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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

Tracking Information
First Submitted Date September 25, 2014
First Posted Date April 20, 2015
Last Update Posted Date July 11, 2017
Actual Study Start Date August 2014
Actual Primary Completion Date June 30, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: September 16, 2016)
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)
Original Primary Outcome Measures
 (submitted: April 15, 2015)
Clearance, Volume of distribution and covariates for the variability of paracetamol, fentanyl, midazolam, phenobarbital, doxapram, sildenafil and levetiracetam 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)
Change History
Current Secondary Outcome Measures
 (submitted: September 16, 2016)
  • 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)
  • 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)
  • 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)
  • 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)
  • 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)
  • 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.
  • 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
  • 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
  • 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
  • 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
  • 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
Original Secondary Outcome Measures
 (submitted: April 15, 2015)
  • 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)
  • 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)
  • 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)
  • 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)
  • 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)
  • 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.
  • 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
  • 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
  • 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
  • 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
Current Other Pre-specified Outcome Measures
 (submitted: April 15, 2015)
  • 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.
  • 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).
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title Population PK/PD of Off Label Drugs in Premature Neonates
Official Title Pharmacokinetic and Pharmacodynamic Modelling of Routinely Used Off Label Drugs in Premature Neonates
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.
Detailed Description

BACKGROUND Approximately 60% of drugs are used off--label in critically ill neonates in the Neonatal Intensive Care Units (NICU). This is even more true for pre--term born neonates in whom pharmacokinetics of these agents may be different due to immature elimination pathways. The lack of sufficient data about efficacy and safety of many of these drugs makes it difficult to have evidence based dosing guidelines for these agents. Therefore the urge for drug research in this population is of great importance. The pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of drugs in premature infants are different from the characteristics found in term neonates, older children and adults. These differences are caused among others by a different body composition, by immaturity of the renal excretion systems, the metabolic pathways in the liver and other organ functions as well as immature drug receptors and transporters. After birth, there is a rapid development of many of these functions, necessitating frequent adaptation of dosage guidelines in the first few weeks of life. Besides age and size, co--morbidity, co--administration of drugs and genetic heterogeneity may further contribute to this extensive inter--individual variability in pharmacokinetics and pharmacodynamics of premature infants. There is a critical lack of evidence--based data of drug dosing in (extremely) preterm neonates.

OBJECTIVE Recently, population PK/PD modeling and simulation studies have enabled the development of evidence--based individualized dosing schemes for children with a limited number of subjects, thus improving drug safety and efficacy. The application of PK/PD modeling in the most critically ill population of premature infants, with the highest variability in the pharmacokinetics of drugs, and the greatest lack of adequate data underscoring optimal dosage, can contribute to the development of rational, individualized and safe dosing regimens.

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 (only studied for the PK). PK/PD analysis 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.

DESIGN This is a prospective observational multicenter study on the pharmacokinetics and pharmacodynamics of paracetamol, fentanyl, midazolam, phenobarbital, doxapram, levetiracetam, sildenafil, ibuprofen and fluconazole routinely administered to preterm infants according to standard protocols. The treatment regimen is left to the discretion of the treating physician in accordance with current guidelines. During this study a limited number of additional blood samples will be drawn from the participants for pharmacokinetic analysis, never exceeding 3% of the total blood volume during any four--week period or 1% at any single time.

It is standard care in the Netherlands for all premature born infants under 32 weeks to get seen by the paediatrician at the age of two years for a check on growth and development. The visit to the day care clinic of the hospital of their admission on birth, enables us to collect qualitative data on growth and physiological development as well as from psychological and neurodevelopmental standardised tests.The collected data enables us to gain a better description of the subjects in our study and to further determine safety of the studied drugs.

POPULATION All preterm infants born with gestational age < 32 weeks who are admitted to one of the participating NICUs are eligible for inclusion. The participating departments are all level III Neonatal Intensive Care Units. Three are situated in an academic hospital (Rotterdam, Nijmegen and Maastricht) and one in a non--academic hospital (Veldhoven). Patients admitted to the 4 NICUs consist of both inborn and outborn neonates with different gestational ages (24--42 weeks). All admitted patients need intensive or high care treatment. Most patients will be admitted on the first postnatal day, but sometimes are referred at older post natal ages (<14 days) to the NICU.

OUTCOME

Primary study parameters/outcome of the study:

1) Pharmacokinetic endpoints for all 9 drugs are clearance en volume of distribution.

Secondary study parameters/outcome of the study (if applicable):

Pharmacodynamics of paracetamol, fentanyl, midazolam, phenobarbital, doxapram, levetiracetam and sildenafil will be explored in all included preterm neonates. Fluconazole will only be studied for the pharmacokinetics. Drug specific effects of drugs (e.g. pain scores for morphine, blood pressure for dopamine) as well as side effects and short term effects on morbidity and outcome will be analyzed. Additional pharmacodynamic endpoints for the 7 PK/PD study drugs is the drug target concentration for each drug that is related to the desired effect.

The parameters to measure the effect of the drugs:

  1. Fentanyl and paracetamol, used as analgetics; clinical endpoint is pain relief, as routinely measured by the validated COMFORTneo scale and the NRS (numeric rating scale) scale.
  2. Midazolam, phenobarbital and levetiracetam, used as anticonvulsive drugs; clinical endpoint is control of convulsions, measured by Cerebral Function Monitoring using amplitude--integrated EEG (aEEG).
  3. Midazolam and fentanyl, used as a sedative drug during endotracheal intubation; clinical endpoint is the intubation readiness score (IRS) and a qualitative intubation score and sedation score.
  4. Midazolam and fentanyl, used as a sedative drug during nursing care is measured by the COMFORTneo scale.
  5. Doxapram, used as treatment for neonatal apnea; clinical endpoint is control of neonatal apnea and endotracheal intubation in case of failure. The first endpoint can be measured by modern monitoring technology, in which central post--monitoring data stored after initiation of treatment will reveal the effect of doxapram on the reduction or elimination of apneas.
  6. Sildenafil, a treatment for PH (pulmonary hypertension); clinical endpoints are level of ventilatory support, oxygen need (repetitive oxygenation index analyses) and BPD (broncho pulmonary dysplasia) development.
  7. Ibuprofen is used to close patent ductus arteriosus (PDA) in different dosages, orally and intravenously in the recruiting sites. Endpoints are measured by cardiac ultrasound: ductus closure (yes/no), ductal diameter and LA/AO ratio

Inter-- and intra--patient variability of the PD and PK parameters of the drugs to be investigated. Parameters with effect on this variability will be identified.

Tertiary outcome:

  1. Development of a minimally invasive Dried Blood Spot analysis method 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. Influence of specific polymorphisms involved in the metabolism of the investigated drugs.
Study Type Observational [Patient Registry]
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration 1 Month
Biospecimen Retention:   Samples With DNA
Description:
blood
Sampling Method Non-Probability Sample
Study Population preterm newborn infants
Condition Premature Birth
Intervention Not Provided
Study Groups/Cohorts 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
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Completed
Estimated Enrollment
 (submitted: April 15, 2015)
600
Original Estimated Enrollment Same as current
Actual Study Completion Date June 30, 2017
Actual Primary Completion Date June 30, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

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

Exclusion Criteria:

- none

Sex/Gender
Sexes Eligible for Study: All
Ages up to 32 Weeks   (Child)
Accepts Healthy Volunteers No
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number NCT02421068
Other Study ID Numbers NL-47440907814
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party Sinno H.P. Simons, Erasmus Medical Center
Study Sponsor Sinno H.P. Simons
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
Investigators
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
PRS Account Erasmus Medical Center
Verification Date July 2017