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 - 20/02/24
, Anie Lapointe, MD, MSc 3, Robin Steinhorn, MD 4, Emmanouil Rampakakis, PhD 5, Jürgen Burhenne, PhD 6, Andreas D. Meid, Dr. Sc. Hum 6, Gzona Bajraktari-Sylejmani, PhD 6, May Khairy, MDCM, FRCPC 7, Gabriel Altit, MDCM, MSc, FRCPC, FAAP 1, 2, Marie-Therese Adamo, BPharm, MSc 8, Alishia Poccia, BSc, RRT 2, Guillaume Gilbert, PhD 9, Christine Saint-Martin, MD 10, Daniela Toffoli, MD 11, Julie Vachon, PhD 12, Elizabeth Hailu, MD, MSc, FAAP 1, Patrick Colin, BPharm, PhD 13, Walter E. Haefeli, MD 6Abstract |
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 (2:1) 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.gov NCT02812433.
Le texte complet de cet article est disponible en PDF.Keywords : hypoxic-ischemic encephalopathy, neonatal brain, neonatal encephalopathy, neurorestoration, neuroprevention, sildenafil
Abbreviations : ADC, aEEG, AEs, AKI, cGMP, CP, DGM, FA, GDD, Lac, MBP, MRI, NAA, NE, PK, PPHN, TH
Plan
Vol 266
Article 113879- mars 2024 Retour au numéro
Article précédent
- Unbound Bilirubin and Acute Bilirubin Encephalopathy in Infants Born Late Preterm and Term with Significant Hyperbilirubinemia
- Sanjiv B. Amin, Satish Saluja, Neelam Kler
- A Dyadic Framework of Care for Opioid-exposed Birthing Persons and Their Infants and Children
- Shahla M. Jilani, Jonathan M. Davis, Matthew Grossman, Hendrée E. Jones, Mishka Terplan, Lauren M. Jansson
Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.
Déjà abonné à cette revue ?