Condition category
Infections and Infestations
Date applied
05/02/2018
Date assigned
07/02/2018
Last edited
07/02/2018
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Typhoid fever is a bacterial infection that can cause severe disease and even death. Typhoid is spread through contaminated food and water, due to poor hygiene and sanitation conditions. In Bangladesh, typhoid fever causes a lot of disease, mostly in children. Previous vaccines have not provided long-term protection for children. A new typhoid vaccine, Vi-TCV, has been developed and has been WHO pre-qualified and is licensed for use in India and Nepal. This vaccine is safe for children and may provide long-term protection. However, this vaccine is not yet available through the routine childhood immunisation programme. Before the government will introduce the vaccine into the routine programme, more information is needed on the level of protection that the vaccine provides. The aim of this study is to find out whether the typhoid vaccine Vi-TCV reduces the incidence of typhoid fever in children.

Who can participate?
Children under the age of 16

What does the study involve?
As per local regulations, a pilot phase will be carried out initially, where 200 children between the ages of 9 months and <16 years will be vaccinated with either the typhoid vaccines or a vaccine that protects against Japanese encephalitis. At the same time a census will be conducted, in order to identify who is currently living in the study catchment area. The study catchment area will then be divided up into 150 clusters or areas. These clusters of households will then be randomly allocated for participants living in them to either receive the typhoid vaccine (Vi-TCV) or a vaccine which protects against Japanese encephalitis. Participants will be followed-up for up to two-years following vaccination. When participants develop a fever during that time, they will be asked to come to the local hospital or the study clinics in the community. If they have a fever over 38 degrees C or if they have had a fever for 2 or more days they receive treatment and a blood test to check if they have typhoid fever. The cost of treatment for suspected or confirmed typhoid is covered by the study. All participants are also monitored for side effects associated with the vaccine. At the end of the study, all of the children who first received the Japanese encephalitis vaccine will be offered the typhoid vaccine too.

What are the possible benefits and risks of participating?
Participants benefit from the study by receiving the typhoid vaccine for free, which is not currently available through the routine immunisation system in Bangladesh. Participants also have free treatment for any suspected or confirmed typhoid infections. The vaccine has been found to be safe in all previous studies, but since this is the largest study of this vaccine to date, there is a risk for participants that a rare side effect, not yet identified, may become apparent in this study.

Where is the study run from?
International Centre for Diarrhoeal Disease Research (Bangladesh)

When is the study starting and how long is it expected to run for?
February 2018 to February 2020

Who is funding the study?
Bill and Melinda Gates Foundation (USA)

Who is the main contact?
Prof. Andrew Pollard

Trial website

Contact information

Type

Scientific

Primary contact

Prof Andrew Pollard

ORCID ID

http://orcid.org/0000-0001-7361-719X

Contact details

Oxford Vaccine Group
Centre for Clinical Vaccinology and Tropical Medicine (CCVTM)
Churchill Hospital Old Road
Oxford
OX3 7LE
United Kingdom

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

OVG 2017/11

Study information

Scientific title

Assessing the impact of a Vi-Polysaccharide Conjugate Vaccine in preventing typhoid infection among Bangladeshi children – a Phase IV trial

Acronym

Study hypothesis

The typhoid vaccine, Vi-TCV, will reduce the incidence of laboratory confirmed typhoid fever in children receiving the vaccine, compared to those receiving a control vaccine.

Ethics approval

1. RRC, 19/12/2017
2. ERC, 22/01/2018
3. Oxford Tropical Research Ethics Council (OxTREC), ref: 5 -18 - approval pending

Study design

Parallel cluster randomised-controlled trial (with a piloting phase in 200 children stratified by age)

Primary study design

Interventional

Secondary study design

Cluster randomised trial

Trial setting

Community

Trial type

Prevention

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet

Condition

Blood culture confirmed typhoid fever

Intervention

Intervention: Vi Typhoid conjugate vaccine (Vi-TCV), trade name: TyBar
Control: Japanese Encephalitis vaccine: trade name: SA14-14-2, Japanese Encephalitis Vaccine, Live

A baseline census innumerates all households within the geographically defined catchment area.

A pilot phase, prior to the main study, individually randomises 200 children, in an area separate from the main trial site, in an age stratified manner to receive either Vi-TCV or the JE vaccine. Safety data is presented to the local DSMB (LDSMB), IRB and to the Directorate General of Drug Administration (DGDA), the National Regulatory Authority of Bangladesh prior to initiating the main cluster randomised trial.

For the pilot phase, two sequential groups of children are studied: children 3-15 years of age (n=100) followed by children 9 months to <3 years of age (n=100), with movement to the next phase contingent only on safety at one week post dosing. After approval by the LDSMB, IRB and the DGDA in Bangladesh, the main Vi-TCV study is initiated.

The main trial is participant- and observer-blinded, cluster-randomised study of the typhoid conjugate vaccine (Vi-TCV), brand name: Tybar-TCV, in Bangladeshi children. The population within a selected geographical catchment area of Mirpur, Dhaka, are offered entry into the study. The aim is to enrol 43,350 eligible, consenting children/guardians within the target age range (9 months to <16 years) residing in the target area at baseline. 150 Residential clusters of ca. 1250 people eachare randomised in a 1:1 ratio to receive Vi-TCV or the control vaccine (SA 14-14-2).

Surveillance for enteric fever are undertaken in health care facilities in Mirpur for all residents of the participating clusters for four months preceding baseline and continuing for approximately 2 years after vaccination, until the end of the study. In this surveillance, all consenting residents from the participating clusters who present with a subjective history of ≥2 days fever and a temperature of ≥38°C have a blood culture taken, and receive appropriate clinical management. Those with positive blood cultures are visited at home to confirm their identity given at the treatment center, to collect information about their illness, and to review the treatment given, and adjust as necessary, based on laboratory testing.

At six month intervals during the two years after baseline, census updates of the population are done in all clusters, and children fulfilling the eligibility criteria for participation who have not received the study vaccines allocated to the cluster will be offered the vaccine, whilst retaining blinding.

Intervention type

Biological/Vaccine

Phase

Drug names

Primary outcome measure

The efficacy and rate reduction of the Vi-TCV in preventing blood culture-confirmed symptomatic infection caused by S. Typhi, measured through the incidence of blood culture confirmed typhoid fever in vaccinees in intervention clusters compared to control clusters.

Secondary outcome measures

1. Vi-TCV vaccine safety, measured as the proportion of participants developing local and solicited adverse events within the first 7 days post-vaccination, and serious adverse events within 6 months of vaccination, as determined through sub-sample at 7 days, and self-reporting at follow-up contact
2. The efficacy and rate reduction of the Vi-TCV in preventing blood culture-confirmed symptomatic infection caused by S. Typhi among all residents in the clusters allocated to Vi-TCV (overall vaccine protection), measued through the incidence of blood culture confirmed typhoid fever in all residents of the intervention clusters compared to control clusters
3. The impact of vaccination with Vi-TCV on rates of participants with a history of ≥2 days of persistent fever, and a temperature of >38 degrees C upon presentation, together with abdominal discomfort, at all study surveillance sites in vaccinees in intervention clusters compared to control clusters.
4. The impact of vaccination with Vi-TCV on all residents of the clusters, as measured by rates of participants with a history of ≥2 days of persistent fever, and a temperature of >38 degrees C upon presentation, together with abdominal discomfort, at all study surveillance sites among all residents of the Vi-TCV clusters compared to the control vaccine clusters
5. The impact of vaccination with Vi-TCV as measured by rates of patients with clinical diagnoses of typhoid fever at a study surveillance site in vaccinees in intervention clusters compared to control clusters
6. The impact of vaccination with Vi-TCV as measured by rates of patients with clinical diagnoses of typhoid fever at a study surveillance site among all residents of the Vi-TCV clusters compared to the control vaccine clusters
7. Paratyphoid infection rates in each vaccination arm as measured by incidence of blood culture confirmed paratyphoid fever in vaccinees in intervention clusters compared to control clusters

Overall trial start date

01/10/2016

Overall trial end date

12/02/2020

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Parent/guardian is willing and competent to provide informed consent. If the participant is 11 to <16 years of age, informed assent will also be sought
2. Aged between 9 months (or eligible for measles vaccination according to local protocol) and <16 years (i.e. up to 15 years 364 days) at time of vaccination
3. Apparently healthy (no complaints of febrile illness) on the day of vaccination
4. Parent/guardian confirms that their child will be willing and be able to comply with study requirements including follow-up contact, according the schedule (Appendix B)
5. Living within the study catchment area at the time of vaccination

Participant type

Healthy volunteer

Age group

Child

Gender

Both

Target number of participants

43,350

Participant exclusion criteria

1. Has knowingly received a typhoid or Japanese encephalitis vaccine in the last three years
2. Known allergy to any of the vaccine components
3. Medical or social reasons that will prevent the participant from conforming to the study requirements as judged by a medical professional
4. Planning to move away from the catchment area within the next month
5. Pregnant at the time of vaccination, as confirmed by a urine test (urine pregnancy test will be done in girls who are married)

Recruitment start date

12/02/2018

Recruitment end date

02/08/2019

Locations

Countries of recruitment

Bangladesh

Trial participating centre

International Centre for Diarrhoeal Disease Research, Bangladesh
68, Shaheed Tajuddin Ahmed Sharani Mohakhali
Dhaka
1212
Bangladesh

Sponsor information

Organisation

University of Oxford

Sponsor details

University Offices
Wellington Square
Oxford
OX1 2JD
United Kingdom

Sponsor type

University/education

Website

Funders

Funder type

Charity

Funder name

Bill and Melinda Gates Foundation

Alternative name(s)

Bill & Melinda Gates Foundation

Funding Body Type

private sector organisation

Funding Body Subtype

foundation

Location

United States of America

Results and Publications

Publication and dissemination plan

It is planned that the results of this trial will be published in high-impact peer reviewed journals within one year of the conclusion of the trial, around February 2021.

IPD sharing statement
The datasets generated during and/or analysed during the current study are/will be available upon request from Prof. Andrew Pollard.

Intention to publish date

01/02/2021

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes