Doxapram Therapy in Preterm Infants (DOXA Trial)

April 3, 2024 updated by: Sinno H.P. Simons, Erasmus Medical Center

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

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).

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

396

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Belgium
      • Antwerp, Belgium, 2650
      • Antwerp, Belgium, 2610
      • Brussels, Belgium, 1160
      • Leuven, Belgium
    • Avenaue Hippocrate 10
    • Brussels Hoofdstedelijk Gewest
      • Brussels, Brussels Hoofdstedelijk Gewest, Belgium, 1160
      • Jette, Brussels Hoofdstedelijk Gewest, Belgium, 1090
    • Henegouwen
      • Charleroi, Henegouwen, Belgium
    • Liege
      • Liège, Liege, Belgium, 4000
        • Suspended
        • Clinique Saint-Vincent Liege
    • West-Vlaanderen
      • Brugge, West-Vlaanderen, Belgium, 8000
  • Canada
    • Alberta
      • Calgary, Alberta, Canada, T2N 2T9
      • Edmonton, Alberta, Canada, T5H 3V9
        • Not yet recruiting
        • Royal Alexandra Hospital
        • Contact:
    • Ontario
      • Hamilton, Ontario, Canada, L8N3Z5
        • Not yet recruiting
        • McMaster Children's Hospital
        • Contact:
    • Quebec
  • Netherlands
      • Groningen, Netherlands, 9713 GZ
        • Recruiting
        • University Medical Center Groningen
        • Contact:
      • Utrecht, Netherlands, 3584 EA
    • Gelderland
      • Nijmegen, Gelderland, Netherlands, 6525 GA
    • Limburg
      • Maastricht, Limburg, Netherlands, 6229 HX
    • Noord-Brabant
      • Veldhoven, Noord-Brabant, Netherlands, 5504 DB
        • Recruiting
        • Maxima Medical Center Veldhoven
        • Contact:
    • Noord-Holland
      • Amsterdam, Noord-Holland, Netherlands, 1105 AZ
    • Overijssel
      • Zwolle, Overijssel, Netherlands, 8025 AB
    • Zuid-Holland
      • Leiden, Zuid-Holland, Netherlands, 2333 ZA
        • Recruiting
        • Leiden University Medical Center
        • Contact:
      • Rotterdam, Zuid-Holland, Netherlands, 3015 GD
        • Recruiting
        • Erasmus Medical Center - Sophia Children's Hospital
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

5 months to 6 months (Child)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Doxapram
Blinded doxapram (2mg/ml, in glucose 5%) loading dose of 2.0 to 2.5 mg/kg administered in 5 to 10 minutes, followed by a continuous infusion of 0.5 - 1.0 mg/kg/hr ('www.kinderformularium.nl') as long as needed. Therapy is down titrated or stopped based on the patients' respiratory 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.
Drug: Doxapram
Loading dose and continuous doxapram infusion.
Other Names:
  • Dopram
Placebo Comparator: Placebo
Placebo (glucose 5%) will also be administered with a loading dose and continuous infusion (in equal amounts of fluid as in experimental arm) by intravenous or gastro-intestinal infusion. The treatment protocol will be equal to the protocol in the doxapram arm.
Drug: Placebo
Loading dose and continuous placebo infusion.
Other Names:
  • Placebo (for Doxapram)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Death or severe disability
Time Frame: 2 years corrected age
Disability will be defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness. Cognitive delay will be defined as a Mental Development Index score of less than 85 on the Bayley Scales of Infant and Toddler Development, Bayley Score of Infant Development (BSID) III scores. Cerebral palsy will be diagnosed if the child had a non-progressive motor impairment characterized by abnormal muscle tone and decreased range or control of movements. The level of gross motor function will be determined with the use of the Gross Motor Function Classification System. Audiometry will be performed to determine the presence or absence of hearing loss. Blindness will be defined as a corrected visual acuity less than 20/200
2 years corrected age

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Broncho pulmonary dysplasia
Time Frame: 36 weeks post menstrual age
Diagnosed according to the National Institute of Child Health and Human Development (NICHD) criteria
36 weeks post menstrual age
Death
Time Frame: until 36 weeks post menstrual age and until hospital discharge
Death at 36 weeks post menstrual age and hospital mortality
until 36 weeks post menstrual age and until hospital discharge
Admission period
Time Frame: through study completion and until discharge home, average 3 months
Length of stay at the intensive care, length of stay in hospital
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
Incidence of endotracheal intubations
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
Number of days on invasive ventilation, number of days on ventilatory support (non-invasive ventilation, CPAP, humidified high flow, low flow), number of days with supplemental oxygen, respiratory complications (airleak, pneumonia, etc), use of (rescue) corticosteroids for respiratory reasons.
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
solitary intestinal perforation, necrotizing enterocolitis > stage 2 according to Bell, feeding problems with need for parental feeding (days with parental feeding after inclusion), body weight (gain, length), head circumference
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
Intraventricular hemorhage(IVH) (all grades, grade III-IV, venous infarction), clinical seizures, periventricular leucomalacia (PVL) > gr 1)
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
Incidence of late onset sepsis (culture proven or clinical suspected) and meningitis after inclusion, need for inotropes/circulatory support
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
Grade of retinopathy (including plus disease and need for therapy)
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
Hearing test
At term equivalent age, 37-42 weeks postmenstrual age, average 3 months
Additional long term outcomes
Time Frame: 2 years corrected age
Readmissions since first discharge home, weight/length/head circumference, behavioral problems (Child Behavior Checklist)
2 years corrected age
Parent reported outcome
Time Frame: 2 years corrected age
Parent reported outcome with the PARCA-R (Parent Report of Children's Abilities-Revised) questionnaire (expected mean standardised scores 100 (SD 15), higher score is better outcome)
2 years corrected age

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Erasmus Medical Center

Collaborators

Universitaire Ziekenhuizen KU Leuven
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Nederlands Neonataal Netwerk (N3), the Netherlands
Maternal, Infant, Child and Youth Research Network (MICYRN)

Investigators

  • Principal Investigator: Anne Smits, MD, PhD, Universitair Ziekenhuis Leuven
  • Study Director: Karel Allegaert, MD, PhD, Universitair Ziekenhuis Leuven

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 15, 2020

Primary Completion (Estimated)

May 1, 2026

Study Completion (Estimated)

May 1, 2034

Study Registration Dates

First Submitted

January 8, 2020

First Submitted That Met QC Criteria

June 11, 2020

First Posted (Actual)

June 12, 2020

Study Record Updates

Last Update Posted (Actual)

April 4, 2024

Last Update Submitted That Met QC Criteria

April 3, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NL72125.078.19
  • 80-84800-9843009 (Other Grant/Funding Number: ZonMw GGG)
  • 2019-003666-41 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Yes

IPD Sharing Time Frame

study protocol, sap and icf will be available at start of recruitment

IPD Sharing Access Criteria

data will be available on request. Requests will be discussed by the steering committee

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • ANALYTIC_CODE
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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