Primary research question

Does maternal oral sildenafil citrate in labour, compared with placebo, reduce the primary composite end point of 10 adverse neonatal outcomes? (table 1).

Secondary research questions

1. Does maternal oral sildenafil citrate in labour reduce the rate of the secondary outcomes of:

   • emergency operative birth for fetal distress;

   • intrapartum stillbirth;

   • death of baby before discharge from hospital;

   • Apgar score <4 at 5 min;

   • cord artery pH <7.0;

   • neonatal encephalopathy;

   • neonatal seizures;

   • neonatal respiratory support >4 hours;

   • neonatal unit (special care or intensive care) admission lasting >48 hours;

   • persistent pulmonary hypertension of the newborn;

   • meconium aspiration syndrome.

2. Is maternal oral sildenafil citrate in labour more cost-effective than placebo?

Study design

This is a two-arm parallel, randomised (1:1), placebo-controlled, double-blind multicentre superiority trial of sildenafil citrate versus placebo for women in labour at term (≥37⁺⁰ weeks).

Patient and public involvement

We involved clinician and consumer groups when designing this trial through the use of electronic media and face-to-face interviews. Of >400 women and clinicians in 68 sites in Australia and overseas, >90% endorsed iSEARCH and, if its hypotheses were confirmed, >85% would want sildenafil citrate to become an option in routine care.

Aim

This study aims to test the hypothesis that up to three doses of oral 50 mg sildenafil citrate (vs placebo) are safe and will improve perinatal and maternal outcomes related to intrapartum hypoxia.

Primary objective

To evaluate whether, compared with placebo, sildenafil citrate reduces the RR of the composite perinatal end point by 35%, from 7% to 4.55%. The composite end point comprises the 10 components shown in table 1.

Secondary objectives

1. To evaluate whether sildenafil citrate results in a RR reduction of caesarean section or instrumental vaginal birth for fetal distress by 25% (from 20% to 15%).

2. To evaluate whether sildenafil citrate results in a reduction of the RR of each individual component of the composite primary outcome, namely:

   • intrapartum stillbirth;

   • death of baby before hospital discharge;

   • Apgar score <4 at 5 min;

   • cord artery pH <7.0;

   • neonatal encephalopathy;

   • neonatal seizures;

   • neonatal respiratory support >4 hours;

   • neonatal unit (special care or intensive care) admission lasting >48 hours;

   • persistent pulmonary hypertension of the newborn;

   • meconium aspiration.

3. To evaluate whether sildenafil is more cost-effective than placebo.

Study period

Recruitment to iSEARCH began on 7 September 2021 and is expected to end by 31 August 2024.

Sample size

The incidence of the composite adverse outcome is estimated at 7% based on data from several of the participating hospitals, the ARRIVE RCT20 and the Australian and New Zealand Neonatal Network.25 To detect a 35% reduction from 7% to 4.55% for an alpha of 0.05 and >80% power with 10% drop out in each arm, needs about 3200 women. This sample size also yields >90% power to detect a 25% reduction for the secondary outcome of caesarean section or instrumental vaginal birth for fetal distress.

Study population

Inclusion criteria:

1. Women with singleton or dichorionic twin pregnancies, planning vaginal birth at term (≥37⁺⁰ weeks gestation).

2. Age ≥18 years.

3. Willing and able to comply with all study requirements.

4. Signed, written informed consent.

Exclusion criteria:

1. A woman should not be enrolled if the responsible clinician or the woman are, for any medical or non­-medical reasons, reasonably certain that sildenafil citrate would be inappropriate for her in comparison with no treatment or some other treatment that could be offered outside the trial.26

2. Triplets or higher order multiple births, which are generally delivered electively before term.

3. Contraindications to the investigational product (sildenafil citrate).

4. Women who are taking any type of nitrate drug therapy or using short-acting nitrate-containing medications during labour (such as sodium nitroprusside, bosentan, fosamprenavir and ritonavir combination, hepatic enzyme inhibitors CYP3A4 including itraconazole, ketoconazole, ritonavir, cimetidine, erythromycin, saquinavir, darunavir or hepatic enzyme substrates CYP3A4), or other medications used to treat pulmonary arterial hypertension such as riociguat and other phosphodiesterase-5 inhibitors, are at risk of potentially life-threatening hypotension.27

5. Severe hepatic or renal impairment.27

Screening, registration and randomisation

All women attending antenatal clinics in participating hospitals from ≥34⁺⁰ weeks will be screened for eligibility by study midwives. Women who consent to participate will be registered in an online trial registration database. Once registered, each woman is assigned a unique study number and receives routine care until spontaneous labour or induction of labour, when randomisation is undertaken. Individuals may only be registered and randomised once. Randomisation is undertaken after the responsible midwife or obstetrician has again confirmed that the woman is eligible. If an eligible woman presents for the first time in labour, screening, registration and randomisation are done together. Once registration and randomisation are completed, the participant is assigned a treatment arm. Randomisation is web-based, using a computer-generated concealed allocation sequence, stratified by study site.

At registration, each woman will be invited to consent to allow data linkage with her child or children’s educational outcomes in the National Assessment Programme—Literacy and Numeracy28 for data to be extracted from Medicare Benefits Schedule and Pharmaceutical Benefits Schemes claims records for herself and her infant and from the Australian cerebral palsy register. Such consent may be withdrawn at any time and without a reason. Each woman will also be invited to give consent to participate in childhood neurodevelopmental follow-up at 2–3 years corrected age. If she consents to this, contact details will be recorded and follow-up assessment will be performed as described below. Any decline for follow-up will be properly explored to ensure that withdrawal is not automatically interpreted to mean complete removal from the study as this may have possible implications for the reliability of trial findings. It may also be disadvantageous to these women because they could miss out on some aspects of the RCT that may matter to them (such as being informed about progress and results of the study).29

Study treatments

The study intervention is oral sildenafil citrate. The control intervention is placebo. Study treatment only begins after transfer to the labour ward either in spontaneous labour or for induction of labour (artificial rupture of membranes±oxytocin). Women are given the first dose by the attending midwife in the labour ward. Women receive sildenafil citrate 50 mg or identical placebo orally every 8 hours to a maximum of three doses, from identical matched treatment packs supplied by the trial pharmacy.

Management of labour and puerperium

Intrapartum FHR monitoring will be performed in all women. Where possible, umbilical artery cord pH will be measured in all women after birth. Classification of FHR abnormalities is based on the Royal Australian and New Zealand College of Obstetricians and Gynaecologists guidelines. In a subset of women, 20 mL of blood will be collected for assay of soluble Fms-like tyrosine kinase-1 (sFlt-1) and PlGF levels. Where possible, these women will also have an ultrasound scan performed to assess the fetoplacental circulation and liquor volume before and after treatment. The ultrasound data and maternal sFlt-1 and PlGF levels will allow post hoc subgroup analysis to identify cohorts at risk of fetal distress that might derive greater benefit from sildenafil citrate treatment. Otherwise, intrapartum management will be in accordance with local hospital guidelines.

To detect possible persistent pulmonary hypertension of the newborn, all infants will also receive routine oxygen saturation screening to detect hypoxaemia, generally 24–48 hours after birth but, if necessary, 4 hours after birth. Infants with oxygen saturations of >95% are very unlikely to have major congenital heart or significant pulmonary disease, including persistent pulmonary hypertension of the newborn.30 Infants with oxygen saturations <95% will receive further assessment by the paediatric team which may include echocardiography.

Trial outcomes

In-hospital maternal and neonatal outcome events occurring from randomisation to discharge home will be collected from medical records into electronic case report forms (eCRFs). Assessments of outcome will be blinded to treatment allocation. All primary outcome data will be routinely available before discharge and collected electronically. There are no formal study assessments visits. Research midwives will contact women 30 days after discharge to ascertain further relevant issues. Childhood follow-up will be conducted by linkage with educational databases and cerebral palsy registers and using parent report questionnaires.31–33

Data analysis

We will adopt recommended approaches34 35 to the analysis and reporting of composite end points, as in previous multicentre perinatal RCTs.36–41 A detailed statistical analysis plan and health economic protocol will be published before unblinding and data analysis begin.42 The Trial Management Committee (TMC) will base any modifications to the original objectives, such as a change in the components of the composite end point, adjudication of events or handling of missing data, on a review of the pooled event rate, pooled adherence rates and pooled missing data while remaining blinded to differences by allocated treatment and to the direction of any treatment effect.43–46 Primary and secondary analyses will adhere to an intention-to-treat basis using generalised linear models (binary or normal). Intervention effect will be presented as RR or mean difference, as appropriate, with 95% CIs. Primary analyses will be unadjusted. Numbers needed to treat to prevent one adverse outcome will be calculated. Where there are differences in baseline characteristics between the two treatment groups that might be associated with outcomes, secondary analyses of the primary outcome will be carried out using multiple (log-binomial) regression. Reporting will follow the Consolidated Standards of Reporting Trials47 and Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis48 guidelines.

There is only one primary outcome. Secondary outcomes include each of the 10 individual components of the primary composite outcome (table 1). For the secondary outcomes, no formal adjustments for multiplicity are planned. Because the secondary outcomes are inter-related and potentially causally attributable to hypoxic birth injury, we will follow the advice outlined by Schulz and Grimes49 and interpret the pattern and consistency of findings across related outcomes, rather than focusing on any single, statistically significant result. Subgroup analyses will be performed by testing for interactions and findings will be reported as exploratory. Results of other end point, subgroup and sensitivity analyses will be interpreted in proper context and with due consideration of the risk of type I error. Interpretation of statistical evidence will also consider the recommendations of Pocock and Stone.50 51

Safety of sildenafil citrate

In our systematic review15 of the efficacy and safety of phosphodiesterase inhibitors (sildenafil citrate or tadalafil) in 10 RCTs in 1090 women in pregnancy, we found that use of phosphodiesterase inhibitors in term labour was not associated with an increase in maternal side effects, including dizziness, flushing, dyspepsia, gastritis, palpitations, arthralgia, dyspnoea, epistaxis, diarrhoea, tremor, headache, myalgia, paraesthesia, oedema, visual changes, vaginal itch, nausea and vomiting, intrapartum antiemetic use, postpartum haemorrhage of ≤1500 mL, anaemia, bronchitis, skin rash, intrapartum fever or placental abruption. Use of phosphodiesterase inhibitors in labour may have been associated with a small increase in vaginal birth (RR 1.24, 95% CI 1.00 to 1.55; p=0.05) and a statistically significant reduction in risk of operative birth for intrapartum fetal compromise (RR 0.58, 95% CI 0.38 to 0.88; p=0.01). The use of sildenafil in labour was not associated with increased risk of perinatal death (RR 0.89, 95% CI 0.56 to 1.43; p=0.64), nor with maternal admissions to intensive care and no maternal deaths were reported.

Chronic use of phosphodiesterase inhibitors for the treatment of severe fetal growth restriction, as in the STRIDER (Sildenafil TheRapy in dismal prognosis early onset fetal growth restriction) trials,52 53 or treatment of pre-eclampsia16 54 55 was associated with a statistically significant increase in the risks of flushing (RR 6.83, 95% CI 1.49 to 31.23; p=0.01) and nasal bleeding (RR 10.53, 95% CI 1.36 to 81.3; p=0.02); an increase in risk of persistent pulmonary hypertension of the newborn (RR 2.52, 95% CI 1.00 to 6.32; p=0.05) and non-statistically significant increase in headaches (RR 1.41, 95% CI 0.97 to 2.05; p=0.08) and flushing (RR 2.59, 95% CI 0.69 to 9.90; p=0.16).15

The international STRIDER RCTs used daily maternal sildenafil doses of 75 mg in pregnant women with severe fetal growth restriction between 20 and 30 weeks’ gestation for up to 10 weeks, that is, cumulative doses of up to 5250 mg.52 53 In 2019, the Dutch STRIDER trial was stopped on the advice of the Data Safety Monitoring Board due to an increase in persistent pulmonary hypertension of the newborn with a non-significant increase in neonatal deaths in the sildenafil citrate group.56 Persistent pulmonary hypertension of the newborn occurred in 16 neonates (18.8%) in the sildenafil citrate group vs 4 neonates (5.1%) in the placebo group (RR 3.67, 95% CI 1.28 to 10.51; p=0.008). A subsequent meta-analysis of 329 participating women in all available trials showed no difference in neonatal deaths.57 However, it is recommended that sildenafil citrate not be prescribed outside of clinical trials.58 The indication and cumulative dosage of sildenafil citrate in the iSEARCH trial are markedly different from the STRIDER trials, as we will only administer a maximum 150 mg in women at term, which is about 35 times lower. Persistent pulmonary hypertension of the newborn will be monitored as one of 10 components of the primary composite end point by the independent data and safety monitoring board, as outlined below.

Safety of sildenafil during breast feeding

Limited data indicate that sildenafil citrate and its active metabolite in breast milk are poorly excreted into breast milk. Amounts ingested by the infant are far below doses given to treat infants and would not be expected to cause any adverse effects in breastfed infants.59 Women taking sildenafil citrate for the treatment of pulmonary hypertension in the UK are advised to continue breast feeding because sildenafil citrate only passes into breast milk in tiny amounts, is unlikely to cause any side effects in the baby and breast feeding will benefit both mother and baby.60 We will monitor concentrations of sildenafil citrate in breast milk and any potentially related adverse events in a subset of women in the trial.

Role of study sponsor and funders

The University of Sydney, as sponsor of iSEARCH, the University of Queensland as administering organisation and the Medical Research Future Fund as funder of iSEARCH have had no role in study design, collection or management of data. Both will also have no role in analysis or interpretation of data, writing of manuscripts or decisions to publish.

The iSEARCH Trial Management Committee

The TMC will oversee study planning, monitoring, progress, review of information from related research and implementation of recommendations from other study committees and external bodies (eg, Human Research Ethics committees). It will consider recommendations from the Independent Data Safety and Monitoring Committee (IDSMC) about whether to continue the study as planned, modify or stop, based on interim analyses or other information. The TMC will consist of all Chief Investigators.

The iSEARCH Trial Coordinating Centre is the NHMRC Clinical Trials Centre (CTC). It will support the TMC in the day-to-day conduct of the trial, and study processes, including data management, ensuring compliance with regulatory requirements and confidentiality of data collection, liaising with ethics committees, biostatistical team, IDSMC and answering queries from participating sites including the receipt and timely management of reports of adverse events. A list of participating sites is available in the trial registration entry at the Australian New Zealand Clinical Trials Registry (ACTRN12621000231842).

Compliance

Participant medication compliance will be monitored and documented in the medical records and eCRFs, which will be held on a secure server, ensuring confidentiality. The iSEARCH trial may be subject to audit or inspection by representatives of the NHMRC CTC or representatives of independent regulatory bodies (eg, the Therapeutic Goods Administration).

Unblinding

Unblinding is not generally necessary for the management of a patient with an adverse event and, as it may have an impact on the study’s validity, is discouraged. The need for unblinding should be very uncommon as the study intervention is rarely associated with severe side effects and it will not delay or prevent standard management of the participant. However, if required, it should be done centrally after discussion with the Study Chair and NHMRC CTC representative using the emergency unblinding number in the study manual.

The Independent Data Safety and Monitoring Committee

The IDSMC will review interim data on the primary outcome, specified adverse events and other evidence after 50% of recruitment or whenever they deem appropriate, as recommended by Haybittle,61 Peto et al,62 Geller and Pocock.63 There will be no adjustment to alpha for interim analyses.

Interim analyses of the primary composite outcome

The IDSMC will advise the TMC if in their view there is proof beyond reasonable doubt of net benefit or harm for the primary composite end point, for example, employing a commonly used formal threshold of p<0.001 for nominal significance, as recommended by Geller and Pocock.63

Interim analyses of mortality

The IDSMC will advise the TMC if in their view there is a difference in mortality due to intrapartum stillbirth and/or 28-day neonatal mortality identified as a deviation from the null indicated by a Haybittle-Peto boundary of 3 SEs from the null, which is equivalent to p<0.0027,61 62 which would be needed to justify recommending early stopping.

Limitations

The postulated 35% reduction in the RR of its primary composite end point is nearly twice as large as the 20% relative reduction in a 10-component composite outcome seen in the ARRIVE trial, which enrolled 6106 women.20 This putative 35% RR reduction in iSEARCH may therefore reflect ‘optimism bias’64–66 and is an important limitation, dictated by financial constraints which precluded a larger study.

The 10 components of the primary composite end point (table 1) are all potentially related to intrapartum hypoxia.20 67 However, a reduction in overall incidence of this end point could not be interpreted as indicating reductions in key individual components such as intrapartum stillbirth, neonatal mortality, Apgar score <4 at 5 min, neonatal encephalopathy or seizures, because the rates of these events vary between 0.1% and 0.5%, at which iSEARCH is greatly underpowered to detect any differences. The three individual components of the composite end point for which the chances of showing a reduction in incidence are greatest are (i) admission to neonatal unit for >48 hours, (ii) respiratory support for >4 hours and (iii) cord pH <7. Their estimated event rates are 3.6%, 4.3% and 2.2%, respectively (table 1) for which our sample of 3200 gives ~80% power to show (although highly optimistic) reductions in RR of 50%–60%. However, unlike some of the other components of the composite outcome (eg, neonatal encephalopathy), these three components are significantly less likely to impact long-term health outcomes.

Regulatory compliance

Conduct of the iSEARCH trial will be informed by the International Conference on Harmonisation Guidelines for Good Clinical Practice68 69 and WHO guidance.29 The study will comply with all applicable laws and regulations and the principles laid down by the World Medical Association in the Declaration of Helsinki 2013. It was registered with the Australian and New Zealand Clinical Trial Registry and ethical and regulatory approvals were obtained before it began. Changes and amendments to the protocol can only be made by the TMC. Approval by the Institutional Human Research Ethics Committee is required prior to the implementation of any amendments.