Clonidine to Treat Iatrogenic-induced Opioid Dependence in Infants

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Neonatal Abstinence Syndrome	Drug: Clonidine HCL; Drug: saline	Phase 2; Phase 3

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	12 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	Efficacy of Clonidine in Reducing Iatrogenic-induced Opioid Dependence in Infants:
Study Start Date :	July 2011
Actual Primary Completion Date :	July 2011
Actual Study Completion Date :	December 2014

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Treatment; Interventions: Infants will receive intravenous or oral clonidine(Duraclon) for the treatment of pain and sedation: Duration: (Clonidine HCL) 1 mcg/kg/dose q4 either iv or po.	Drug: Clonidine HCL; At day 5 on opioid and/or benzodiazepine (BZD), the infant will be randomized to receive either placebo (normal saline) or clonidine 1μg/kg/q 4 hrs to a maximum dose of 2μg/kg/q 4. Weaning from the study drug: When the opioid is no longer required, 24 hrs later the study drug (placebo or study drug) will be reduced by 50% and then discontinued 24 hours later provided that the Modified Finnegan scores remain between < 9.; Other Name: Duraclon
Placebo Comparator: Control; Intervention: Infants will receive place (saline) (if receiving it IV) or orally (sterile water) if receiving it orally	Drug: saline; Infants randomized to placebo will be administered IV saline or oral sterile water in the same volume as study drug. The placebo will be give every 4 hrs as outlined in the algorithm for the study.; Other Name: placebo, sterile water, saline

Outcome Measures

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Primary Outcome Measures :

1. Time to Complete Detoxification [ Time Frame: up to 4 weeks ]
   Time to complete detoxification is defined as 48 hrs off all opioids/benzodiazepines and study drug with acceptable withdrawal scores of <9 (on average we expect the infant to be enrolled in the study for 2-4 weeks). The scale used to assess withdrawal was the Modified Finnegan Neonatal Withdrawal Scale, which ranges from 0-41, 0 represents no withdrawal and 41 represent maximum withdrawal.

Secondary Outcome Measures :

1. Cardiovascular Side-effects Changes HR and BP [ Time Frame: 48 hrs after starting study drug and for 48hrs after stopping study drug ]
   Changes in Heart Rate (HR) and BP for 48 hrs after starting study drug and for 48hrs after stopping study drug
2. Cumulative Dose of Opioid and Benzodiazepine [ Time Frame: 2-4 weeks ]
   We will determine the total amount of opioid and benzodiazepine needed from the start of detoxification to the end of the the detoxification.

Eligibility Criteria

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Ages Eligible for Study:	up to 90 Days (Child)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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

Contacts and Locations

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Locations

United States, Maryland
Johns Hopkins Hospital
Baltimore, Maryland, United States, 21287

Sponsors and Collaborators

Johns Hopkins University

National Institute on Drug Abuse (NIDA)

Investigators

Principal Investigator:	Estelle B Gauda, MD	Johns Hopkins University

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications:

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.

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.

Pohl-Schickinger A, Lemmer J, Hübler 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.

Responsible Party:	Johns Hopkins University
ClinicalTrials.gov Identifier:	NCT01360450 History of Changes
Other Study ID Numbers:	Clonidine NICU-NAS; R21DA029295-01 ( U.S. NIH Grant/Contract )
First Posted:	May 25, 2011
Results First Posted:	September 13, 2017
Last Update Posted:	September 13, 2017
Last Verified:	August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by Johns Hopkins University:

opioid withdrawal; Neonatal Pain, Agitation, and Sedation Scale (NPASS); duraclon

Additional relevant MeSH terms:

Neonatal Abstinence Syndrome; Infant, Newborn, Diseases; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Analgesics, Opioid; Clonidine; Narcotics; Central Nervous System Depressants; Physiological Effects of Drugs; Analgesics	Sensory System Agents; Peripheral Nervous System Agents; Antihypertensive Agents; Sympatholytics; Autonomic Agents; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action