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Pharmacokinetics of Amiodarone in Children (PK-AMIO)

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ClinicalTrials.gov Identifier: NCT03842020
Recruitment Status : Recruiting
First Posted : February 15, 2019
Last Update Posted : March 19, 2019
Sponsor:
Collaborator:
URC-CIC Paris Descartes Necker Cochin
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Tracking Information
First Submitted Date  ICMJE February 4, 2019
First Posted Date  ICMJE February 15, 2019
Last Update Posted Date March 19, 2019
Actual Study Start Date  ICMJE February 13, 2019
Estimated Primary Completion Date July 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 12, 2019)
  • Maximal Concentration (Cmax) of amiodarone [ Time Frame: Hour 0 to Hour 24 ]
  • Area under the plasma concentration versus time curve (AUC) of amiodarone [ Time Frame: Hour 0 to Hour 24 ]
  • Clearance of amiodarone [ Time Frame: Hour 0 to Hour 24 ]
  • Volume of distribution of amiodarone [ Time Frame: Hour 0 to Hour 24 ]
  • Half time of amiodarone [ Time Frame: Hour 0 to Hour 24 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03842020 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 18, 2019)
  • Rhythm disorder [ Time Frame: Day 0 ]
    to assess Efficacity - Detection of the rhythm disorder on an ECG or scope (during hospitalization or consultation), or an ECG holter: absence of rhythm disorders at the atrial, junctional or ventricular level Or oral report from parents of rhythm disorder between 2 consultations (palpitation, heart rate acceleration)
  • Altered liver function [ Time Frame: At the beginning of Amiodarone treatment until through study completion, an average of 18 months ]
    to assess Tolerance - from blood tests or clinical follow-up : gammaglutamyl transferase (GGT) U/L , Alkaline Phosphatase (ALP) U/L, Alanine Transaminase (ALT) U/L Aspartate Transaminase (AST) U/L,Total / conjugated/ free bilirubin µmol/L
  • Thyroid Dysfunction [ Time Frame: At the beginning of Amiodarone treatment until through study completion, an average of 18 months ]
    to assess Tolerance - from blood tests or clinical follow-up : (TSH µmol/l, Free Tri-iodothyronine (FT3) and Free Thyroxine (FT4) pmol/L)
  • QT and corrected QT duration [ Time Frame: At the beginning of Amiodarone treatment until through study completion, an average of 18 months ]
    to assess Tolerance - QT and corrected QT duration in milliseconds with an ECG
  • Blood pressure : (PAS)/(PAD) (mmHg) [ Time Frame: At the beginning of Amiodarone treatment until through study completion, an average of 18 months ]
    to assess Tolerance
Original Secondary Outcome Measures  ICMJE
 (submitted: February 12, 2019)
  • Rhythm disorder [ Time Frame: Day 0 ]
    to assess Efficacity - Detection of the rhythm disorder on an ECG or scope (during hospitalization or consultation), or an ECG holter: absence of rhythm disorders at the atrial, junctional or ventricular level Or oral report from parents of rhythm disorder between 2 consultations (palpitation, heart rate acceleration)
  • Altered liver function [ Time Frame: At the beginning of Amiodarone treatment until through study completion, an average of 18 months ]
    to assess Tolerance - from blood tests or clinical follow-up : GGT U/L ,ALP U/L, ALT U/L AST U/L,Total / conjugated/ free bilirubin µmol/L
  • Thyroid Dysfunction [ Time Frame: At the beginning of Amiodarone treatment until through study completion, an average of 18 months ]
    to assess Tolerance - from blood tests or clinical follow-up : (TSH µmol/l, FT3 and FT4 pmol/L)
  • QT and corrected QT duration [ Time Frame: At the beginning of Amiodarone treatment until through study completion, an average of 18 months ]
    to assess Tolerance - QT and corrected QT duration in milliseconds with an ECG
  • Blood pressure : PAS/PAD (mmHg) [ Time Frame: At the beginning of Amiodarone treatment until through study completion, an average of 18 months ]
    to assess Tolerance
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pharmacokinetics of Amiodarone in Children
Official Title  ICMJE Population Pharmacokinetics and Pharmacodynamics of Amiodarone in Children": PK-AMIO
Brief Summary

PK-AMIO study is a population pharmacokinetic study of Amiodarone in children in order to :

  • study the pharmacokinetic parameters (Pop PK) of Amiodarone in children;
  • identify covariates explaining the variability of these pharmacokinetic parameters;
  • study the relationship between the concentration, the efficacy of treatment and its tolerance to optimize the use of Amiodarone in pediatrics.

Indeed, there is no consensus on the optimal oral dosage in children. Few pharmacokinetic studies have been performed with only a small number of patients per study. Our study will include 70 children aged 0 to 18 years old.

Detailed Description

The incidence of supraventricular rhythm disorders in children is 1/250 to 1/1000. Amiodarone is used until the age of 1 year to limit the risk of recurrence. Efficiency is around 60% with no predictive factors identified. According to the study by Dallefeld (2018), unexplained inter-individual variability in pharmacokinetic parameters is 200%. Its adverse effects are numerous and affect 10% of patients. The concentration-effect relationship is poorly known. Amiodarone can cause hypotension and bradycardia. Liver and thyroid function should be monitored as well. Amiodarone is metabolised by cytochromes, mainly CYP3A4. Drug interactions and cytochrome variation in the neonatal period may alter its elimination kinetics. Pharmacokinetic studies have been conducted in adults with target concentrations of 0.5 to 2.5 mg/l.

The efficacy of oral amiodarone in children has been shown in studies in 1980; however, there is no consensus on optimal dosage. Despite its widespread use in children, few pharmacokinetic studies have been conducted in a small number of patients at different doses. The population pharmacokinetics and pharmacodynamics of Amiodarone in children, as well as its general and scientific interest, will be studied in this study. The lack of efficacy and the occurrence of adverse events of Amiodarone in children may be related to the large inter-individual pharmacokinetic variability.

Currently, more than 200 children treated with Amiodarone are being followed at Necker-Enfants malades Hospital.

This prospective study will be conducted in three paediatric services of Necker-Enfants malades Hospital in Paris, France.

Patient selection will take place in the 3 paediatric services. The senior physician proposes the study to holders of parental authority whose child receives or will receive the treatment during its follow-up or hospitalization.

After verification of the inclusion and exclusion criteria, the consent of the parents or parental authority and the child, according to his age, will be obtained.

After agreement, and/or signature of the parents and the non-oral opposition of the child in age to understand the information, the child is sampled according to the following scheme:

  • The samples taken during the introduction of the treatment in hospital will be made to observe the pharmacokinetics at the first dose: 3 samples will be taken in the following time windows: [H0-H3]; [H5-H9] and just before the next dose administration (H24).
  • During the maintenance treatment, a sample will be taken during a scheduled consultation or during a hospitalization.
  • Blood PK samples will be drawn until 1 month after end of treatment.

All patients' samples will be kept for to be analyzed at the Pharmacology department of the Cochin hospital.

No intervention or no charge will be made for this study.

This population pharmacokinetic study in children aims to analyze the concentration-effectiveness and concentration-tolerance relationship to optimize its use.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE Heart Rhythm Disorder
Intervention  ICMJE Other: Blood pharmacokinetic samples
1 or 3 sample(s) will be taken in the following time windows: [H0-H3]; [H5-H9] and just before the next set [H24], depending if the child is or is not admitted to hospital
Other Name: Amiodarone dosage
Study Arms  ICMJE Experimental: Amiodarone dosage
Blood pharmacokinetics samples
Intervention: Other: Blood pharmacokinetic samples
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 12, 2019)
70
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2021
Estimated Primary Completion Date July 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • All children from 0 to 18 years old treated with Amiodarone for any rhythm disorder, and followed to Necker-Enfants maladies hospital.

Exclusion Criteria:

  • Absence of parental and / or child consent
  • Known liver dysfunction
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 18 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jean-Marc TRELUYER, MD, PhD +33 (0)1 58 41 34 81 jean-marc.treluyer@aphp.fr
Contact: Prissile BAKOUBOULA, PhD +33 (0)1 71 19 64 94 prissile.bakouboula@aphp.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03842020
Other Study ID Numbers  ICMJE APHP180299
2018-A02327-48 ( Registry Identifier: ID-RCB )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE URC-CIC Paris Descartes Necker Cochin
Investigators  ICMJE
Study Director: Jean-Marc TRELUYER, MD, PhD Assistance Publique - Hôpitaux de Paris
Study Director: Damien BONNET, MD, PhD Assistance Publique - Hôpitaux de Paris
Study Director: Sylvain RENOLLEAU, MD, PhD Assistance Publique - Hôpitaux de Paris
Principal Investigator: Amelia LEHNERT, MD, PhD Assistance Publique - Hôpitaux de Paris
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date February 2019

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