The Use of Methadone in Newborn Infants

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2012 by Children's Research Institute
Sponsor:
Information provided by (Responsible Party):
Children's Research Institute
ClinicalTrials.gov Identifier:
NCT01327079
First received: March 30, 2011
Last updated: May 14, 2014
Last verified: April 2012
  Purpose

This proposed investigation will test the following hypotheses: 1) Enzymatic activity of CYP2B6 characterized by the formation clearance of methadone to EDDP (CLf,EDDP), is directly related to both gestational and postnatal age; 2) variations in the CYP2B6 gene (SNPs) are associated with variable activity of the CYP2B6 enzyme (as measured by the formation clearance, CLf,EDDP), and 3) the elimination rate of methadone and its major metabolite EDDP in neonates is dependent on the glomerular filtration rate and therefore on the stage of development (defined by both gestational and postnatal age). The investigators propose to develop a PK model for methadone dosing in neonates that takes into account both developmental stage and genetic variability. The long-term goal of the proposed investigations is to improve dosing of methadone in neonates exposed to opioids in utero or post-natally, leading to improved control of their withdrawal syndrome and decreased adverse drug reactions associated with the current use of methadone in these vulnerable patients. More immediately, the investigators will develop a PK model for methadone dosing based on relevant developmental and genetic characteristics. The acquired knowledge based on the proposed study will lead to a more efficacious treatment of pain or opiate withdrawal syndrome in newborn infants with a decreased chance of adverse drug reactions.


Condition Intervention Phase
Premature Birth of Newborn
Critically Ill
Drug: Methadone
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Optimizing the Use of Methadone in Newborn Infants

Resource links provided by NLM:


Further study details as provided by Children's Research Institute:

Primary Outcome Measures:
  • Methadone PK and EDDP [ Time Frame: 36 months ] [ Designated as safety issue: No ]
    Primary outcome: Plasma and urine levels of methadone and EDDP (2-ethylidene- 1,5-dimethyl-3,3-diphenylpyrrolidine, the main metabolite of methadone). Secondary endpoints: CYP2DB6 genetic variability.


Secondary Outcome Measures:
  • DNA [ Time Frame: 36 months ] [ Designated as safety issue: No ]
    Secondary endpoints: CYP2DB6 genetic variability.


Estimated Enrollment: 60
Study Start Date: December 2010
Estimated Study Completion Date: March 2015
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group 1

Gestational age less than 29 weeks We will substitute for one study dose 0.1 mg morphine with 0.1 mg methadone, whereas if the infant has been treated with fentanyl substitute for that one study dose 1 μg fentanyl with 0.1 mg methadone.

Administration of inulin:

Inulin will be administered as a glucose 10%-inulin solution containing 25 gr. inulin/L, at an infusion rate of 0.6 mL/kg/h. After 24 h, the inulin clearance will be calculated.

Drug: Methadone

If the infant has been treated with morphine than substitute for that one study dose 0.1 mg morphine with 0.1 mg methadone, whereas if the infant has been treated with fentanyl substitute for that one study dose 1 μg fentanyl with 0.1 mg methadone.

Administration of inulin:

Inulin will be administered as a glucose 10%-inulin solution containing 25 gr. inulin/L, at an infusion rate of 0.6 mL/kg/h. After 24 h, the inulin clearance will be calculated.

Other Name: inulin
Drug: Methadone

If the infant has been treated with morphine than substitute for that one study dose 0.1 mg morphine with 0.1 mg methadone, whereas if the infant has been treated with fentanyl substitute for that one study dose 1 μg fentanyl with 0.1 mg methadone.

Administration of inulin:

Inulin will be administered as a glucose 10%-inulin solution containing 25 gr. inulin/L, at an infusion rate of 0.6 mL/kg/h. After 24 h, the inulin clearance will be calculated.

Other Name: inulin (Sinistrin)
Experimental: Group 2

Gestational age greater then 29 weeks We will substitute for that one study dose 0.1 mg morphine with 0.1 mg methadone, whereas if the infant has been treated with fentanyl substitute for that one study dose 1 μg fentanyl with 0.1 mg methadone.

Administration of inulin:

Inulin will be administered as a glucose 10%-inulin solution containing 25 gr. inulin/L, at an infusion rate of 0.6 mL/kg/h. After 24 h, the inulin clearance will be calculated.

Drug: Methadone

If the infant has been treated with morphine than substitute for that one study dose 0.1 mg morphine with 0.1 mg methadone, whereas if the infant has been treated with fentanyl substitute for that one study dose 1 μg fentanyl with 0.1 mg methadone.

Administration of inulin:

Inulin will be administered as a glucose 10%-inulin solution containing 25 gr. inulin/L, at an infusion rate of 0.6 mL/kg/h. After 24 h, the inulin clearance will be calculated.

Other Name: inulin (Sinistrin)

Detailed Description:

The investigators will identify and recruit from the NICU of CNMC 60 preterm neonates uniformly distributed with respect to gestational age and encompassing GA's of from 22 to less than 43 weeks.

  • Stratified Selection by Gestational Age (GA): The study neonates will be selected to achieve balance in the following GA strata: (22-24 wks, 25-26 wks, 27-28 wks, 29-30 wks, 31-32 wks, 33-37 wks; 38-43 wks). Stratification will be done to ensure broad representation by GA. As described below, analyses will treat GA as a continuous variable.
  • Randomization will assign a newborn infant to group 1 (n=30) or group 2 (n=30).
  • Study medications: Methadone and inulin administration Blood and urine will be collected for the purposes of this research project. Blood will be drawn from the indwelling arterial catheter that already is in place for clinical purposes. The amount of blood obtained for all study related determinations will be minimized and kept at less than 3 mL/kg of blood per 48 hour period. The study will last 60 hours for group 1 and 72 hours for group.
  • DNA study 0.3ml whole blood will be collected from each subject
  • PK study Blood samples (0.2 mL per sample) will be taken in 30 newborn infants at t=0, 1, 4, 12, 36, 60 h (group 1) after the administration of one dose of methadone, and in 30 newborn infants at t=0, 2, 8, 24, 48, 72 hr (group 2) after the administration of methadone. A total of 1.5 ml of blood will be collected from each subject
  • Urine Collection Urine samples will be collected from each infant's diaper (wood pulp based study diapers) every 3-4 hours over the first 24 hour period or alternatively, from an indwelling urinary catheter placed based on clinical indications unrelated to the study protocol.
  Eligibility

Ages Eligible for Study:   22 Weeks to 43 Weeks
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Newborn infants of both genders and all races who have:

    • a postnatal age of less than 3 months
    • an indwelling (peripheral or umbilical) arterial line, and
    • already treated with an opioid (morphine or fentanyl) for clinical reasons

Exclusion Criteria:

  • Neonates with severe asphyxia grade III or IV intraventricular hemorrhage,
  • Neonates with major congenital malformations or facial malformations (e.g., cleft lip and palate), neurological disorders
  • Neonates receiving continuous or intermittent neuromuscular blockers neonates will be excluded who have:

    • clinical or biochemical evidence of hepatic and renal failure (including systemic hypoperfusion
    • received drugs that are CYP2B6 substrates
    • been exposed in utero to methadone, despite the fact that they indeed receive a CYP2B6 substrate through their mother, will not be excluded but will be analyzed as a subgroup
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01327079

Contacts
Contact: Elaine F Williams, RN, MSN 203-476-2245 efwillia@cnmc.org
Contact: Ruby M Daniels 202-476-2176 rmdaniel@cnmc.org

Locations
United States, District of Columbia
Childrens Research Institute Recruiting
Washington, District of Columbia, United States, 20010
Contact: Elaine F Williams, RN, MSN    202-476-2245    efwillia@cnmc.org   
Contact: Ruby M Daniels    202-476-2216    rmdaniel@cnmc.org   
Principal Investigator: John N van den Anker, MD, PhD         
Childrens's Research Institute Recruiting
Washington, District of Columbia, United States, 20010
Contact: Elaine F Williams, RN, MSN    202-476-2245    efwillia@cnmc.org   
Contact: Ruby M Daniels    202-476-2176    rndaniel@cnmc.org   
Sponsors and Collaborators
Children's Research Institute
  More Information

No publications provided

Responsible Party: Children's Research Institute
ClinicalTrials.gov Identifier: NCT01327079     History of Changes
Other Study ID Numbers: 4781, IV Methadone
Study First Received: March 30, 2011
Last Updated: May 14, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Children's Research Institute:
NICU
Methadone
neonates

Additional relevant MeSH terms:
Critical Illness
Premature Birth
Disease Attributes
Obstetric Labor Complications
Obstetric Labor, Premature
Pathologic Processes
Pregnancy Complications
Methadone
Analgesics
Analgesics, Opioid
Antitussive Agents
Central Nervous System Agents
Central Nervous System Depressants
Narcotics
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Respiratory System Agents
Sensory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 21, 2014