Effect of Sildenafil in association to Hypothermia on survival without brain lesions In term Neonates with hypoxic-ischemic Encephalopathy: a randomized, double-blinded, placebo-controlled, multicenter trial

Status Authorised, recruitment pending · 1 EU/EEA countries · 6 sites · Protocol APHP180603

Overview

Sponsor-declared trial summary

Phase Phase II and Phase III (Integrated)

Status Authorised, recruitment pending

Participants planned 556

Countries 1

Sites 6

Hypoxic ischemic encephalopathy

Step 1: - Main objective will find to study pharmacokinetics features of IV sildenafil in neonates with HIE and treated by controlled hypothermia. Step 2: - Main objective will find to demonstrate the superiority of IV sildenafil and controlled hypothermia compared to Placebo and controlled hypothermia, on survival wi…

Key facts

Sponsor: Assistance Publique Hopitaux De Paris
Participant type: Pediatric, Patients
Age range: 0-17 years
Gender: Male and Female
Therapeutic area: Diseases [C] - Nervous System Diseases [C10]
Decision date (initial): 2024-11-27
Transition trial: No
Low-intervention: No
Rare-disease indication: No
Vulnerable population: No
Funding sources: Ministry of Health - PHRC

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Therapy

Step 1:
- Main objective will find to study pharmacokinetics features of IV sildenafil in neonates with HIE and treated by controlled hypothermia.

Step 2:
- Main objective will find to demonstrate the superiority of 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.

Secondary objectives 5

Step 1: Identify factors for interindividual variability in PK parameters of sildenafil
Step 1: Investigate potential treatment-related adverse events
Step 1: Study the association between individual exposure and brain MRI findings.
Step 2: to assess the potential benefits of the association of hypothermia + sildenafil compared to hypothermia + Placebo on EEG recordings, brain MRI and spectroscopy, and 2-year neuro-developmental outcomes
Step 2 to assess the safety of sildenafil on potential adverse events.

Conditions and MedDRA coding

Hypoxic ischemic encephalopathy

Version	Level	Code	Term	System organ class
25.0	LLT	10086948	Hypoxic ischemic encephalopathy neonatal	100000004848

Study design 2 periods

#	Title	Allocation	Blinding	Roles blinded	Arms
1	Step 1 Phase 2 PK study of IV sildenafil in neonates with HIE and treated by servo-controlled hypothermia (33.5 +/- 0.5 °C) to confirm the sildenafil dose to be given in the Phase 3 trial	Not Applicable	None		Controlled hypothermia + Sildenafil Citrate IV: Controlled hypothermia is initiated before 6 hours after birth (servo control at 33.5 +/-0.5°C for 72 hours, followed by 12 hours of rewarming to 36.5°C) and sildenafil citrate IV (Revatio®, 10 mg/12.5 mL, VIATRIS) is started, with a loading dose of 0.4 mg/kg initiated after at least 1 hour of active hypothermia and before 12 hours of age and given over 3 hours, followed by a maintenance infusion of 1.6 mg/kg/24 hours, stopped just before rewarming.
2	Step 2 Phase III / pivotal, multicenter, placebo-controlled, double-blinded, 2 parallel groups randomized clinical trial. Infants will be randomly assigned 1:1 to either hypothermia + sildenafil or hypothermia + Placebo group. This trial aims to demonstrate the superiority of hypothermia + sildenafil treatment compared to hypothermia + Placebo.	Randomised Controlled	Double	[{"id":126531,"code":1,"name":"Subject"},{"id":126530,"code":2,"name":"Investigator"}]	hypothermia + IV sildenafil: As soon as the patient will be randomized, eligible patient will be treated by controlled hypothermia initiated before 6h after birth (servo-controlled 33.5 +/-0.5°C during 72 hours followed by a 12-hours rewarming period up to 36.5°C) + IV sildenafil Citrate (Revatio®, 10 mg/12.5 mL, VIATRIS), loading dose of 0.4 mg/kg delivered after at least 1 hour of active hypothermia and before 12 hours of life over 3 hours, followed by a maintenance infusion at 1.6 mg/kg/day stopped just before rewarming (i.e., 72 hours of hypothermia). hypothermia + Placebo: As soon as the patient will be randomized, eligible patient will be treated by controlled hypothermia initiated before 6h after birth (servo-controlled 33.5 +/-0.5°C during 72 hours followed by a 12-hours rewarming period up to 36.5°C) + placebo of IV sildenafil Citrate, loading dose of 0.4 mg/kg delivered after at least 1 hour of active hypothermia and before 12 hours of life over 3 hours, followed by a maintenance infusion at 1.6 mg/kg/day stopped just before rewarming (i.e., 72 hours of hypothermia).

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

Neonates born at or after 36 weeks’ gestation, treated by therapeutic servo-controlled hypothermia (33.5 +/- 0.5 °C) for neonatal HIE,
Experimental treatment will be started > 1h of active hypothermia and <12h of life
Social security coverage
Informed written consent of one of the two holders of parental authority

Exclusion criteria 6

Chromosomal aberrations and major malformations evidenced after birth
Decision for “comfort care only” before study drug administration
Severe clinical conditions including uncontrolled hemorrhagic syndrome, severe hemodynamic failure at initiation
Known hypersensitivity to the active substance or to any of the excipients
Concomitant administration of nitrates or nitric oxide donors, Inhaled Nitric Oxide (NO), other PDE5 inhibitors, inhibitors of CYP3A4 (eg, ketoconazole, itraconazole, ritonavir)
Participation in another interventional study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

Primary endpoint of step 1 will be the measured plasma concentrations of Sildenafil.
Primary endpoint of step 2 will be survival without brain lesions at hospital discharge on brain MRI. The MRI will be performed between the end of rewarming (day 3.5) and day 5

Secondary endpoints 5

Step 1: estimated clearance parameters and volumes of distribution for IV sildenafil
Step 1: area under the plasma sildenafil concentration-time curve and the maximum plasma sildenafil concentration achieved (individual exposure)
Step 1: brain damage-free survival at hospital discharge on MRIs performed between 3.5 to 5 days and/or 10-30 days” (treatment efficacy)
Step 2: Secondary end-points, related to potential benefits, will be based on changes in EEG patterns, detailed analysis of MRIs and spectroscopy, and 2-year assessment (neurodevelopmental impairment, autism spectrum disorders assessed using M-CHAT (Modified Checklist for Autism in Toddlers), PARCA-R and Parenting Stress Index-Short Form (PSI-SF).
Step 2: Secondary end-points, related to safety, will include incidence of low systemic pressure requiring hemodynamic support, and cardiac function assessment.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Revatio 0.8 mg/ml solution for injection

PRD10006987 · Product

Active substance: Sildenafil
Pharmaceutical form: SOLUTION FOR INJECTION
Route of administration: INTRAVENOUS
Max daily dose: 2 mg/Kg milligram(s)/kilogram
Max total dose: 5.2 mg/Kg milligram(s)/kilogram
Max treatment duration: 3 Day(s)
Authorisation status: Authorised
ATC code: G04BE03 — SILDENAFIL
Marketing authorisation: EU/1/05/318/002
MA holder: UPJOHN EESV
MA country: Liechtenstein
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation: Assistance Publique Hopitaux De Paris
Address: Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux
City: Paris Cedex 10
Postcode: 75475
Country: France

Scientific contact point

Organisation: Assistance Publique Hopitaux De Paris
Contact name: Prof. Pierre-Louis LEGER

Public contact point

Organisation: Assistance Publique Hopitaux De Paris
Contact name: Prof. Pierre-Louis LEGER

Locations

1 EU/EEA country · 6 investigational sites

By country

Country	MS status	Planned subjects	Sites
France	Authorised, recruitment pending	556	6
Rest of world	—	0	—