The STRIDER Canada trial was a national multisite individual participant double-blind, placebo-controlled randomised controlled trial (NCT02442492 [registered 13 May 2015]). (Figure 1. CONSORT diagram). An independent Data Safety Monitoring Board (DSMB) monitored the progress of the trial and all serious adverse events (SAEs). As the trial was halted early, only three sites became active, BC Women’s Hospital and Health Centre (BC Women’s, Vancouver), Ste Justine (Montréal), and Centre hospitalier universitaire de Québec (Québec).
Women were eligible to be approached to provide written informed consent if they were aged ≥18 years with a singleton pregnancy at 18 +0 – 27 +6 weeks’ gestation, estimated fetal weight <700g, and at least one of (i) fetal AC <10 th percentile for GA (local criteria); or (ii) reduced fetal growth velocity (<50% of anticipated) and either abnormal uterine artery Doppler or prior early-onset FGR with adverse perinatal outcome (defined as either a perinatal or infant death related to FGR or a life-altering complication of either prematurity or FGR [e.g., hypoxic-ischaemic encephalopathy, cerebral palsy, or chronic lung disease]).
Exclusion criteria were (i) decision made to terminate the index pregnancy; (ii) reversed end-diastolic flow by umbilical artery Doppler; (iii) prior participation in a STRIDER trial; (iv) maternal factors (e.g., pre-eclampsia or gestational hypertension [index pregnancy]; known HIV positive status [drug-drug interaction between sildenafil and antiretrovirals]; known significant maternal heart disease; current cocaine or crystal meth drug use; receiving prazosin, other peripheral alpha-blockers, or nitrates; or allergy to sildenafil); or (v) fetal factors (e.g., known aneuploidy, anomaly, syndrome, or congenital infection confirmed at enrolment).
Once consent had been obtained, eligibility was confirmed in real-time by Alere (San Diego, CA) Triage™ plasma PlGF <5 th percentile for GA (7); for gestational ages 18 +0 – 20 +0 weeks, the 5 th percentile was determined from samples from women attending the BC Women’s EMMA (Evaluating Maternal Markers of Adverse placental outcomes) Clinic at 16 +0 – 24 +0 weeks who delivered normally-grown infants (10th – 90th percentile for GA) at term without either hypertension or diabetes. The EMMA Clinic 5 th percentile PlGF values were contiguous with the NORMALS cohort 5% percentile line (7).
Randomisation was centrally controlled using a web-based computerised randomisation platform integrated System for Trial Allocation and Randomisation (iSTAR) developed by the PRE-EMPT (PREgnancy Evidence, Monitoring, Partnerships & Treatment) team, BC Children’s Hospital Research Institute (BCCHR). Randomisation was stratified by centre with random blocks of 2 or 4. Women were randomised to receive either sildenafil (25mg three times daily) or matched placebo (three times daily). Each study drug bottle contained 30 over-encapsulated capsules (to mask arms), equivalent to a 10-day supply of either sildenafil or placebo. Sildenafil tablets were sourced from Pharmascience Inc (DIN 02317559). The Bay Area Health Trust (BARL), ON, made placebo capsules through the process of over-encapsulation.
STRIDER Canada was a pragmatic trial; in the absence of standardised care available at all participating centres, the Canadian STRIDER trial protocol allowed centres to provide their usual pattern of care. All women received enhanced fetal and maternal surveillance based on concurrent Society of Obstetricians and Gynaecologists of Canada guidance regarding the diagnosis management of FGR (8).
At enrolment, baseline data were collected regarding current and past medical history and demographics including ethnicity, past obstetric history, medication use, allergies, aneuploidy screening, invasive testing, and congenital infection results.
Fetal biometry (biparietal diameter, head circumference, AC, and femur length) and Doppler indices (uterine artery, umbilical artery, middle cerebral artery, and ductus venosus) were collected from the latest pre-randomisation ultrasound scan. Similarly, data for maternal assessment prior to randomisation were collected for PlGF, complete blood count, renal (creatinine, urea) and liver function (aspartate and alanine transaminase, albumin), urinalysis, and blood pressure measurements. Doppler indices, PlGF testing, and blood pressure measurements were repeated at 48 hours post-1st dose. All participants undertook weekly maternal and fetal assessments and PlGF testing. Other clinically-indicated care was undertaken as per local practice or at the discretion of a treating clinician. No special restrictions were required with regards to diet, activities, or other lifestyle items.
In addition, each participant was given a patient medication diary and were encouraged to note any missed doses, adverse events, and symptoms. The dairy and pill counts were reviewed by the study team during antenatal visits.
Decisions to deliver were made by the treating physicians according to local practice. If undelivered, all participants discontinued the study drug once they reached 31 +6 weeks GA.
Primary outcome: gestational age at delivery (d) (sildenafil vs placebo). The unit of analysis was ‘fetus’. Secondary outcomes: livebirth, survival to hospital discharge, intact discharge, and combined non-CNS severe morbidity.
Stopping rule: STRIDER Canada would be halted if two other STRIDER trials determined any potential benefit or harm before the STRIDER Canada trial was completed.
All data were entered into a REDCap (Research Electronic Data Capture, Vanderbilt University) platform developed and co-ordinated on behalf of all the STRIDER trials by the PRE-EMPT team. This approach was to facilitate the a priori planned STRIDER consortium individual participant data (IPD) meta-analysis (9).
Continuous variables were reported as means [95% confidence interval (CI)] for the between-arm mean difference. Categorical variables were presented as counts (percentages) and compared using chi-squared tests. P<0.05 was considered statistically significant. Data were analysed in R statistical software (version 3.6.3; R Foundation for Statistical Computing, Vienna, Austria).
Halting the trial
The STRIDER Canada trial was halted when the highly-publicised interim analysis of the Dutch STRIDER signaled the potential for harm to the neonate (increased risk in persistent pulmonary hypertension of the newborn) and a non-significant trend towards increased neonatal mortality (10). Initially, the trial was halted to enable a full and considered review of the evidence at that time, without exposing more pregnancies to potential harm. At that time, the UK group had published their results (11) and the STRIDER NZAus group had completed their trial, but not yet published their results (12); neither trial had identified any signal of benefit from sildenafil. Consultations were held within the trial steering group, with the UBC Clinical Research Ethics Board, and the DSMB. While no party felt that it would unethical to continue with the trial as the STRIDER Canada was recruiting women earlier, requiring low PlGF as an entry criterion, and not recruiting women with persistent reversed umbilical artery end-diastolic flow, the consensus was that it would be futile to continue given both the publicity and lack of evidence of potential benefit from either the NZAus or UK STRIDER trials. Therefore, the trial was halted.