Sildenafil Plus Hypothermia to Treat Neonatal Encephalopathy (SHINE1)

March 30, 2026 updated by: Assistance Publique - Hôpitaux de Paris

Effect of Sildenafil in Association to Hypothermia on Survival Without Brain Lesions In Term Neonates With Hypoxic-ischemic Encephalopathy (SHINE): Pharmacokinetic Study - Step 1

The main objective of this study is to assess pharmacokinetics features of IV sildenafil in neonates with hypoxic-ischemic encephalopathy and treated by controlled hypothermia. This phase 2 study will prepare a large phase 3 randomized controlled trial to demonstrate the superiority of a combinatory therapy associating IV sildenafil and controlled hypothermia compared to Placebo and controlled hypothermia, on survival without brain lesions on MRI at discharge, in neonates born after 36 weeks of gestation.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Neonatal hypoxic-ischemic encephalopathy (HIE) following birth asphyxia is a major cause of death or long-term disability in term neonates, affecting about 1-4 per 1.000 live births and consequently 30.000 infants/year in Europe. Incidence and consequences of HIE are even more common and severe in less privileged settings, affecting about 1 million infants every year worldwide.

In recent years, therapeutic hypothermia became the standard of care to improve outcomes after perinatal hypoxic-ischemic insults. Despite hypothermia and state-of-the-art neonatal intensive care, 45-50% of children with moderate or severe HIE (i.e., 12.000 - 15.000 infants/year in Europe) still die or suffer from long-term neurodevelopmental impairment. Therefore, additional early neuroprotective interventions, beside hypothermia, are warranted to further improve the outcomes of HIE.

The best conceivable treatment for HIE is the restoration of cerebral blood flow (CBF) as soon as possible because its decrease 12-24 hours indicates poor prognosis in term newborns with HIE in human and rodents. Recently, the inhalation of nitric oxide (NO) has been found to be beneficial in several preclinical models of ischemia, but NO-dosage and time period of exposure seem to be crucial for beneficial effects. Another option that enhances the effects of endogenous NO is to increase the cyclic guanosine monophosphate (cGMP) concentration by blocking its degradation by phosphodiesterases (PDEs). In particular, sildenafil, a potent selective PDE-5 inhibitors, prolong the action of cGMP in multiple vascular territories. Recent findings strongly indicate that sildenafil citrate treatment induced a significant increase in CBF, reduces HI damage and improves motor locomotion in neonatal rats. In addition, anti-inflammatory effects of sildenafil may provide protection against lesion extension in the late phase after brain ischemia in neonatal mice. Together, these data strongly suggest that sildenafil, already used in neonatal pulmonary hypertension - a co-morbid condition that could worsen brain injury - may represent an interesting therapeutic strategy for neonatal neuroprotection. SHINE project aims to test its added value in addition to hypothermia to prevent neonatal death and brain damage following HIE. Pharmacokinetics (PK) data from oral administration suggest that serum concentrations within therapeutic targets are achieved with a dosage corresponding to the bioavailability of oral sildenafil under therapeutic hypothermia. However, plasma concentrations of continuous IV sildenafil infusion in neonates under hypothermic conditions with HIE has never been analysed justifying a PK study. This PK study sildenafil is mandatory to (i) ensure that the a priori IV dose determined as biologically effective remains within the therapeutic target with metabolic et PK changes potentially induced by both HIE condition and controlled hypothermia, (ii) ensure the absence of overdose and/or side effects of this dosage, at any time of the hypothermia treatment and rewarming, and (iii) adjust, if necessary, the dosage to reach the therapeutic target.

The investigators will perform a phase 2 pharmacokinetics observational study of IV sildenafil in neonates with HIE and exposed to controlled hypothermia (33.5°C) to ensure the safety and confirm the relevance of the sildenafil IV dose to be given in infants with hypothermia in the Phase 3 trial.

The pharmaco-statistical analysis will be conducted using non-linear mixed effects modeling to calculate the PK parameters of sildenafil as well as the inter-individual and the residual variabilities.

Study Type

Interventional

Enrollment (Estimated)

24

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • France
      • Paris, France, 75005
        • Unité de Recherche Clinique, Entrepôts de données et Pharmacologie GHU Paris Centre
        • Contact:
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • 1/Neonates born at or after 36 weeks' gestation, treated by therapeutic servo-controlled hypothermia for neonatal hypoxic ischemic encephalopathy.

Therapeutic hypothermia should be decided according to French national guidelines.

  • 2/ Social security coverage
  • 3/ Informed consent of one of the two holders of parental authority.

Exclusion Criteria:

  • 1/ Chromosomal aberrations and major malformations evidenced after birth
  • 2/ Decision for "comfort care only" before study drug administration,
  • 3/ Uncontrolled hemorrhagic syndrome,
  • 4/ Severe hemodynamic failure at initiation, requiring at least two therapies (including either volume expansion, hydrocortisone or inotropes)
  • 5/ Known hypersensitivity to the active substance or to any of the excipients
  • 6/ Concomitant administration of nitrates or nitric oxide donors, Inhaled Nitric Oxide, other PDE5 inhibitors, inhibitors of CYP3A4
  • 7/ Participation in another interventional study

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: intervention group
Controlled hypothermia + open-label IV Sildenafil
Drug: Sildenafil Citrate (IV)
Controlled hypothermia initiated before 6h after birth (servo-controlled 33.5°C during 72h followed by a 12-h rewarming period up to 36.5°C), open-label IV Sildenafil Citrate (Revatio®, 10 mg/12.5 mL, Pfizer) 0.4 mg/kg delivered over 3 hours, followed by a maintenance infusion at 1.6 mg/kg/day for 72h
Other Names:
  • Revatio

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Plasma concentrations of Sildenafil within the first 5 days following treatment initiation.
Time Frame: From 3 hours after initiation of sildenafil and 48 hours after end of maintenance continuous infusion
Pharmacokinetics features of IV sildenafil in neonates with HIE and treated by controlled hypothermia.
From 3 hours after initiation of sildenafil and 48 hours after end of maintenance continuous infusion

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Estimated clearance parameters
Time Frame: From initiation of sildenafil and 48 hours after end of maintenance continuous infusion
Pharmacokinetics features of IV sildenafil in neonates with HIE and treated by controlled hypothermia.
From initiation of sildenafil and 48 hours after end of maintenance continuous infusion
volumes of distribution for IV sildenafil (l)
Time Frame: From initiation of sildenafil and 48 hours after end of maintenance continuous infusion
Pharmacokinetics features of IV sildenafil in neonates with HIE and treated by controlled hypothermia.
From initiation of sildenafil and 48 hours after end of maintenance continuous infusion
Area under the plasma sildenafil concentration-time curve
Time Frame: From initiation of sildenafil and 48 hours after end of maintenance continuous infusion
Pharmacokinetics features of IV sildenafil in neonates with HIE and treated by controlled hypothermia.
From initiation of sildenafil and 48 hours after end of maintenance continuous infusion
Maximum plasma sildenafil concentration achieved (individual exposure)
Time Frame: From initiation of sildenafil and 48 hours after end of maintenance continuous infusion
Pharmacokinetics features of IV sildenafil in neonates with HIE and treated by controlled hypothermia.
From initiation of sildenafil and 48 hours after end of maintenance continuous infusion
Brain damage-free survival at hospital discharge on MRIs performed between 3.5 to 5 days and/or 10-30 days
Time Frame: between 3.5 to 5 postnatal days
Brain damage-free survival at hospital discharge on MRIs performed between 3.5 to 5 days and/or 10-30 days
between 3.5 to 5 postnatal days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assistance Publique - Hôpitaux de Paris

Collaborators

URC-CIC Paris Descartes Necker Cochin

Investigators

  • Study Director: Olivier BAUD, MD, PhD, Hôpitaux Universitaires de Genève et Inserm U1141, Paris

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

October 1, 2026

Primary Completion (Estimated)

June 1, 2027

Study Completion (Estimated)

May 1, 2029

Study Registration Dates

First Submitted

September 24, 2024

First Submitted That Met QC Criteria

January 30, 2025

First Posted (Actual)

February 5, 2025

Study Record Updates

Last Update Posted (Actual)

March 31, 2026

Last Update Submitted That Met QC Criteria

March 30, 2026

Last Verified

March 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • P180603
  • 2023-508928-35-00 (Ctis)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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