Doxapram Therapy in Preterm Infants (DOXA Trial)

NCT ID: NCT04430790

Last Updated: 2024-04-04

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE3

Total Enrollment

396 participants

Study Classification

INTERVENTIONAL

Study Start Date

2020-06-15

Study Completion Date

2034-05-01

Brief Summary

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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

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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.

Conditions

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Apnea of Prematurity Respiratory Insufficiency

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Doxapram versus placebo
Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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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.

Group Type EXPERIMENTAL

Doxapram

Intervention Type DRUG

Loading dose and continuous doxapram infusion.

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.

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

Loading dose and continuous placebo infusion.

Interventions

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Doxapram

Loading dose and continuous doxapram infusion.

Intervention Type DRUG

Placebo

Loading dose and continuous placebo infusion.

Intervention Type DRUG

Other Intervention Names

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Dopram Placebo (for Doxapram)

Eligibility Criteria

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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.
Minimum Eligible Age

23 Weeks

Maximum Eligible Age

29 Weeks

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

OTHER

Sponsor Role collaborator

Nederlands Neonataal Netwerk (N3), the Netherlands

UNKNOWN

Sponsor Role collaborator

Universitaire Ziekenhuizen KU Leuven

OTHER

Sponsor Role collaborator

Maternal, Infant, Child and Youth Research Network (MICYRN)

UNKNOWN

Sponsor Role collaborator

Erasmus Medical Center

OTHER

Sponsor Role lead

Responsible Party

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Sinno H.P. Simons

Principal investigator

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Anne Smits, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Universitair Ziekenhuis Leuven

Karel Allegaert, MD, PhD

Role: STUDY_DIRECTOR

Universitair Ziekenhuis Leuven

Locations

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St Luc Louvain

Brussels, Avenaue Hippocrate 10, Belgium

Site Status RECRUITING

Delta Hospital Brussels

Brussels, Brussels Capital, Belgium

Site Status RECRUITING

University Hospital Brussels

Jette, Brussels Capital, Belgium

Site Status RECRUITING

Grand Hospital de Charleroi

Charleroi, Henegouwen, Belgium

Site Status RECRUITING

Clinique Saint-Vincent Liege

Liège, Liege, Belgium

Site Status SUSPENDED

Academisch Ziekenhuis Sint-Jan

Bruges, West-Vlaanderen, Belgium

Site Status RECRUITING

Sint Augustinus Hospital Antwerp

Antwerp, , Belgium

Site Status RECRUITING

University Hospital Antwerp

Antwerp, , Belgium

Site Status RECRUITING

Chirec-Delta Hospital

Brussels, , Belgium

Site Status RECRUITING

University Hospitals Leuven

Leuven, , Belgium

Site Status RECRUITING

Foothills Medical Centre

Calgary, Alberta, Canada

Site Status NOT_YET_RECRUITING

Royal Alexandra Hospital

Edmonton, Alberta, Canada

Site Status NOT_YET_RECRUITING

McMaster Children's Hospital

Hamilton, Ontario, Canada

Site Status NOT_YET_RECRUITING

Montreal Children's Hospital

Montreal, Quebec, Canada

Site Status NOT_YET_RECRUITING

Centre Mère-Enfent Soleil

Québec, Quebec, Canada

Site Status NOT_YET_RECRUITING

Radboudumc Amalia Children's Hospital Nijmegen

Nijmegen, Gelderland, Netherlands

Site Status RECRUITING

Maastricht University Medical Center

Maastricht, Limburg, Netherlands

Site Status RECRUITING

Maxima Medical Center Veldhoven

Veldhoven, North Brabant, Netherlands

Site Status RECRUITING

Amsterdam University Medical Center

Amsterdam, North Holland, Netherlands

Site Status RECRUITING

Isala Clinics Zwolle

Zwolle, Overijssel, Netherlands

Site Status RECRUITING

Leiden University Medical Center

Leiden, South Holland, Netherlands

Site Status RECRUITING

Erasmus Medical Center - Sophia Children's Hospital

Rotterdam, South Holland, Netherlands

Site Status RECRUITING

University Medical Center Groningen

Groningen, , Netherlands

Site Status RECRUITING

UMC Utrecht - Wilhelmina Kinderziekenhuis

Utrecht, , Netherlands

Site Status RECRUITING

Countries

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Belgium Canada Netherlands

Central Contacts

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Sinno HP Simons, MD, PhD

Role: CONTACT

+31641376695

Jeroen J Hutten, MD, PhD

Role: CONTACT

Facility Contacts

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Katherine Carkeek

Role: primary

Dorottya Kelen

Role: primary

Ingrid van limberghen

Role: primary

Vincent Cassart

Role: primary

Luc Cornette

Role: primary

Katleen Plaskie

Role: primary

michiel Voeten

Role: primary

Olivia Williams

Role: primary

Anne Smits

Role: primary

Lara Leijser, MD PhD

Role: primary

Brenda Law, MD

Role: primary

Samira Samiee-Zafaghandy

Role: primary

Wissam Shalish

Role: primary

Role: backup

Georges Caouette

Role: primary

Willem de Boode

Role: primary

Matthias Hutten

Role: primary

Ellen de Kort

Role: primary

Jeroen Hutten

Role: primary

Marieke Hemels

Role: primary

Arjan te Pas

Role: primary

Andre Kroon

Role: primary

Peter Dijk

Role: primary

Inge Zonnenberg

Role: primary

References

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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.

Reference Type BACKGROUND
PMID: 37817255 (View on PubMed)

Other Identifiers

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80-84800-9843009

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

2019-003666-41

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

NL72125.078.19

Identifier Type: -

Identifier Source: org_study_id

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