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

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

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.

Study Overview

• Status: Completed
• Conditions: Infections, Rotavirus
• Intervention / Treatment: Biological: Rotarix™; Biological: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 2089
• Phase: Phase 3

Contacts and Locations

Study Locations

• Malawi
  • Bangwe, Blantyre, Malawi, 3
    • GSK Investigational Site
  • Limbe, Blantyre, Malawi, 3
    • GSK Investigational Site
  • Ndirande, Blantyre, Malawi, 3
    • GSK Investigational Site
  • Zingwanga, Blantyre, Malawi, 3
    • GSK Investigational Site
• South Africa
  • Brits, South Africa, 0250
    • GSK Investigational Site
  • Diepkloof, Soweto, South Africa
    • GSK Investigational Site
  • Diepsloot, South Africa
    • GSK Investigational Site
  • Eldorado Park Ext 9, Soweto, South Africa
    • GSK Investigational Site
  • Karenpark, South Africa, 0118
    • GSK Investigational Site
  • Mamelodi, South Africa
    • GSK Investigational Site
  • Mamelodi East, South Africa
    • GSK Investigational Site
  • Shoshanguve, South Africa
    • GSK Investigational Site
  • Tembisa, South Africa
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 2 months (Child)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

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

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

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Madhi SA, Cunliffe NA, Steele D, Witte D, Kirsten M, Louw C, Ngwira B, Victor JC, Gillard PH, Cheuvart BB, Han HH, Neuzil KM. Effect of human rotavirus vaccine on severe diarrhea in African infants. N Engl J Med. 2010 Jan 28;362(4):289-98. doi: 10.1056/NEJMoa0904797.
• Gruber JF, Becker-Dreps S, Hudgens MG, Brookhart MA, Thomas JC, Jonsson Funk M. Timing and predictors of severe rotavirus gastroenteritis among unvaccinated infants in low- and middle-income countries. Epidemiol Infect. 2018 Apr;146(6):698-704. doi: 10.1017/S0950268818000626. Epub 2018 Mar 22.
• Cunliffe N et al. Efficacy of human rotavirus vaccine RIX4414 in Africa during the first year of life. Abstract presented at the 27th Annual Meeting of the European Society for Paediatric Infectious Disease (ESPID), Brussels, Belgium, 9-13 June 2009.
• Cunliffe NA, Witte D, Ngwira BM, Todd S, Bostock NJ, Turner AM, Chimpeni P, Victor JC, Steele AD, Bouckenooghe A, Neuzil KM. Efficacy of human rotavirus vaccine against severe gastroenteritis in Malawian children in the first two years of life: a randomized, double-blind, placebo controlled trial. Vaccine. 2012 Apr 27;30 Suppl 1(0 1):A36-43. doi: 10.1016/j.vaccine.2011.09.120.
• Cunliffe NA et al. Efficacy of Human Rotavirus Vaccine RIX4414 in Malawian Infants in the first two years of life. Abstract presented at the 6th African Rotavirus Symposium, Johannesburg, South Africa, 2-3 August 2010.
• Madhi S et al. Efficacy of the human rotavirus vaccine RIX4414 against rotavirus G2P[4]/g8p[4] strains in South African infants. Abstract presented at the 6th world congress of the World Society for Pediatric Infectious Diseases (WSPID), Buenos Aires, Argentina, 18-22 November 2009.
• Madhi SA, Kirsten M, Louw C, Bos P, Aspinall S, Bouckenooghe A, Neuzil KM, Steele AD. Efficacy and immunogenicity of two or three dose rotavirus-vaccine regimen in South African children over two consecutive rotavirus-seasons: a randomized, double-blind, placebo-controlled trial. Vaccine. 2012 Apr 27;30 Suppl 1:A44-51. doi: 10.1016/j.vaccine.2011.08.080.
• Nakagomi T, Nakagomi O, Dove W, Doan YH, Witte D, Ngwira B, Todd S, Duncan Steele A, Neuzil KM, Cunliffe NA. Molecular characterization of rotavirus strains detected during a clinical trial of a human rotavirus vaccine in Blantyre, Malawi. Vaccine. 2012 Apr 27;30 Suppl 1(0 1):A140-51. doi: 10.1016/j.vaccine.2011.09.119.
• Neuzil K et al. Immunogenicity of human rotavirus vaccine RIX4414 in South African and Malawian infants. Abstract presented at the 6th world congress of the World Society for Pediatric Infectious Diseases (WSPID), Buenos Aires, Argentina, 18-22 November 2009.
• Neuzil K et al. RIX4414 is protective against severe RVGE caused by diverse rotavirus serotypes during the first year of life in African infants. Abstract presented at the 27th Annual Meeting of the European Society for Paediatric Infectious Disease (ESPID), Brussels, Belgium, 9-13 June 2009.
• Steele AD et al. Efficacy of human rotavirus vaccine, Rotarix™ against severe gastroenteritis caused by diverse circulating rotavirus strains in African infants. Abstract presented at the 7th World Congress for World Society for Pediatric Infectious Diseases (WSPID). Melbourne, Australia, 16-19 November 2011.
• Steele D et al. Diverse circulating rotavirus strains during the first year of life in African infants. Abstract presented at 10th International symposium on dsRNA Viruses, Hamilton Island, QLD, Australia, 21-25 June 2009.
• Madhi SA, Cunliffe NA, Steele D, Witte D, Kirsten M, Louw C, Ngwira B, Victor JC, Gillard PH, Cheuvart BB, Han HH, Neuzil KM. Effect of human rotavirus vaccine on severe diarrhea in African infants. Malawi Med J. 2016 Sep;28(3):108-114.
• Steele AD, Neuzil KM, Cunliffe NA, Madhi SA, Bos P, Ngwira B, Witte D, Todd S, Louw C, Kirsten M, Aspinall S, Van Doorn LJ, Bouckenooghe A, Suryakiran PV, Han HH. Human rotavirus vaccine Rotarix provides protection against diverse circulating rotavirus strains in African infants: a randomized controlled trial. BMC Infect Dis. 2012 Sep 13;12:213. doi: 10.1186/1471-2334-12-213.

Helpful Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Study record dates

Study Major Dates

• Study Start: October 1, 2005
• Primary Completion (Actual): June 1, 2008
• Study Completion (Actual): June 1, 2008

Study Registration Dates

• First Submitted: October 18, 2005
• First Submitted That Met QC Criteria: October 18, 2005
• First Posted (Estimate): October 19, 2005

Study Record Updates

• Last Update Posted (Estimate): December 9, 2016
• Last Update Submitted That Met QC Criteria: October 27, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: HRV vaccine; Rotavirus gastroenteritis
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Reoviridae Infections; Rotavirus Infections; Physiological Effects of Drugs; Immunologic Factors; Vaccines
• Other Study ID Numbers: 102248

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

1. Individual Participant Data Set
   Information identifier: 102248
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register. The results of this study 102248 are summarised with study 111274 on the GSK Clinical Study Register.
2. Informed Consent Form
   Information identifier: 102248
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Statistical Analysis Plan
   Information identifier: 102248
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Dataset Specification
   Information identifier: 102248
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Annotated Case Report Form
   Information identifier: 102248
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Clinical Study Report
   Information identifier: 102248
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Study Protocol
   Information identifier: 102248
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register