Doxapram Therapy in Preterm Infants (DOXA Trial)

Official title

Doxapram Versus Placebo in Preterm Newborns: An International Double Blinded Multicenter Randomized Controlled Trial

Overview

Preterm infants often suffer from apnea of prematurity (AOP; a cessation of breathing) due to immaturity of the respiratory system. AOP can lead to oxygen shortage and a low heart rate which might harm the development of the newborn, especially the central nervous system. In order to prevent oxygen shortage, infants are treated with non-invasive respiratory support and caffeine. Despite these treatments, many preterm newborns still suffer from AOP and need invasive mechanical ventilation. Although this will result in complete resolution of AOP, invasive mechanical ventilation has the disadvantage of being a major risk of chronic lung disease and impaired neurodevelopmental outcome. Restrictive invasive ventilation is therefore advocated nowadays in preterm infants. Doxapram is a respiratory stimulant that has been administered off-label to treat AOP. Doxapram, as add-on treatment, seems to be effective in treating AOP and to prevent invasive mechanical ventilation. It is unclear if a preterm infant benefit from doxapram treatment on the longer term. This study compares doxapram to placebo and hypothesizes that doxapram will protect preterm infants from both invasive ventilation (and related lung disease) and AOP related oxygen shortage (and related impaired brain development).

Detailed description

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.

Interventions

• Drug Doxapram
  Loading dose and continuous doxapram infusion.
• Drug Placebo
  Loading dose and continuous placebo infusion.

Primary outcome measures

• Death or severe disability [Time frame: 2 years corrected age]

Secondary outcome measures (12)

• Broncho pulmonary dysplasia [Time frame: 36 weeks post menstrual age]
• Death [Time frame: until 36 weeks post menstrual age and until hospital discharge]
• Admission period [Time frame: through study completion and until discharge home, average 3 months]
• Endotracheal intubations [Time frame: Day 3, 7, 14, and 21 after start of study medication]
• Oxygenation days and complications [Time frame: During first hospital admittance and through study completion, average of 3 months]
• Gastro-intestinal outcome measures [Time frame: During first hospital admittance and until 36 weeks post menstrual age]
• Neurological outcome measures [Time frame: During first hospital admittance or at term equivalent age (37-42 weeks postmenstrual age), average 3 months]
• Complications during neonatal period [Time frame: During first hospital admittance or at term equivalent age (37-42 weeks postmenstrual age), average 3 months]
• Retinopathy of prematurity [Time frame: During first hospital admittance or at term equivalent age (37-42 weeks postmenstrual age), average 3 months]
• Hearing [Time frame: At term equivalent age, 37-42 weeks postmenstrual age, average 3 months]
• Additional long term outcomes [Time frame: 2 years corrected age]
• Parent reported outcome [Time frame: 2 years corrected age]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Belgium · 10 centers

• St Luc Louvain — Brussels
• Delta Hospital Brussels — Brussels
• University Hospital Brussels — Jette
• Grand Hospital de Charleroi — Charleroi
• Clinique Saint-Vincent Liege — Liège
• Academisch Ziekenhuis Sint-Jan — Bruges
• Sint Augustinus Hospital Antwerp — Antwerp
• University Hospital Antwerp — Antwerp
• … and 2 more centers

Netherlands · 9 centers

• Radboudumc Amalia Children's Hospital Nijmegen — Nijmegen
• Maastricht University Medical Center — Maastricht
• Maxima Medical Center Veldhoven — Veldhoven
• Amsterdam University Medical Center — Amsterdam
• Isala Clinics Zwolle — Zwolle
• Leiden University Medical Center — Leiden
• Erasmus Medical Center - Sophia Children's Hospital — Rotterdam
• University Medical Center Groningen — Groningen
• … and 1 more center

Canada · 5 centers

• Foothills Medical Centre — Calgary
• Royal Alexandra Hospital — Edmonton
• McMaster Children's Hospital — Hamilton
• Montreal Children's Hospital — Montreal
• Centre Mère-Enfent Soleil — Québec

Publications

• Poppe JA, Flint RB, Smits A, Willemsen SP, Storm KK, Nuytemans DH, Onland W, Poley MJ, de Boode WP, Carkeek K, Cassart V, Cornette L, Dijk PH, Hemels MAC, Hermans I, Hutten MC, Kelen D, de Kort EHM, Kroon AA, Lefevere J, Plaskie K, Stewart B, Voeten M, van Weissenbruch MM, Williams O, Zonnenberg IA, Lacaze-Masmonteil T, Pas ABT, Reiss IKM, van Kaam AH, Allegaert K, Hutten GJ, Simons SHP. Doxapram PMID 37817255

Identifiers

NCT: NCT04430790 · NL72125.078.19 · 80-84800-9843009 · 2019-003666-41

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗