The STRIDER trials: ongoing research

Funding

Wessel Ganzevoort a [email protected] Christian Gluud b Ken Lim c Ben Mol d Katie Groom e a Department of Obstetrics, Academic Medical Center, Amsterdam, 1100 DD, Netherlands Department of Obstetrics Academic Medical Center Amsterdam DD 1100 Netherlands b Copenhagen Trial Unit, Copenhagen University Hospital, Copenhagen, Denmark Copenhagen Trial Unit Copenhagen University Hospital Copenhagen Denmark c Department of Obstetrics, BC Women's Hospital, University of British Colombia, Vancouver, BC, Canada Department of Obstetrics BC Women's Hospital University of British Colombia Vancouver BC Canada d Department of Obstetrics, University of Adelaide, Adelaide, SA, Australia Department of Obstetrics University of Adelaide Adelaide SA Australia e Department of Obstetrics, University of Auckland, Auckland, New Zealand Department of Obstetrics University of Auckland Auckland New Zealand The report 1 published by Andrew Sharp and his STRIDER UK colleagues in The Lancet Child & Adolescent Health of the first STRIDER trial to be completed is a fine example of what collaboration and an efficient national clinical trial network can produce. The STRIDER UK trial reports on what was thought to be a promising novel therapy for fetal growth restriction. However, sildenafil given during pregnancy to women carrying a fetus with severe early-onset fetal growth restriction did not seem to prolong pregnancy when compared with women who received placebo, and did not seem to improve (or worsen) immediate short-term outcomes. We agree with Gordon C S Smith in his accompanying Comment that the short time interval from first participant recruitment to publication of the results is heartening. 2 However, this Comment also suggests that the efforts of an international network might have yielded a negative result. We would like to highlight that the conclusive answer of whether this therapy is effective is not yet known. As acknowledged by the authors, the STRIDER UK trial did not have sufficient power to assess truly relevant and meaningful outcomes. The STRIDER UK trial is part of an international collaboration (the STRIDER Individual Patient Data [IPD] Consortium) that encompasses similar trials funded and underway across clinical trial networks in the Netherlands, New Zealand, Australia, Canada, and Ireland. 3 This collaboration is embedded in the Global Obstetrics Network; 4 a network that was initiated to provide a forum for international interaction and to foster communication between groups undertaking clinical studies in obstetrics. The STRIDER IPD Consortium aims to resolve the underlying question: does sildenafil improve outcomes for fetuses with severe early-onset fetal growth restriction with a dismal prognosis? The novel approach is not only the collaborative design of the trials, but also the prospectively planned systematic review with trial level and IPD meta-analyses. 5 This approach provides an efficient use of scarce resources, will provide adequate power to optimise resolution of the research question, and facilitate subgroup analyses. Only the immediate short-term outcomes of the first trial to be completed have been presented by Sharp and colleagues. Other trials within the initiative are in progress at different stages; either close to presentation of their data or well underway with recruitment of participants. For the short-term outcomes, the STRIDER UK trial does not exclude a type II error (incorrectly retaining a false null hypothesis, also known as a false negative finding), particularly not in subgroups. Assessment of long-term neurodevelopmental and cardiometabolic outcomes in infants who survive are also in progress across the different trials. It is essential that, before this intervention is considered to be tested and rejected, combined analyses with sufficient power to assess meaningful outcomes must be completed. 6 Additionally, predefined subgroup analyses should be undertaken as it is conceivable that the intervention might work differently among different subgroups. If the final verdict is that the intervention is ineffective for all outcomes and in all subgroups, this outcome might be disappointing for clinicians who are just as eager as their patients to find an effective treatment, but important to guide future research and prevent ongoing use of an ineffective and potentially harmful treatment. However, it would be regrettable if a premature negative verdict would prevent an effective treatment reaching clinical practice. We strongly support the authors conclusion that sildenafil should not be prescribed for fetal growth restriction outside of research studies with explicit participants' consent and would like to emphasise the importance of completing recruitment in ongoing trials and assessment of the longer term outcomes for these unique cohorts of children. WG is the principal investigator of the ZonMW-funded Dutch (STRIDER) trial, which is underway in the Netherlands and part of the International STRIDER Consortium. KL is the co-principal investigator of the CIHR funded Canadian (STRIDER) trial, which is underway in Canada and part of the International STRIDER Consortium. BM is supported by an National Health and Medical Research Council Practitioner Fellowship (GNT1082548) and reports consultancy for ObsEva, Merck, and Guerbet. KG is the principal investigator of the HRC-NZ funded New Zealand and Australian (STRIDER) trial, which is underway in New Zealand and Australia and part of the International STRIDER Consortium. CG declares no competing interests.