STRIDER NZAus A Randomised Controlled Trial of S ildenafil T he r apy I n D ismal Prognosis E arly-Onset Intrauterine Growth R estriction (New Zealand and Australia). Dr Katie Groom, Professor Philip Baker, Professor Lesley McCowan, Professor Peter Stone University Of Auckland
Sildenafil potentiates the effect of NO Placental vascular casts in May cause vasodilatation of vessels responsive to NO. a mouse model of IUGR This may include vessels within the fetal and/or maternal compartments of the uteroplacental circulation. Sildenafil has the potential to increase uteroplacental circulation and perfusion resulting in improved gaseous and nutrient exchange Before sildenafil treatment and improved fetal growth and well-being? Observational study Sildenafil naive Sildenafil treated After sildenafil treatment daily AC growth between US (d/d) Images courtesy Phil Baker daily AC growth between US (d/d) Wilcoxon p = 0.2513 Wilcoxon p = 0.0039 2 2 Comparsion of 10 sildenafil exposed to 17 1 1 non-exposed women with severe IUGR 0 0 ) ) ) ) d d e e v v e e ï ï t t a a a a n n e e ( ( r r t t y y ( ( Von Dadelzsen BJOG 2011, t t i i y y l l t i i t b i i b l l i i i i b b g g i i 118 (5): p. 624-8. i i l l g g e e i i - - l l e e e t s - - r o e t p s r p p o p
STRIDER NZAus HRC funded. ACTRN 12612000584831 Hypothesis: Sildenafil therapy compared to placebo therapy will increase the likelihood of increased fetal growth velocity (measured by change in expected/observed increase in abdominal circumference per day) in pregnancies complicated by severe early onset IUGR. Study design: A bi-national multicentre double blind randomised placebo controlled trial. Study population: A total of 122 women with pregnancies affected by severe early onset IUGR identified from participating MFM centres across NZ and Australia. Inclusion criteria Exclusion criteria 1. Known major fetal anomaly/syndrome/ congenital infection deemed likely cause for 1. Singleton pregnancy IUGR. 2a. At ≥22 0 weeks and ≤ 27 6 weeks: AC 2. Known fetal aneuploidy. measure ≤3rd percentile for GA 3. Plan made for termination. OR 2b. At ≥28 0 weeks and ≤ 29 6 weeks: EFW 4. Maternal disease (e.g. preeclampsia) <700g where it is expected that delivery is necessary within next 48 hours. USS measurements for eligibility must have been carried out ≤24 hours prior to randomisation . 5. Any contraindication to sildenafil therapy.
STRIDER NZAus Treatment: Women will be randomised to one of two groups. Sildenafil group Placebo group Oral sildenafil citrate - 25mg tds Matching placebo tablet - 1 tab tds Treatment will continue until delivery or 32 0 weeks gestation (or intrauterine demise). Trial schedule: Antenatal care and timing of delivery determined by clinician. Maternal & fetal surveillance at 48 hours ( USS & BP only ), days 5, 10, 14 and then weekly: Maternal – BP, urinalysis, blood tests (FBC, LFT and renal) Fetal USS – Measurements to include AC, BPD, HC & FL; AF assessment; Doppler waveforms of UA, UV, DV, MCA and maternal uterine artery. Computerised CTG - FHR short term variability. Weekly once viable, if available. Routine clinical assessment and scan data to be used wherever possible. Exception = 48 hour scan. Post- treatment: Delivery and neonatal data collection. Vascular physiology studies in Auckland cohort Questionnaire 6-12 wks after delivery & request for possible paediatric follow-up at 18- 36m
What about outcome for infants? By collaboration with an international consortium we will also examine the hypothesis that sildenafil therapy compared to placebo therapy will increase the rate of survival free of major handicap. The IPD Collaboration has worked on study design, outcomes and data collection. All STRIDER trials will use very similar methodologies and outcomes to ensure they are comparable and compatible for analysis. Likely 4 individual trials: NZ/Aus; UK/Ireland (funded); Netherlands (funded); Canada Planned IPD analysis power example: Primary outcome of survival free of major morbidity at time of hospital discharge. With an estimate of 21% (placebo) vs 35 % (sildenafil), α 0.05, two sided test and 90 % power to detect difference, a total of 504 women need to be randomised ( 229 per group and 10% drop-out rate).
STRIDER NZAus Thank you to all who have expressed interest so far Recruiting centres across Australia and New Zealand Assistance with set-up ($1000 at site activation) and NZ $1000 per recruit Contact: Katie Groom k.groom@auckland.ac.nz +64 21 245 9622 Trial Manager: Laura Mackay laura.mackay@auckland.ac.nz +64 9 3737599 ext 81366 stridernzaus@auckland.ac.nz Recruitment to commence in January 2014
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