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Early Versus Late BCG Vaccination in HIV-1 Exposed Infants in Uganda in Uganda

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02606526
Recruitment Status : Recruiting
First Posted : November 17, 2015
Last Update Posted : August 29, 2022
Sponsor:
Collaborators:
University of Bergen
Radboud University Medical Center
Information provided by (Responsible Party):
Makerere University

Tracking Information
First Submitted Date  ICMJE November 12, 2015
First Posted Date  ICMJE November 17, 2015
Last Update Posted Date August 29, 2022
Study Start Date  ICMJE July 2016
Estimated Primary Completion Date March 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 24, 2022)
  • Severe illness [ Time Frame: The first 14 weeks of life ]
    Among children <2 months of age, severe illness (other than TB) will be defined as illness that is associated with any of the following danger signs observed or verified by a clinician: inability to feed or vomiting of everything and unable to keep anything down, lethargy or unconsciousness, severe lower chest in-drawing, axillary temperature of ≥37.5 deg C or <35.5 deg C, grunting, cyanosis, convulsions or a history of convulsions (except epilepsy), and/or requires hospitalization and/or results in death. Among children ≥2 months of age, severe illness (other than TB) will be defined as illness that is associated with at least one of the following danger signs observed by a clinician: inability to drink or breastfeed lethargy or unconsciousness, vomiting of all feeds, convulsions or a history of convulsions (except epilepsy), and/or requires hospitalization and/or results in death. Events resulting from violent injury or burns will not be considered.
  • Innate and adaptive immune responses against mycobacterial and non-mycobacterial antigens. [ Time Frame: 14 weeks post BCG vaccination ]
    The following immunological outcomes will be measured in a sub-sample of 180 infants: Innate immune responses (IL-6, TNF, IL-10, IL-1b) against TLR-agonists and adaptive immune responses (IFNy, IL-17, IL-10 and IL-22) against mycobacterial (ESAT-6/CFT10 and PPD) and non-mycobacterial antigens (C.albicans, S. aureus and SARS-CoV-2 spike peptides).
Original Primary Outcome Measures  ICMJE
 (submitted: November 16, 2015)
  • Proportion of infants with severe illness [ Time Frame: The first 14 weeks of life ]
    Among children <2 months of age, severe illness (other than TB) will be defined as illness that: is associated with any of the following danger signs observed or verified by a study clinician: inability to feed or vomiting of everything and unable to keep anything down, lethargy or unconsciousness, severe lower chest in-drawing, axillary temperature of ≥37.5oC or <35.5oC, grunting, cyanosis, convulsions or a history of convulsions, and/or results in hospitalization and/or results in death. Among children ≥2 months of age, severe illness (other than TB) will be defined as illness that: is associated with at least one of the following danger signs observed by a clinician: inability to drink or breastfeed lethargy or unconsciousness, vomiting of all feeds, convulsions or a history of convulsions, and/or results in hospitalization and/or results in death. Hospitalization and death resulting from violent injury or burns will not contribute to the severe illness definition.
  • Production of TNF, IL-1beta, IL-6 and IFN-γ in response to mycobacterial (M. tuberculosis and PPD) and non-mycobacterial pathogens (E. coli, C.albicans and S. aureus) [ Time Frame: 14 weeks post BCG vaccination ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 24, 2022)
  • Severe illness from 48 h after randomization to 14 weeks of life [ Time Frame: 48 hours to 14 weeks of life ]
  • Severe illness in weeks 0-52 and 14-52 of life [ Time Frame: First 0-52 and 14-52 weeks of life ]
    Among children <2 months of age, severe illness (other than TB) will be defined as an acute illness that is associated with any of the following danger signs observed or verified by a clinician: inability to feed or vomiting of everything and unable to keep anything down, lethargy or unconsciousness, severe lower chest in-drawing, axillary temperature of ≥38.0 deg C or <35.5 deg C, grunting, cyanosis, convulsions or a history of convulsions (except epilepsy), and/or requires hospitalization and/or results in death. Among children ≥2 months of age, severe illness (other than TB) will be defined as an acute illness that is associated with at least one of the following danger signs observed by a clinician: inability to drink or breastfeed lethargy or unconsciousness, vomiting of all feeds, convulsions or a history of convulsions (except epilepsy), and/or requires hospitalization and/or results in death. Events resulting from violent injury or burns will not be considered.
  • Adverse events [ Time Frame: First 52 weeks of life ]
  • Infant death [ Time Frame: First year of life ]
  • BCG scar at 52 weeks of age [ Time Frame: First year of life ]
    Presence or absence of a BCG scar at the vaccination site
  • Growth up to 52 weeks of life [ Time Frame: First year of life ]
  • Severe illness until 6 weeks of age [ Time Frame: 6 weeks ]
  • Severe illness until 14 weeks of age within strata of presence or absence of maternal BCG scar [ Time Frame: 14 weeks ]
Original Secondary Outcome Measures  ICMJE
 (submitted: November 16, 2015)
  • Proportion of infants with severe illness in the first 14-52 weeks and 0-52 weeks of life [ Time Frame: First 14-52 weeks and 0-52 weeks of life ]
    Among children <2 months of age, severe illness (other than TB) will be defined as illness that: is associated with any of the following danger signs observed or verified by a study clinician: inability to feed or vomiting of everything and unable to keep anything down, lethargy or unconsciousness, severe lower chest in-drawing, axillary temperature of ≥37.5oC or <35.5oC, grunting, cyanosis, convulsions or a history of convulsions, and/or results in hospitalization and/or results in death. Among children ≥2 months of age, severe illness (other than TB) will be defined as illness that: is associated with at least one of the following danger signs observed by a clinician: inability to drink or breastfeed lethargy or unconsciousness, vomiting of all feeds, convulsions or a history of convulsions, and/or results in hospitalization and/or results in death. Hospitalization and death resulting from violent injury or burns will not contribute to the severe illness definition.
  • Adverse events [ Time Frame: First 52 weeks of life ]
  • Infant death [ Time Frame: First year of life ]
  • Proportion of infants with BCG scarring [ Time Frame: 12 weeks post vaccination ]
    Presence or absence of a BCG scar at the vaccination site
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Early Versus Late BCG Vaccination in HIV-1 Exposed Infants in Uganda in Uganda
Official Title  ICMJE A Randomised Controlled Trial in HIV-1 Exposed Ugandan Infants to Estimate Additional Benefits (Non-specific Effects) of BCG
Brief Summary

BCG vaccination may have non-specific effects (NSE) i.e., additional benefits on childhood morbidity and mortality that are separate the vaccine's effect on the incidence of disseminated tuberculosis. Though the available literature is mostly from observational study designs, and is fraught with controversy, BCG vaccination at birth, in a high risk population of HIV exposed children, may protect infants against serious infections other than TB. Yet, other studies indicate that giving BCG later in infancy, when the immune system is more mature, may offer even greater protection. The appropriate timing of BCG vaccination could therefore be up for revision. This study will therefore compare BCG vaccination at birth with BCG vaccination at 14 weeks of age in HIV exposed (HE) babies.

Methods: This is an individually randomized clinical trial in 4,500 HIV exposed infants. The intervention is an intra-dermal administration of 0.05 ml of BCG vaccine within 24 hours of birth while the comparator will be an intra-dermal administration of 0.05ml of BCG vaccine at 14 weeks of age.

The main study outcomes include:

  1. Severe illness in the first 14 weeks of life,
  2. Innate and adaptive immune responses to mycobacterial, non-mycobacterial antigens and TLR-agonists
  3. Severe illness in the first 14-52 weeks and 0-52 weeks of life.

The study will be carried in two health centers and one district hospital in Uganda.

Implications: A well-timed BCG vaccination could have important additional benefits in HE infants. This trial could inform the development of programmatically appropriate timing of BCG vaccination for HE infants.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE
  • Severe Illness
  • Septicaemia
  • Diarrhoea
  • Lower Respiratory Infection
Intervention  ICMJE
  • Biological: BCG at birth
    See previous description
  • Biological: Control arm: Delayed BCG
    See previous description
Study Arms  ICMJE
  • Experimental: Intervention arm: BCG at birth
    Infants randomized to this arm will receive an intra-dermal administration of 0.05 ml of BCG vaccine within 24h of birth
    Intervention: Biological: BCG at birth
  • Active Comparator: Control arm: BCG at 14 weeks of age
    Infants randomized to this arm will receive intra-dermal administration of 0.05 ml of BCG vaccine at 14 weeks of age
    Intervention: Biological: Control arm: Delayed BCG
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 24, 2022)
4500
Original Estimated Enrollment  ICMJE
 (submitted: November 16, 2015)
2192
Estimated Study Completion Date  ICMJE December 2024
Estimated Primary Completion Date March 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

A baby born at a participating study clinic will be included if s/he:

  1. has a mother with a positive HIV test (ELISA or rapid test)
  2. is receiving peri-exposure prophylaxis as part of the standard/national guidelines in Uganda
  3. has a mother that is of legal age for participation in clinical research studies in Uganda or is an emancipated minor
  4. has a mother/caregiver that resides within the study area, is not intending to move out of the area in the next 4 months and is likely to be traceable for up to 12 months
  5. has a mother/caregiver that gives informed consent to random assignment to either of the two trial arms
  6. has a mother that has received antiretroviral therapy (ART) for at least 4 weeks

Exclusion Criteria:

A new-born child will be excluded if she/he has:

  1. an identified serious congenital malformation(s)
  2. severe illness requiring hospitalization
  3. a birth weight < 2.0 kg
  4. a mother participating in another clinical trial on the day of enrolment or a mother who will participate in another clinical trial within the next month.
  5. a mother or other household member with symptoms and signs of tuberculosis on the day of enrolment
  6. a severely ill mother with (a) condition(s) requiring hospitalization
  7. a baby with an Apgar score at 5 minutes <7
  8. a twin or triplet
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 1 Day   (Child)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Victoria Nankabirwa, MD, MPH, PhD +256755757460 nankabirwav@gmail.com
Contact: Olive Namugga, MD +256790515426 olivedejackie@yahoo.com
Listed Location Countries  ICMJE Uganda
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02606526
Other Study ID Numbers  ICMJE 2015-114
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Makerere University
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Makerere University
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • University of Bergen
  • Radboud University Medical Center
Investigators  ICMJE
Principal Investigator: Victoria Nankabirwa, MD, MPH, PhD Department of Epidemiology and Biostatistics, School of Public Health, College of Health Sciences, Makerere University
Principal Investigator: Halvor Sommerfelt, MD, PhD CISMAC, Center forInternational Health, University of Bergen
PRS Account Makerere University
Verification Date August 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP