Evaluation of Intravenous Sildenafil Combined with Therapeutic Hypothermia on Neuroprotection in Term Neonates with Hypoxic-Ischemic Encephalopathy

The primary objective of the SHINE trial is to evaluate the **pharmacokinetics** of intravenous sildenafil in neonates with **hypoxic-ischemic encephalopathy** (HIE) undergoing controlled hypothermia. Additionally, the study aims to demonstrate the superiority of intravenous sildenafil combined with controlled hypothermia over placebo with controlled hypothermia in improving survival without brain lesions on MRI at discharge in neonates born after 36 weeks of gestation. This is clinically relevant as it may offer a therapeutic advantage in reducing brain injury in this vulnerable population.

Secondary objectives include:

• Identifying factors contributing to interindividual variability in pharmacokinetic parameters of sildenafil.
• Investigating potential treatment-related adverse events.
• Studying the association between individual exposure and brain MRI findings.
• Assessing the potential benefits of combining hypothermia with sildenafil compared to hypothermia with placebo on EEG recordings, brain MRI, spectroscopy, and 2-year neurodevelopmental outcomes.
• Evaluating the safety of sildenafil concerning potential adverse events.

The clinical trial focuses on neonates diagnosed with **hypoxic ischemic encephalopathy** (HIE) who are born at or after 36 weeks of gestation. The study population includes both male and female subjects, with no specific mention of the total number of participants, as this information was not provided by the sponsor. Participants are required to be treated with therapeutic servo-controlled hypothermia, maintaining a temperature of 33.5 ± 0.5 °C. The experimental treatment is initiated between 1 hour of active hypothermia and within 12 hours of life. The trial does not specifically target a vulnerable population, and participants must have social security coverage and informed written consent from one of the two holders of parental authority. The selection criteria ensure that the study population is homogenous in terms of gestational age and treatment protocol, allowing for a focused investigation into the pharmacokinetics of IV sildenafil and its potential superiority in combination with controlled hypothermia over placebo in improving survival without brain lesions as observed on MRI at discharge.

The clinical trial is designed to evaluate the **effectiveness** of intravenous **sildenafil** in conjunction with controlled hypothermia on survival without brain lesions in neonates with **hypoxic ischemic encephalopathy**. This study is structured as a randomized, double-blind, placebo-controlled, multicenter trial. The trial is divided into two main steps: the first step focuses on the pharmacokinetics of sildenafil in neonates, while the second step aims to demonstrate the superiority of sildenafil combined with hypothermia over placebo in improving survival outcomes without brain lesions as assessed by MRI at hospital discharge. The trial is expected to commence recruitment in September 2024 and conclude by October 2031.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as gestational age of 36 weeks or more, treatment with therapeutic hypothermia, and informed consent from a parent. The experimental treatment will be initiated between 1 and 12 hours of life. Follow-up visits will include assessments of plasma sildenafil concentrations, clearance parameters, and volumes of distribution. The primary endpoint for step one is the measurement of plasma concentrations of sildenafil, while step two focuses on survival without brain lesions at discharge. Secondary endpoints include changes in EEG patterns, detailed MRI analyses, and a two-year follow-up for neurodevelopmental outcomes.

The expected duration of participant involvement is up to 3 days for the initial treatment phase, with additional follow-up assessments extending to 2 years post-treatment. Conditions that may lead to early termination from the study include withdrawal of consent or adverse events that compromise participant safety. The end-of-study visit will involve a comprehensive evaluation of the participant's health status and the collection of final data for analysis. The trial's design ensures rigorous assessment of both efficacy and safety, with a focus on improving clinical outcomes for neonates with hypoxic ischemic encephalopathy.

The clinical trial involves the administration of **Revatio 0.8 mg/ml solution for injection**, which contains the active substance **sildenafil**. This experimental medication is provided in the form of a **solution for injection** and is administered via the **intravenous** route. The dosing regimen specifies a maximum daily dose of 2 mg/kg and a total maximum dose of 5.2 mg/kg. The treatment period is limited to a maximum of 3 days. The pharmaceutical product is manufactured by UPJOHN EESV and is classified under the ATC code G04BE03. The active substance, sildenafil, is of chemical origin.

In this randomized, double-blinded, placebo-controlled, multicenter trial, the experimental treatment is compared against a **placebo**. The placebo is administered in conjunction with controlled hypothermia, serving as the comparator treatment to evaluate the efficacy of sildenafil in improving survival without brain lesions in neonates with hypoxic-ischemic encephalopathy. The study aims to assess the pharmacokinetics of intravenous sildenafil and its potential superiority over placebo when used alongside hypothermia therapy. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint for Step 1 involves measuring the plasma concentrations of **Sildenafil** in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing controlled hypothermia. For Step 2, the primary endpoint is the survival of neonates without brain lesions, as determined by magnetic resonance imaging (MRI) at hospital discharge. The MRI assessments will be conducted between the end of rewarming (day 3.5) and day 5.

Secondary endpoints for Step 1 include the estimation of clearance parameters and volumes of distribution for intravenous **Sildenafil**, as well as the area under the plasma concentration-time curve and the maximum plasma concentration achieved, which reflects individual exposure. Additionally, brain damage-free survival at hospital discharge will be evaluated through MRIs performed between 3.5 to 5 days and/or 10-30 days.

For Step 2, secondary endpoints related to potential benefits will focus on changes in EEG patterns, detailed MRI and spectroscopy analyses, and a 2-year assessment of neurodevelopmental outcomes, including autism spectrum disorders using the Modified Checklist for Autism in Toddlers (M-CHAT), PARCA-R, and the Parenting Stress Index-Short Form (PSI-SF). Safety-related secondary endpoints will include the incidence of low systemic pressure requiring hemodynamic support and cardiac function assessment.