Doxapram Therapy in Preterm Infants (DOXA Trial)

The main objective of the trial is to investigate if doxapram is safe and effective in reducing the composite outcome of death and neurodevelopmental impairment/severe disability at 2 years corrected age as compared to placebo. This multicenter double blinded randomized placebo-controlled superiority trial will be conducted in multiple neonatal intensive care units in the Netherlands and Belgium, including 8 years follow-up. After written informed-consent the patients will be randomized into the doxapram treatment group or the placebo treatment group. Randomization will be stratified based on center and gestational age < or >= 26 weeks.

The participating departments include Dutch and Belgian Neonatal Intensive care units. The units include both academic and non-academic level III and IV units that are specialized in the care for critically ill and preterm born infants. Postnatal ages of patients at doxapram start vary from directly after birth up to months for the most-preterm born infants.

Blinded continuous doxapram or placebo (glucose 5%) will be infused as long as needed. Therapy is down titrated or stopped based on the patients' condition. If endotracheal intubation is needed study drug is stopped. After extubation study drug may be restarted. Switch to gastro-enteral administration is allowed if no iv-access is needed for other reasons. Next to study drug infusion, there will be no other study-related interventions. All outcome variables are already collected as standard of care. In a subset of patients doxapram plasma levels will be determined to validate the doxapram pharmacokinetic (PK) model. Blood will only be collected during routine blood sampling, with a maximum amount of 0.6 ml. Economic and cost-effectiveness evaluation will be performed. The national protocol for preterm birth advices follow-up at 2, 5.5 and 8 years respectively, as in the current study. Additional questionnaires will be used to collect data on the quality of life of patients and their parents.

Inclusion criteria

• Admitted to the neonatal intensvie care unit (NICU) of one of the participating centres
• Written informed consent of both parents or legal representatives
• Gestational age at birth < 29 weeks
• Caffeine therapy, adequately dosed (see also under co-medication)
• Optimal Non-invasively supported with nasal Continuous Positive Airway Pressure (CPAP) or ventilation ((S)NIPPV, NIV-NAVA, BIPAP/Duopap, SIPAP)
• Apnea that require a medical intervention as judged by the attending physician

Exclusion criteria

• Previous use of open label doxapram
• Use of theophylline (to replace doxapram)
• Chromosomal defects (e.g. trisomy 13, 18, or 21)
• Major congenital malformations that: compromise lung function (e.g. surfactant protein deficiencies, congenital diaphragmatic hernia); result in chronic ventilation (e.g. Pierre Robin sequence); increase the risk of death or adverse neurodevelopmental outcome (congenital cerebral malformations, chromosomal abnormalities);
• Palliative care or treatment limitations because of high risk of impaired outcome.