Doxapram versus placebo in preterm newborns: a study protocol for an international double blinded multicentre randomized controlled trial (DOXA-trial)
Trials, vol. 24, pp. 656
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
Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus University Medical Center Sophia Children's Hospital, Room Sk-4113, Wytemaweg 80, 3015 CN, Rotterdam, the Netherlands
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Erasmus MC · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, the Netherlands
Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus University Medical Center Sophia Children's Hospital, Room Sk-4113, Wytemaweg 80, 3015 CN, Rotterdam, the Netherlands
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Universitair Ziekenhuis Leuven · KU Leuven
Affiliation as printed
Department of Development and Regeneration, KU Leuven, Leuven, Belgium
Neonatal Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium
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Affiliation as printed
Department of Biostatistics, Erasmus University Medical Center, Rotterdam, the Netherlands
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Erasmus MC · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus University Medical Center Sophia Children's Hospital, Room Sk-4113, Wytemaweg 80, 3015 CN, Rotterdam, the Netherlands
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Emma Kinderziekenhuis · Amsterdam University Medical Centers
Affiliation as printed
Department of Neonatology, Emma Children's Hospital, Amsterdam UMC, Amsterdam, the Netherlands
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Emma Kinderziekenhuis · Amsterdam University Medical Centers · Amsterdam Reproduction Development
Affiliation as printed
Amsterdam Reproduction & Development, Amsterdam, the Netherlands
Department of Neonatology, Emma Children's Hospital, Amsterdam UMC, Amsterdam, the Netherlands
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Erasmus MC · Erasmus MC - Sophia Children’s Hospital · Erasmus University Rotterdam
Affiliation as printed
Department of Paediatric Surgery and Intensive Care, Erasmus University Medical Center Sophia Children's Hospital, Rotterdam, the Netherlands
Institute for Medical Technology Assessment (iMTA), Erasmus University Rotterdam, Rotterdam, the Netherlands
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Radboud University Nijmegen · Radboud University Medical Center · Amalia Kinderziekenhuis · Radboud Institute for Health Sciences
Affiliation as printed
Department of Neonatology, Radboud University Medical Center, Radboud Institute for Health Sciences, Amalia Children's Hospital, Nijmegen, the Netherlands
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Cliniques Universitaires Saint-Luc
Affiliation as printed
Neonatal Intensive Care Unit, Cliniques Universitaires Saint Luc, Brussels, Belgium
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Affiliation as printed
Department of Neonatology, Grand hôpital de Charleroi, Charleroi, Belgium
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Affiliation as printed
Department Neonatology, AZ St-Jan, Bruges, Belgium
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University Medical Center Groningen · Beatrix Kinderziekenhuis
Affiliation as printed
Division of Neonatology, Department of Paediatrics, Beatrix Children's Hospital, University Medical Centre Groningen, Groningen, the Netherlands
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Affiliation as printed
Department of Neonatology, Isala, Zwolle, Zwolle, the Netherlands
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Universitair Ziekenhuis Leuven
Affiliation as printed
Neonatal Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium
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Maastricht University Medical Centre · Maastricht University
Affiliation as printed
Division of Neonatology, Department of Pediatrics, Maastricht University Medical Center, Maastricht, the Netherlands
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Université Libre de Bruxelles · Erasmus Hospital
Affiliation as printed
Neonatal Department, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
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Affiliation as printed
Division of Neonatology, Department of Pediatrics, Máxima Medical Center, Veldhoven, the Netherlands
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Erasmus MC · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus University Medical Center Sophia Children's Hospital, Room Sk-4113, Wytemaweg 80, 3015 CN, Rotterdam, the Netherlands
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Vrije Universiteit Brussel · Universitair Ziekenhuis Brussel
Affiliation as printed
Neonatology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
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GZA Ziekenhuizen Campus Sint-Augustinus
Affiliation as printed
Department of Neonatology, GasthuisZusters Antwerpen, Antwerp, Belgium
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Affiliation as printed
Quality Management in Clinical Research (QMCR), University of Alberta, Edmonton, AB, Canada
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Affiliation as printed
Department of Neonatal Intensive Care, University Hospital Antwerp, Edegem, Belgium
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Emma Kinderziekenhuis · Amsterdam University Medical Centers · Amsterdam Reproduction Development
Affiliation as printed
Amsterdam Reproduction & Development, Amsterdam, the Netherlands
Department of Neonatology, Emma Children's Hospital, Amsterdam UMC, Amsterdam, the Netherlands
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Centre Hospitalier Interrégional Edith Cavell
Affiliation as printed
Neonatology and Neonatal Intensive Care Unit, CHIREC-Delta Hospital, Brussels, Belgium
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University Medical Center Utrecht · Wilhelmina Children's Hospital
Affiliation as printed
Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands
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University of Calgary · Maternal Infant Child and Youth Research Network
Affiliation as printed
Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Maternal Infant Child & Youth Research Network (MICYRN), Vancouver, Canada
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Arjan B. te Pas Aachen Division of Neonatology Department of Paediatrics, Willem-Alexander Children's Hospital
Leiden University · Leiden University Medical Center · Willem-Alexander Kinderziekenhuis
Affiliation as printed
Division of Neonatology, Department of Paediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Centre, Leiden, the Netherlands
Division of Neonatology, Department of Paediatrics, Willem-Alexander Children's Hospital, Leiden University Medical Centre, Leiden, the Netherlands
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Erasmus MC · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus University Medical Center Sophia Children's Hospital, Room Sk-4113, Wytemaweg 80, 3015 CN, Rotterdam, the Netherlands
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Emma Kinderziekenhuis · Amsterdam University Medical Centers · Amsterdam Reproduction Development
Affiliation as printed
Amsterdam Reproduction & Development, Amsterdam, the Netherlands
Department of Neonatology, Emma Children's Hospital, Amsterdam UMC, Amsterdam, the Netherlands
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Affiliation as printed
Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
Department of Development and Regeneration, KU Leuven, Leuven, Belgium
Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, the Netherlands
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Emma Kinderziekenhuis · Amsterdam University Medical Centers · Amsterdam Reproduction Development
Affiliation as printed
Amsterdam Reproduction & Development, Amsterdam, the Netherlands
Department of Neonatology, Emma Children's Hospital, Amsterdam UMC, Amsterdam, the Netherlands
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Sinno H. P. Simons corresponding
Erasmus MC · Erasmus MC - Sophia Children’s Hospital
Affiliation as printed
Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus University Medical Center Sophia Children's Hospital, Room Sk-4113, Wytemaweg 80, 3015 CN, Rotterdam, the Netherlands. s.simons@erasmusmc.nl
Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus University Medical Center Sophia Children's Hospital, Room Sk-4113, Wytemaweg 80, 3015 CN, Rotterdam, the Netherlands
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