Evaluation of Darbepoetin Alfa in Reducing Brain Injury in Neonates with Perinatal Arterial Ischemic Stroke: A Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the efficacy of **darbepoetin alfa** in reducing brain injury in neonates diagnosed with **Perinatal Arterial Ischemic Stroke (PAIS)**. This is a double-blind, randomized, placebo-controlled, multicenter trial involving infants with MRI-confirmed PAIS. The study aims to determine whether the administration of darbepoetin can mitigate the neurological damage associated with PAIS, potentially reducing or preventing the lifelong consequences of such brain injuries in term newborns. The clinical relevance of this objective lies in the potential development of a therapeutic intervention using erythropoiesis-stimulating agents (ESAs) like darbepoetin, which could significantly improve outcomes for affected neonates.

The clinical trial involves a total of **40 participants** who are newborns with a gestational age of 36 weeks or more, including both male and female subjects. The study population is specifically selected based on a confirmed diagnosis of **Perinatal Arterial Ischemic Stroke (PAIS)** through MRI, with involvement of the cortical spinal tract. Participants are required to be less than four days post-onset of clinical symptoms at the time of enrollment. The trial focuses on a vulnerable population, as it includes neonates, and necessitates written informed consent from the custodial parent(s). The selection criteria ensure that the study targets infants who are at risk of PAIS-related brain injury, aiming to evaluate the potential therapeutic effects of darbepoetin in reducing such injuries. No specific lifestyle considerations such as diet or physical activity are applicable due to the age and condition of the participants.

The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled study to evaluate the efficacy of **darbepoetin alfa** in reducing brain injury in neonates diagnosed with **Perinatal Arterial Ischemic Stroke (PAIS)**. The trial will involve multiple centers and is categorized as a Phase 4 study. The primary objective is to assess the difference in stroke tissue loss between the treatment and placebo groups, measured by changes in lesion size and brain growth from the onset of the insult to 6-8 weeks of age. Secondary endpoints include evaluating the development of unilateral spastic cerebral palsy (USCP) and cognitive development at 18 months using standardized assessments.

Participants will be newborns of at least 36 weeks gestation with an MRI-confirmed diagnosis of acute PAIS. The study will commence with a screening visit to confirm eligibility, which includes obtaining written informed consent from the custodial parent(s). Eligible participants will be randomized to receive either darbepoetin alfa or a saline placebo, administered intravenously. The maximum treatment period is one week, with a maximum daily dose of 10 micrograms per kilogram and a total dose not exceeding 20 micrograms per kilogram.

Study visits will include an initial screening visit, followed by treatment administration visits, and subsequent follow-up visits to monitor the participants' progress. The end-of-study visit will occur at 18 months of age, where comprehensive neurological assessments will be conducted. The expected duration of participant involvement is approximately 18 months, from the initial screening to the final assessment. Conditions that may lead to early termination from the study include withdrawal of consent by the parent(s) or any adverse events that compromise the safety of the participant.

The trial is anticipated to start recruitment in July 2024 and is expected to conclude by December 2026. The study aims to provide insights into the potential of erythropoiesis-stimulating agents like darbepoetin alfa in mitigating the long-term consequences of PAIS-related brain injury in term newborns.

The clinical trial involves the administration of **darbepoetin alfa**, marketed under the name Aranesp, as the experimental medication. Aranesp is provided as a **solution for injection** in a pre-filled syringe, specifically formulated for pediatric use. The pharmaceutical form is a solution for injection, and the medication is administered intravenously. The dosage is set at 10 micrograms per kilogram, with a maximum total dose of 20 micrograms per kilogram. The treatment period is limited to one day. The active substance, darbepoetin alfa, is a protein-based agent classified under the ATC code B03XA02. The medication is manufactured by Amgen Europe B.V. and is authorized for use in the European Union.

The study also includes a non-experimental treatment, which is a placebo in the form of a sterile normal saline solution. This saline solution contains 9.0 grams of sodium chloride (NaCl) per liter, equating to a 0.90% concentration. The saline serves as a comparator treatment to evaluate the efficacy of darbepoetin alfa in the study. The administration route and dosing schedule for the saline solution are not specified in the provided data. The use of saline as a placebo is intended to maintain the double-blind nature of the trial, ensuring unbiased results in assessing the therapeutic potential of darbepoetin alfa in reducing brain injury in neonates with perinatal arterial ischemic stroke (PAIS).

Efficacy in this clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint focuses on determining the difference in the degree of stroke tissue loss between treatment with **darbepoetin alfa** and placebo. This will be measured by the change in lesion size and brain growth from the time of onset of the insult to 6-8 weeks of age. Additionally, differences in Diffusion Tensor Imaging (DTI) parameters of selected regions of interest will be assessed between the two groups.

The secondary endpoints involve assessing the development of unilateral spastic cerebral palsy (USCP) and cognitive development at 18 months of age. This will be evaluated using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) and the Pediatric Stroke Outcome Measure (PSOM) scores. A comprehensive neurological assessment will also be conducted, including the Gross Motor Function Classification System (GMFCS) and several hand function tests such as the Manual Ability Classification System (MACS), the Hand Assessment of Infants (HAI), and the Assisting Hand Assessment (AHA). These assessments will be compared between the darbepoetin and placebo groups.