Clinical trial NCT04430790: Doxapram Therapy in Preterm Infants (DOXA Trial)
Official title: Doxapram Versus Placebo in Preterm Newborns: An International Double Blinded Multicenter Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Apnea of Prematurity
Respiratory Insufficiency
Keywords: Preterm infants
Hypoxia
Doxapram
Lead sponsor: Erasmus Medical Center
Sponsor class: OTHER
Collaborators: name: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: Nederlands Neonataal Netwerk (N3), the Netherlands
name: Universitaire Ziekenhuizen KU Leuven
name: Maternal, Infant, Child and Youth Research Network (MICYRN)
First posted: 2020-06-12
Enrollment: 396
Sex: ALL
Minimum age (years): 23
Maximum age (years): 29
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Doxapram versus placebo
Primary purpose: TREATMENT

Brief summary: 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.

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.

Primary outcomes:
measure: Death or severe disability
timeFrame: 2 years corrected age
Secondary outcomes:
measure: Broncho pulmonary dysplasia
timeFrame: 36 weeks post menstrual age
measure: Death
timeFrame: until 36 weeks post menstrual age and until hospital discharge
measure: Admission period
timeFrame: through study completion and until discharge home, average 3 months
measure: Endotracheal intubations
timeFrame: Day 3, 7, 14, and 21 after start of study medication
measure: Oxygenation days and complications
timeFrame: During first hospital admittance and through study completion, average of 3 months
measure: Gastro-intestinal outcome measures
timeFrame: During first hospital admittance and until 36 weeks post menstrual age
measure: Neurological outcome measures
timeFrame: During first hospital admittance or at term equivalent age (37-42 weeks postmenstrual age), average 3 months
measure: Complications during neonatal period
timeFrame: During first hospital admittance or at term equivalent age (37-42 weeks postmenstrual age), average 3 months
measure: Retinopathy of prematurity
timeFrame: During first hospital admittance or at term equivalent age (37-42 weeks postmenstrual age), average 3 months
measure: Hearing
timeFrame: At term equivalent age, 37-42 weeks postmenstrual age, average 3 months
measure: Additional long term outcomes
timeFrame: 2 years corrected age
measure: Parent reported outcome
timeFrame: 2 years corrected age
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: St Luc Louvain
state: Avenaue Hippocrate 10
city: Brussels
country: Belgium
facility: Delta Hospital Brussels
state: Brussels Hoofdstedelijk Gewest
city: Jette
country: Belgium
facility: University Hospital Brussels
state: Brussels Hoofdstedelijk Gewest
city: Charleroi
country: Belgium
facility: Grand Hospital de Charleroi
state: Henegouwen
city: Liège
country: Belgium
facility: Clinique Saint-Vincent Liege
state: Liege
city: Brugge
country: Belgium
facility: Academisch Ziekenhuis Sint-Jan
state: West-Vlaanderen
city: Antwerp
country: Belgium
facility: Sint Augustinus Hospital Antwerp
city: Antwerp
country: Belgium
facility: University Hospital Antwerp
city: Brussels
country: Belgium
facility: Chirec-Delta Hospital
city: Leuven
country: Belgium
facility: University Hospitals Leuven
city: Calgary
country: Canada
facility: Foothills Medical Centre
state: Alberta
city: Edmonton
country: Canada
facility: Royal Alexandra Hospital
state: Alberta
city: Hamilton
country: Canada
facility: McMaster Children's Hospital
state: Ontario
city: Montreal
country: Canada
facility: Montreal Children's Hospital
state: Quebec
city: Quebec City
country: Canada
facility: Centre Mère-Enfent Soleil
state: Quebec
city: Nijmegen
country: Netherlands
facility: Radboudumc Amalia Children's Hospital Nijmegen
state: Gelderland
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
state: Limburg
city: Veldhoven
country: Netherlands
facility: Maxima Medical Center Veldhoven
state: Noord-Brabant
city: Amsterdam
country: Netherlands
facility: Amsterdam University Medical Center
state: Noord-Holland
city: Zwolle
country: Netherlands
facility: Isala Clinics Zwolle
state: Overijssel
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
state: Zuid-Holland
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center - Sophia Children's Hospital
state: Zuid-Holland
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Utrecht
country: Netherlands
facility: UMC Utrecht - Wilhelmina Kinderziekenhuis
Study officials:
affiliation: Universitair Ziekenhuis Leuven
name: Anne Smits, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Universitair Ziekenhuis Leuven
name: Karel Allegaert, MD, PhD
role: STUDY_DIRECTOR
References:
citation: 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 versus placebo in preterm newborns: a study protocol for an international double blinded multicentre randomized controlled trial (DOXA-trial). Trials. 2023 Oct 10;24(1):656. doi: 10.1186/s13063-023-07683-5.