STRIDER (Sildenafil TheRapy in dismal prognosis early onset fetal growth restriction): an international consortium of randomised placebo-controlled trials

A Pels, L C Kenny, Z Alfirevic, P N Baker, Peter von Dadelszen, C Gluud, C T Kariya, B W Mol, A T Papageorghiou, A G van Wassenaer-Leemhuis, W Ganzevoort, K M Groom, international STRIDER Consortium, A Pels, L C Kenny, Z Alfirevic, P N Baker, Peter von Dadelszen, C Gluud, C T Kariya, B W Mol, A T Papageorghiou, A G van Wassenaer-Leemhuis, W Ganzevoort, K M Groom, international STRIDER Consortium

Abstract

Background: Severe, early-onset fetal growth restriction due to placental insufficiency is associated with a high risk of perinatal mortality and morbidity with long-lasting sequelae. Placental insufficiency is the result of abnormal formation and function of the placenta with inadequate remodelling of the maternal spiral arteries. There is currently no effective therapy available. Some evidence suggests sildenafil citrate may improve uteroplacental blood flow, fetal growth, and meaningful infant outcomes. The objective of the Sildenafil TheRapy In Dismal prognosis Early onset fetal growth Restriction (STRIDER) collaboration is to evaluate the effectiveness of sildenafil versus placebo in achieving healthy perinatal survival through the conduct of randomised clinical trials and systematic review including individual patient data meta-analysis.

Methods: Five national/bi-national multicentre randomised placebo-controlled trials have been launched. Women with a singleton pregnancy between 18 and 30 weeks with severe fetal growth restriction of likely placental origin, and where the likelihood of perinatal death/severe morbidity is estimated to be significant are included. Participants will receive either sildenafil 25 mg or matching placebo tablets orally three times daily from recruitment to 32 weeks gestation.

Discussion: The STRIDER trials were conceived and designed through international collaboration. Although the individual trials have different primary outcomes for reasons of sample size and feasibility, all trials will collect a standard set of outcomes including survival without severe neonatal morbidity at time of hospital discharge. This is a summary of all the STRIDER trial protocols and provides an example of a prospectively planned international clinical research collaboration. All five individual trials will contribute to a pre-planned systematic review of the topic including individual patient data meta-analysis.

Trial registrations: New Zealand and Australia: ACTRN12612000584831 . Registered 30/05/2012. Canada: NCT02442492 . Registered 05/05/2015. Ireland: CT 900/572/1 . Registered 15/07/2015. The Netherlands: NCT02277132 . Registered 29/09/2014. United Kingdom: ISRCTN39133303 . Registered 31/07/2014.

Keywords: Fetal growth restriction; Neonatal morbidity; Neonatal mortality; Placental insufficiency; Randomised placebo controlled trial; Sildenafil.

Conflict of interest statement

Ethics approval and consent to participate

New Zealand/Australia: New Zealand Health and Disability Ethics Committee (CEN/12/06/028/AM05), Royal Brisbane & Women’s Hospital Human Research Ethics Committee (HREC/14/ORBW/178), and King Edward Memorial Hospital Ethics Committee (2014071EW).

Canada: University of British Columbia/Children’s and Women’s Health Centre of BC Research Ethics Board (H15–00899).

Ireland: provisional approval by Cork University Teaching Hospital Ethics Committee (ECM 5 (9) 02/02/16), full approval will be granted on confirmation of sponsorship (pending).

The Netherlands: MET AMC (NL41894.018.14).

The United Kingdom: 14.NE.0011.

All participating women are provided with written and verbal information regarding the trial they are going to enter and provide signed informed consent in advance of participation. Any protocol modifications once the trials are underway will be reviewed by the local Ethics Committee. Appropriate clinical trial insurance is in place for participants of each trial in the event that any participant experiences harm as a consequence of participation in these trials.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

    1. Lee MJ, Conner EL, Charafeddine L, Woods JR, Jr, Del Priore G. A critical birth weight and other determinants of survival for infants with severe intrauterine growth restriction. Ann N Y Acad Sci. 2001;943:326–339. doi: 10.1111/j.1749-6632.2001.tb03813.x.
    1. Petersen SG, Wong SF, Urs P, Gray PH, Gardener GJ. Early onset, severe fetal growth restriction with absent or reversed end-diastolic flow velocity waveform in the umbilical artery: perinatal and long-term outcomes. Aust N Z J Obstet Gynaecol. 2009;49(1):45–51. doi: 10.1111/j.1479-828X.2008.00938.x.
    1. Batton DG, DeWitte DB, Espinosa R, Swails TL. The impact of fetal compromise on outcome at the border of viability. Am J Obstet Gynecol. 1998;178(5):909–915. doi: 10.1016/S0002-9378(98)70522-8.
    1. Shah PS, et al. Prediction of survival without morbidity for infants born at under 33 weeks gestational age: a user friendly grpahical tool. Arch Dis Child Fetal Neonatal Ed. 2012;97:F110–F115. doi: 10.1136/archdischild-2011-300143.
    1. Bower S, Kingdom J, Campbell S. Objective and subjective assessment of abnormal uterine artery Doppler flow velocity waveforms. Ultrasound Obstet Gynecol. 1998;12(4):260–264. doi: 10.1046/j.1469-0705.1998.12040260.x.
    1. Moore RJ, Strachan BK, Tyler DJ, Duncan KR, Baker PN, Worthington BS, Johnson IR, Gowland PA. In utero perfusing fraction maps in normal and growth restricted pregnancy measured using IVIM echo-planar MRI. Placenta. 2000;21(7):726–732. doi: 10.1053/plac.2000.0567.
    1. Product monograph Viagra. Sildenafil as sildenafil citrate. Pfizer Canada Inc., 2015.
    1. Stanley JL, Andersson IJ, Poudel R, Rueda-Clausen CF, Sibley CP, Davidge ST, Baker PN. Sildenafil citrate rescues fetal growth in the catechol-o-methyl transferase knockout mouse model. Hypertension. 2012;59:1021–1028. doi: 10.1161/HYPERTENSIONAHA.111.186270.
    1. Refuerzo JS, Sokol RJ, Aranda JV, Hallak M, Hotra JW, Kruger M, Sorokin Y. Sildenafil citrate and fetal outcome in pregnant rats. Fetal Diagn Ther. 2006;21:259–263. doi: 10.1159/000091352.
    1. Sanchez-Aparicio P, Mota-Rojas D, Nava-Ocampo AA, Trujillo-Ortega ME, Alfaro-Rodriguez A, Arch E, Alonso-Spilsbury M. Effects of sildenafil on the fetal growth of guinea pigs and their ability to survive induced intrapartum asphyxia. Am J Obstet Gynecol. 2008;198:127.e1-6. doi: 10.1016/j.ajog.2007.06.068.
    1. Satterfield MC, Bazer FW, Spencer TE, Wu G. Sildenafil citrate treatment enhances amino acid availability in the conceptus and fetal growth in an ovine model of intrauterine growth restriction. J Nutr. 2010;140:251–258. doi: 10.3945/jn.109.114678.
    1. Wareing M, Myers JE, O'Hara M, Baker PN. Sildenafil citrate (Viagra) enhances vasodilatation in fetal growth restriction. J Clin Endocrinol Metab. 2005;90:2550–2555. doi: 10.1210/jc.2004-1831.
    1. Oyston CJ, Stanley JL, Baker PN. Potential targets for the treatment of preeclampsia. Expert Opin Ther Targets. 2015;19:1517–1530. doi: 10.1517/14728222.2015.1088004.
    1. Lacassie HJ, Germain AM, Valdés G, Fernández MS, Allamand F, López H. Management of Eisenmenger syndrome in pregnancy with sildenafil and L-arginine. Obstet Gynecol. 2004;103(5 Pt 2):1118–1120. doi: 10.1097/01.AOG.0000125148.82698.65.
    1. Sun X, Wang K, Wang W, Li B. Clinical study on sildenafil treatment of pregnant women with pulmonary arterial hypertension. Zhonghua Fu Chan Ke Za Zhi. 2014;49(6):414–418.
    1. Samangaya RA, et al. A randonised double blinded placebo-controlled study of the phosphodiesterase type 5 inhibitor sildenafil for the treatment of preeclampsia. Hypertens Pregnancy. 2009;28:369–382. doi: 10.3109/10641950802601278.
    1. von Dadelszen P, et al. Sildenafil citrate therapy for severe early-onset intrauterine growth restriction. BJOG. 2011;118(5):624–628. doi: 10.1111/j.1471-0528.2010.02879.x.
    1. Lin TH, YN S, Shih JC, Hsu HC, Lee CN. Resolution of high uterine pulsatility index and notching following sildenafil citrate treatment in a growth-restricted pregnancy. Ultrasound Obstet Gynecol. 2012;40(5):609–610. doi: 10.1002/uog.11142.
    1. Panda S, Das A, Md Nowroz H. Sildenafil citrate in fetal growth restriction. J Reprod Infertil. 2014;15(3):168–169.
    1. Molelekwa V, Akhter P, McKenna P, Bowen M, Walsh K. Eisenmenger’s syndrome in a 27 week pregnancy—management with bosentan and sildenafil. Ir Med J. 2005;98(3):87–88.
    1. Streit M, Speich R, Fischler M, Ulrich S. Successful pregnancy in pulmonary arterial hypertension associated with systemic lupus erythematosus: a case report. J Med Case. 2009;3:7255. doi: 10.4076/1752-1947-3-7255.
    1. Ganzevoort W, Alfirevic Z, von Dadelszen P, Kenny L, Papageorghiou A, van Wassenaer-Leemhuis A, Gluud C, Mol BW, Baker PN. STRIDER: Sildenafil therapy in dismal prognosis early-onset intrauterine growth restriction--a protocol for a systematic review with individual participant data and aggregate data meta-analysis and trial sequential analysis. Syst Rev. 2014;3:23. doi: 10.1186/2046-4053-3-23.
    1. Protocol STRIDER New Zealand/Australia: [doi:10.5281/zenodo.56150].
    1. Protocol STRIDER Canada: [doi:10.5281/zenodo.56152].
    1. Protocol STRIDER United Kingdom: [doi:10.5281/zenodo.56153].
    1. Protocol STRIDER The Netherlands: [doi:10.5281/zenodo.56148].
    1. Protocol STRIDER Ireland: [doi:10.5281/zenodo.496143].
    1. DMC Charter STRIDER New Zealand/Australia: [doi:10.5281/zenodo.56149].
    1. DMC Charter STRIDER Canada: [doi:10.5281/zenodo.56151].
    1. DMC Charter STRIDER United Kingdom: [doi:10.5281/zenodo.56154].
    1. DMC Charter STRIDER The Netherlands: [doi:10.5281/zenodo.56147].
    1. DMC Charter STRIDER Ireland: [doi:10.5281/zenodo.535768].
    1. Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med. 2001;135(11):982–989. doi: 10.7326/0003-4819-135-11-200112040-00010.
    1. Savovic J, Jones HE, Altman DG, et al. Influence of reported study design characteristics on intervention effect estimates from randomized, controlled trials. Ann Intern Med. 2012;157:429–438. doi: 10.7326/0003-4819-157-6-201209180-00537.
    1. Wood L, Egger M, Gluud LL, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ. 2008;336:601–605. doi: 10.1136/.
    1. Chan AW, Hrobjartsson A, Haahr MT, Gotzsche PC, Altman DG. Empirical evidence for selective reporting of outcomes in randomized trials: comparison of protocols to published articles. JAMA. 2004;291(20):2457–2465. doi: 10.1001/jama.291.20.2457.
    1. Skoog M, Saarimäki JM, Gluud C, Sheinin M, Erlendsson K, Aamdal S, et al. Transparency and registration in clinical research in the Nordic countries. Nordic Trial Alliance, NordForsk; 2015 1–108.
    1. Garattini S, Jakobsen JC, Wetterslev J, Berthele V, Banzi R, Rath A, et al. Evidence-based clinical practice: overview of threats to the validity of evidence and how to minimise them. European J Intern Med. 2016;32:13–21. doi: 10.1016/j.ejim.2016.03.020.
    1. Järvinen et al. On blinded analysis and conclusions. J Clin Epidemiol 67 (2014) 769e772.
    1. Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. Industry sponsorship and research outcome. Coch Database Syst Rev. 2012;12:MR000033.
    1. Little RJ, D'Agostino R, Cohen ML, Dickersin K, Emerson SS, Farrar JT, Frangakis C, Hogan JW, Molenberghs G, Murphy SA, Neaton JD, Rotnitzky A, Scharfstein D, Shih WJ, Siegel JP, Stern H. The prevention and treatment of missing data in clinical trials. N Engl J Med. 2012;367:1355–1360. doi: 10.1056/NEJMsr1203730.
    1. Molenberghs G, Kenward MG. Missing data in clinical studies. Chichester: Wiley; 2007.

Source: PubMed

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