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Feasibility and Safety of Sildenafil to Repair Brain Injury Secondary to Birth Asphyxia (SANE-01): A Randomized, Double-blind, Placebo-controlled Phase Ib Clinical Trial.
Wintermark, Pia; Lapointe, Anie; Steinhorn, Robin; Rampakakis, Emmanouil; Burhenne, Jürgen; Meid, Andreas D; Bajraktari-Sylejmani, Gzona; Khairy, May; Altit, Gabriel; Adamo, Marie-Therese; Poccia, Alishia; Gilbert, Guillaume; Saint-Martin, Christine; Toffoli, Daniela; Vachon, Julie; Hailu, Elizabeth; Colin, Patrick; Haefeli, Walter E.
Afiliação
  • Wintermark P; Division of Newborn Medicine, Department of Pediatrics, McGill University, Montreal, Quebec, Canada; Research Institute of the McGill University Health Center, McGill University, Montreal, Quebec, Canada. Electronic address: pia.wintermark@gmail.com.
  • Lapointe A; Department of Neonatology, Sainte-Justine Hospital, University of Montreal, Montreal, Quebec, Canada.
  • Steinhorn R; Department of Pediatrics, University of California San Diego, and Rady Children's Hospital, San Diego, CA.
  • Rampakakis E; JSS Medical Research, Montreal, Québec, Canada.
  • Burhenne J; Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany.
  • Meid AD; Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany.
  • Bajraktari-Sylejmani G; Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany.
  • Khairy M; Department of Pediatrics, McGill University, Montreal, Québec, Canada.
  • Altit G; Division of Newborn Medicine, Department of Pediatrics, McGill University, Montreal, Quebec, Canada; Research Institute of the McGill University Health Center, McGill University, Montreal, Quebec, Canada.
  • Adamo MT; Pharmacy Department, McGill University Health Center, Montreal, Québec, Canada.
  • Poccia A; Research Institute of the McGill University Health Center, McGill University, Montreal, Quebec, Canada.
  • Gilbert G; MR Clinical Science, Philips Healthcare, Mississauga, Ontario, Canada.
  • Saint-Martin C; Department of Radiology, McGill University, Montreal, Québec, Canada.
  • Toffoli D; Department of Ophthalmology, McGill University, Montreal, Québec, Canada.
  • Vachon J; Member of the Ordre des Psychologues du Quebec, Montreal, Québec, Canada.
  • Hailu E; Division of Newborn Medicine, Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
  • Colin P; Patrick Colin Consultant Inc, Montreal, Québec, Canada.
  • Haefeli WE; Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany.
J Pediatr ; 266: 113879, 2024 Mar.
Article em En | MEDLINE | ID: mdl-38142044
ABSTRACT

OBJECTIVE:

To test feasibility and safety of administering sildenafil in neonates with neonatal encephalopathy (NE), developing brain injury despite therapeutic hypothermia (TH). STUDY

DESIGN:

We performed a randomized, double-blind, placebo-controlled phase Ib clinical trial between 2016 and 2019 in neonates with moderate or severe NE, displaying brain injury on day-2 magnetic resonance imaging (MRI) despite TH. Neonates were randomized (21) to 7-day sildenafil or placebo (2 mg/kg/dose enterally every 12 hours, 14 doses). Outcomes included feasibility and safety (primary outcomes), pharmacokinetics (secondary), and day-30 neuroimaging and 18-month neurodevelopment assessments (exploratory).

RESULTS:

Of the 24 enrolled neonates, 8 were randomized to sildenafil and 3 to placebo. A mild decrease in blood pressure was reported in 2 of the 8 neonates after initial dose, but not with subsequent doses. Sildenafil plasma steady-state concentration was rapidly reached, but decreased after TH discontinuation. Twelve percent of neonates (1/8) neonates died in the sildenafil group and 0% (0/3) in the placebo group. Among surviving neonates, partial recovery of injury, fewer cystic lesions, and less brain volume loss on day-30 magnetic resonance imaging were noted in 71% (5/7) of the sildenafil group and in 0% (0/3) of the placebo group. The rate of death or survival to 18 months with severe neurodevelopmental impairment was 57% (4/7) in the sildenafil group and 100% (3/3) in the placebo group.

CONCLUSIONS:

Sildenafil was safe and well-absorbed in neonates with NE treated with TH. Optimal dosing needs to be established. Evaluation of a larger number of neonates through subsequent phases II and III trials is required to establish efficacy. CLINICAL TRIAL REGISTRATION ClinicalTrials.govNCT02812433.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Asfixia Neonatal / Lesões Encefálicas / Hipóxia-Isquemia Encefálica / Hipotermia Induzida / Doenças do Recém-Nascido Limite: Humans / Newborn Idioma: En Revista: J Pediatr Ano de publicação: 2024 Tipo de documento: Article País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Asfixia Neonatal / Lesões Encefálicas / Hipóxia-Isquemia Encefálica / Hipotermia Induzida / Doenças do Recém-Nascido Limite: Humans / Newborn Idioma: En Revista: J Pediatr Ano de publicação: 2024 Tipo de documento: Article País de publicação: Estados Unidos