Introduction of an Oral Live Human Rotavirus (Rotarix) Vaccine in Matlab
Condition: Rotavirus Gastroenteritis
MeSH terms: Gastroenteritis
Study type: Interventional
Phase: Phase 4

Summary: 
      The study will be conducted in the Matlab Health and Demographic Surveillance System (HDSS)
      field area of the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B)
      to determine the population effectiveness of Rotarix in Bangladeshi children. Villages in
      both intervention and government comparison areas will be included in this evaluation. We
      propose to introduce Rotarix into half of the villages of the Matlab HDSS. In villages
      randomized to receive the vaccine, all eligible children will be offered Rotarix during their
      first two Expanded Programme on Immunization (EPI) visits, as would routinely be done if
      Rotarix were included in the Government EPI schedule. In villages randomized not to receive
      Rotarix, children will receive their EPI vaccinations exactly as they would have in the
      absence of this study. Administration of Rotarix will be conducted by regular EPI staff, but
      ICDDR,B study staff will be present to document informed consent and collect study-specific
      information. The Ministry of Health will be an active partner in this evaluation since they
      will be the agency which may follow up with any subsequent vaccine programme. Vaccination
      with Rotarix will be recorded on the infant's immunization card which is normally used by the
      EPI programme, but also on a separate study-specific data collection form.

      Vaccination with Rotarix will continue from study initiation through June 30, 2011.
      Surveillance for rotavirus gastroenteritis will occur at Matlab Diarrhoeal Hospital and the
      community treatment centres of the Matlab HDSS continuously throughout the study period.
      Diarrheal illness information collected through surveillance will be linked to Rotarix
      study-specific data through the subject's HDSS identification numbers. The primary study
      endpoint will be the occurrence of an illness episode of acute diarrhoea, among infants and
      children admitted to a medical facility, determined to be caused by wild-type rotavirus found
      in a stool specimen. At the end of the surveillance period, rates of this primary study
      endpoint among age-eligible infants will be compared for villages randomized to receive
      Rotarix versus for villages randomized not to receive Rotarix. We expect that the rates of
      rotavirus diarrhoea will be significantly lower among children from the vaccinated villages.

      The first participant was enrolled in the study on September 23, 2008. Till date (May 12,
      2010) a total of 2,882 participants have been enrolled and received first dose. 2,684
      participants received second dose of Rotarix. There were 1013 cases gastroentritis reported
      to diarrhoeal treatment centres among <2 years old children from the vaccinated and
      unvaccinated villages. There were six death cases among the children who received Rotarix
      vaccine. These death cases were not related to the vaccines/study products.
    

Detailed description: 
      This trial will determine the population effectiveness of Rotarix in Bangladeshi infants. The
      study will be conducted in both the government comparison area and the intervention area of
      the Matlab HDSS. To carry out the evaluation, we will introduce the Rotarix vaccine into half
      of the villages of the HDSS area. In villages randomized to receive Rotarix, the study will
      be explained to parents and if they consent to their child's participation and the child is
      eligible, the child will receive two doses of Rotarix during their first two EPI visits
      (scheduled for 6 and 10 weeks of age), if possible, as would routinely be done if Rotarix
      were included in the government programme. Administration of Rotarix will be conducted by
      regular EPI staff, but ICDDR,B study staff will be present to document informed consent and
      collect study-specific information. Vaccination with Rotarix will be recorded on the infant's
      immunization card which is normally used by the EPI programme, but also on a separate
      study-specific data collection form. Participation in the study will not affect a subject's
      receipt of other routine childhood immunizations or other medical care. In villages
      randomized not to receive Rotarix, children will receive their EPI vaccinations exactly as
      they would have in the absence of this study.

      Surveillance for will be conducted at the Matlab Diarrhoeal Hospital and the two community
      treatment centres at Nayergaon and Kalirbazaar, which facilitate quick and easy accessibility
      of treatment for life-threatening diarrhoeal diseases from the HDSS area. The main study
      outcome will be episodes of rotavirus diarrhoea among children admitted to Matlab Diarrhoeal
      Hospital or either of the two community treatment centres (Nayergaon and Kalirbazaar). Study
      personnel will record the child's symptoms and clinical history, and collect a fecal specimen
      for laboratory testing for rotavirus. The identity of the child will be confirmed through the
      HDSS subject identification number system. All patients coming to the Matlab Diarrhoea
      Hospital and Nayergoan community treatment centre from these villages are already included in
      the Matlab diarrhoea surveillance system, and faecal samples are routinely tested for
      rotavirus and other pathogens, with results linked to demographic and health databases of the
      HDSS. Kalirbazaar treatment centre is not currently included in the current surveillance
      system, but we will establish surveillance at this centre during this study. For enrolled
      participants who present to one of the treatment facilities, illness information and test
      results will be linked to HDSS demographic data and study-specific data collected at
      enrolment through the subject's HDSS number. For residents not enrolled who present to a
      treatment facility, illness information will be linked only to HDSS demographic data, as is
      already being done as part of surveillance activities.

      Rates of acute gastroenteritis caused by rotavirus and other agents among age-eligible
      infants will be compared for infants (vaccinated and unvaccinated) from villages randomized
      to receive Rotarix versus for those (unvaccinated) from villages randomized not to receive
      Rotarix. We expect that the rates of diarrhoea will be significantly lower among children
      from the vaccinated villages, but that rates of diarrhoea caused by other pathogens may be
      similar. (This second analysis - a "control analysis" - will be helpful to verify a lack of
      bias in health seeking behaviours since one would expect that cholera, ETEC, Salmonella and
      Shigella gastroenteritis rates would be similar in the two groups.). These cases will be
      detected from all patients of all ages who come to the Matlab Diarrhoeal Hospital or the
      community treatment centres (Nayergaon or Kalirbazaar), but the primary analysis will include
      only those rotavirus diarrhoea cases among children who had been age-eligible for vaccination
      in their respective villages.

      Although not a blinded evaluation, the introduction of bias will be reduced in several ways.
      First, the vaccine teams located in the EPI centres that are completely separate from the
      clinical settings where clinicians will be conducting surveillance. Second, the clinicians
      are separated from those scientists conducting laboratory testing. Third, laboratory assays
      for rotavirus will be carried out in the laboratory in Dhaka using coded specimens and are
      not conducted at the time of illness (since they have little clinical value). Although a
      parent could inform the clinician as to his/her child's participation in the study, this is
      believed to be an unlikely or important source of bias for two reasons. One, most rotavirus
      gastroenteritis is not seen until later than 6 months after an infant's second dose of
      Rotarix, and there will be no active follow-up among parents after last receipt of Rotarix.
      Thus, there is a reduced likelihood that parents will remember that their child had received
      a vaccination targeted specifically against one type of severe diarrhoea. Second, Matlab
      Diarrhoeal Hospital and the community treatment centres have been caring for severe diarrhoea
      for many years and the entire community is already accustomed to attending the facilities for
      such illnesses. Thus, there is a reduced likelihood parents of vaccinated and unvaccinated
      infants are going to have differential diarrhoeal illness treatment-seeking behaviors.

      Again, the study will be conducted in both the government comparison area and the
      intervention area of Matlab HDSS. Enrolment will begin in the government comparison area no
      later than June 1, 2008. Enrolment will begin in the intervention area January 1, 2009.
      Surveillance for rotavirus diarrhoea will occur continuously and concurrently to enrolment
      activities. Enrolment in both areas will cease on June 30, 2010, but surveillance for
      rotavirus gastroenteritis will occur until December 31, 2010.

      By in January 1, 2009, it is expected that less than 15% of children less than 2 years of age
      in the intervention area will have received Rotateq in the Merck trial. Nonetheless, we will
      stratify randomization within the intervention area by rates of participation in that trial
      for each village. Additionally, because we will have the full dataset for Matlab for the
      Rotateq trial, we will be able to analyze any impact of that Rotateq trial on the Rotarix
      evaluation within the intervention area.
    

Intervention name(s): Rotavirus Vaccine (ROTARIX)
Intervention type(s): Biological
Intervention description(s): Rotavirus Vaccine two doses four weeks apart
Other intervention name(s): ROTARIX
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: vaccine effectiveness, rotavirus, diarrhoea, Bangladesh