Doxapram versus placebo in preterm newborns: a study protocol for an international double blinded multicentre randomized controlled trial (DOXA-Trial)
Abstract
Abstract Background Apnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an increased risk of death or disability. In addition to caffeine therapy and non-invasive respiratory support, doxapram might be used to reduce hypoxemic episodes and the need for invasive mechanical ventilation in preterm infants, thereby possibly improving their long-term outcome. However, high-quality trials on doxapram are lacking. The DOXA-trial therefore aims to investigate the safety and efficacy of doxapram compared to placebo in reducing the composite outcome of death or severe disability at 18 to 24 months corrected age. Methods The DOXA-trial is a double blinded, multicentre, randomized, placebo-controlled trial conducted in the Netherlands, Belgium and Canada. A total of 396 preterm infants with a gestational age below 29 weeks, suffering from AOP unresponsive to non-invasive respiratory support and caffeine will be randomized to receive doxapram therapy or placebo. The primary outcome is death or severe disability, defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness, at 18–24 months corrected age. Secondary outcomes are short-term neonatal morbidity, including duration of mechanical ventilation, bronchopulmonary dysplasia and necrotising enterocolitis, hospital mortality, adverse effects, pharmacokinetics, and cost-effectiveness. Analysis will be on an intention-to-treat principle. Discussion Doxapram has the potential to improve neonatal outcomes by improving respiration, but the safety concerns need to be weighed against the potential risks of invasive mechanical ventilation. It is unknown if the use of doxapram improves the long-term outcome. This forms the clinical equipoise of the current trial. This international, multicentre trial will provide the needed high-quality evidence on the efficacy and safety of doxapram in the treatment of AOP in preterm infants. Trial registration ClinicalTrials.gov NCT04430790 and EUDRACT 2019-003666-41. Prospectively registered on respectively June and January 2020.
Authors 33
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Erasmus MC · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Erasmus MC Sophia Children Hospital: Erasmus MC Sophia Kinderziekenhuis
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Affiliation as printed
Erasmus Medical Centre: Erasmus MC
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Universitair Ziekenhuis Leuven · KU Leuven
Affiliation as printed
UZ Leuven: Katholieke Universiteit Leuven Universitaire Ziekenhuizen Leuven
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Affiliation as printed
Erasmus Medical Center: Erasmus MC
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Erasmus MC · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Erasmus MC Sophia Children Hospital: Erasmus MC Sophia Kinderziekenhuis
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Emma Kinderziekenhuis · Amsterdam University Medical Centers
Affiliation as printed
Emma Childrens' Hospital UMC: Emma Kinderziekenhuis Amsterdam UMC
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Amsterdam UMC Location University of Amsterdam · Emma Kinderziekenhuis · Amsterdam University Medical Centers
Affiliation as printed
Emma Childrens Hospital AMC: Emma Kinderziekenhuis Amsterdam UMC
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Affiliation as printed
iMTA: Erasmus Universiteit Rotterdam Institute for Medical Technology Assessment
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Radboud University Medical Center
Affiliation as printed
UMCN: Radboudumc
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Affiliation as printed
AZ Saint-Lucas: AZ Sint-Lucas
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Affiliation as printed
Grand Hôpital de Charleroi: Grand Hopital de Charleroi
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Affiliation as printed
AZ Sint-Jan AV: AZ Sint-Jan Brugge-Oostende AV
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University Medical Center Groningen · Beatrix Kinderziekenhuis
Affiliation as printed
Universitair Medisch Centrum Groningen Beatrix Kinderziekenhuis
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Affiliation as printed
Isala Hospitals: Isala
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Universitair Ziekenhuis Leuven · KU Leuven
Affiliation as printed
UZ Leuven: Katholieke Universiteit Leuven Universitaire Ziekenhuizen Leuven
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Maastricht University Medical Centre
Affiliation as printed
Maastricht UMC+: Maastricht Universitair Medisch Centrum+
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Affiliation as printed
Erasme Hospital: Hopital Erasme
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Affiliation as printed
Maxima Medical Centre: Maxima Medisch Centrum
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Erasmus MC · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Erasmus MC Sophia Children Hospital: Erasmus MC Sophia Kinderziekenhuis
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Universitair Ziekenhuis Brussel
Affiliation as printed
UZ Brussel: Universitair Ziekenhuis Brussel
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GZA Ziekenhuizen Campus Sint-Augustinus · GZA Ziekenhuizen
Affiliation as printed
GZA Hospital Saint Augustine Campus: GZA Ziekenhuizen
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Affiliation as printed
University of Alberta
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Affiliation as printed
UZA: Universitair Ziekenhuis Antwerpen
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Emma Kinderziekenhuis · Amsterdam University Medical Centers
Affiliation as printed
Emma Childrens' Hospital UMC: Emma Kinderziekenhuis Amsterdam UMC
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Affiliation as printed
Algemeen Ziekenhuis Delta: AZ Delta vzw
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University Medical Center Utrecht · Wilhelmina Children's Hospital
Affiliation as printed
UMC Utrecht - Locatie WKZ: Universitair Medisch Centrum Utrecht - Locatie Wilhelmina Kinderziekenhuis
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Affiliation as printed
UCalgary Cumming School of Medicine: University of Calgary Cumming School of Medicine
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Arjan B. te Pas Aachen
Leiden University Medical Center · Willem-Alexander Kinderziekenhuis
Affiliation as printed
Leids Universitair Medisch Centrum Willem Alexander Kinderziekenhuis
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Erasmus MC · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Erasmus MC Sophia Children Hospital: Erasmus MC Sophia Kinderziekenhuis
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Emma Kinderziekenhuis · Amsterdam University Medical Centers
Affiliation as printed
Emma Childrens' Hospital UMC: Emma Kinderziekenhuis Amsterdam UMC
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Affiliation as printed
KU Leuven University: Katholieke Universiteit Leuven
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Emma Kinderziekenhuis · Amsterdam University Medical Centers
Affiliation as printed
Emma Childrens' Hospital UMC: Emma Kinderziekenhuis Amsterdam UMC
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Affiliation as printed
Erasmus Medical Centre: Erasmus MC
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