Doxapram Therapy in Preterm Infants (DOXA Trial)
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|ClinicalTrials.gov Identifier: NCT04430790|
Recruitment Status : Recruiting
First Posted : June 12, 2020
Last Update Posted : June 27, 2022
|Condition or disease||Intervention/treatment||Phase|
|Apnea of Prematurity Respiratory Insufficiency||Drug: Doxapram Drug: Placebo||Phase 3|
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 (Clinical Trial)|
|Estimated Enrollment :||398 participants|
|Intervention Model:||Parallel Assignment|
|Intervention Model Description:||Doxapram versus placebo|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||Doxapram Versus Placebo in Preterm Newborns: An International Double Blinded Multicenter Randomized Controlled Trial|
|Actual Study Start Date :||June 15, 2020|
|Estimated Primary Completion Date :||May 1, 2024|
|Estimated Study Completion Date :||May 1, 2030|
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.
Loading dose and continuous doxapram infusion.
Other Name: 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.
Loading dose and continuous placebo infusion.
Other Name: Placebo (for Doxapram)
- 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
- Broncho pulmonary dysplasia [ Time Frame: 36 weeks post menstrual age ]Diagnosed according to the National Institute of Child Health and Human Development (NICHD) criteria
- Death [ Time Frame: until 36 weeks post menstrual age and until hospital discharge ]Death at 36 weeks post menstrual age and hospital mortality
- 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
- Endotracheal intubations [ Time Frame: Day 3, 7, 14, and 21 after start of study medication ]Incidence of endotracheal intubations
- 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.
- 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
- 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)
- 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
- 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)
- Hearing [ Time Frame: At term equivalent age, 37-42 weeks postmenstrual age, average 3 months ]Hearing test
- Additional long term outcomes [ Time Frame: 2 years corrected age ]Readmissions since first discharge home, weight/length/head circumference, behavioral problems (Child Behavior Checklist)
- 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)
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04430790
|Contact: Sinno HP Simons, MD, PhDemail@example.com|
|Contact: Jeroen J Hutten, MD, PhDfirstname.lastname@example.org|
|Principal Investigator:||Anne Smits, MD, PhD||Universitair Ziekenhuis Leuven|
|Study Director:||Karel Allegaert, MD, PhD||Universitair Ziekenhuis Leuven|