Doxapram Therapy in Preterm Infants (DOXA Trial)

NCT04430790 | Recruiting Phase 3 DMC

• 3 other identifiers: NL72125.078.1980-84800-98430092019-003666-41
• Study Type: interventional
• Target: 396
• Locations: 3 countries
• Sites: 24

Brief 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. 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).

Conditions

Apnea of Prematurity; Respiratory Insufficiency

Keywords

Preterm infants; Hypoxia; Doxapram

Outcome Measures

Primary Outcomes (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

  2 years corrected age

Secondary Outcomes (12)

• Broncho pulmonary dysplasia

  36 weeks post menstrual age

• Death

  until 36 weeks post menstrual age and until hospital discharge

• Admission period

  through study completion and until discharge home, average 3 months

• Endotracheal intubations

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

• Oxygenation days and complications

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

Study Arms (2)

Doxapram

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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

Interventions

Doxapram DRUG

Loading dose and continuous doxapram infusion.

Also known as: Dopram

Doxapram

Placebo DRUG

Loading dose and continuous placebo infusion.

Also known as: Placebo (for Doxapram)

Placebo

Eligibility Criteria

• Age: 23 Weeks - 29 Weeks
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

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

Study Sites (24)

St Luc Louvain

Brussels, Avenaue Hippocrate 10, 1200, Belgium

RECRUITING

Delta Hospital Brussels

Brussels, Brussels Capital, 1160, Belgium

RECRUITING

University Hospital Brussels

Jette, Brussels Capital, 1090, Belgium

RECRUITING

Grand Hospital de Charleroi

Charleroi, Henegouwen, Belgium

RECRUITING

Clinique Saint-Vincent Liege

Liège, Liege, 4000, Belgium

SUSPENDED

Academisch Ziekenhuis Sint-Jan

Bruges, West-Vlaanderen, 8000, Belgium

RECRUITING

Sint Augustinus Hospital Antwerp

Antwerp, 2610, Belgium

RECRUITING

University Hospital Antwerp

Antwerp, 2650, Belgium

RECRUITING

Chirec-Delta Hospital

Brussels, 1160, Belgium

RECRUITING

University Hospitals Leuven

Leuven, Belgium

RECRUITING

Foothills Medical Centre

Calgary, Alberta, T2N 2T9, Canada

NOT YET RECRUITING

Royal Alexandra Hospital

Edmonton, Alberta, T5H 3V9, Canada

NOT YET RECRUITING

McMaster Children's Hospital

Hamilton, Ontario, L8N3Z5, Canada

NOT YET RECRUITING

Montreal Children's Hospital

Montreal, Quebec, QC H4A 3J1, Canada

NOT YET RECRUITING

Centre Mère-Enfent Soleil

Québec, Quebec, G1V 4G2, Canada

NOT YET RECRUITING

Radboudumc Amalia Children's Hospital Nijmegen

Nijmegen, Gelderland, 6525 GA, Netherlands

RECRUITING

Maastricht University Medical Center

Maastricht, Limburg, 6229 HX, Netherlands

RECRUITING

Maxima Medical Center Veldhoven

Veldhoven, North Brabant, 5504 DB, Netherlands

RECRUITING

Amsterdam University Medical Center

Amsterdam, North Holland, 1105 AZ, Netherlands

RECRUITING

Isala Clinics Zwolle

Zwolle, Overijssel, 8025 AB, Netherlands

RECRUITING

Leiden University Medical Center

Leiden, South Holland, 2333 ZA, Netherlands

RECRUITING

Erasmus Medical Center - Sophia Children's Hospital

Rotterdam, South Holland, 3015 GD, Netherlands

RECRUITING

University Medical Center Groningen

Groningen, 9713 GZ, Netherlands

RECRUITING

UMC Utrecht - Wilhelmina Kinderziekenhuis

Utrecht, 3584 EA, Netherlands

RECRUITING

Related Publications (1)

• 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.

  PMID: 37817255 BACKGROUND

MeSH Terms

Conditions

Apnea; Respiratory Insufficiency; Hypoxia

Interventions

Doxapram

Condition Hierarchy (Ancestors)

Respiration Disorders; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pyrrolidinones; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Anne Smits, MD, PhD

  Universitair Ziekenhuis Leuven

  PRINCIPAL INVESTIGATOR

• Karel Allegaert, MD, PhD

  Universitair Ziekenhuis Leuven

  STUDY DIRECTOR

Central Study Contacts

Sinno HP Simons, MD, PhD

CONTACT

+31641376695; s.simons@erasmusmc.nl

Jeroen J Hutten, MD, PhD

CONTACT

g.j.hutten@amsterdamumc.nl

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal investigator

Model Details: Doxapram versus placebo

Study Record Dates

• First Submitted: January 8, 2020
• First Posted: June 12, 2020
• Study Start: June 15, 2020
• Primary Completion: May 1, 2026
• Study Completion (Estimated): May 1, 2034
• Last Updated: April 4, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: study protocol, sap and icf will be available at start of recruitment
• Access Criteria: data will be available on request. Requests will be discussed by the steering committee

Locations

NL (9); CA (5); BE (10)