Evaluation of Immunogenicity and Safety of Two Formulations of GSK Biologicals' Human Rotavirus (HRV) Vaccine (444563), in Healthy Infants Starting at Age 6-12 Weeks

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the clinical consistency of three production lots of the Porcine circovirus (PCV)-free liquid formulation of oral live attenuated human rotavirus (HRV) vaccine and to evaluate the PCV-free liquid formulation of HRV vaccine as compared to the currently licensed lyophilised formulation of the HRV vaccine in terms of immunogenicity, reactogenicity and safety when administered as a two-dose vaccination in healthy infants starting at age 6-12 weeks. No new subjects will be enrolled in the extension phase of the study.

Detailed Description
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Experimental design: Phase IIIA, observer-blind, randomised (1:1:1:1), controlled, multi-centric, with four parallel groups and a staggered enrolment (Part A and Part B). Duration of the study: The intended duration of the study, per subject, will be approximately 7-8 months including the 6 months of extended safety follow-up period after the last dose of HRV vaccine. Epoch 001: Primary starting at Visit 1 (Day 0) and ending at the safety follow-up contact (Month 7-8). Primary completion Date (PCD): Visit 3 (Month 2-4). End of Study (EoS): Last testing results released of samples collected at Visit 3 or Last Subject Last Visit (LSLV) (Follow up contact at month 7-8). Study Groups: PCV-free HRV liquid formulation lot A (also referred to as Liq_A Group) PCV-free HRV liquid formulation lot B (also referred to as Liq_B Group) PCV-free HRV liquid formulation lot C (also referred to as Liq_C Group) GSK Biologicals' currently licensed lyophilised HRV formulation (also referred to as Lyo Group) Control:active control-GSK Biologicals' currently licensed lyophilised HRV vaccine Vaccination schedule: Two doses of HRV vaccine to be administered according to a 0, 1-2 month schedule according to the immunisation schedule for RV vaccine. Note that as a result of internal change in data standards terminology, the study data collected was converted to cDISC and the statistical analysis plan was amended accordingly. Day 0 in the study design was replaced by Day 1; consequently, Day n was replaced by Day n+1. Thus, the time frames (Day 0, Day n) of Outcome Measures described in this study record are different to that denoted in the full protocol document posted.

Official Title
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Immunogenicity and Safety Study of Two Formulations of GlaxoSmithKline (GSK) Biologicals' Human Rotavirus (HRV) Vaccine (444563), in Healthy Infants Starting at Age 6-12 Weeks

Conditions
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Infections, Rotavirus, Rotavirus Vaccines

Intervention / Treatment
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* Biological: HRV PCV-free liquid vaccine
* Biological: Rotarix


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects' parent(s)/LAR(s) who, in the opinion of the investigator can and will comply with the requirements of the protocol. Written informed consent obtained from the parent(s)/LAR(s) (Legally acceptable representatives) of the subject prior to performing any study specific procedure. A male or female infant between, and including, 6 and 12 weeks (42-90 days) of age at the time of the first study vaccination. Born full-term (i.e., between a gestation period of 37 weeks 0 days and 41 weeks 6 days). Healthy subjects as established by medical history and clinical examination before entering into the study. Exclusion Criteria: Child in care Use of any investigational or non-registered product other than the study vaccines during the period starting 30 days before the first dose of study vaccines (Day-29 to Day 0), or planned use during the study period. Chronic administration of immunosuppressants or other immune-modifying drugs since birth. For corticosteroids, this will mean prednisone (0.5 mg/kg/day, or equivalent). Inhaled and topical steroids are allowed. Administration of immunoglobulins and/or any blood products since birth or planned administration during the study period. Administration of long-acting immune-modifying drugs at any time during the study period. Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting 30 days before the first dose of vaccine administration and ending at Visit 3, with the exception of the inactivated influenza vaccine, which is allowed at any time during the study and other licensed 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 vaccine/product. Uncorrected congenital malformation of the gastrointestinal tract that would predispose for Intussusception (IS). History of IS. Family history of congenital or hereditary immunodeficiency. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination. Major congenital defects or serious chronic illness. Previous vaccination against RV. Previous confirmed occurrence of RVGE. GE within 7 days preceding the study vaccine administration. History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccines. Hypersensitivity to latex. Acute disease and/or fever at the time of enrolment. Fever is defined as temperature ≥38.0°C/100.4°F. The preferred location for measuring temperature in this study will be the oral cavity, the axilla and the rectum. Subjects with a minor illness (such as mild diarrhoea, mild upper respiratory infection) without fever may be enrolled at the discretion of the investigator.

Ages Eligible for Study
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Minimum Age: 6 Weeks
Maximum Age: 12 Weeks

Sexes Eligible for Study
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All

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Liq_A Group<br>All subjects will receive two doses of PCV-free HRV liquid formulation lot A, at 6 and 12 weeks of age | Biological: HRV PCV-free liquid vaccine<br>* Subjects will receive two doses of PCV-free HRV vaccine at 6 and 12 weeks of age. The vaccine will be administered orally<br>|
| Experimental: Liq_B Group<br>All subjects will receive two doses of PCV-free HRV liquid formulation lot B, at 6 and 12 weeks of age | Biological: HRV PCV-free liquid vaccine<br>* Subjects will receive two doses of PCV-free HRV vaccine at 6 and 12 weeks of age. The vaccine will be administered orally<br>|
| Experimental: Liq_C Group<br>All subjects will receive two doses of PCV-free HRV liquid formulation lot C, at 6 and 12 weeks of age | Biological: HRV PCV-free liquid vaccine<br>* Subjects will receive two doses of PCV-free HRV vaccine at 6 and 12 weeks of age. The vaccine will be administered orally<br>|
| Active Comparator: Lyo Group<br>All subjects will receive two doses of currently licensed lyophilised HRV vaccine, at 6 and 12 weeks of age | Biological: Rotarix<br>* Subjects will receive two doses of currently licensed lyophilised HRV vaccine at 6 and 12 weeks of age. The vaccine will be administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-Rota Virus (Anti-RV) Immunoglobulin A (IgA) Antibody Concentrations in the Human Rotavirus (HRV) Liquid Formulation Groups (Liq_A, Liq_B and Liq_C) | Antibody concentrations against Rota Virus (RV) were determined as Geometric Mean Antibody Concentration (GMC) and expressed as Units per milliliter (U/mL). | At Month 2-4 (i.e. approximately 1-month or 2-months after second dose of HRV vaccine according to the immunisation schedule for RV vaccine administration in participating countries) | 
| Percentage of Seroconverted Subjects With RV Antibody Concentrations Above or Equal to Cut-off Value in Porcine Circovirus (PCV) -Free Liquid HRV Vaccine (Pooled HRV Liquid Group) and Control Group | Seroconversion rate (SCR) was defined as the percentage of subjects who were initially seronegative (i.e., with anti-RV IgA antibody concentration less than (<) 20 U/mL before the first dose of HRV vaccine) and developed anti-RV IgA antibody concentration greater than or equal to (≥) 20 U/mL at Month 2-4 (1-2 months after dose 2). SCR was analysed using Enzyme Linked Immunosorbent Assay (ELISA). For this outcome measure, the three groups (Liq_A, Liq_B & Liq_C) were pooled into a single group (Liq_Pool group) as they all received PCV free-liquid HRV vaccine, and as pre-specified in the protocol, the immunological non-inferiority of the Liq_Pool group was compared to the currently licensed lyophilized HRV vaccine (Lyo_Control group) in terms of seroconversion rates of 1-2 months after Dose 2. | At Month 2-4 (i.e. approximately 1-month or 2-months after second dose of HRV vaccine according to the immunisation schedule for RV vaccine administration in participating countries) | 
| Percentage of Seroconverted Subjects With RV Antibody Concentrations Above or Equal to 20 U/mL in Porcine Circovirus (PCV)-Free Liquid HRV Vaccine (Individual HRV Liquid Groups) and Lyophilised Control Group | Seroconversion rate (SCR) was defined as the percentage of subjects who were initially seronegative (i.e., with anti-RV IgA antibody concentration less than (<) 20 U/mL before the first dose of HRV vaccine) and developed anti-RV IgA antibody concentration greater than or equal to (≥) 20 U/mL at Month 2-4 (1-2 months after dose 2). SCR was analysed using Enzyme Linked Immunosorbent Assay (ELISA). The analysis was assessed to demonstrate the immunogenicity of PCV-free liquid HRV vaccine as compared to the currently licensed lyophilised HRV vaccine (individual HRV liquid groups) in terms of seroconversion rates 1-2 months after Dose 2. | At Month 2-4 (i.e. approximately 1-month or 2-months after second dose of HRV vaccine according to the immunisation schedule for RV vaccine administration in participating countries) | 
| Anti-RV IgA Antibody Concentrations in the PCV-free Liquid HRV Vaccine (Pooled HRV Liquid Group) and Lyophilised Control Group | Antibody concentrations against RV were determined as GMCs and expressed as U/mL. For this outcome measure, the three groups (Liq_A, Liq_B & Liq_C) were pooled into a single group (Liq_Pool group) as they all received PCV free-liquid HRV vaccine, and as pre-specified in the protocol, the immunological non-inferiority of the Liq_Pool group was compared to the currently licensed lyophilized HRV vaccine (Lyo_Control group) in terms of antibody concentrations at 1-2 months after Dose 2. | At Month 2-4 (i.e. approximately 1-month or 2-months after second dose of HRV vaccine according to the immunisation schedule for RV vaccine administration in participating countries) | 
| Anti-RV IgA Antibody Concentrations in the PCV-free Liquid HRV Vaccine (Individual HRV Liquid Groups) and Lyophilised Control Group | Antibody concentrations against RV were determined as GMCs and expressed as U/mL. The analysis was assessed to demonstrate the immunogenicity of the PCV-free liquid HRV vaccine (individual HRV liquid groups) to that of the currently licensed lyophilised HRV vaccine in terms of serum anti-RV IgA antibody concentrations 1-2 months after Dose 2. | At Month 2-4 (i.e. approximately 1-month or 2-months after second dose of HRV vaccine according to the immunisation schedule for RV vaccine administration in participating countries) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With Anti-RV IgA Concentrations (Pooled HRV Liquid Group) | Antibody concentrations ≥90 U/mL were determined and expressed as GMCs, assessed for the pooled HRV liquid groups and Control Group. The GMC calculations were performed by taking the anti-log of the mean of the log concentration transformations. For this outcome measure, the three groups (Liq_A, Liq_B & Liq_C) were pooled into a single group (Liq_Pool group) as they all received PCV free-liquid HRV vaccine, and as pre-specified in the protocol, the immunogenicity of the Liq_Pool group was compared to the currently licensed lyophilized HRV vaccine (Lyo_Control group) in terms of percentage of subjects with anti-RV IgA antibody concentrations ≥ 90 U/mL, 1-2 months after Dose 2 | At Month 2-4 (i.e. approximately 1-month or 2-months after second dose of HRV vaccine according to the immunisation schedule for RV vaccine administration in participating countries) | 
| Percentage of Subjects With Anti-RV IgA Concentrations (Individual HRV Liquid Groups) | Antibody concentrations ≥90 U/mL were determined and expressed as GMCs, assessed for the individual HRV liquid groups and Control Group. The GMC calculations were performed by taking the anti-log of the mean of the log concentration transformations. The analysis was performed to assess the immunogenicity of the PCV-free liquid HRV vaccine (pooled HRV liquid groups) and the currently licensed lyophilised HRV vaccine, in terms of percentage of subjects with anti-RV IgA antibody concentrations ≥ 90 U/mL 1-2 months after Dose 2. | At Month 2-4 (i.e. approximately 1-month or 2-months after second dose of HRV vaccine according to the immunisation schedule for RV vaccine administration in participating countries) | 
| Number of Subjects With Any Solicited General Adverse Events (AEs). | Assessed solicited general AEs were cough/runny nose, diarrhea, fever (defined as temperature ≥ 38.0°C), irritability/fussiness, loss of appetite and vomiting. Any solicited general AE is defined as any occurrence of the specified symptom, irrespective of intensity grade and relationship to vaccination. | During the 8 days (Day 1 to Day 8) follow-up period after each dose of HRV vaccine | 
| Number of Subjects With Any Unsolicited AEs. | 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. Any is defined as the occurrence of any unsolicited AE irrespective of its intensity grade and relationship to vaccination. | During the 31 day (Day 1 to Day 31) follow-up period after HRV vaccination across doses | 
| Number of Subjects With Any Serious Adverse Events (SAEs) | SAEs assessed include any untoward medical occurrence that resulted in death, were life-threatening, required hospitalization or prolongation of existing hospitalization or resulted in disability/incapacity. | During the entire study period (Day 1 to Month 7-8) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Safety, Healthy infants, Immunogenicity, Human Rotavirus (HRV)