Clonidine to Treat Iatrogenic-induced Opioid Dependence in Infants

Neonatal Abstinence Syndrome Clinical Trial

Official title:

Efficacy of Clonidine in Reducing Iatrogenic-induced Opioid Dependence in Infants:

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01360450
• Other study ID #: Clonidine NICU-NAS
• Secondary ID: R21DA029295-01
• Status: Terminated
• Phase: Phase 2/Phase 3
• First received: October 13, 2010
• Last updated: August 11, 2014
• Start date: July 2011
• Est. completion date: December 2014

Study information

• Verified date: August 2014
• Source: Gauda, Estelle B., M.D.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 13
• Est. completion date: December 2014
• Est. primary completion date: July 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 90 Days

Eligibility

Inclusion Criteria:

• >35 week 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 NAS scoring inaccurate

• Major chromosomal abnormality (with the exception of Trisomy 21)

• Infant already enrolled in another randomized, controlled clinical trial

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Neonatal Abstinence Syndrome

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	Johns Hopkins Hospital	Baltimore	Maryland

Sponsors (2)

Lead Sponsor	Collaborator
Gauda, Estelle B., M.D.	National Institute on Drug Abuse (NIDA)

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. — View 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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to complete detoxification	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).	2-4 weeks	No
Secondary	Cardiovascular side-effects changes HR and BP	Changes in HR and BP for 48 hrs after starting study drug and for 48hrs after stopping study drug	48 hrs after starting study drug and for 48hrs after stopping study drug	Yes
Secondary	Cumulative dose of opioid and benzodiazepine	We will determine the total amount of opioid and benzodiazepine needed from the start of detoxification to the end of the the detoxification.	2-4 weeks	No