Sildenafil Plus Hypothermia to Treat Neonatal Encephalopathy

NCT ID: NCT06810284

Last Updated: 2025-02-05

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-07-31
• Study Completion Date: 2028-01-31

Brief Summary

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.

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.

Conditions

Hypoxic-Ischemic Encephalopathy

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

intervention group

Controlled hypothermia + open-label IV Sildenafil

Group Type: EXPERIMENTAL

Sildenafil Citrate (IV)

Intervention Type: DRUG

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

Interventions

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

Intervention Type: DRUG

Other Intervention Names

Revatio

Eligibility Criteria

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

• Maximum Eligible Age: 12 Hours
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Olivier BAUD, MD, PhD

Role: STUDY_DIRECTOR

Hôpitaux Universitaires de Genève et Inserm U1141, Paris

Locations

Unité de Recherche Clinique, Entrepôts de données et Pharmacologie GHU Paris Centre

Paris, , France

Countries

France

Central Contacts

Pierre-Louis LEGER, MD, PhD

Role: CONTACT

pierre-louis.leger@aphp.fr

01 71 73 86 13 ext. +33

Adèle BELLINO

Role: CONTACT

adele.bellino@aphp.fr

01 58 41 11 95 ext. +33

Facility Contacts

Pierre-Louis LEGER, MD, PhD

Role: primary

pierre-louis.leger@aphp.fr

01 71 73 86 13 ext. +33

References

Yazdani A, Howidi B, Shi MZ, Tugarinov N, Khoja Z, Wintermark P. Sildenafil improves hippocampal brain injuries and restores neuronal development after neonatal hypoxia-ischemia in male rat pups. Sci Rep. 2021 Nov 11;11(1):22046. doi: 10.1038/s41598-021-01097-6.

Reference Type: BACKGROUND

PMID: 34764335 (View on PubMed)

Yazdani A, Khoja Z, Johnstone A, Dale L, Rampakakis E, Wintermark P. Sildenafil Improves Brain Injury Recovery following Term Neonatal Hypoxia-Ischemia in Male Rat Pups. Dev Neurosci. 2016;38(4):251-263. doi: 10.1159/000448327. Epub 2016 Sep 10.

Reference Type: BACKGROUND

PMID: 27614933 (View on PubMed)

Moretti R, Leger PL, Besson VC, Csaba Z, Pansiot J, Di Criscio L, Gentili A, Titomanlio L, Bonnin P, Baud O, Charriaut-Marlangue C. Sildenafil, a cyclic GMP phosphodiesterase inhibitor, induces microglial modulation after focal ischemia in the neonatal mouse brain. J Neuroinflammation. 2016 Apr 28;13(1):95. doi: 10.1186/s12974-016-0560-4.

Reference Type: BACKGROUND

PMID: 27126393 (View on PubMed)

Charriaut-Marlangue C, Nguyen T, Bonnin P, Duy AP, Leger PL, Csaba Z, Pansiot J, Bourgeois T, Renolleau S, Baud O. Sildenafil mediates blood-flow redistribution and neuroprotection after neonatal hypoxia-ischemia. Stroke. 2014 Mar;45(3):850-6. doi: 10.1161/STROKEAHA.113.003606. Epub 2014 Jan 28.

Reference Type: BACKGROUND

PMID: 24473179 (View on PubMed)

Other Identifiers

2023-508928-35-00

Identifier Type: CTIS

Identifier Source: secondary_id

P180603

Identifier Type: -

Identifier Source: org_study_id