Clinical trial NCT00241644: Vaccine Efficacy Against Rotavirus Diarrhea; Vaccine Given With Routine Childhood Vaccinations in Healthy African Infants
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Infections, Rotavirus
Keywords: Rotavirus gastroenteritis
HRV vaccine
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2005-10-19
Enrollment: 2089
Sex: ALL
Minimum age (years): 5
Maximum age (years): 10
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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.

Primary outcomes:
measure: Number of Subjects With Severe Rotavirus Gastroenteritis (RV GE) Caused by the Circulating Wild-type Rotavirus Strain
timeFrame: From 2 weeks after the last vaccine or placebo dose up to 1 year of age
Secondary outcomes:
measure: Number of Subjects With Severe Rotavirus Gastroenteritis Caused by the Circulating Wild-type Rotavirus Strain, Classified by Rotavirus Type
timeFrame: From 2 weeks after the last vaccine or placebo dose up to 1 year of age
measure: Number of Subjects Reporting Any Rotavirus Gastroenteritis Caused by the Circulating Wild-type Rotavirus Strain
timeFrame: From 2 weeks after the last vaccine or placebo dose up to 1 year of age
measure: Number of Subjects With Severe Rotavirus Gastroenteritis Caused by the Circulating Wild-type Rotavirus Strain
timeFrame: From the first vaccine or placebo dose up to 1 year of age
measure: In South Africa, Number of Subjects With Severe Rotavirus Gastroenteritis Caused by the Circulating Wild-type Rotavirus Strain
timeFrame: From 2 weeks after the third dose of vaccine or placebo up to 1 year of age
measure: Number of Subjects Reporting Severe Gastroenteritis of Any Cause
timeFrame: From 2 weeks after the last vaccine or placebo dose up to 1 year of age
measure: 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
timeFrame: From 2 weeks after the last vaccine or placebo dose up to 1 year of age
measure: 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
timeFrame: During the period from 2 weeks after the last dose of vaccine or placebo until study end
measure: 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
timeFrame: During the period from 1 year of age to study end
measure: 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
timeFrame: During the period from 2 weeks after the last dose of vaccine or placebo until study end
measure: 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
timeFrame: During the period from 1 year of age to study end
measure: 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
timeFrame: During the period from 2 weeks after the last dose of vaccine or placebo until study end
measure: 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
timeFrame: During the period from 1 year of age to study end
measure: Number of Subjects With Adverse Events (AEs) or Serious Adverse Events (SAEs) Leading to Drop Out
timeFrame: From the first dose of vaccine or placebo up to end of the study
measure: Number of Subjects Reporting Serious Adverse Events (SAEs)
timeFrame: From the first dose of vaccine or placebo up to end of the study
measure: Geometric Mean Concentration of Anti-rotavirus Immunoglobulin A (IgA) Antibodies in Initially Seronegative Subjects
timeFrame: One month after the last vaccine dose
measure: Number of Seroconverted Subjects
timeFrame: One month after the last vaccine or placebo dose
measure: Geometric Mean Concentration of Anti-rotavirus Immunoglobulin A (IgA) Antibodies
timeFrame: One month after the last vaccine or placebo dose
measure: Number of Seropositive Subjects
timeFrame: One month after the last vaccine or placebo dose
Other outcomes:
Locations:
city: Bangwe, Blantyre
country: Malawi
facility: GSK Investigational Site
city: Limbe, Blantyre
country: Malawi
facility: GSK Investigational Site
city: Ndirande, Blantyre
country: Malawi
facility: GSK Investigational Site
city: Zingwanga, Blantyre
country: Malawi
facility: GSK Investigational Site
city: Brits
country: South Africa
facility: GSK Investigational Site
city: Diepkloof, Soweto
country: South Africa
facility: GSK Investigational Site
city: Diepsloot
country: South Africa
facility: GSK Investigational Site
city: Eldorado Park Ext 9, Soweto
country: South Africa
facility: GSK Investigational Site
city: Karenpark
country: South Africa
facility: GSK Investigational Site
city: Mamelodi East
country: South Africa
facility: GSK Investigational Site
city: Mamelodi
country: South Africa
facility: GSK Investigational Site
city: Shoshanguve
country: South Africa
facility: GSK Investigational Site
city: Tembisa
country: South Africa
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.