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Apnea of PrematurityPhase 3NCT04430790

Doxapram Therapy in Preterm Infants (DOXA Trial)

A Phase 3 study testing Doxapram in people with Apnea of Prematurity and Respiratory Insufficiency, run by Erasmus Medical Center at 24 sites in 3 countries.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 23 to 29 weeks
What is being tested?
Doxapram
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
396 participants
Where
24 sitesin 3 countries
Study dates
15 Jun 2020to 1 May 2034
Phase
Phase 3
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 23 to 29 weeks
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • 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

Who cannot join

  • 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.

Trial locations and contacts

24 sites in 3 countries. Contact the study team or a site near you to ask about taking part.

Sinno HP Simons, MD, PhD contact

+31641376695

s.simons@erasmusmc.nl

Jeroen J Hutten, MD, PhD contact

g.j.hutten@amsterdamumc.nl

24 sites in 3 countries

Belgium10 sites, 9 recruiting

  • Sint Augustinus Hospital Antwerp

    Antwerp, 2610

    Katleen Plaskie, Katleen.Plaskie@gza.be

    Recruiting

  • University Hospital Antwerp

    Antwerp, 2650

    michiel Voeten, michiel.voeten@uza.be

    Recruiting

  • Academisch Ziekenhuis Sint-Jan

    Bruges, West-Vlaanderen, 8000

    Luc Cornette, Luc.Cornette@azsintjan.be

    Recruiting

  • St Luc Louvain

    Brussels, Avenaue Hippocrate 10, 1200

    Katherine Carkeek, katherine.carkeek@saintluc.uclouvain.be

    Recruiting

  • Delta Hospital Brussels

    Brussels, Brussels Capital, 1160

    Dorottya Kelen, Dorottya.Kelen@erasme.ulb.ac.be

    Recruiting

  • Chirec-Delta Hospital

    Brussels, 1160

    Olivia Williams, brussels.doc@gmail.com

    Recruiting

  • Grand Hospital de Charleroi

    Charleroi, Henegouwen

    Vincent Cassart, Vincent.cassart@ghdc.be

    Recruiting

  • University Hospital Brussels

    Jette, Brussels Capital, 1090

    Ingrid van limberghen, ingrid.vanlimberghen@uzbrussel.be

    Julie Lefevere

    Recruiting

  • University Hospitals Leuven

    Leuven

    Anne Smits, anne.smits@uzleuven.nl

    Recruiting

  • Clinique Saint-Vincent Liege

    Liège, Liege, 4000

    Suspended

Other trials in Belgium

Netherlands9 sites, 9 recruiting

  • Amsterdam University Medical Center

    Amsterdam, North Holland, 1105 AZ

    Jeroen Hutten, g.j.hutten@amsterdam.nl

    Recruiting

  • University Medical Center Groningen

    Groningen, 9713 GZ

    Peter Dijk, p.h.dijk@umcg.nl

    Recruiting

  • Leiden University Medical Center

    Leiden, South Holland, 2333 ZA

    Arjan te Pas, a.b.te_pas@lumc.nl

    Recruiting

  • Maastricht University Medical Center

    Maastricht, Limburg, 6229 HX

    Matthias Hutten, matthias.hutten@mumc.nl

    Recruiting

  • Radboudumc Amalia Children's Hospital Nijmegen

    Nijmegen, Gelderland, 6525 GA

    Willem de Boode, Willem.deBoode@radboudumc.nl

    Recruiting

  • Erasmus Medical Center - Sophia Children's Hospital

    Rotterdam, South Holland, 3015 GD

    Andre Kroon, a.a.kroon@erasmusmc.nl

    Recruiting

  • UMC Utrecht - Wilhelmina Kinderziekenhuis

    Utrecht, 3584 EA

    Inge Zonnenberg, i.a.zonnenberg-2@umcutrecht.nk

    Recruiting

  • Maxima Medical Center Veldhoven

    Veldhoven, North Brabant, 5504 DB

    Ellen de Kort, e.dekort@mmc.nl

    Recruiting

  • Isala Clinics Zwolle

    Zwolle, Overijssel, 8025 AB

    Marieke Hemels, m.a.c.hemels@isala.nl

    Recruiting

Other trials in Netherlands

Canada5 sites, 5 recruiting

  • Foothills Medical Centre

    Calgary, Alberta, T2N 2T9

    Lara Leijser, MD PhD, lara.leijser@ucalgary.ca

    Not yet recruiting

  • Royal Alexandra Hospital

    Edmonton, Alberta, T5H 3V9

    Brenda Law, MD, blaw2@ualberta.ca

    Not yet recruiting

  • McMaster Children's Hospital

    Hamilton, Ontario, L8N3Z5

    Samira Samiee-Zafaghandy, samiees@mcmaster.ca

    Not yet recruiting

  • Montreal Children's Hospital

    Montreal, Quebec, QC H4A 3J1

    Wissam Shalish

    wissam.shalish@mcgill.ca

    Not yet recruiting

  • Centre Mère-Enfent Soleil

    Québec, Quebec, G1V 4G2

    Georges Caouette, Georges.Caouette@crchudequebec.ulaval.ca

    Not yet recruiting

Other trials in Canada

About this study

Official title: 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).

Read the 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.

Being tested
Doxapram, Placebo
Keywords
Preterm infants, Hypoxia, Doxapram
Medical subject headings
Apnea, Respiratory Insufficiency, Hypoxia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DoxapramDrug

    Also called Dopram

    Loading dose and continuous doxapram infusion.

  • PlaceboDrug

    Also called Placebo (for Doxapram)

    Loading dose and continuous placebo infusion.

Study groups in NCT04430790
Study groupRoleWhat they receive
DoxapramExperimentalBlinded 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.
Receives: Drug: Doxapram
PlaceboPlacebo comparatorPlacebo (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.
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Death or severe disability

    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

    Measured: 2 years corrected age

Secondary outcomes (12)

  1. Broncho pulmonary dysplasia

    Diagnosed according to the National Institute of Child Health and Human Development (NICHD) criteria

    Measured: 36 weeks post menstrual age

  2. Death

    Death at 36 weeks post menstrual age and hospital mortality

    Measured: until 36 weeks post menstrual age and until hospital discharge

  3. Admission period

    Length of stay at the intensive care, length of stay in hospital

    Measured: through study completion and until discharge home, average 3 months

  4. Endotracheal intubations

    Incidence of endotracheal intubations

    Measured: Day 3, 7, 14, and 21 after start of study medication

  5. Oxygenation days and complications

    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.

    Measured: During first hospital admittance and through study completion, average of 3 months

  6. Gastro-intestinal outcome measures

    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

    Measured: During first hospital admittance and until 36 weeks post menstrual age

  7. Neurological outcome measures

    Intraventricular hemorhage(IVH) (all grades, grade III-IV, venous infarction), clinical seizures, periventricular leucomalacia (PVL) > gr 1)

    Measured: During first hospital admittance or at term equivalent age (37-42 weeks postmenstrual age), average 3 months

  8. Complications during neonatal period

    Incidence of late onset sepsis (culture proven or clinical suspected) and meningitis after inclusion, need for inotropes/circulatory support

    Measured: During first hospital admittance or at term equivalent age (37-42 weeks postmenstrual age), average 3 months

  9. Retinopathy of prematurity

    Grade of retinopathy (including plus disease and need for therapy)

    Measured: During first hospital admittance or at term equivalent age (37-42 weeks postmenstrual age), average 3 months

  10. Hearing

    Hearing test

    Measured: At term equivalent age, 37-42 weeks postmenstrual age, average 3 months

  11. Additional long term outcomes

    Readmissions since first discharge home, weight/length/head circumference, behavioral problems (Child Behavior Checklist)

    Measured: 2 years corrected age

  12. Parent reported outcome

    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)

    Measured: 2 years corrected age

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Jun 2020
  2. Study start15 Jun 2020
  3. Primary completion1 May 2026 (estimated)
  4. Study completion1 May 2034 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Doxapram versus placebo
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
396 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04430790
Sponsor's protocol ID
NL72125.078.19
Other IDs
80-84800-9843009, 2019-003666-41, 2019
Status last verified
Apr 2024
First submitted
8 Jan 2020
Last updated
4 Apr 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: Yes

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 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.

    PubMed 37817255

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Doxapram in people with Apnea of Prematurity and Respiratory Insufficiency, run by Erasmus Medical Center at 24 sites in 3 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 4 Apr 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 24 sites in Belgium, Netherlands, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Sinno HP Simons, MD, PhD (+31641376695, s.simons@erasmusmc.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Death or severe disability (time frame: 2 years corrected age). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04430790, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Apr 2024.

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