To Determine the Safety and Immunogenicity of an Oral Whole Cell ShanChol Cholera Vaccine in Bangladesh
Condition: Healthy
MeSH terms: Cholera
Study type: Interventional
Phase: Phase 2

Summary: 
      Background: Severe dehydrating cholera due to V. cholerae O1 is an important public health
      problem in Bangladesh and many other developing countries. V. cholerae O1 is a major
      bacterial pathogen causing around 5 million cases and at least 200,000 deaths in adults and
      children each year. It can be assumed that there are at least 300,000 severe cases and 1.2
      million infections in people in Bangladesh alone. The rate of cholera varies from around 1 to
      8 per 1000 population and the highest attack rate is in children 2- to 9-year years of age .
      Cholera is now also being documented in very young children. Currently enteric vaccine
      approaches are regarded as the most accessible short term and practical means to prevent and
      control such illnesses to prevent disease and epidemics in resource poor settings with
      limited public health and sanitary facilities.

      An effective inactivated whole cell bivalent cholera vaccine against Vibrio cholerae O1 and
      O139 was produced and implemented for public health purposes in Vietnam since the 1990s. This
      bivalent vaccine has been found to be safe and to confer significant protection against El
      Tor cholera in both children and adults and has over the last decade being used in the
      Vietnam to protect against cholera. This vaccine has further been reformulated by the IVI to
      meet WHO requirements and is now being produced in WHO prequalified vaccine company in India.

      The reformulated vaccine has been shown to be safe and immunogenic in Indian children as well
      as adults. A large Phase III study of the vaccine, has recently been carried out in Kolkata,
      India in over 120,000 participants aged from one year and above. Results of the study are
      encouraging and the vaccine gives over 60% protection against cholera. The vibriocidal
      antibody response rate was 80% in children and 53% in adults. Following this study, the
      vaccine, designated as ShanChol has been licensed in India in April 2009. The vaccine is now
      being marketed in India and is available at a cost affordable for developing country
      settings.

      Objective: The aim of the proposed study is to assess if the orally administered, killed,
      bivalent whole-cell cholera vaccine, ShanChol will be safe and immunogenic in different age
      groups in Bangladesh in children and adults.

      Study design: This will be a randomized, double blind, placebo-controlled study on a total of
      330 subjects, 165 vaccine and 165 placebo recipients. The specific aims will be to determine:
      i) safety and determine adverse events if any (ii) determine immune responses.

      Relevance: The study of ShanChol on Bangladeshi children and adults will be able to give
      information regarding the safety and immunogenicity of the vaccine in Bangladeshi subjects.
      This information will be important for proceeding with larger studies in Bangladesh and if
      proven useful for introduction the cholera vaccine in the country in the future.
    

Detailed description: 
      Adults as well as children, both males and females will be recruited in the study from the
      urban suburbs around Dhaka city in Mirpur where we have been conducting other epidemiological
      and vaccine related studies. The community will be informed by our field staffs and
      interested persons might be enrolled in the study on the basis of inclusion/exclusion
      criteria.

      Part I- Adults- 18-45 years of age (n=110):

      Since this oral bivalent whole-cell cholera vaccine has not been tested in Bangladesh before,
      the study will be carried out in 3 age groups, i.e. adults, followed by toddlers and younger
      children. These study participants will be recruited from the field site in Mirpur. For this
      purpose, 55 adults (18-45 year old) will be given 2 doses of the bivalent whole-cell cholera
      vaccine and 55 adults will be given placebo. Safety will be clinically monitored for side
      effects for 3 days after each dose of study agent by home visits. Participants will be
      randomized to receive either 2 doses of the vaccine or placebo, given 14 days apart.

      Part II- Children 2-5 years (n=110):

      If the vaccine is found safe in the adult study, it will be tested in the toddlers in the
      field consisting of 55 children in each group. The children will be clinically monitored for
      side effects for 3 days after each dose of vaccine.

      Part III- Children 12-23 months (n=110):

      Children in the field site will be recruited for the study and study carried out as described
      above.

      Study procedure:

      Each phase of the study (Part I onwards) will be completed and based on the development, and
      progress, the next phase will be initiated. If the vaccine is found to be without adverse
      effects on the adults it will be tested in the children, 2-5 years of age and followed by the
      younger age group 12-23 months of age. The results will be presented to the Data Safety
      Monitoring Board after completing the safety surveillance part of each phase of the study and
      before proceeding to the next study group.

      Surveillance for side effects:

      The safety of the study agents will be monitored after the intervention has been initiated.
      In the community, supervision will be carried out by the physician and the trained research
      assistants and adverse reactions including diarrhea, vomiting, nausea and other local and
      systemic reactions recorded. For the all three groups, 3 consecutive days after the each dose
      of study agent, the participants or their guardians will be interviewed for recall of
      symptoms by health workers. All side-effects will be recorded up to 28 days in reaction
      surveillance forms for local and systemic reactions. If any adverse event or serious adverse
      events notified within the study period field clinic will be available for reporting and
      possible management of the event. Reported symptoms other than appetite loss will be graded
      as mild (noticeable), moderate (affecting normal daily activities) or severe (suspending
      normal daily activities). A clinical record form will be used to record all clinical signs
      and symptoms. In case of serious adverse effects the data will be entered in a separate form
      . If required the study subject will be hospitalized at the Mirpur Treatment Center or the
      ICDDR,B Dhaka Hospital under supervision of the study physicians..

      Safety endpoint and safety evaluation:

      The primary end point for evaluating safety will be defined as the occurrence of any of the
      following diarrhoea, vomiting or abdominal cramps of at least moderate grade. Diarrhea will
      be defined as three or more loose or liquid stools in any 24-h period over the 3 day
      surveillance period.

      STUDY INTERVENTION Vaccine Each dose of the vaccine contains whole cell inactivated heat
      killed and formalin killed bacteria consisting of 600 ELISA Units (EU) of lipopolysaccharide
      (LPS). It consists of formalin-killed V. cholerae Inaba, El Tor biotype (strain Phil 6973).
      It also contains 300 EU LPS of heat-killed V. cholerae Ogawa classical biotype (Cairo 50);
      300 EU LPS of formalin killed V. cholerae Ogawa classical biotype (Cairo 50); 300 EU LPS of
      heat-killed V. cholerae Inaba, classical biotype (Cairo 48); and 600 EU LPS of formalin
      killed V. cholerae O139 (4260B) (9). The vaccine has no detectable cholera toxin. The study
      agents (Vaccine or placebo) is packaged as liquid formulations in 1.5-ml doses. The vaccine
      will be given in two doses separated by a two week interval and administered by oral syringe
      without a needle after which each participant will be offered water. No buffer will be co
      administered.

      Placebo The placebo consists of heat-killed Escherichia coli K12 and is identical in
      appearance to the vaccine. This strain has been used for placebo related studies in previous
      oral vaccine clinical trials in Bangladesh and elsewhere.

      Random Allocation Eligible participants will be assigned to receive the vaccine or placebo in
      a 1:1 ratio according to the randomization schedule. Individual randomization lists for
      adults, toddlers and infants will be generated by statistician in IVI who will not involved
      in the study in any way.

      The study agents will be labeled by different letter codes for three different phases at
      Shantha Biotechnics according to the list provided by IVI.

      The field staff will allocate the study agents to the participants according to the next
      available number on entry into the trial which will be linked with the randomization list
      provided by IVI.

      The randomization list will contain sequential numbers unique to each participant, and the
      block randomization (fixed block length of 4) process will be employed to ensure an effective
      balance between the interventions.

      Data Safety Monitoring Board (DSMB):

      A 4-5 member data safety and monitoring board (DSMB) will be formulated for this study by the
      Ethical Review Committee (ERC) of ICDDR,B. This will be comprised of members of the ERC,
      staff members of ICDDR,B and individuals from other institutions in Bangladesh. The team will
      also comprise an International member. The members will not be involved in the study in any
      way.

      Blinding and Code Breaking Procedures Vials will be labeled by letter codes at Shanta
      Biotechnics according to the list provided by IVI. All study personnel and participants will
      be blinded to treatment assignment during the duration of the study.

      The identity of the study agent will not be known to the participant or their
      parent/guardian, nor to personnel involved in the conduct or monitoring of the trial, such as
      investigators, study nurses/personnel before the completion of the study.

      The PI will hold the sealed randomization list for use if necessary in case of adverse events
      that may be seen in the study by the DSMB. Otherwise the list will not be unblinded until
      completion of the study, and complete entry and editing of relevant data before initiation of
      the analyses. The entire data set will be locked prior to unblinding. If the intervention
      assignment is un-blinded due to any reason, the DSMB will be notified within 24 hours.

      Subject withdrawal during the study Respective participants or parents of participating
      children may discontinue his/her participation at any time after enrollment without providing
      any reason. No replacement will occur for such withdrawals.

      The following criteria should be checked at each visit subsequent to the intake of study
      agent

        1. Use of any immunosuppressive or immune-modifying drugs during the study period (for
           corticosteroids this would mean ≥0.5 mg/kg.day)

        2. Administration of immunoglobulins or any blood product during the study period If any of
           the above occurs that might compromise per protocol assessment (PP); however, they will
           not be withdrawn from the study and their data will be used in an "intention to treat"
           (ITT) analysis. The investigator(s) might also withdraw a participant if, in his/her
           clinical opinion, that is in the best interest of the participant concerned or if it is
           considered to be non-compliant with the protocol. A participant might also be withdrawn
           due to protocol violation, death or early termination of the study by the sponsor.
           Wherever possible, the tests and evaluations at termination visit, as specified in the
           protocol, will be carried out.

           Duration of the study period for individual participants The participants will remain in
           the study for up to 28 days.

           Schedule and description of observations and visits:

           The following schedule will be used in the study and the case report forms will be
           completed on each study day:

        3. Day 0: After describing the study and initial verbal consent, medical history will be
           obtained and a thorough physical examination will be performed by a physician that will
           include measurement of the vitals signs. Once all eligibility criteria are met,the
           participant and in case of children the parent will be asked to sign the informed
           consent form. A blood and stool sample would be collected for determining the baseline
           immunological assay for immune responses. Following this, the participant will be
           allocated to the study intervention according to the randomization list (vaccine or
           placebo). Voluntary and solicited reactogenicity will be assessed symptoms and immediate
           adverse events recorded with 1 h of intake of the study agent. The participants will
           then be allowed to go home

        4. Day 1: Participants return to the study center to be monitored for voluntary and
           solicited symptoms and adverse events.

        5. Day 2: Participants will return to the study centre or will be visited at home (in
           exceptional circumstances, when parents cannot bring the participant to the study
           centre) to monitor for voluntary and solicited symptoms and adverse events.

        6. Day 7: (up to +3 days): Participants return to the study center. Blood sample will be
           collected at clinic and stool sample will be collected from home or at clinic for
           testing of vaccine specific immunologic responses in study participants.

        7. Day 14: (± 2 days): Participants return to the study center. The participant will be
           allocated to the study intervention for second time according to the randomization list
           (vaccine or placebo).by a blinded third party dispenser.

        8. Day 14-16: Participants return to the study centre or will be visited at home (in
           exceptional circumstances, when parents cannot bring the participant to the study
           centre) to monitor for voluntary and solicited symptoms and adverse events. Voluntary
           and solicited reactogenicity will be assessed symptoms and immediate adverse events.

        9. Day 21: (± 3 days) Blood and stool will be sampled for testing of vaccine specific post
           immunization response.

       10. Day 28: (± 3 days) Clinical evaluation and Study Termination Sample Size Calculation and
           Outcome (Primary and Secondary) Variable(s) Safety and Immunogenicity study of the
           Shantha cholera vaccine: The ''non-inferiority'' approach using a 1 -sided 95%
           confidence interval was used to calculate the sample size since this allowed us to rule
           out clinically unacceptable high rates of diarrheal adverse event occurring during the 3
           days after either dose as well as establish that the vaccine induced adequate
           seroconversion to V. cholerae O1 among recipients. Assuming a 10% diarrheal rate among
           placebo and vaccine recipients alike, to exclude a vaccine-placebo difference in the
           rate of diarrhea of greater than 20% (upper boundary of the 1-tailed 95% confidence
           interval) with a power of 0.9, the minimum number of subjects required for each group
           was in each group for both adverse event was 46. The sample size is calculated with the
           assumptions that it is important to evaluate whether the vaccine induces acceptable
           serum vibriocidal responses in relation to the placebo group. Based on an immunogenicity
           study of the whole-cell killed oral cholera vaccine in Bangladesh, we make the following
           assumptions. For serum vibriocidal responses, defined as >4-fold increases between
           baseline and post-second dose in either Inaba or Ogawa antibodies, for each age group
           (12-23 months, 2-5 years and 18-45 years), we assume 1) the background rate of responses
           in the placebo group will be 5% after the second dose and 2) the true rate of
           vibriocidal responses in the vaccine groups is 25%. At p <0.05 (1-tailed), 0.8 power,
           and a 1 to 1 allocation of vaccine and placebo, a total of 46 subjects per group would
           be needed. Thus for safety and immunological responses the number is 46 per group. With
           15% attrition rate, it is 53. We will select 55 in each group (110 per age group for
           both vaccine and placebo recipient).

      We will, therefore, select 55 subjects per arm in each age group, with a total of 330
      subjects.
    

Intervention name(s): ShanChol Cholera Vaccine; Placebo
Intervention type(s): Biological; Other
Intervention description(s): 55 adults (18-45 year old) will be given 2 doses of the bivalent whole-cell cholera vaccine 55 Toddlers(2-5 years) will be given 2 doses of the bivalent whole-cell cholera vaccine 55 Younger children(12-23 months)will be given 2 doses of the bivalent whole-cell cholera vaccine; 55 adults (18-45 year old) will be given 2 doses placebo, 55 Toddlers(2-5 years) will be given 2 doses of placebo, and 55 Younger children(12-23 months)will be given 2 doses of placebo
Other intervention name(s): ShanCholCholera Vaccine
Intervention MeSH terms: Vaccines
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Health Services Research
Keywords: safety; immunogenicity; Healthy Participants