Statistical Analysis Plans for BLOW2 Trial
Creators: name: Shann, Frank Athol
Publisher: name: OSF Registries
Year: 2023
Subjects: subject: Infectious Disease
subject: Maternal and Child Health
subject: Biological Factors
subject: Clinical Epidemiology
subject: Chemicals and Drugs
subject: Public Health
subject: Medicine and Health Sciences
subject: Medical Specialties
subject: Critical Care
subject: Pediatrics
subject: BCG and mortality and infection in low-birth-weight neonates

description: Statistical Analysis Plans for BLOW2 Trial: BCG-Denmark and neonatal mortality in neonates weighing less than 2000 g in India, randomized controlled trial 

Background 

Four small randomized trials in low-birth-weight neonates have previously suggested that the Danish strain of Bacillus Calmette-Guerin (BCG) might reduce all-cause neonatal (28-day) mortality by reducing death from infections other than tuberculosis in high-mortality settings. These effects may be explained by induction of heterologous immunity, "trained" innate immune responses, and rapid induction of emergency granulopoiesis. In the BLOW2 open-label trial, infants weighing &lt;2000 g in three neonatal intensive care units in India were randomized 1:1 to receive 0.1 ml of BCG-Denmark (Green Signal Bio Pharma, Chennai) by intradermal injection plus oral polio vaccine either (1) soon after birth [Early-BCG Group] or (2) delayed until at least the time of discharge [Control Group]. The primary outcome was all-cause neonatal mortality, and the main secondary outcome was neonatal mortality from infection. 

This documentation 

The Statistical Analysis Plans (SAPs) for the BLOW2 trial are deposited here because the final SAP (version 5.0, dated 4 August 2022) was approved and signed by the Chief Investigators on 17 November 2022 and then posted on the Madras Medical College website (www.mmc.ac.in). However, soon afterwards, the MMC website went down (“www.mmc.ac’s DNS address could not be found”), and it is still down on 22 December 2023. 

Trial registration and statistical analysis plan (SAP)

The trial was registered prospectively (before the first infant was randomised) at Clinical Trials Registry India CTRI/2017/01/007676 on 11 January 2017 (http://tinyurl.com/2s4rwzy8); the registration included an outline of the proposed statistical analysis. The first child was randomised on 1 February 2017. The first SAP, version 1.0, dated 29 March 2017, was adapted from the analysis outlined in CTRI/2017/01/007676; this plan was amended on four occasions.

SAP 2.0, 18 November 2018. PMID 29579158 Table 3 (and later PMID 31677386 and PMID 33893799) showed that BCG-Denmark reduced mortality from infection rather than non-infectious causes, so the DSMB recommended on 7 November 2018 that death from infection be added as a secondary outcome.

SAP 3.0, 11 October 2021. A substantial proportion of infants in the control group were given BCG and OPV at about the time of discharge from hospital and few deaths occurred between discharge and 28 days of age so, on 17 September 2021, the DSMB recommended that the main analysis not be censored for BCG and OPV in the control group because this would cause bias by removing time with a low risk of death from the control group and not the early-BCG group. PMID 33893799 (online 24 April 2021) suggested that BCG might have a reduced effect on mortality in infants delivered by caesarean section, so C-section was added as a possible explanatory variable (in addition to the prespecified variables: BCG status of the mother, birth weight, gestation, sex, season, and inborn or outborn status).

SAP 4.0, 1 August 2022. This amendment added that multivariable fractional polynomial models would be used to test whether transformation was needed of the continuous explanatory variables gestational age and birth weight.

SAP 5.0, 4 August 2022. Because the CTRI trial registration stated that, in the primary analysis, Controls would be censored at the time they received BCG (which would cause bias because of removal of low-risk time in Controls but not in the BCG group), an analysis that censored for BCG in Controls was added as a sensitivity analysis.

Data analysis commenced on 21 November 2022.