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Pharmacokinetics, -Dynamics and Safety of Intravenous Paracetamol in Neonates (PARANEO)

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. Identifier: NCT00969176
Recruitment Status : Completed
First Posted : September 1, 2009
Last Update Posted : December 22, 2010
Information provided by:
Universitaire Ziekenhuizen Leuven

Tracking Information
First Submitted Date  ICMJE August 27, 2009
First Posted Date  ICMJE September 1, 2009
Last Update Posted Date December 22, 2010
Study Start Date  ICMJE September 2009
Actual Primary Completion Date December 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 31, 2009)
Pharmacokinetics of intravenous paracetamol in neonates [ Time Frame: during administration of iv paracetamol and up to 24 hours after last administration ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 31, 2009)
  • Pharmacodynamics of intravenous paracetamol in neonates [ Time Frame: during administration of iv paracetamol and up to 6 hours after the last administration ]
  • Safety of intravenous paracetamol in neonates [ Time Frame: during and up to 48 h after last intravenous administration ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Pharmacokinetics, -Dynamics and Safety of Intravenous Paracetamol in Neonates
Official Title  ICMJE Single and Multiple Dose Trial to Evaluate Pharmacokinetics, -Dynamics and Safety of iv Paracetamol in Preterm and Term Neonates
Brief Summary The purpose of this study is triple, i.e. document single dose pharmacokinetics and -dynamics of intravenous paracetamol in preterm and term neonates after a loading dose (20 mg/kg iv bolus paracetamol), document multiple dose pharmacokinetics and -dynamics of intravenous paracetamol in preterm and term neonates, based on the daily doses routinely used within the neonatal intensive care unit and as reported in literature. Finally, document safety of single and repeated dose of intravenous paracetamol in preterm and term neonates.
Detailed Description

Prospective, single center, open label study on the pharmacokinetics, -dynamics and safety of intravenous paracetamol in preterm and term neonates admitted in the neonatal intensive care unit, University Hospitals Leuven, Belgium. Patients will be included in this study after formal written informed consent of the parent(s). If a painful procedure is anticipated (e.g. surgery), parents should be informed preferably at least 24 h before the clinical indication will appear. Sixty neonates (i.e. < 29 days of postnatal age), either preterm (< 37 weeks gestational age) or term neonates will be included. At least 24 will be preterm neonates in order to ensure that the evaluated population reflects the typical population taken care for at the unit and in order to comply with the suggestions of EMEA (EMEA/CHMP/18922/05). The decision to prescribe paracetamol will be made by the attending neonatologist and in line with the current standing orders in the unit, i.e. either as a monotherapy for mild to moderate pain, independent of the cause (either postoperative, traumatic or medical) of pain or as part of multimodal analgesia for severe pain.

Before initiation of treatment and during any analgesic treatment, prospective evaluation of pain based on a validated and implemented pain scale (Leuven Neonatal Pain Scale, LNPS, Eur J Clin Pharmacol, 2003) is performed to further titrate treatment as needed. Additional administration or adaptation of any other analgesics as well as other concomitant medications will be recorded.

Paracetamol will be administered by either peripheral venous access or by deep venous catheter, ensuring that the study drug will always be administered alone and will be followed by an appropriate flush of normal saline, in line with the current guidelines at the unit. As soon as clinically feasible, the route of administration will be changed from intravenous to either oral (preferred) or rectal administration in line with the guidelines in the unit Plasma samples will be collected through an arterial line if present for clinical needs. In neonates without arterial access, plasma samples will only be collected when venipuncture is performed for clinical indications. The assessment of plasma pharmacokinetics will be based on a population pharmacokinetic approach in line with the EMEA guidelines on pharmacokinetic study in preterm and term neonates. The Leuven unit has published experience with such an approach (Eur J Clin Pharmacol, 2004) in the assessment of propacetamol pharmacokinetics.

Based on this population PK approach, we will focus on both early sampling (distribution volume, loading dose) and late sampling (clearance) while the total blood volume collected will not exceed 1.8 mL/kg for the complete study in line with the guidelines of EMEA on clinical research in children (EMEA website). It is a standing order at the unit that the procedural pain related to venous puncture is routinely treated with oral glucose (30 %).

When feasible, urine collections will be simultaneously performed (urinary bladder catheter in place for clinical indications, or by Uricol collection bag) in order to document aspects of paracetamol metabolism in neonates based on renal clearance in line with earlier studies reported on the assessment of paracetamol metabolism in early life (Acta Pediatric 2005). We anticipate urine collection in at least 20 neonates, of whom at least 8 preterm neonates.

We hereby have the intention to collect data on both pharmacokinetics, metabolism and pharmacodynamics of this drug in neonates.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Pain
  • Fever
Intervention  ICMJE Drug: paracetamol
Intravenous paracetamol administration in neonates, loading dose 20 mg/kg, followed by a Gestational age-dependent maintenance dose of 10-20 mg/kg/24 h, divided in 4 doses (each 6h)
Other Name: perfusalgan, perfalgan, paracetamol sintetica
Study Arms  ICMJE No Intervention: paracetamol
not applicable, since all included cases will receive intravenous paracetamol
Intervention: Drug: paracetamol
Publications * Allegaert K, Naulaers G, Vanhaesebrouck S, Anderson BJ. The paracetamol concentration-effect relation in neonates. Paediatr Anaesth. 2013 Jan;23(1):45-50. doi: 10.1111/pan.12076. Epub 2012 Nov 21.

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Estimated Enrollment  ICMJE
 (submitted: August 31, 2009)
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE December 2010
Actual Primary Completion Date December 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Clinical indication of IV administration of paracetamol in neonates, as evaluated by the attending neonatologist

Exclusion Criteria:

  • Recent administration of paracetamol (< 48 h) or clinical contra-indication for administration of paracetamol (hepatic failure).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 28 Days   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT00969176
Other Study ID Numbers  ICMJE S51597
EUdraCT nr 2009-011243-39
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Allegaert Karel, University Hospitals Leuven, Belgium
Study Sponsor  ICMJE Universitaire Ziekenhuizen Leuven
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: karel allegaert, MD, PhD Universitaire Ziekenhuizen Leuven
PRS Account Universitaire Ziekenhuizen Leuven
Verification Date December 2010

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP