Sildenafil Plus Hypothermia to Treat Neonatal Encephalopathy

NCT06810284 | Not Yet Recruiting Phase 2 DMC

• 2 other identifiers: P1806032023-508928-35-00
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

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.

Conditions

Hypoxic-Ischemic Encephalopathy

Keywords

Hypoxic-ischemic encephalopathy; Sildenafil; Neuroprotection; newborn

Outcome Measures

Primary Outcomes (1)

• Plasma concentrations of Sildenafil within the first 5 days following treatment initiation.

  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 Outcomes (5)

• Estimated clearance parameters

  From initiation of sildenafil and 48 hours after end of maintenance continuous infusion

• volumes of distribution for IV sildenafil (l)

  From initiation of sildenafil and 48 hours after end of maintenance continuous infusion

• Area under the plasma sildenafil concentration-time curve

  From initiation of sildenafil and 48 hours after end of maintenance continuous infusion

• Maximum plasma sildenafil concentration achieved (individual exposure)

  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

  between 3.5 to 5 postnatal days

Study Arms (1)

intervention group

EXPERIMENTAL

Controlled hypothermia + open-label IV Sildenafil

Drug: Sildenafil Citrate (IV)

Interventions

Sildenafil Citrate (IV) 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

Also known as: Revatio

intervention group

Eligibility Criteria

• Age: Up to 12 Hours
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

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

You may not qualify if:

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

Sponsors & Collaborators

• URC-CIC Paris Descartes Necker Cochin: collaborator
• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

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

Paris, 75005, France

Location

Related Publications (4)

• 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.

  PMID: 34764335 RESULT

• 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.

  PMID: 27614933 RESULT

• 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.

  PMID: 27126393 RESULT

• 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.

  PMID: 24473179 RESULT

MeSH Terms

Conditions

Hypoxia-Ischemia, Brain

Interventions

Sildenafil Citrate

Condition Hierarchy (Ancestors)

Brain Ischemia; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hypoxia, Brain; Vascular Diseases; Cardiovascular Diseases; Hypoxia; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Olivier BAUD, MD, PhD

  Hôpitaux Universitaires de Genève et Inserm U1141, Paris

  STUDY DIRECTOR

Central Study Contacts

Pierre-Louis LEGER, MD, PhD

CONTACT

01 71 73 86 13; pierre-louis.leger@aphp.fr

Adèle BELLINO

CONTACT

01 58 41 11 95; adele.bellino@aphp.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 24, 2024
• First Posted: February 5, 2025
• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): May 1, 2029
• Last Updated: March 31, 2026

Record last verified: 2026-03

Locations

FR (1)