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Population PK/PD of Off Label Drugs in Premature Neonates (DINO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02421068
Recruitment Status : Completed
First Posted : April 20, 2015
Last Update Posted : July 11, 2017
Sponsor:
Collaborators:
ZonMw: The Netherlands Organisation for Health Research and Development
Leiden Amsterdam Centre for Drug Research (LACDR)
Dutch Knowledge Centre for Pediatric Pharmacotherapy (NKFK)
Centre for Human Drug Research, Netherlands
Radboud University
Information provided by (Responsible Party):
Sinno H.P. Simons, Erasmus Medical Center

Brief Summary:
This study will provide information on the pharmacokinetics, safety and effectiveness of off--label drugs used in critically ill premature infants: doxapram, fentanyl, midazolam, paracetamol, phenobarbital, sildenafil, levetiracetam, ibuprofen and fluconazole. PK/PD analysis with NONMEM (non-linear mixed effects modelling) will result in (adapted) dosage guidelines, thus contributing towards an improvement in the quality of care and cost efficiency. Furthermore the development of Dried Blood Spot (DBS) analysis is investigated for these drugs as a minimally invasive method for conventional patient care and to perform pharmacological studies in children. The adapted dosage guidelines will be implemented directly into clinical practice in collaboration with the NKFK. Therefore the study is designed as an observational multicenter study to be able to collect sufficient data for the drugs of interest.

Condition or disease
Premature Birth

Show Show detailed description

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Study Type : Observational [Patient Registry]
Estimated Enrollment : 600 participants
Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 1 Month
Official Title: Pharmacokinetic and Pharmacodynamic Modelling of Routinely Used Off Label Drugs in Premature Neonates
Actual Study Start Date : August 2014
Actual Primary Completion Date : June 30, 2017
Actual Study Completion Date : June 30, 2017

Group/Cohort
Preterm neonates
All neonates that receive at least one of the 9 drugs (phenobarbital, paracetamol, levetiracetam, midazolam, sildenafil, fentanyl, doxapram, ibuprofen, fluconazole) are included in the studied cohort



Primary Outcome Measures :
  1. Clearance, Volume of distribution and covariates for the variability of paracetamol, fentanyl, midazolam, phenobarbital, doxapram, sildenafil, levetiracetam, ibuprofen, and fluconazole in premature born neonates [ Time Frame: Participants will be followed for the duration of admission to the NICU, an expected average of 9 weeks. Note that registration and blood sampling only take place when a study drug is being administered ]
    Clearance, Volume of distribution and variability in premature born neonates will be calculated by population modelling (NONMEM) of the collected data: drug dosages(mg/kg), measured plasmaconcentrations (mg/L) and their metabolites, and patientcharacteristics (body weight, post natal age, gestational age, renal function, gender)


Secondary Outcome Measures :
  1. EC50 of midazolam on treatment of convulsions [ Time Frame: Participants will be followed for the duration of admission to the NICU, an expected average of 9 weeks. Note that registration and blood sampling only take place when a study drug is being administered ]
    EC50 describes the relationship between the midazolam concentration and the effect on convulsions at the aEEG, and will be calculated by population modelling (NONMEM)

  2. EC50 of phenobarbital on treatment of convulsions [ Time Frame: Participants will be followed for the duration of admission to the NICU, an expected average of 9 weeks. Note that registration and blood sampling only take place when a study drug is being administered ]
    EC50 describes the relationship between the phenobarbital concentration and the effect on convulsions at the aEEG, and will be calculated by population modelling (NONMEM)

  3. EC50 of levetiracetam on treatment of convulsions [ Time Frame: Participants will be followed for the duration of admission to the NICU, an expected average of 9 weeks. Note that registration and blood sampling only take place when a study drug is being administered ]
    EC50 describes the relationship between the levetiracetam concentration and the effect on convulsions at the aEEG, and will be calculated by population modelling (NONMEM)

  4. EC50 of fentanyl as analgetic [ Time Frame: Participants will be followed for the duration of admission to the NICU, an expected average of 9 weeks. Note that registration and blood sampling only take place when a study drug is being administered ]
    EC50 describes the relationship between the fentanyl concentration and the effect on analgesia measures with the COMFORTneo score, and will be calculated by population modelling (NONMEM)

  5. EC50 of paracetamol as analgetic [ Time Frame: Participants will be followed for the duration of admission to the NICU, an expected average of 9 weeks. Note that registration and blood sampling only take place when a study drug is being administered ]
    EC50 describes the relationship between the paracetamol concentration and the effect on analgesia measures with the COMFORTneo score, and will be calculated by population modelling (NONMEM)

  6. EC50 of fentanyl as sedative drug during endotracheal intubation [ Time Frame: Participants will be followed for the duration of admission to the NICU, an expected average of 9 weeks. Note that registration and blood sampling only take place when a study drug is being administered ]
    EC50 describes the relationship between the paracetamol concentration and the effect on analgesia measures with the COMFORTneo score, and will be calculated by population modelling (NONMEM)clinical endpoint is the intubation readiness score (IRS) and a qualitative intubation score and sedation score.

  7. EC50 of fentanyl as sedative drug during nursing care [ Time Frame: Participants will be followed for the duration of admission to the NICU, an expected average of 9 weeks. Note that registration and blood sampling only take place when a study drug is being administered ]
    level of sedation measured by the COMFORTneo scale during nursing. Outcome measure COMFORTneo 6 - 30

  8. EC50 of midazolam as sedative drug during nursing care [ Time Frame: Participants will be followed for the duration of admission to the NICU, an expected average of 9 weeks. Note that registration and blood sampling only take place when a study drug is being administered ]
    level of sedation measured by the COMFORTneo scale during nursing. Outcome measure COMFORTneo 6 - 30

  9. EC50 of doxapram as treatment for neonatal apnea [ Time Frame: Participants will be followed for the duration of admission to the NICU, an expected average of 9 weeks. Note that registration and blood sampling only take place when a study drug is being administered ]
    control of neonatal apnea (reduction or elimination of apneas) using modern monitoring technology, and endotracheal intubation in case of failure. Outcome measure: Yes or No

  10. EC50 of sildenafil as treatment for PH [ Time Frame: Participants will be followed for the duration of admission to the NICU, an expected average of 9 weeks. Note that registration and blood sampling only take place when a study drug is being administered ]
    level of ventilatory support, oxygen need (repetitive oxygenation index analyses), respiratory index and BPD development

  11. EC50 of ibuprofen for patent ductus arteriosus (PDA) closure [ Time Frame: Participants will be followed for the duration of admission to the NICU, an expected average of 9 weeks. Note that registration and blood sampling only take place when a study drug is being administered ]
    closure of PDA, significance of PDA


Other Outcome Measures:
  1. Development of a minimally invasive Dried Blood Spot analysis method [ Time Frame: Participants will be followed for the duration of admission to the NICU, an expected average of 9 weeks. Note that the validation of the Dried Blood Spot analysis can take place when a study drug is being administered ]
    The dried blood spot analyses will be validated to perform future pharmacokinetic studies in neonates. The measured concentration of the drugs in the dried blood spot samples will be compared with the concentration of the blood samples in the vial, which is the current validated standard method. The validity of the DBS method will be the endpoint.

  2. Pharmacogenetic profile [ Time Frame: Participants will be followed for the duration of admission to the NICU, an expected average of 9 weeks. Note that registration and blood sampling only take place when a study drug is being administered ]
    Influence of specific Single Nucleotide Polymorphisms on the genes that code for the enzymes that might be involved in the metabolism of the investigated drugs. Some of the related enzymes are CYP3A4 (sildenafil, midazolam, fentanyl), CYP2D6 (sildenafil), UGT (paracetamol), CYP2C9 and CYP2C19 (phenobarbital).


Biospecimen Retention:   Samples With DNA
blood


Information from the National Library of Medicine

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Ages Eligible for Study:   up to 32 Weeks   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
preterm newborn infants
Criteria

Inclusion Criteria:

  • prescription of one of the seven drug of interest
  • parental informed consent

Exclusion Criteria:

- none


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): NCT02421068


Locations
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Netherlands
MUMC
Maastricht, Netherlands, 6229 HX
Radboud UMC
Nijmegen, Netherlands, 6525 GA
Erasmus MC - Sophia Children's Hospital
Rotterdam, Netherlands, 3015 CN
Maxima Medical Center
Veldhoven, Netherlands, 5504 DB
Sponsors and Collaborators
Sinno H.P. Simons
ZonMw: The Netherlands Organisation for Health Research and Development
Leiden Amsterdam Centre for Drug Research (LACDR)
Dutch Knowledge Centre for Pediatric Pharmacotherapy (NKFK)
Centre for Human Drug Research, Netherlands
Radboud University
Investigators
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Study Director: Ronald de Groot, MD, PhD Radboud UMC
Study Chair: Dick Tibboel, MD, PhD Erasmus MC
Study Chair: David Burger, PharmD, PhD Radboud UMC
Additional Information:

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Responsible Party: Sinno H.P. Simons, MD PhD, Erasmus Medical Center
ClinicalTrials.gov Identifier: NCT02421068    
Other Study ID Numbers: NL-47440907814
First Posted: April 20, 2015    Key Record Dates
Last Update Posted: July 11, 2017
Last Verified: July 2017
Keywords provided by Sinno H.P. Simons, Erasmus Medical Center:
Paracetamol
Fentanyl
Phenobarbital
Doxapram
Midazolam
Sildenafil
Levetiracetam
Pharmacokinetics
Pharmacology
Fluconazole
Ibuprofen
Additional relevant MeSH terms:
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Premature Birth
Obstetric Labor, Premature
Obstetric Labor Complications
Pregnancy Complications