Clinical trial NCT02606526: Early Versus Late BCG Vaccination in HIV-1 Exposed Infants in Uganda in Uganda
Official title: A Randomised Controlled Trial in HIV-1 Exposed Ugandan Infants to Estimate Additional Benefits (Non-specific Effects) of BCG
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Severe Illness
Septicaemia
Diarrhoea
Lower Respiratory Infection
Lead sponsor: Makerere University
Sponsor class: OTHER
Collaborators: name: University of Bergen
name: Radboud University Medical Center
First posted: 2015-11-17
Enrollment: 4500
Sex: ALL
Maximum age (years): 1
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.


Eligibility criteria: 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

Primary outcomes:
measure: Severe illness
timeFrame: The first 14 weeks of life
measure: Innate and adaptive immune responses against mycobacterial and non-mycobacterial antigens.
timeFrame: 14 weeks post BCG vaccination
Secondary outcomes:
measure: Severe illness from 48 h after randomization to 14 weeks of life
timeFrame: 48 hours to 14 weeks of life
measure: Severe illness in weeks 0-52 and 14-52 of life
timeFrame: First 0-52 and 14-52 weeks of life
measure: Adverse events
timeFrame: First 52 weeks of life
measure: Infant death
timeFrame: First year of life
measure: BCG scar at 52 weeks of age
timeFrame: First year of life
measure: Growth up to 52 weeks of life
timeFrame: First year of life
measure: Severe illness until 6 weeks of age
timeFrame: 6 weeks
measure: Severe illness until 14 weeks of age within strata of presence or absence of maternal BCG scar
timeFrame: 14 weeks
Other outcomes:
Locations:
city: Kampala
country: Uganda
facility: Health Centers in Mukono and Kampala districts
Study officials:
affiliation: School of Public Health, Makerere University
name: Victoria Nankabirwa, MD, MPH, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: CISMAC, Center for International Health, University of Bergen
name: Halvor Sommerfelt, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Nankabirwa V, Tumwine JK, Mugaba PM, Tylleskar T, Sommerfelt H; PROMISE- EBF Study Group. Child survival and BCG vaccination: a community based prospective cohort study in Uganda. BMC Public Health. 2015 Feb 22;15:175. doi: 10.1186/s12889-015-1497-8.
citation: Nankabirwa V, Tumwine JK, Namugga O, Tylleskar T, Ndeezi G, Robberstad B, Netea MG, Sommerfelt H. Early versus late BCG vaccination in HIV-1-exposed infants in Uganda: study protocol for a randomized controlled trial. Trials. 2017 Mar 31;18(1):152. doi: 10.1186/s13063-017-1881-z.