Doxapram Therapy in Preterm Infants (DOXA Trial)

Respiratory Insufficiency Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04430790
• Other study ID #: NL72125.078.19
• Secondary ID: 80-84800-9843009
• Status: Recruiting
• Phase: Phase 3
• Start date: June 15, 2020
• Est. completion date: May 1, 2034

Study information

• Verified date: April 2024
• Source: Erasmus Medical Center
• Contact: Sinno HP Simons, MD, PhD
• Phone: +31641376695
• Email: s.simons[@]erasmusmc.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 396
• Est. completion date: May 1, 2034
• Est. primary completion date: May 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 23 Weeks to 29 Weeks

Eligibility

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.

Related Conditions & MeSH terms

• Apnea of Prematurity
• Respiratory Insufficiency

Intervention

Drug:
• Doxapram
Loading dose and continuous doxapram infusion.
• Placebo
Loading dose and continuous placebo infusion.

Locations

Country	Name	City	State
Belgium	Sint Augustinus Hospital Antwerp	Antwerp
Belgium	University Hospital Antwerp	Antwerp
Belgium	Academisch Ziekenhuis Sint-Jan	Brugge	West-Vlaanderen
Belgium	Chirec-Delta Hospital	Brussels
Belgium	Delta Hospital Brussels	Brussels	Brussels Hoofdstedelijk Gewest
Belgium	St Luc Louvain	Brussels	Avenaue Hippocrate 10
Belgium	Grand Hospital de Charleroi	Charleroi	Henegouwen
Belgium	University Hospital Brussels	Jette	Brussels Hoofdstedelijk Gewest
Belgium	University Hospitals Leuven	Leuven
Belgium	Clinique Saint-Vincent Liege	Liège	Liege
Canada	Foothills Medical Centre	Calgary	Alberta
Canada	Royal Alexandra Hospital	Edmonton	Alberta
Canada	McMaster Children's Hospital	Hamilton	Ontario
Canada	Montreal Children's Hospital	Montreal	Quebec
Canada	Centre Mère-Enfent Soleil	Quebec City	Quebec
Netherlands	Amsterdam University Medical Center	Amsterdam	Noord-Holland
Netherlands	University Medical Center Groningen	Groningen
Netherlands	Leiden University Medical Center	Leiden	Zuid-Holland
Netherlands	Maastricht University Medical Center	Maastricht	Limburg
Netherlands	Radboudumc Amalia Children's Hospital Nijmegen	Nijmegen	Gelderland
Netherlands	Erasmus Medical Center - Sophia Children's Hospital	Rotterdam	Zuid-Holland
Netherlands	UMC Utrecht - Wilhelmina Kinderziekenhuis	Utrecht
Netherlands	Maxima Medical Center Veldhoven	Veldhoven	Noord-Brabant
Netherlands	Isala Clinics Zwolle	Zwolle	Overijssel

Sponsors (5)

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

Countries where clinical trial is conducted

Belgium,  Canada,  Netherlands, 

References & 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Broncho pulmonary dysplasia	Diagnosed according to the National Institute of Child Health and Human Development (NICHD) criteria	36 weeks post menstrual age
Secondary	Death	Death at 36 weeks post menstrual age and hospital mortality	until 36 weeks post menstrual age and until hospital discharge
Secondary	Admission period	Length of stay at the intensive care, length of stay in hospital	through study completion and until discharge home, average 3 months
Secondary	Endotracheal intubations	Incidence of endotracheal intubations	Day 3, 7, 14, and 21 after start of study medication
Secondary	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.	During first hospital admittance and through study completion, average of 3 months
Secondary	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	During first hospital admittance and until 36 weeks post menstrual age
Secondary	Neurological outcome measures	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
Secondary	Complications during neonatal period	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
Secondary	Retinopathy of prematurity	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
Secondary	Hearing	Hearing test	At term equivalent age, 37-42 weeks postmenstrual age, average 3 months
Secondary	Additional long term outcomes	Readmissions since first discharge home, weight/length/head circumference, behavioral problems (Child Behavior Checklist)	2 years corrected age
Secondary	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)	2 years corrected age