The CoDiNOS trial protocol: an international randomised controlled trial of intravenous sildenafil versus inhaled nitric oxide for the treatment of pulmonary hypertension in neonates with congenital diaphragmatic hernia

Abstract

Introduction: Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that impairs normal lung development, causing pulmonary hypertension (PH). PH in CDH newborns is the main determinant for morbidity and mortality. Different therapies are still mainly based on 'trial and error'. Inhaled nitric oxide (iNO) is often the drug of first choice. However, iNO does not seem to improve mortality. Intravenous sildenafil has reduced mortality in newborns with PH without CDH, but prospective data in CDH patients are lacking.

Methods and analysis: In an open label, multicentre, international randomised controlled trial in Europe, Canada and Australia, 330 newborns with CDH and PH are recruited over a 4-year period (2018-2022). Patients are randomised for intravenous sildenafil or iNO. Sildenafil is given in a loading dose of 0.4 mg/kg in 3 hours; followed by continuous infusion of 1.6 mg/kg/day, iNO is dosed at 20 ppm. Primary outcome is absence of PH on day 14 without pulmonary vasodilator therapy and/or absence of death within the first 28 days of life. Secondary outcome measures include clinical and echocardiographic markers of PH in the first year of life. We hypothesise that sildenafil gives a 25% reduction in the primary outcome from 68% to 48% on day 14, for which a sample size of 330 patients is needed. An intention-to-treat analysis will be performed. A p-value (two-sided) <0.05 is considered significant in all analyses.

Ethics and dissemination: Ethics approval has been granted by the ethics committee in Rotterdam (MEC-2017-324) and the central Committee on Research Involving Human Subjects (NL60229.078.17) in the Netherlands. The principles of the Declaration of Helsinki, the Medical Research Involving Human Subjects Act and the national rules and regulations on personal data protection will be used. Parental informed consent will be obtained.

Trial registration number: NTR6982; Pre-results.

Keywords: congenital diaphragmatic hernia; nitric oxide; pulmonary hypertension; sildenafil; therapeutics.

Figure 1

Trial flow chart. Flow chart showing the steps of the trial, from birth until 12 months. CoDiNOS, Congenital Diaphragmatic hernia Nitric Oxide versus Sildenafil;CDH, congenital diaphragmatic hernia; SAE, serious adverse event; SUSAR, suspected unexpected serious adverse reaction.

Figure 2

Protocol to wean study drug. Flow chart showing the protocol to wean off inhaled nitric oxide or intravenous sildenafil. INO, inhaled nitric oxide.

Figure 3

Treatment flow chart of systemic hypotension. Flow chart that is added to the treatment protocol, showing the treatment plan for systemic hypotension. LV, left ventricular; SVR, systemic vascular resistance; VA ECMO, veno-arterial extracorporeal membrane oxygenation; ?, if available.