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Clonidine to Treat Iatrogenic-induced Opioid Dependence in Infants

This study has been terminated.

(The study was treminated because of low accural)

Sponsor:

ClinicalTrials.gov Identifier:

NCT01360450

First Posted: May 25, 2011

Last Update Posted: September 13, 2017

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.

Collaborator:

National Institute on Drug Abuse (NIDA)

Information provided by (Responsible Party):

Johns Hopkins University

Purpose

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	Intervention	Phase
Neonatal Abstinence Syndrome	Drug: Clonidine HCL Drug: saline	Phase 2 Phase 3


Study Type:	Interventional
Study Design:	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:

Resource links provided by NLM:

Drug Information available for: Clonidine Clonidine hydrochloride

U.S. FDA Resources

Further study details as provided by Johns Hopkins University:

Primary Outcome Measures:

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:

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
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.


Enrollment:	12
Study Start Date:	July 2011
Study Completion Date:	December 2014
Primary Completion Date:	July 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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

Arms

Assigned Interventions

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

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

Information from the National Library of Medicine

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, Learn About Clinical Studies.


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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01360450

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

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 Submitted:	October 13, 2010
First Posted:	May 25, 2011
Results First Submitted:	June 9, 2017
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

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