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Trial record 1 of 7 for:    doxapram
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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
Sponsor:
Collaborators:
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Nederlands Neonataal Netwerk (N3), the Netherlands
Universitaire Ziekenhuizen KU Leuven
Information provided by (Responsible Party):
Sinno H.P. Simons, Erasmus Medical Center

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).

Condition or disease Intervention/treatment Phase
Apnea of Prematurity Respiratory Insufficiency Drug: Doxapram Drug: Placebo Phase 3

Detailed 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 398 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Doxapram versus placebo
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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.
Drug: Doxapram
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.
Drug: Placebo
Loading dose and continuous placebo infusion.
Other Name: Placebo (for Doxapram)




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. Broncho pulmonary dysplasia [ Time Frame: 36 weeks post menstrual age ]
    Diagnosed according to the National Institute of Child Health and Human Development (NICHD) criteria

  2. Death [ Time Frame: until 36 weeks post menstrual age and until hospital discharge ]
    Death at 36 weeks post menstrual age and hospital mortality

  3. 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

  4. Endotracheal intubations [ Time Frame: Day 3, 7, 14, and 21 after start of study medication ]
    Incidence of endotracheal intubations

  5. 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.

  6. 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

  7. 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)

  8. 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

  9. 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)

  10. Hearing [ Time Frame: At term equivalent age, 37-42 weeks postmenstrual age, average 3 months ]
    Hearing test

  11. Additional long term outcomes [ Time Frame: 2 years corrected age ]
    Readmissions since first discharge home, weight/length/head circumference, behavioral problems (Child Behavior Checklist)

  12. 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)



Information from the National Library of Medicine

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Ages Eligible for Study:   23 Weeks to 29 Weeks   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

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


Contacts
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Contact: Sinno HP Simons, MD, PhD +31641376695 s.simons@erasmusmc.nl
Contact: Jeroen J Hutten, MD, PhD g.j.hutten@amsterdamumc.nl

Locations
Show Show 19 study locations
Sponsors and Collaborators
Erasmus Medical Center
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Nederlands Neonataal Netwerk (N3), the Netherlands
Universitaire Ziekenhuizen KU Leuven
Investigators
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Principal Investigator: Anne Smits, MD, PhD Universitair Ziekenhuis Leuven
Study Director: Karel Allegaert, MD, PhD Universitair Ziekenhuis Leuven
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Responsible Party: Sinno H.P. Simons, Principal investigator, Erasmus Medical Center
ClinicalTrials.gov Identifier: NCT04430790    
Other Study ID Numbers: NL72125.078.19
80-84800-9843009 ( Other Grant/Funding Number: ZonMw GGG )
2019-003666-41 ( EudraCT Number )
First Posted: June 12, 2020    Key Record Dates
Last Update Posted: June 27, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Yes
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (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
URL: https://dmp.radboudumc.nl/plans/31885/export.pdf?export%5Bquestion_headings%5D=true

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Sinno H.P. Simons, Erasmus Medical Center:
Preterm infants
Hypoxia
Doxapram
Additional relevant MeSH terms:
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Respiratory Insufficiency
Respiration Disorders
Respiratory Tract Diseases
Doxapram
Central Nervous System Stimulants
Physiological Effects of Drugs
Respiratory System Agents