Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT01989026 |
| Other study ID # |
CVK-2013-1303771 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
October 2013 |
| Est. completion date |
October 1, 2017 |
Study information
| Verified date |
June 2018 |
| Source |
Bandim Health Project |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Recent studies show that BCG vaccination reduces neonatal mortality by more than 40%. This
effect cannot be explained by prevention of tuberculosis, which is very rare among infants.
The protective effect of BCG vaccination is seen already within the first week. It seems that
BCG provides a non-specific beneficial immune modulation - thereby reducing overall
mortality. Mortality is very high among newborns admitted to the neonatal intensive care
unit. If BCG has immediate beneficial effects on the immune system, vaccinating children with
BCG as early as possible may save lives. The investigators will test this hypothesis in a
randomized trial among newborns in Guinea-Bissau, randomizing newborns admitted to the
neonatal intensive care unit at the National Hospital 1:1 to BCG immediately or at discharge
(usual practice).
Description:
Observational studies in high-mortality areas have shown that the BCG vaccine is associated
with marked benefits in child survival. These results cannot be explained by prevention of
tuberculosis, which is rare during the firsts years of life. These observations have recently
been tested at the Bandim Health Project (BHP) in Guinea-Bissau in randomized trials among
low birth weight (LBW, <2500 g) children. According to local practice, BCG is typically
postponed in LBW infants until 4-6 weeks of age. Results showed that providing BCG at the
time of discharge from the hospital compared with BCG later reduced neonatal mortality by
more than 40%. The protective effect started already within the first three days. Based on
verbal autopsies, BCG protected the children against neonatal septicemia and pneumonia.
Recent immunological studies have indicated that BCG induces epigenetic changes which
reprogram the innate immune system to increased pro-inflammatory responses against unrelated
pathogens; hence, BCG may indeed have a non-specific beneficial effect protecting against
other infections.
BCG is recommended at birth by the World Health Organization (WHO), but is rarely given
immediately at birth. In Guinea-Bissau, at the National Hospital's maternity ward, children
are currently vaccinated at discharge. For children who are born healthy, this usually means
1-2 days after the delivery. However, very small children and ill children are admitted to
the neonatal intensive care unit (NICU), and often stay there for days to weeks before they
are discharged - and only receive BCG at the time of discharge. The mortality among children
in the NICU is alarmingly high - it was 14% (254/1877) among children admitted to the NICU
from November 2007 to May 2013 (unpublished data). A substantial number of children that died
had normal birth weight and high Apgar scores. In most cases the underlying cause of death
was infectious diseases, which could potentially be affected by BCG vaccination. Hence, the
present aim is to conduct a randomized trial at the NICU to study the effect of providing BCG
immediately (intervention group) versus BCG at discharge (control group). The primary outcome
will be mortality during hospital stay, with cause of death, growth and length of stay as
secondary outcomes.
HYPOTHESIS
Providing BCG vaccination upon admission to newborn children in the NICU incubators, rather
than at discharge, is associated with 40% reduction in mortality at the NICU for children
weighing >1250 g.
METHODS
Setting
The randomized trial will be conducted by the Bandim Health Project in Guinea-Bissau, at the
NICU at the National Hospital Simão Mendes. The Bandim Health Project (BHP) maintains a
health and demographic surveillance system (HDSS) in six suburban districts of the capital of
Guinea-Bissau and covers approximately 102,000 inhabitants. All houses in the study area are
visited monthly to register new pregnancies and births. All children below 3 years of age are
followed through home visits every third month. The National Hospital where many women from
the study area give birth is a few kilometers away. The BHP has worked at the hospital's
maternity ward for many years, conducting trials of different health interventions and other
observational studies to reduce infant mortality.
Study design
Children will be randomly allocated (1:1) to BCG at admission or at discharge (as per current
standard of care).
Enrolment procedures
The BHP team is present at the maternity ward every day. The team will visit the NICU and
identify children admitted since their last visit. The mother will have the study explained
in the local language (Portuguese Creole), and also receive a written explanation in
Portuguese. She will be briefly interviewed about background factors (education, previous
deliveries, etc.). Anthropometric measures will be obtained and a Ballard score assessed by a
trained nurse.
Randomization
Provided consent, the mother will draw a lot which indicates if the child will receive BCG
immediately or BCG at discharge as usual. To ensure equal distribution of different
categories of children and calendar time, randomization will be done in blocks within two
groups of children; a) children at the NICU who are in an incubator (most severely ill); b)
children at the NICU who are not in incubator (less ill, including also children born by
caesarean section whose mother is indisposed). Randomization will further be stratified by
sex and weight group (1250-1499g, 1500-1999g, 2000-2499g, 2500+ g) in blocks of 16.
Intervention
Immediately after randomization, children who were allocated to BCG vaccine will be
vaccinated intradermally with 0.05 ml BCG vaccine (Statens Serum Institute, Denmark). The
control group will receive BCG at discharge. All children will receive oral polio vaccine
(OPV) at the time of BCG vaccination.
The study is therefore testing BCG+OPV at admission to the NICU (intervention arm) vs.
BCG+OPV at discharge from NICU (control arm). Same-sex twin pairs will receive the same
treatment.
Blinding
The BHP team will be in charge of randomization and vaccination. These procedures will take
place without the participation of the NICU staff. BCG vaccination leaves a small mark on the
skin of the child, which vanishes quickly, leaving no sign until a papule is formed several
weeks later. To further ensure blinding of hospital staff, a small gauze patch will be placed
over the injection site in both groups, for the entire hospital stay.
Follow-up
-At the hospital
The BHP team will visit the NICU every day and ascertain the vital status of all enrolled
children and that the plasters have not been removed. All clinical and biological parameters
registered by the NICU staff, including weight, temperature and respiratory frequency will
also be recorded. The main outcome is survival during the stay at the NICU.
-After discharge
At the day of discharge, the BHP team will assure that all children randomised to the control
group receive BCG and OPV before leaving the hospital. The children being discharged will be
offered transport to their home. All included children included from Bissau will be followed
for adverse events, survival, growth and morbidity with home visits after 3 days, 2 months, 6
months and 12 months of age.
-Statistical analysis
The mortality data will be analyzed in Cox proportional hazards models. Due to the expected
high number of twins, all analyses will be adjusted for interdependency between twins. We
will analyze the overall effect of BCG on survival, and by cause of death. Length of stay and
weight gain at discharge among surviving children will be analyzed using linear regression.
To prevent bias which could arise if BCG was particularly beneficial for survival among the
smallest children, control and intervention children will be matched based on birth weight,
and pairs of children in which one child dies will be excluded from the analysis. There will
be a natural variation in the time from birth to enrolment into the trial. All analyses will
be adjusted for time from birth to enrolment. All analyses will be conducted stratified by
weight group, sex and season (dry (Dec-May) vs rainy (June-Nov)), since we have previously
observed that both factors may modify the response to BCG and other vaccines. It is a
secondary hypothesis that the early effect is strongest for boys and in the dry season.
Public health campaigns which also affect newborn children, for example polio vaccination
campaigns, could interfere with the trial. If such campaigns are implemented also for
children in the ICU, the children will be censored in the analysis at the time of the
intervention. Likewise if there are strikes, shortage of electricity or other events which
interfere with the health services, the children will censored in the analysis after
discussion with the DSMB.
-Sample size
The NICU admits around 350-400 children per year who are placed in the incubators. Around 94%
weigh more than 1250 g. The median length of stay is 6 days. With a mortality of 12%, we
would need to enroll 1262 children to detect a 40% difference in mortality between
BCG-vaccinated and BCG-unvaccinated children with 80% power and a significance level of 5%.
This corresponds to 122 deaths. If mortality declines (as it has done over the last years in
the BHP study area), the event number would have to be slightly higher; with a mortality of
11% we would need to continue to 123 deaths to maintain the same power; if it declines to 10%
it would be 124 deaths, etc.
Based on this data, the investigators expect to reach the needed number of events during a
period of 4 years, taking into account that some children will have died before they can be
enrolled and some children will be too ill to be enrolled.
ETHICAL CONSIDERATIONS The study protocol has been approved by The Danish Central Ethical
Committee and the National Ethical Committee in Guinea-Bissau. The trial will be registered
at clinicaltrials.gov. In previous studies BCG was safe for LBW children and even more
beneficial among the smallest children. A local clinical monitor and a Data Safety and
Monitoring Board (DSMB) will be appointed.
