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The Dutch STRIDER


Sildenafil TheRapy In Dismal prognosis Early onset fetal growth Restriction


Go to the STRIDER website


Objective
Severe, early-onset fetal growth restriction (FGR) due to placental insufficiency is associated with a high risk of perinatal morbidity with long-lasting sequelae and mortality. Placental insufficiency is the result of abnormal formation and function of the placenta (placentation) with inadequate remodelling of the maternal spiral (uteroplacental) arteries. There is currently no therapy available with demonstrated effectiveness. Evidence suggests Sildenafil citrate improves uteroplacental blood flow, growth, and meaningful outcomes.
The objective is to evaluate the effectiveness of sildenafil (versus placebo) in achieving healthy perinatal survival.

 

Study design
Multicenter nationwide randomized placebo-controlled clinical trial.

 

Study population
Women with a singleton pregnancy between 20 and 30 weeks with severe fetal growth restriction of likely placental origin, and with estimated significant likelihood of perinatal death.

 

Intervention
Sildenafil 25mg or placebo tablet orally three times daily.

 

Outcome measures
Primary: Perinatal healthy survival, i.e. survival without severe neonatal morbidity at term age.
Secondary:
1) to evaluate whether Sildenafil citrate, compared to placebo, increases the likelihood of improved fetal growth velocity assessed by ultrasound abdominal circumference measurements (AC);
2) to evaluate whether Sildenafil citrate, compared to placebo, increases the likelihood of age-adequate performance on the two-year Bayley scales of infant development (BSID)-III (composite cognitive score and composite motor score);
3) to assess co-incidence and severity of the maternal syndrome of pre-eclampsia / HELLP-syndrome
4) to evaluate fetal and placental dopplers at study entrance and development of Doppler parameters during treatment

 

Power/data analysis
Assumptions for power calculations are made on the basis of clinical relevance and a pilot cohort[1]. In the pilot cohort a 29% rate of intact survival until discharge (placebo-treated) vs 50% (Sildenafil-treated) was seen. We have decided for a difference of 15% to be clinically relevant. A 29% rate of intact survival until discharge (placebo-treated) vs 44% (Sildenafil-treated), with an of 0.05, we will have 80% power to detect this difference if we randomise 161 women per group. Therefore, accepting a 10% drop-out rate, the total sample size will be 354 women. We have a history of very low rates of loss to follow-up in our RCTs. Also, we shall minimise loss to follow-up by having the site study co-ordinator establish a close relationship with the study participants, through regular study contacts (at the planned weekly antenatal assessments (minimum), during hospitalisation(s), and at delivery, as applicable) and the availability to answer any questions about the Trial.

The 10 tertiary care centers in the Dutch Consortium for women's health and reproductivity studies each see an approximate 3-4 patients with severe fetal growth restriction of likely placental origin every month. With an expected uptake of the trial in 50% of patients (missed inclusions from failure to seek informed consent, denial of informed consent) each center may be able to recruit 20 patients per year. With some centers expected not to recruit optimally, a sum total of 120 patients per year is realistic. Enrolment of participants will be over 3-year duration.  The clinical outcomes for non-consenting women will be tracked to evaluate the external validity of the STRIDER Trial findings.

 

Time schedule
See power/data analysis

 

Projectleaders
Wessel Ganzevoort, perinatologist, Academisch Medisch Centrum

 

Methodology
Christiana Naaktgeboren, methodologist, Universitair Medisch Centrum Utrecht

 

Subsidy
Zon-MW funded

 

Contact
Anouk Pels, researcher, Academisch Medisch Centrum:
a.pels@amc.uva.nl