohort 2 South Africa and the Cohort in Malawi: Number of Subjects With Severe Rotavirus Gastroenteritis Caused by the Circulating Wild-type Rotavirus Strains, Classified by Rotavirus Type | Number of subjects presenting with three or more looser than normal stools or watery stools within a day, occurring after administration of dose 1 of study vaccine in which rotavirus other than vaccine strain was identified in a stool sample with a score ≥ 11 on the 20-point Vesikari scoring system. Rotavirus types were G1 wild type (WT) and non-G1. | During the period from 1 year of age to study end | 
| Number of Subjects With Adverse Events (AEs) or Serious Adverse Events (SAEs) Leading to Drop Out | An AE is 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. An 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. | From the first dose of vaccine or placebo up to end of the study | 
| Number of Subjects Reporting Serious Adverse Events (SAEs) | An 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. | From the first dose of vaccine or placebo up to end of the study | 
| Geometric Mean Concentration of Anti-rotavirus Immunoglobulin A (IgA) Antibodies in Initially Seronegative Subjects | An initially seronegative subject is a subject whose IgA antibody concentration was below the assay cut-off value of 20 Units per milliliter (U/mL) before administration of the first vaccine dose. | One month after the last vaccine dose | 
| Number of Seroconverted Subjects | Seroconverted subjects are defined as subjects with appearance of anti-rotavirus IgA antibody concentration ≥ 20 U/mL in subjects initially (i.e. prior to the first dose of vaccine or placebo) seronegative for rotavirus. | One month after the last vaccine or placebo dose | 
| Geometric Mean Concentration of Anti-rotavirus Immunoglobulin A (IgA) Antibodies | Geometric mean concentrations are given as Units per milliliter (U/mL). | One month after the last vaccine or placebo dose | 
| Number of Seropositive Subjects | Seropositive subjects are defined as subjects with anti-rotavirus IgA antibody concentration ≥ 20 U/mL. | One month after the last vaccine or placebo dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HRV vaccine, Rotavirus gastroenteritis