This study has been transitioned to CTIS with ID 2024-515625-29-00 check the CTIS register for the current data. The main objective of our trial is to investigate if doxapram is safe and effective in reducing the composite outcome of death and…
ID
Source
Brief title
Condition
- Neonatal respiratory disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary outcome will be death or severe disability at the age of 2 years
corrected age.
(or survival without severe disability)
Disability will be defined as 1 or more of the following:
- cognitive delay (Mental Development Index score <85 (1 SD below the mean of
100) on the Bayley Scales of Infant and Toddler Development, BSID III scores)
- cerebral palsy (diagnosed if the child had a non-progressive impairment
characterized by abnormal muscle tone and decreased range or control of
movements, determined with the Gross Motor Function Classification System)
- severe hearing loss (using audiometry)
- bilateral blindness (defined as a corrected visual acuity < 20/200)
Secondary outcome
Short term outcome variables include (international definitions will be used as
described in the National registration guidelines):
- BPD at 36 weeks post menstrual age according to NICHD criteria.
- Death at the age of 36 weeks post menstrual age and at hospital discharge
(hospital mortality)
- combined outcome death or BPD at 36 wk PMA
- Short term neonatal co-morbidity :
o Incidence of endotracheal intubations after start study medication
o number of days on invasive ventilation,
o number of days on ventilatory support (non-invasive ventilation,
CPAP, humidified high flow),
o number of days with supplemental oxygen
o length of stay on the intensive care
o cumulative number of apnea , number of incidents associated with
bradycardia (optional)
o incidence of late onset sepsis (culture proven or clinical suspected)
after inclusion,
o solitary intestinal perforation
o necrotizing enterocolitis > stage 2 according to Bell,
o IVH
o PVL
o Growth, length, HC at 36 weeks PMA
o retinopathy of prematurity
- Additional long term outcome at 2 years corrected age
o readmissions since first discharge home
o weight, length and head circumference at 24 months c.a.
o behavioral problems (Child Behavior Checklist)
- Parent reported outcome with the PARCA-R questionnaire
- Long term follow-up until the age of 5.5 and 8 years to determine long term
effects on neurodevelopment (including subscores of primary outcome such as
Bayley III Scales ), health, quality of life.
- Adverse-effects and potential adverse drug reactions will be monitored and
analyzed.
Background summary
Preterm infants are at high risk of respiratory failure due to immaturity of
the respiratory system. Respiratory failure is caused by a comprised lung
function and impaired control of breathing. Compromised lung function results
in impaired gas exchange and an increased work of breathing. Impaired control
of breathing leads to apnea of prematurity (AOP; a cessation of breathing)
which can lead to hypoxemia and bradycardia. Hypoxemia and bradycardia might
harm the development of the newborn, especially the central nervous system.
In order to prevent hypoxemia, 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. No adequately powered trial,
however, is performed to study the effectiveness and safety of doxapram in this
setting in long-term. It is unclear if a preterm infant benefit from doxapram
treatment on the longer term.
This study hypothesizes that doxapram will protect preterm infants from both
invasive ventilation (and related lung disease) and apnea of prematurity
related hypoxia (and related impaired brain development). In this way the
long-term outcome will be improved.
Study objective
This study has been transitioned to CTIS with ID 2024-515625-29-00 check the CTIS register for the current data.
The main objective of our 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.
Study design
Multicenter double blinded randomized placebo-controlled superiority trial
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.
Intervention
Blinded continuous doxapram or placebo (glucose 5%) infusion 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.
Study burden and risks
Doxapram is already frequently used in our NICU's. Data on safety or long-term
effectiveness are lacking. Although doxapram seems effective to avoid
endotracheal intubation, long term safety and effectiveness needs to be
studied. Adverse events and side effects will be monitored. Next to the 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 PK model.
Blood will only be collected during routine blood sampling, with a maximum
amount of 0.6 ml. Extensive economic 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.
Wytemaweg 90
Rotterdam 3015 CN
NL
Wytemaweg 90
Rotterdam 3015 CN
NL
Listed location countries
Age
Inclusion criteria
In order to be eligible to participate in this study, a subject must meet all
of the following criteria:
- Admitted to the NICU of one of the participating centres
- Written informed consent of both parents or legal representatives
- Gestational age at birth under 29 weeks
- Caffeine therapy, adequately dosed (see also under co-medication)
- Optimal non-invasively supported according to the local treatment policy
(with nasal CPAP or ventilation ((S)NIPPV, BIPAP/Duopap)
- Apnea that require a medical intervention (indication to start doxapram if
not in trial) as judged by the attending physician (*)
(*)
There is considerable variability between centers and physicians when the
frequency and duration of apnea are considered unacceptable and an intervention
(doxapram or intubation) is needed. For this reason, we have chosen a pragmatic
study design with less strict inclusion criteria.
Exclusion criteria
A potential subject who meets any of the following criteria will be excluded
from participation in this study:
- 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
*Considerations
Several conditions, such as sepsis, pneumonia, necrotizing enterocolitis (NEC)
and patent ductus arteriosus (PDA) may present with apnea and respiratory
failure. Distinction from apnea caused by prematurity is difficult or even
impossible. Therefore, the suspicions of one of these diagnoses is not
considered an exclusion criterion. However, systemic disease may result in a
decision to primarily intubate the infant and not to include the patient in the
trial at that time point. This decision is left to the attending physician and
medical team.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-515625-29-00 |
| EudraCT | EUCTR2019-003666-41-NL |
| ClinicalTrials.gov | NCTvolgt |
| CCMO | NL72125.078.19 |