Evaluation of Allopurinol Sodium and Hypothermia in Neonatal Hypoxic-Ischemic Encephalopathy: Impact on Neurodevelopmental Outcomes

The primary objective of this study is to evaluate whether early postnatal administration of **allopurinol** compared to placebo, in addition to standard care including therapeutic hypothermia if indicated, reduces the incidence of death or severe neurodevelopmental impairment in newborns with asphyxia and early clinical signs of hypoxic-ischemic encephalopathy (HIE) at 24 months of age. Severe neurodevelopmental impairment is defined as cerebral palsy, or cognitive or language impairment, with the latter assessed using the Bayley Scales of Infant and Toddler Development (3rd edition) with scores below 85. This objective is clinically relevant as it addresses the potential for improving long-term neurocognitive outcomes in affected neonates.

Secondary objectives include: - Evaluating the effect of allopurinol in addition to hypothermia on components of the primary outcome variable, including brain injury assessed by magnetic resonance imaging, amplitude-integrated electroencephalogram, full-scale electroencephalogram, laboratory biomarkers, and markers of peroxidation. - Assessing the safety of allopurinol in neonates treated with hypothermia. - Studying the pharmacokinetics of allopurinol and mannitol in neonates treated with and without hypothermia.

The clinical trial involves a total of **51 participants** who are newborns diagnosed with **hypoxic-ischemic encephalopathy** (HIE), a type of brain injury resulting from events during labor and childbirth such as placental abruption, uterine rupture, or umbilical cord complications. The study population includes both male and female subjects, categorized under age range code 2, indicating they are neonates. Participants were selected based on the presence of severe perinatal metabolic acidosis or the need for ongoing cardiopulmonary resuscitation at 5 minutes after birth, along with early clinical signs of potentially evolving encephalopathy. The trial population is considered vulnerable due to the age and health status of the subjects. Lifestyle considerations such as diet and physical activity are not applicable given the age of the participants. The sponsor has not provided additional information regarding specific lifestyle habits or other selection criteria beyond those mentioned.

The clinical trial is designed to evaluate the efficacy of **allopurinol sodium** in conjunction with standard therapeutic hypothermia for newborns exhibiting early clinical signs of **hypoxic-ischemic encephalopathy** (HIE). This is a Phase III, randomized, double-blind, placebo-controlled trial. The primary objective is to determine whether the addition of allopurinol reduces the incidence of death or severe neurodevelopmental impairment at 24 months of age. The trial is expected to conclude by June 2026, with recruitment having commenced in March 2018.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as severe perinatal metabolic acidosis or ongoing cardiopulmonary resuscitation at 5 minutes post-birth. Following randomization, participants will receive either allopurinol or placebo intravenously. Follow-up visits will be scheduled to monitor the participants' health and development, with assessments including the Bayley Scales of Infant and Toddler Development. The end-of-study visit will occur at 24 months of age to evaluate the primary and secondary endpoints, including survival without severe neurodevelopmental impairment and the incidence of cerebral palsy.

The expected duration of participant involvement is approximately two years. Conditions that may lead to early termination from the study include withdrawal of consent, significant adverse events, or any situation where continued participation is deemed not in the best interest of the participant. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure the safety and well-being of all participants.

The clinical trial involves the administration of **ACEPURIN**, a pharmaceutical product containing **allopurinol sodium** as the active substance. This medication is provided in the form of a **solution for infusion**. The product is manufactured by ACE Pharmaceuticals BV and is identified by the marketing authorization number RVG 09974. The **allopurinol sodium** is of chemical origin and is classified under the ATC code M04AA01. The medication is administered intravenously, with a maximum daily dose of 30 mg/kg and a total maximum dose of 30 mg/kg. The treatment period is limited to one day. The primary objective of the trial is to assess the efficacy of **allopurinol sodium** in reducing the incidence of death or severe neurodevelopmental impairment in newborns with asphyxia and early clinical signs of hypoxic-ischemic encephalopathy.

In addition to the experimental treatment, the trial includes the use of **MANNITOL** as a comparator treatment. **MANNITOL** is an irrigation solution with the active substance of the same name, also of chemical origin. The administration route for **MANNITOL** is through a solution for infusion. The dosing schedule for **MANNITOL** mirrors that of the experimental treatment, with a maximum daily dose of 30 mg/kg and a total maximum dose of 30 mg/kg, administered over a one-day period. The role of **MANNITOL** in the trial is to serve as a placebo, providing a basis for comparison against the effects of **allopurinol sodium**.

The efficacy of the clinical trial titled "Effect of Allopurinol in addition to hypothermia for hypoxic-ischemic Brain Injury on Neurocognitive Outcome" will be assessed through a series of primary and secondary endpoints. The primary endpoint is the incidence of death or severe neurodevelopmental impairment at the age of two years, defined as cerebral palsy or cognitive or language impairment, with the latter measured by the Bayley Scales of Infant and Toddler Development (3rd edition) with scores below 85.

Secondary endpoints include a dichotomized composite endpoint of survival without neurodevelopmental impairment versus death or language-composite-score <85 or cognitive-composite-score <85 or presence of cerebral palsy. The incidence of cerebral palsy will be analyzed using the Cochrane-Mantel-Haenszel test. Additional assessments include the GMFCS-score for motor impairments, and the Motor-Composite-Score, Cognitive-Composite-Score, and Language-Composite-Score from the Bayley III, each dichotomized at a cut-off of <85 versus ≥85. Single components of the primary endpoint will be graphically displayed, stratified by treatment groups.