Clinical trial NCT01360450: Clonidine to Treat Iatrogenic-induced Opioid Dependence in Infants
Official title: Efficacy of Clonidine in Reducing Iatrogenic-induced Opioid Dependence in Infants:
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Neonatal Abstinence Syndrome
Keywords: opioid withdrawal
Neonatal Pain, Agitation, and Sedation Scale (NPASS)
duraclon
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: National Institute on Drug Abuse (NIDA)
First posted: 2011-05-25
Enrollment: 12
Sex: ALL
Minimum age (years): 5
Maximum age (years): 90
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Thousands of critically ill infants (and children) are exposed to opioids and benzodiazepines to achieve sedation and analgesia as part of routine care in neonatal and pediatric intensive care units. While the use of these agents are undisputedly beneficial in reducing pain and anxiety, improving ventilation, reducing pulmonary vascular resistance and improving outcomes; the consequence is often the development of tolerance and physiologic dependence - similar to prenatal exposure from these same classes of drugs. The investigators have recently reported the results of randomized placebo control trial showing that the addition of clonidine (central alpha 2 agonist) to tapering doses of opioids was efficacious and safe in treating opioid dependence in infants who had moderate to severe neonatal abstinence syndrome from prenatal drug exposure to opioids. Currently, the investigators propose to perform a double-blind, randomized placebo control trial in a cohort of critically ill infants without prenatal drug exposure at Johns Hopkins Hospital to test the overall hypothesis that early addition of clonidine to a cohort of critically ill neonates on mechanical ventilation who are receiving opioids and benzodiazepines for analgesia and sedation will be efficacious and safe in reducing both the incidence and severity of withdrawal symptoms (NICU-NAS); as well as, reducing the time to complete sedative and analgesic drug detoxification. The hypothesis will be tested by addressing 2 specific aims that will determine: 1) the efficacy and safety of clonidine in critically ill infants, and 2) pharmacokinetics and pharmacodynamics using population-based pharmacokinetics in this vulnerable infant population who have only been exposed to these drugs as part of their routine care. Many "standard of care practices" are incorporated in neonatal and pediatric care prior to evidence based studies. This proposal will fill a much needed gap in translating what the investigators have learned about basic mechanisms mediating dependence and withdrawal to proven therapies for vulnerable pediatric populations.

Detailed description: The study will test the following 2 specific aims:

Specific Aim 1

To determine the efficacy and short-term safety of clonidine in reducing the severity of iatrogenic neonatal abstinence syndrome (NAS) by decreasing the time required for complete sedative and analgesic drug detoxification. The investigators will enroll 88 neonates at risk for having moderate to severe NAS in a randomized, double-blinded placebo controlled trial comparing opioid/benzodiazepine administration combined with a placebo (control) vs. opioid/benzodiazepine combined with clonidine. Principal outcome measure will be the difference in length of treatment for complete detoxification. Early safety of clonidine will be determined by monitoring for cardiorespiratory side effects that might be associated with clonidine use in this high risk population.

Specific Aim 2

To determine the pharmacokinetics and pharmacodynamics of clonidine in this critically ill infant population. The investigators will estimate the dose-exposure-response relationship of clonidine in neonates at risk for developing iatrogenic by using nonlinear mixed-effects population pharmacokinetic (PK)-pharmacodynamic (PD) analysis.

Eligibility criteria: Inclusion Criteria:

* \>35 week Gestational Age (GA) at birth
* \<3 months (90 days) old chronological age at the time of enrollment
* Exposed to a minimum five days of continuous narcotic infusion

Exclusion Criteria:

* Neurologic abnormality which would make Neonatal Abstinence Score (NAS) scoring inaccurate
* Major chromosomal abnormality (with the exception of Trisomy 21)
* Infant already enrolled in another randomized, controlled clinical trial

Primary outcomes:
measure: Time to Complete Detoxification
timeFrame: up to 4 weeks
Secondary outcomes:
measure: Cardiovascular Side-effects Changes HR and BP
timeFrame: 48 hrs after starting study drug and for 48hrs after stopping study drug
measure: Cumulative Dose of Opioid and Benzodiazepine
timeFrame: 2-4 weeks
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
Study officials:
affiliation: Johns Hopkins University
name: Estelle B Gauda, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Agthe AG, Kim GR, Mathias KB, Hendrix CW, Chavez-Valdez R, Jansson L, Lewis TR, Yaster M, Gauda EB. Clonidine as an adjunct therapy to opioids for neonatal abstinence syndrome: a randomized, controlled trial. Pediatrics. 2009 May;123(5):e849-56. doi: 10.1542/peds.2008-0978. Epub 2009 Apr 27.
citation: Leikin JB, Mackendrick WP, Maloney GE, Rhee JW, Farrell E, Wahl M, Kelly K. Use of clonidine in the prevention and management of neonatal abstinence syndrome. Clin Toxicol (Phila). 2009 Jul;47(6):551-5. doi: 10.1080/15563650902980019.
citation: Pohl-Schickinger A, Lemmer J, Hubler M, Alexi-Meskishvili V, Redlin M, Berger F, Stiller B. Intravenous clonidine infusion in infants after cardiovascular surgery. Paediatr Anaesth. 2008 Mar;18(3):217-22. doi: 10.1111/j.1460-9592.2008.02413.x.