Clonidine to Treat Iatrogenic-induced Opioid Dependence in Infants

NCT01360450 | Terminated Phase 2 Results DMC

• 2 other identifiers: Clonidine NICU-NASR21DA029295-01
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

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.

Conditions

Neonatal Abstinence Syndrome

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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). 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.

  up to 4 weeks

Secondary Outcomes (2)

• Cardiovascular Side-effects Changes HR and BP

  48 hrs after starting study drug and for 48hrs after stopping study drug

• Cumulative Dose of Opioid and Benzodiazepine

  2-4 weeks

Study Arms (2)

Treatment

EXPERIMENTAL

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

Control

PLACEBO COMPARATOR

Intervention: Infants will receive place (saline) (if receiving it IV) or orally (sterile water) if receiving it orally

Drug: saline

Interventions

Clonidine HCL DRUG

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.

Also known as: Duraclon

Treatment

saline DRUG

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.

Also known as: placebo, sterile water, saline

Control

Eligibility Criteria

• Age: 5 Days - 90 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• \>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

You may not qualify if:

• 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

Sponsors & Collaborators

• Johns Hopkins University: lead
• National Institute on Drug Abuse (NIDA): collaborator

Study Sites (1)

Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

Related 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.

  PMID: 19398463 BACKGROUND

• 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.

  PMID: 19566381 BACKGROUND

• 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.

  PMID: 18230064 BACKGROUND

MeSH Terms

Conditions

Neonatal Abstinence Syndrome; Psychomotor Agitation

Interventions

Clonidine; Sodium Chloride

Condition Hierarchy (Ancestors)

Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Dyskinesias; Neurologic Manifestations; Nervous System Diseases; Psychomotor Disorders; Neurobehavioral Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Aberrant Motor Behavior in Dementia; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Imidazolines; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Results Point of Contact

• Title: Estelle B Gauda
• Organization: Johns Hopkins Medical Institution

egauda1@jhmi.edu

4106140151

Study Officials

• Estelle B Gauda, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 13, 2010
• First Posted: May 25, 2011
• Study Start: July 1, 2011
• Primary Completion: July 1, 2011
• Study Completion: December 1, 2014
• Last Updated: September 13, 2017
• Results First Posted: September 13, 2017

Record last verified: 2017-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)