Study to Assess the Efficacy, Immunogenicity and Safety of Liquid Human Rotavirus Vaccine, in Healthy Chinese Infants

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the efficacy, immunogenicity and safety of GSK Biologicals' liquid human rotavirus vaccine in healthy Chinese infants 6 to 16 weeks of age.

Detailed Description
-----------------
Subjects can receive routine childhood vaccination according to the expanded program of immunisation recommendations in China. There will be two treatment groups (liquid human rotavirus vaccine and placebo). The study will also have two immunogenicity subgroups comprising of few subjects from both the treatment groups. The immunogenicity subgroup 1 will assess the immunogenicity of the liquid human rotavirus vaccine and the immunogenicity subgroup 2 will assess the immunogenicity of liquid human rotavirus vaccine and also the immunogenicity of oral poliovirus vaccine and diphtheria tetanus and acellular pertussis vaccine given concomitantly with liquid human rotavirus vaccine or placebo. This protocol posting has been updated following the Protocol Amendment 2, dated 05 August 2011. The impacted section in the protocol posting is: Outcome Measures Section.

Official Title
-----------------
Efficacy, Immunogenicity and Safety of Two Doses of GlaxoSmithKline (GSK) Biologicals' Oral Live Attenuated Liquid Human Rotavirus (HRV) Vaccine (444563), in Healthy Infants

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

Intervention / Treatment
-----------------
* Biological: GSK Biologicals' liquid human rotavirus vaccine 444563
* Biological: Placebo
* Biological: Infanrix™
* Biological: Institute of Medical Biology Chinese Academy of Medical Sciences' Oral poliovirus vaccine (OPV)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects who the investigator believes that their parents/Legally Acceptable Representatives can and will comply with the requirements of the protocol. A male or female infant of Chinese origin between, and including, 6 and 16 weeks of age at the time of the first vaccination. Written informed consent obtained from the parents/Legally Acceptable Representatives of the subject. Healthy subjects as established by medical history and clinical examination before entering into the study. Born after a gestation period of 36 to 42 weeks inclusive. Exclusion Criteria: Child in care. Use of any investigational or non-registered product other than the study vaccine within 30 days preceding the first dose of study vaccine, or planned use during the study period. Chronic administration of immunosuppressants or other immune-modifying drugs since birth. Planned administration/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 the first dose of the human rotavirus vaccine or placebo except for the routine childhood vaccinations. 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. Any clinically significant history of gastrointestinal disease including any uncorrected congenital malformation (such as Meckel's diverticulum) of the gastrointestinal tract that would predispose for intussusception . Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination. Family history of congenital or hereditary immunodeficiency. History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine. Major congenital defects or serious chronic illness. History of confirmed rotavirus gastroenteritis. Acute disease and/or fever at the time of enrolment. Gastroenteritis within 7 days preceding the study vaccine or placebo administration. Administration of immunoglobulins and/or any blood products since birth or planned administration during the study period. In addition to the criteria mentioned above, the following criteria will be applicable to all subjects in the immunogenicity subgroup 2: History of diphtheria, tetanus and pertussis disease. History of seizures or progressive neurological disease. Previous vaccination against diphtheria, tetanus, pertussis and poliomyelitis.

Ages Eligible for Study
-----------------
Minimum Age: 6 Weeks
Maximum Age: 16 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 Group<br>Subjects aged between and including 6 and 16 weeks at the time of first vaccination received 2 doses of Rotarix™ vaccine, liquid formulation, at Day 0 and at Month 1. As part of the routine childhood vaccination according to the Expanded Program of Immunization (EPI) recommendations in China, subjects in this group also received 3 doses of Infanrix™ vaccine and 3 doses of the oral poliovirus vaccine manufactured by the Institute of Medical Biology of the Chinese Academy of Medical Sciences (OPV). The Infanrix™ and the OPV vaccines were administered independently of (Sub-cohort 1) or concomitantly with (Sub-cohort 2) the Rotarix™ vaccine. When administered concomitantly, subjects received the 3 doses of Infanrix™ vaccine at Months 1, 2 and 3, and the 3 doses of the OPV vaccine at Day 0, Month 1 and Month 2. The Rotarix™ and OPV vaccines were administered orally; the Infanrix™ vaccine was administered intramuscularly in the left anterolateral thigh. | Biological: GSK Biologicals' liquid human rotavirus vaccine 444563<br>* Oral administration<br>Biological: Infanrix™<br>* Intramuscular administration<br>* Other names: DTPa;Biological: Institute of Medical Biology Chinese Academy of Medical Sciences' Oral poliovirus vaccine (OPV)<br>* Oral administration<br>|
| Placebo Comparator: Placebo Group<br>Subjects aged between and including 6 and 16 weeks at the time of first vaccination received 2 doses of Placebo at Day 0 and at Month 1. As part of the routine childhood vaccination according to the Expanded Program of Immunization (EPI) recommendations in China, subjects in this group also received 3 doses of Infanrix™ vaccine and 3 doses of the oral poliovirus vaccine manufactured by the Institute of Medical Biology of the Chinese Academy of Medical Sciences (OPV). The Infanrix™ and the OPV vaccine were administered independently of (Sub-cohort 1) or concomitantly with (Sub-cohort 2) the Placebo. When administered concomitantly, subjects received the 3 doses of Infanrix™ vaccine at Months 1, 2 and 3, and the 3 doses of the OPV vaccine at Day 0, Month 1 and Month 2. The Placebo and the OPV vaccine were administered orally; the Infanrix™ vaccine was administered intramuscularly in the left anterolateral thigh. | Biological: Placebo<br>* Oral administration<br>Biological: Infanrix™<br>* Intramuscular administration<br>* Other names: DTPa;Biological: Institute of Medical Biology Chinese Academy of Medical Sciences' Oral poliovirus vaccine (OPV)<br>* Oral administration<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Severe Episode(s) of Rotavirus Gastroenteritis (RVGE) Caused by the Circulating Wild Type (WT) Strains | A gastroenteritis episode was classified positive for rotavirus (RV) and caused by the circulating wild-type (WT) RV strains if RV other than the vaccine strain was identified in a stool sample collected during the episode. Severe RVGE was defined as an episode of RV GE with score equal to or higher than (>=) 11 on a 20-point Vesikari scoring system. | From Month 1 ½ to Month 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Any Episode(s) of Rotavirus Gastroenteritis (RVGE) Caused by the Circulating Wild-type Strains | A gastroenteritis episode was classified positive for rotavirus (RV) and caused by the circulating wild-type (WT) RV strains if RV other than the vaccine strain was identified in a stool sample collected during the episode. | From Month 1 ½ to Month 21 | 
| Number of Subjects With Any Episode(s) of Rotavirus Gastroenteritis (RVGE) of Any Type. | A gastroenteritis episode was classified positive for rotavirus (RV) if RV was identified in a stool sample collected during the episode. RV types assessed were G1 Wild Type (G1WT), G2, G3, G9, GX (G type unknown, but not vaccine strain), P4, P8 Wild Type (P8WT), P9, PX (P type unknown, but not vaccine strain) and Pooled Non-G1WT. | From Month 1 ½ to Month 21 | 
| Number of Subjects With Severe Episode(s) of Rotavirus Gastroenteritis (RVGE) of Any Type. | A gastroenteritis episode was classified positive for rotavirus (RV) if RV was identified in a stool sample collected during the episode. Severe RVGE was defined as an episode of RVGE with score equal to or higher than (>=) 11 on a 20-point Vesikari scoring system. RV types assessed were G1 Wild Type (G1WT), G2, G3, G9, GX (G type unknown, but not vaccine strain), P4, P8 Wild Type (P8WT), P9, PX (P type unknown, but not vaccine strain) and Pooled Non-G1WT. | From Month 1 ½ to Month 21 | 
| Number of Subjects With Episodes of Rotavirus Gastroenteritis (RVGE) Caused by the Circulating Wild Type (WT) Strains Requiring Hospitalization | A gastroenteritis episode was classified positive for rotavirus (RV) and caused by the circulating WT RV strains if RV other than the vaccine strain was identified in a stool sample collected during the episode. | From Month 1 ½ to Month 21 | 
| Number of Subjects With Any and Severe Gastroenteritis (GE) Due to Any Cause | Severe GE was defined as an episode of GE with score equal to or higher than (>=) 11 on a 20-point Vesikari scoring system. This outcome measure concerns results for GE episodes due to any cause. | From Month 1 ½ to Month 21 | 
| Number of Subjects With Any Solicited General Symptoms Following Vaccination With the Rotarix Vaccine/Placebo | Assessed solicited general symptoms were fever,defined as axillary temperature (T) above or equal to [>=] 37.5 degrees Celsius [°C] (if GSK scale) or >= 37.1°C (if Chinese scale), fussiness/irritability, loss of appetite, cough/runny nose, diarrhea and vomiting. Any = any occurrence of the specified solicited general symptom regardless of the intensity grade or relationship to vaccination. This outcome measure was only assessed in subjects from Sub-cohort 1, who received the EPI vaccination independently of study vaccination with the Rotarix vaccine/placebo. | Within the 8-day (Days 0-7) follow-up periods after any dose of Rotarix vaccine/placebo | 
| Number of Subjects With Any Solicited General Symptoms Following Administration of the Co-administered EPI Vaccines | Solicited general symptoms assessed following administration of the co-administered EPI vaccines were drowsiness, gastrointestinal symptoms, fussiness/irritability, loss of appetite, and fever, defined as axillary temperature (T) above or equal to [>=] 37.5 degrees Celsius [°C] (if GSK scale) or >= 37.1°C (if Chinese scale ). Any = any occurrence of the specified solicited general symptom regardless of the intensity grade or relationship to vaccination. This outcome measure was only assessed in subjects from Sub-cohort 2, who received the EPI vaccination concomitantly with study vaccination with the Rotarix vaccine/placebo. | Within the 8-day (Days 0-7) follow-up periods following Doses 1 and 2 of the OPV vaccine and Dose 1 of the Infanrix vaccine | 
| Number of Subjects With Any Solicited Local Symptoms Following Dose 2 of the Rotarix Vaccine/Placebo | Solicited local symptoms assessed following administration of the co-administered EPI vaccines were pain, swelling, and redness. Any = any occurrence of the specified solicited local symptom regardless of the intensity grade. This outcome measure was only assessed in subjects from Sub-cohort 2, who received the EPI vaccination concomitantly with study vaccination with the Rotarix vaccine/placebo. | Within the 8-day (Days 0-7) follow-up periods following Dose 2 of the Rotarix vaccine/placebo | 
| Number of Subjects With Any Unsolicited Adverse Events (AEs) | An unsolicited AE 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. Any = occurrence of an unsolicited AE regardless of the intensity grade or relationship to vaccination. | Within the 31-day (Days 0-30) follow-up periods following any dose of the Rotarix vaccine or placebo | 
| Number of Subjects With Any Serious Adverse Events (SAEs) | SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, or result in disability/incapacity. Any = occurrence of an SAE regardless of the intensity grade or relationship to vaccination. | Throughout the entire study period (from Day 0 to Study End at Month 21) | 
| Number of Seroconverted Subjects for Anti-rotavirus (Anti-RV) Immunoglobulin A (IgA) Antibodies | A seroconverted subject was defined as a subject seronegative at baseline (Day 0) with the appearance of anti-RV IgA antibody concentration greater than or equal to (≥) 20 units per milliliter (U/mL) at the time point assessed. A seronegative subject was defined as a subject with anti-RV IgA antibody concentration lower than (<) 20 U/mL. | At Month 2 and at 12 months of age | 
| Number of Seroconverted Subjects for Anti-rotavirus (Anti-RV) Immunoglobulin A (IgA) Antibodies. | A seroconverted subject was defined as a subject seronegative at baseline (Day 0) with the appearance of anti-RV IgA antibody concentration greater than or equal to (≥) 20 units per milliliter (U/mL) at the time point assessed. A seronegative subject was defined as a subject with anti-RV IgA antibody concentration lower than (<) 20 U/mL. | At Month 2 and at 12 months of age | 
| Number of Subjects Seropositive for Anti-rotavirus (Anti-RV) Immunoglobulin A (IgA) Antibodies. | A subject seropositive for anti-rotavirus (anti-RV) immunoglobulin A (IgA) antibodies was defined as a subject anti-RV IgA antibody concentration greater than or equal to (≥) the seropositivity cut-off of 20 units per milliliter (U/mL). | At Day 0, Month 2 and at 12 months of age | 
| Anti-rotavirus (Anti-RV) Immunoglobulin A (IgA) Antibody Concentrations | Concentrations were expressed as geometric mean concentrations (GMCs), in units per milliliter (U/mL). The cut-off of the assay was the seropositivity cut-off (≥ 20 U/mL). | At Day 0, Month 2 and at 12 months of age | 
| Anti-rotavirus (Anti-RV) Immunoglobulin A (IgA) Antibody Concentrations. | Concentrations were expressed as geometric mean concentrations (GMCs), in units per milliliter (U/mL). The cut-off of the assay was the seropositivity cut-off (≥ 20 U/mL). | At Day 0, Month 2 and at 12 months of age. | 
| Anti-rotavirus (Anti-RV) Immunoglobulin A (IgA) Antibody Concentrations. | Concentrations were expressed as geometric mean concentrations (GMCs), in units per milliliter (U/mL). The cut-off of the assay was the seropositivity cut-off (≥ 20 U/mL). | At Day 0, Month 2 and at 12 months of age | 
| Number of Subjects Seroprotected Against Diphtheria and Tetanus | A subject seroprotected against diphtheria/tetanus was defined as a subject with an anti-diphtheria (anti-D)/anti-tetanus (anti-T) antibody concentrations greater than or equal to (≥) 0.1 international units per milliliter (IU/mL). This outcome measure concerns solely subjects in Sub-cohort 2, who received the EPI vaccination concomitantly with study vaccination with the Rotarix vaccine/placebo | At Day 0 and at Month 4 | 
| Anti-Diphtheria (Anti-D) and Anti-tetanus (Anti-T) Antibody Concentrations | Concentrations were expressed as geometric mean concentrations (GMCs) in international unit per milliliter (IU/mL). The cut-off of the assay was the seroprotection cut-off assay (≥ 0.1 IU/mL). This outcome measure concerns solely subjects in Sub-cohort 2, who received the EPI vaccination concomitantly with study vaccination with the Rotarix vaccine/placebo. | At Day 0 and at Month 4 | 
| Number of Subjects Seroprotected Against Poliovirus Types 1, 2 and 3. | A subject seroprotected against poliovirus types 1, 2 and 3 was defined as a subject with anti-poliovirus type 1 (anti-polio 1)/anti-polio 2/anti-polio 3 antibody titer greater than or equal to (≥) 8 estimated doses 50% (ED50). This outcome measure concerns solely subjects in Sub-cohort 2, who received the EPI vaccination concomitantly with study vaccination with the Rotarix vaccine/placebo (cf. population definition below). | At Day 0 and at Month 4 | 
| Titers for Anti-poliovirus Type 1 (Anti-polio 1), Anti-polio 2 and Anti-polio 3 Antibodies | Titers were expressed as geometric mean titers (GMTs). The cut-off of the assay was the seroprotection cut-off (≥ 8 estimated doses 50% [ED50] for anti-poliovirus type 1 [anti-polio 1]/anti-polio 2/anti-polio 3 antibodies. This outcome measure concerns solely subjects in Sub-cohort 2, who received the EPI vaccination concomitantly with study vaccination with the Rotarix vaccine/placebo. | At Day 0 and at Month 4 | 
| Number of Subjects Seropositive for Anti-pertussis Toxoid (Anti-PT), Anti-filamentous Haemagglutinin (Anti-FHA) and Anti-pertactin (Anti-PRN) Antibodies. | Antibody assessment was performed by enzyme-linked immunosorbent assay (ELISA). A subject seropositive for anti-PT/anti-FHA/anti-PRN antibodies was defined as a subject with an anti-PT/anti-FHA/anti-PRN antibody concentrations greater than or equal to (≥) 5 ELISA units per milliliter (EL.U/mL). This outcome measure concerns solely subjects in Sub-cohort 2, who received the EPI vaccination concomitantly with study vaccination with the Rotarix vaccine/placebo. | At Day 0 and at Month 4 | 
| Concentrations of Anti-pertussis Toxoid (Anti-PT), Anti-filamentous Haemagglutinin (Anti-FHA) and Anti-pertactin (Anti-PRN) Antibodies | Antibody assessment was performed by enzyme-linked immunosorbent assay (ELISA). Concentrations were expressed as geometric mean concentrations (GMCs) in ELISA units per milliliter (EL.U/mL). The cut-off of the assay was the seropositivity cut-off (≥ 5 EL.U/mL) for all antibodies assessed (anti-PT, anti-FHA and anti-PRN). This outcome measure concerns solely subjects in Sub-cohort 2, who received the EPI vaccination concomitantly with study vaccination with the Rotarix vaccine/placebo. | At Day 0 and at Month 4 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Liquid human retrovirus vaccine