Evaluation of Doxapram Hydrochloride Monohydrate Versus Placebo in the Management of Apnea of Prematurity in Preterm Neonates: A Multicenter Randomized Controlled Trial

The primary objective of this international, double-blinded, multicenter randomized controlled trial is to evaluate the **safety** and **efficacy** of doxapram in reducing the composite outcome of death and neurodevelopmental impairment/severe disability at 18 to 24 months corrected age in preterm newborns with **apnea of prematurity**, compared to a placebo. This is clinically relevant as it addresses the critical need for effective interventions to improve long-term outcomes in this vulnerable population.

The clinical trial involves a total of **96 participants** diagnosed with **apnea of prematurity**. The study population includes both male and female subjects, specifically focusing on a vulnerable population of neonates. Participants are selected based on specific criteria, including a gestational age at birth of less than 29 weeks and a postnatal age of at least 120 hours. All participants are admitted to the NICU of one of the participating centers and have received caffeine therapy, adequately dosed, along with optimal non-invasive respiratory support. The trial targets those experiencing frequent and/or severe apneas that necessitate medical intervention as determined by the attending physician. The selection process ensures that participants have provided written informed consent according to national guidelines, either from both parents or legal representatives in the Netherlands, or at least one parent or legal representative in Belgium and Canada. The study does not specify any particular lifestyle considerations such as diet or physical activity, as the focus is on a neonatal population within a controlled clinical setting.

The clinical trial is designed to evaluate the safety and efficacy of **doxapram hydrochloride monohydrate** in reducing the composite outcome of death and neurodevelopmental impairment or severe disability in preterm newborns with **apnea of prematurity**. This is a Phase III, randomized, double-blind, controlled trial comparing doxapram to a placebo. The trial is expected to run from April 2020 to April 2027, with participant involvement lasting up to 10 days, the maximum treatment period for the investigational product.

Participants will be preterm newborns admitted to the NICU, with a gestational age at birth of less than 29 weeks and a postnatal age of at least 120 hours. They must be receiving caffeine therapy and optimal non-invasive respiratory support. The inclusion visit will involve screening to ensure eligibility based on these criteria. Written informed consent from parents or legal representatives is required. The primary endpoint is the composite outcome of death or severe disability at 18 to 24 months corrected age, with both outcomes analyzed separately.

Study visits will include the initial screening, followed by regular monitoring visits to assess the safety and efficacy of the treatment. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination. Conditions that may lead to early termination include adverse reactions or withdrawal of consent. The trial will utilize intravenous administration of the investigational product, with a maximum daily dose of 48 mg/kg and a total dose not exceeding 2 mg/kg/hour. The trial is not classified as low intervention, and the investigational product is not an orphan drug.

The clinical trial involves the administration of **doxapram hydrochloride monohydrate**, an experimental medication, to evaluate its safety and efficacy in preterm newborns. The pharmaceutical form of the medication is a **solution for infusion**, and it is administered intravenously. The dosing regimen includes a maximum daily dose of 48 mg/kg and a maximum total dose of 2 mg/kg/hour. The treatment period is limited to a maximum of 10 days. The active substance, doxapram hydrochloride monohydrate, is of chemical origin and is classified under the ATC code R07AB01. The medication is not formulated specifically for pediatric use.

In this trial, a placebo is used as a comparator treatment. The placebo is a **Glucose 5% 50 ml** solution, which serves as a control to assess the effects of the experimental medication. The placebo does not contain any active pharmaceutical ingredients and is not associated with any specific pharmaceutical form or route of administration in the context of this study. The use of a placebo allows for a double-blinded study design, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby minimizing bias in the assessment of the trial's outcomes.

Efficacy in the clinical trial titled "Doxapram versus placebo in preterm newborns: An international double blinded multicenter randomized controlled trial" will be assessed by evaluating the primary endpoint, which is the composite outcome of death or severe disability at 18 to 24 months corrected age. Both components of this composite outcome will also be analyzed separately to provide a comprehensive understanding of the treatment's impact. The trial aims to determine if **doxapram** is effective in reducing these outcomes compared to a placebo. The assessment will involve a follow-up period extending to 18-24 months corrected age, during which the occurrence of death and the presence of severe disability will be systematically recorded and analyzed. The trial is designed to ensure rigorous evaluation through its randomized controlled methodology, providing robust data on the efficacy of doxapram in the specified patient population.