STRIDER NZAus A Randomised Controlled Trial of S ildenafil T he r apy - - PowerPoint PPT Presentation
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
A Randomised Controlled Trial of Sildenafil Therapy In Dismal Prognosis Early-Onset Intrauterine Growth Restriction (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
May cause vasodilatation of vessels responsive to NO. 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 and improved fetal growth and well-being?
Sildenafil naive Sildenafil treated
p r e
l i g i b i l i t y ( n a ï v e ) p
t
l i g i b i l i t y ( n a ï v e ) 1 2
Wilcoxon p = 0.2513
daily AC growth between US (d/d)
p r e
l i g i b i l i t y ( t r e a t e d ) p
t
l i g i b i l i t y ( t r e a t e d ) 1 2
Wilcoxon p = 0.0039
daily AC growth between US (d/d)
Observational study
Von Dadelzsen BJOG 2011, 118(5): p. 624-8.
Comparsion of 10 sildenafil exposed to 17 non-exposed women with severe IUGR
Placental vascular casts in a mouse model of IUGR Before sildenafil treatment After sildenafil treatment
Images courtesy Phil Baker
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
measure ≤3rd percentile for GA OR
<700g
USS measurements for eligibility must have been carried out ≤24 hours prior to randomisation.
Exclusion criteria
congenital infection deemed likely cause for IUGR.
where it is expected that delivery is necessary within next 48 hours.
HRC funded. ACTRN 12612000584831
Sildenafil group Oral sildenafil citrate - 25mg tds Placebo group Matching placebo tablet - 1 tab tds Treatment: Women will be randomised to one of two groups. 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 Treatment will continue until delivery or 320 weeks gestation (or intrauterine demise).
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
What about outcome for infants?
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).
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