Single Dose Oral Cholera Vaccine Study in Dhaka, Bangladesh

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Brief Title

Single Dose Oral Cholera Vaccine Study in Dhaka, Bangladesh

Official Title

An Individually Randomized, Placebo-controlled Trial to Measure the Protection Conferred by a Single Dose Regimen of Bivalent, Killed, Whole Cell Oral Cholera Vaccine (Shanchol™) in Dhaka, Bangladesh

Brief Summary

      Bangladesh remains endemic for cholera, which experiences biannual outbreaks with additional
      epidemics seen during times of floods, cyclones or any natural disaster. It affects all age
      groups with the majority of fatal cases occurring in children . Therefore, immunization
      against cholera remains an important public health component in the prevention and control of
      the disease .The current two-dose regimen of the internationally available oral cholera
      vaccines (OCV) create a logistical and programmatic challenge for use in national programs or
      during epidemics ,so it is important to determine if a single dose vaccine will be protective
      in regions where cholera is endemic. If the vaccine is found to be efficacious following a
      single dose, this will have profound implications for the use of the vaccine in areas with
      limited resources particularly in complex emergencies where a multiple dose regimen is
      difficult to deploy. A single-dose regimen of this vaccine will improve its 'field ability'
      and allow the vaccine to be used for outbreak control, especially in difficult settings where
      the risk of cholera is extremely high and provisions for clean water and sanitation are not
      available. With low OCV production rates, larger populations could be immunized against
      cholera if a single dose is found to be efficacious. A single-dose schedule could facilitate
      the inclusion of a global stockpile strategy.

      The study design is a two-arm individually randomized double-blind placebo-controlled trial.
      The primary outcome of the study is the proportion of persons receiving 1 dose of vaccine or
      placebo who are detected with diarrhea with faecal excretion of V. cholera O1 in the study
      treatment centres from 7 days to 6 months after dosage and whose identity is confirmed
      through home visit.
    

Detailed Description

      Background:

      Cholera is a serious public health problem worldwide. Recently, unprecedented outbreaks have
      been seen in many countries including Zimbabwe, Haiti, Pakistan, Nepal, Guinea, Cuba, Congo,
      and Sierra Leone. These cholera outbreaks cause undue suffering with high mortality and
      morbidity figures as well as economic and social disruption. Bangladesh remains endemic for
      cholera, which peaks biannually with further increases seen during floods and cyclones .It
      affects all age groups, although the majority of fatal cases occur in children. Therefore,
      immunization against cholera remains an important public health tool for preventing and
      controlling the disease .

      Considerable progress has been made during the last decade in the development of new
      generation oral vaccines against cholera. Dukoral , a killed whole cell V. cholerae O1 with
      recombinant B-subunit (rBS-WC), was the first to be licensed internationally and has been
      available mostly in developed countries as a traveller's vaccine. This vaccine is licensed in
      over 50 countries, including Bangladesh. The WHO now recommends Dukoral for both endemic and
      epidemic cholera. However, two disadvantages limit the broader use of Dukoral. First, its
      current price is high. Second, Dukoral needs to be administered with a buffer, which
      complicates large scale deployment.

      The Shanchol vaccine is licensed in India and the vaccine was prequalified by the WHO in
      2011.The technology for vaccine manufacturing has been transferred to Shantha Biotechnics in
      India (now owned by Sanofi) by IVI. A large double-blind placebo controlled phase III trial
      by NICED and IVI has evaluated the efficacy of the vaccine produced by Shantha in preventing
      diarrhea from cholera in 70,000 people in Kolkata. An analysis of the phase III trial after
      three years concluded that the vaccine was 66% efficacious . Advantages of the Shanchol™
      vaccine include that its cost is lower and does not require administration with buffer, thus
      making it more feasible for use in mass vaccination programs in resource poor settings.

      The current multi-dose schedules for both Dukoral and Shanchol™ have restricted the
      application of the oral cholera vaccine in situations where they are most needed. Getting a
      vaccine to the same people twice poses difficulties in the control of cholera in both endemic
      and epidemic settings. In a study performed in a cholera-endemic area in Kolkata, India it
      was found that Shanchol™ induces significant vibriocidal responses even after a single dose
      .This study is designed to determine the protective efficacy and duration of protection
      offered by a single dose regimen and is not intended to replace the recommended 2 dose
      regimen in endemic areas. This will be useful for epidemics and outbreaks situation.

      Study population:

      Mirpur has been selected for this study. Mirpur is a part of the Dhaka metropolitan area with
      an estimated population of over 2.5 million people. Different socio-economic groups of
      communities live in the area. The icddr,b hospitals treat more patients from Mirpur than from
      any other part of Dhaka. We have selected 9 wards in Mirpur (7-13, 15 and 41) for the study
      out of 16 wards. The selection has been based on the high number of cholera patients from
      these wards visiting the icddr,b hospitals over the last few years. Before starting the study
      we will commission a census of these high cholera incidence wards in Mirpur. The census team
      will create geographic information system (GIS) database by digitizing buildings and other
      structures in the target wards using satellite derived images. The digitized buildings and
      structures will be verified for ground verification. The census team will visit each building
      and ascertain whether or not people are living in the building. Based on this survey, the
      team will assess whether the people living in each building/structure are a high risk group
      or not. The census team then will collect verbal consent from the respondent and other
      information about the household . We will conduct a de jure census and will enumerate 324,178
      high risk residents from the target wards.

      Census of study population:

      A paperless data collection system will be used in the census survey and subsequent census
      updates will also be performed biannually using handheld devices, a Samsung tab ("TAB"). The
      demographic surveillance will be conducted by community health workers to update the
      population through vital demographic events including births, deaths, internal and external
      migrations.

      Name and description of study agents:

        1. Bivalent oral killed cholera vaccine: each dose of this vaccine contains V. cholerae O1
           Inaba El Tor strain Phil 6973 formalin killed 600 ELISA units (EU) of Lipopolysaccharide
           (LPS) V. cholerae O1 Ogawa classical strain Cairo 50 heat killed 300 EU of LPS V.
           cholerae O1 Ogawa classical strain Cairo 50 formalin killed 300 EU of LPS V. cholerae O1
           Inaba classical strain Cairo 48 heat killed 300 EU of LPS V. cholerae O139 strain 4260B
           formalin killed 600 EU of LPS

        2. Non Biological placebo: The composition of the placebo is as follows :

      Ingredients Per 1.5 ml dose Starch: 60mg Ponceau 4R dye : 0.019 mg Brilliant blue : 0.003mg
      Tetrazine dye : 0.02 mg Xanthum gum : 3 mg Preservative: 0.002%(w/v)of Thiomersal (equivalent
      to .03 mg per 1.5 ml) Water : Up to 1.5 ml

      Administration of vaccine or placebo:

      The agent to be received by the participants will be determined by the randomization number
      on the vial. Vials will be consecutively numbered, but individually randomized into the
      vaccine or placebo arm. After shaking the vial properly, it will be opened and given to the
      participant. The contents will be poured into the mouth by the recipient, followed by intake
      of a small volume of water.

      Census update:

      The census in the study population will be updated every six months after intervention with
      the study agents.

      Disease Surveillance:

      All patients from the study area presenting for care at the hospital with diarrhea will be
      included in routine hospital surveillance.The diarrheal disease surveillance for the project
      will be conducted at icddr,b hospitals at Mohakhali and Mirpur and other health facilities
      for patients coming from the Mirpur study area (wards 7-13 , 15 and 41). Clinical staff at
      each of the two hospitals and other facilities will evaluate each patient at the hospital
      triage area and provide treatment as per the routine procedure.

      Immunological assays using blood specimens from study participants:

      Blood: Immunological analyses will be conducted in a small subgroup (334 participants) of
      participants .To account for unblocked unique number coding, we plan on enrolling 500
      participants (less than 5 years, 5 to less than 15 years and 15 years of age or older; so as
      to obtain at least 108 in each age group) from the vaccination sites. Venous blood (2-5 ml)
      will be collected from these participants prior to immunization and 14 days after intake of
      the study agent.

      Active follow up for safety:

      We will select 6,000 participants purposively from the study participants after verbal
      consent is obtained. These 6,000 participants will be actively followed once every two weeks
      for safety outcomes for a 28 day period after study agent administration.

      Primary Analysis at 6 months of follow-up:

      Primary analysis will be planned at 6 months following dosing.

      Analysis at 6, 12, 18 and 24 months of follow-up:

      Primary analysis is to be performed at 6 months. The following available time points (12, 18
      and/or 24 months will be for secondary analysis points.

      Surveillance for 24 months Surveillance will be continued to complete 2 years of follow-up.
      Blinding will be maintained until the end of the follow-up period. The analysis at the 2
      years of follow-up point will still be performed in a blinded manner.

      Verbal Autopsy:

      We will carry out 'Verbal Autopsy' in our study area where deaths will be identified through
      a household search by home visits which will be conducted by study staff. We will use two
      questionnaires for verbal autopsy, one for children aged 1 year to 14 years and the other for
      person aged 15 years and above. After identification, trained medical professional will visit
      homes of the deceased to perform verbal autopsy.

      Pregnancy Outcome Study:

      Pregnancy status in married women will be ascertained at least two months after vaccination
      by home visits of trained field staff. Those who will be confirmed for pregnancy at this time
      point will be followed up at 6 months as well as with further visits monthly to ascertain
      pregnancy outcome after delivery. A pregnancy follow up questionnaire will be used after
      consent taking for these visits
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

Number of participants with a single dose regimen oral cholera vaccine Shanchol will get protection

Secondary Outcome

 Number of participants get protection with a single dose Shanchol after dosing against culture-proven V. cholerae O1 diarrhea

Condition

Cholera

Intervention

Shanchol

Study Arms / Comparison Groups

 Shanchol
Description:  

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

204438

Start Date

December 9, 2012

Completion Date

December 31, 2017

Primary Completion Date

December 1, 2017

Eligibility Criteria

        Inclusion Criteria:

        Healthy subjects > 1 year of age and above Living in high risk area for cholera Provision
        of Informed consent for participating in the study by participant /parent or guardian as
        well as verbal assent for children 11-17 years.

        Exclusion Criteria:

        Pregnant women Aged less than 1 year History of taking cholera vaccine
      

Gender

All

Ages

1 Year - N/A

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

, , 

Location Countries

Bangladesh

Location Countries

Bangladesh

Administrative Informations


NCT ID

NCT02027207

Organization ID

PR-12090


Responsible Party

Sponsor

Study Sponsor

International Centre for Diarrhoeal Disease Research, Bangladesh

Collaborators

 International Vaccine Institute

Study Sponsor

, , 


Verification Date

June 2015