Clonidine to Treat Iatrogenic-induced Opioid Dependence i... | NCT01360450

ID	Type	Description	Link
R21DA029295-01	U.S. NIH Grant/Contract		View source

Name	Class
National Institute on Drug Abuse (NIDA)	NIH

Clonidine to Treat Iatrogenic-induced Opioid Dependence i... | NCT01360450 | Trialant

Description Module

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.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
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

Name	Type	Description	Arm Group Labels	Other Names
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.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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

Measure	Description	Time Frame
Cardiovascular Side-effects Changes HR and BP	Changes in Heart Rate (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
Cumulative Dose of Opioid and Benzodiazepine

Contacts/Locations Module

Name	Affiliation	Role
Estelle B Gauda, MD	Johns Hopkins University	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Johns Hopkins Hospital		Baltimore	Maryland	21287	United States

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
19398463	Background	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.
19566381	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.

Arm/Group Information

ID	Title	Description
FG000	Treatment	Infants will receive intravenous or oral clonidine(Duraclon) for the treatment of pain and sedation Clonidine Hydrochloride: 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.
FG001	Control	Infants will receive place (saline) (if receiving it IV) or orally (sterile water) if receiving it orally 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.

Periods

Title

Milestones

Reasons Not Completed

Overall Study

Type	Comment	Milestone Data
STARTED		FG0006 subjects FG0016 subjects
Completed Treatment		FG0006 subjects FG0016 subjects
COMPLETED		FG0006 subjects FG0016 subjects
NOT COMPLETED		FG0000 subjects FG0010 subjects

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Treatment	Infants will receive intravenous or oral clonidine(Duraclon) for the treatment of pain and sedation 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.

Units	Counts
Participants	BG000

Baseline Measures

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Categorical			Count of Participants

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

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). 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.

Posted

Mean

Standard Deviation

days

up to 4 weeks

ID	Title	Description
OG000	Treatment	Infants will receive intravenous or oral clonidine(Duraclon) for the treatment of pain and sedation 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.

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Treatment	Infants will receive intravenous or oral clonidine(Duraclon) for the treatment of pain and sedation 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.

More Info Module

Certain Agreements

Title	Organization	Phone	Extension	Email
Estelle B Gauda	Johns Hopkins Medical Institution	4106140151		egauda1@jhmi.edu

Condition Browse Module

ID	Term
D009357	Neonatal Abstinence Syndrome
D011595	Psychomotor Agitation

ID	Term
D007232	Infant, Newborn, Diseases
D009358	Congenital, Hereditary, and Neonatal Diseases and Abnormalities
D019966	Substance-Related Disorders
D064419	Chemically-Induced Disorders

Intervention Browse Module

ID	Term
D003000	Clonidine
D012965	Sodium Chloride

ID	Term
D048288	Imidazolines
D007093	Imidazoles
D001393	Azoles
D006573	Heterocyclic Compounds, 1-Ring

Race (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
American Indian or Alaska Native	BG0000 BG0010 BG0020
Asian	BG0000 BG0011 BG0021
Native Hawaiian or Other Pacific Islander	BG0000 BG0010 BG0020
Black or African American	BG0000 BG0013 BG0023
White	BG0006 BG0011 BG0027
More than one race	BG0000 BG0010 BG0020
Unknown or Not Reported	BG0000 BG0011 BG0021

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		ANOVA	2 sided ANOVA	>0.05	yes the P value was adjusted for multiple comparisons.	Mean Difference (Final Values)	0.05			2-Sided						Mean difference between the two treatment arms		Other

Secondary

Cardiovascular Side-effects Changes HR and BP

Changes in Heart Rate (HR) and BP for 48 hrs after starting study drug and for 48hrs after stopping study drug

No data is available for this outcome measure, as it was not collected.

Posted

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

ID	Title	Description
OG000	Treatment	Infants will receive intravenous or oral clonidine(Duraclon) for the treatment of pain and sedation Clonidine Hydrochloride: 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.
OG001	Control	Infants will receive place (saline) (if receiving it IV) or orally (sterile water) if receiving it orally 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.

Units	Counts
Participants	OG0000 OG0010

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.

No data is available for this outcome measure, as it was not collected.

Posted

2-4 weeks

ID	Title	Description
OG000	Treatment	Infants will receive intravenous or oral clonidine(Duraclon) for the treatment of pain and sedation Clonidine Hydrochloride: 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.
OG001	Control	Infants will receive place (saline) (if receiving it IV) or orally (sterile water) if receiving it orally 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.

Units	Counts
Participants	OG0000 OG0010