BCG Revaccination in Children and Adolescents (BRiC)

Efficacy of BCG Revaccination Compared With Oral Chemoprophylaxis in Household Contacts Aged 6-18 Years for Prevention of Tuberculosis Disease - A Phase III Open Labelled Randomised Controlled Trial

Bacille Calmette Guerin (BCG) vaccine is one of the most used vaccines of the world, to reduce the risks of natural tuberculous infection. The efficacy of BCG vaccination in newborns is well known and has a documented protective effect against meningitis and disseminated TB in children. However, there is considerable uncertainty on BCG revaccination. It is known that BCG revaccination enhances immune responses, but it is yet to be established if BCG revaccination can help prevent TB disease in household contacts.

The primary aim of this study is to assess the efficacy of BCG revaccination compared to oral chemoprophylaxis in preventing TB disease in house hold contacts aged 6-18 years.

The study is designed as a multicentre randomised controlled trial with two groups of healthy household contacts aged 6-18 years receiving either the BCG vaccine or oral chemoprophylaxis. They will be followed up for 24 months to compare the incidence of TB disease in each arm.

Study Overview

• Status: Suspended
• Conditions: Tuberculosis; Tuberculosis Infection
• Intervention / Treatment: Biological: BCG vaccine; Drug: Oral Chemoprophylaxis

Detailed Description

Objectives

Primary:

To demonstrate the effect of BCG revaccination in comparison to oral chemoprophylaxis on the incidence of Mycobacterium tuberculosis disease in healthy household contacts aged 6-18 years.

Secondary:

• To compare the safety of BCG revaccination with oral chemoprophylaxis
• To study the efficacy of BCG revaccination in comparison to oral chemoprophylaxis in preventing Mycobacterium tuberculosis infection
• To study the immunogenicity of BCG revaccination

Methodology The aim of this study is to assess the efficacy of BCG revaccination compared to oral chemoprophylaxis in preventing TB disease in house hold contacts aged 6-18 years. The study is designed as a multicentre randomised controlled trial with two groups of healthy household contacts aged 6-18 years receiving either the BCG vaccine or oral chemoprophylaxis. A total of 9200 children will be recruited across 7 sites in India. Children will be randomised into 2 study arms: 1) BCG; 2) Oral chemoprophylaxis.

All children will be household contacts of microbiologically confirmed pulmonary TB patients. Contacts of MDR TB adults will also be included in the study. Both C-Tb skin test positive and negative children will be included. Similarly, both well-nourished and malnourished children will be included. All children will be followed up for 24 months post recruitment and the incidence of TB (all forms - PTB / EPTB) will be compared between the groups. TB will be diagnosed as per the NTEP guidelines and LTBI will be based on the C-TB skin test results.

Immunology bloods will be done in 10% of the participants - 920 children at baseline, 3, 6 12 and 24 months. The immunology component of this trial is designed so as to decipher clearly the effects of BCG revaccination on adaptive and innate cell responses. Full Blood Count for Monocyte/Lymphocyte ratio, Whole Blood culture for Intracellular Staining, Innate assays, Mycobacterial Growth Inhibition Assay and acute phase proteins will be performed between groups

• Study Type: Interventional
• Enrollment (Estimated): 9200
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Aishwarya Venkataraman, MRCPCH; Phone Number: 9533 +44 2836 9500; Email: venkataraman.a@icmr.gov.in

Study Locations

• India
  • Tamil NADU
    • Chennai, Tamil NADU, India, 600031
      • Dr Aishwarya Venkataraman

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 16 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Healthy household contacts aged 6 to 18 yr
• Previously vaccinated with BCG at birth or least 5 years ago - evidence of scar or documented immunisation record.
• General good health - through history and baseline screening
• Agrees to continue in the study for 2 years post enrollment
• Children previously treated for LTBI and completed treatment at least 6 months ago - can also be included. However, they should be current HHC

Exclusion Criteria:

• Any acute illness on recruitment day (Evaluate the child again at a later stage)
• Fever ≥38 degree Celsius on recruitment day (Evaluate the child again at a later)
• History of autoimmune disease
• Pregnancy - female participants > 15 years of age will have pregnancy test done after caretakers and participants informed consent
• Evidence of active TB disease
• On treatment for active TB disease or LTBI
• HIV positive or any history or present possible immunodeficiency condition
• History of allergic reactions to vaccines in past
• Pre-existing liver dysfunction
• ALT/AST is ≥ 3 times upper limit of normal (ULN) in the presence of symptoms or ≥ 5 times the ULN in the absence of symptoms and/or total bilirubin greater than ULN along with raised ALT/AST.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: vaccine - Bacille Calmette-Guérin vaccine (BCG ); Bacille Calmette-Guérin vaccine (BCG ) dose 0.1ml intradermal	Biological: BCG vaccine; 0.1ml BCg vaccine to be given intradermally
Other: Chemoprophylaxis - as per NTEP guidelines; Oral chemoprophylaxis: according to the existing standard of care (NTEP guidelines) Either six months of isoniazid (10mg/kg) or Rifapentine and isoniazid weekly for 3 months for DS TB Levofloxicillin or standard of care drug for DR TB: 15-20mg/kg/day	Drug: Oral Chemoprophylaxis; Oral chemoprophylaxis will be standard of care - either 6 months of Isoniazid or 3 months of weekly Isoniazid and Rifapentine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of TB (all forms - PTB / EPTB) as per NTEP guidelines	Incidence of TB in BCG revaccinated and oral chemoprophylaxis groups (age and gender stratified)	over 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	Incidence of adverse events in children in each arm	24 months
MTB infection	Incidence of MTB infection in both groups	24 months

Collaborators and Investigators

• Sponsor: Tuberculosis Research Centre, India
• Collaborators: All India Institute of Medical Sciences, Bhubaneswar; Institute of Child Health, Chennai; All India Institute of Medical Sciences, Guwahati; The Grant Medical College & Sir J.J. Group of Hospitals; All India Institute of Medical Sciences, Patna; Rajendra Institute of Medical Sciences, Ranchi; National Institute of Tuberculosis and Respiratory Diseases, New Delhi; Rajiv Gandhi Hospital, Chennai; Madurai Medical College; Government Vellore Medical College, Vellore
• Investigators: Principal Investigator: Aishwarya Venkataraman, MRCPCH, ICMR-National Institute for Research in Tuberculosis

Study record dates

Study Major Dates

• Study Start (Estimated): July 15, 2024
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: March 28, 2022
• First Submitted That Met QC Criteria: April 8, 2022
• First Posted (Actual): April 15, 2022

Study Record Updates

• Last Update Posted (Actual): December 18, 2023
• Last Update Submitted That Met QC Criteria: December 11, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Vaccine; TB; BCG; LTBI; Anti tuberculous Chemoprophylaxis
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Latent Infection; Tuberculosis; Latent Tuberculosis; Physiological Effects of Drugs; Immunologic Factors; Adjuvants, Immunologic; BCG Vaccine
• Other Study ID Numbers: 2022 005

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No