Clonidine Versus Phenobarbital as Adjunctive Therapy for Neonatal Abstinence Syndrome

• Sponsor: University of Tennessee Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT03670160
• Collaborator: (none)
• Enrollment: 25
• Location: 1
• Arms: 2
• Actual Duration (Months): 20
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

The purpose of this study is to compare clonidine versus phenobarbital as adjunctive therapy in those infants who have failed monotherapy with morphine sulfate for neonatal abstinence syndrome (NAS).

Condition or Disease	Intervention/Treatment	Phase
Neonatal Abstinence Syndrome	Drug: Phenobarbital; Drug: Clonidine	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Clonidine Versus Phenobarbital as Adjunctive Therapy for Neonatal Abstinence Syndrome
• Actual Study Start Date: Oct 1, 2018
• Actual Primary Completion Date: May 31, 2020
• Actual Study Completion Date: May 31, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Phenobarbital Phenobarbital loading dose 20mg/kg in 2 divided doses, then 5 mg/kg/day divided every 12 hours. Phenobarbital continued throughout the infants hospitalization.	Drug: Phenobarbital; Phenobarbital loading dose 20 mg/kg in 2 divided doses, then 5 mg/kg/day divided every 12 hours. Phenobarbital dose will be adjusted to obtain desired trough of 25 to 30 mcg/mL. Levels will be obtained on Day 6 then weekly thereafter. Phenobarbital will be tapered over 4 weeks upon discharge from the hospital. The standardized taper is based the patient specific dose at the time of discharge.
Active Comparator: Clonidine Clonidine 5 mcg/kg/day divided every 3 hours. Clonidine will be continued to achieve control of NAS symptoms. Clonidine may be weaned after successful discontinuation of oral morphine sulfate. Infants will not be discharged on clonidine.	Drug: Clonidine; Clonidine 5 mcg/kg/day divided every 3 hours. Clonidine will be increased by 1.5 mcg/kg/day to achieve control of NAS symptoms based upon standardized scoring for neonatal abstinence syndrome. Clonidine will be weaned by 25% every 24 hours after successful discontinuation of oral morphine sulfate. Infants will not be discharged on clonidine.

Outcome Measures

Primary Outcome Measures

1. Time From Initiation of Adjunctive Therapy Until Hospital Discharge [From date of randomization until hospital discharge, up to 4 months]

   Number of days from initiation of adjunctive therapy until hospital discharge

Secondary Outcome Measures

1. Length of Stay [From date of randomization until hospital discharge, up to 4 months]

   Number of days of hospital admission

2. Length of Oral Morphine Sulfate Therapy [From date of randomization until hospital discharge, up to 4 months]

   Number of days of oral morphine sulfate therapy

3. Number of Patients Requiring Triple Therapy [From date of randomization until hospital discharge, up to 4 months]

   Number of patients requiring a third agent to control withdrawal symptoms

4. Readmission Rate [From date of randomization until 30 days after hospital discharge or discontinuation of phenobarbital, up to 6 months]

   Number of patients readmitted to the hospital within 30 days of hospital discharge or discontinuation of phenobarbital.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 35 Weeks and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Infants greater than or equal to 35 weeks gestation age

• Admitted to the neonatal intensive care unit

• Failed monotherapy with morphine sulfate therapy

Exclusion Criteria:

• Neonatal abstinence syndrome due to iatrogenic causes

• Unable to take oral medications at any point during their treatment

• Infants in the custody of the Department of Child Protective Services with no legal guardian identified at the time of enrollment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Tennessee Medical Center	Knoxville	Tennessee	United States	37920

Sponsors and Collaborators

• University of Tennessee Medical Center

Investigators

• Principal Investigator: Carrie Brusseau, PharmD, University of Tennessee Medical Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 3, 2020

More Information

Publications

None provided.

• Responsible Party: University of Tennessee Medical Center
• ClinicalTrials.gov Identifier: NCT03670160
• Other Study ID Numbers: UHS-OB-0001
• First Posted: Sep 13, 2018
• Last Update Posted: Nov 10, 2021
• Last Verified: Nov 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Neonatal Abstinence Syndrome; Syndrome; Clonidine; Phenobarbital

Study Results

Participant Flow

Arm/Group Title	Phenobarbital	Clonidine
Arm/Group Description	Phenobarbital loading dose 20mg/kg in 2 divided doses, then 5 mg/kg/day divided every 12 hours. Phenobarbital continued throughout the infants hospitalization. Phenobarbital: Phenobarbital loading dose 20 mg/kg in 2 divided doses, then 5 mg/kg/day divided every 12 hours. Phenobarbital dose will be adjusted to obtain desired trough of 25 to 30 mcg/mL. Levels will be obtained on Day 6 then weekly thereafter. Phenobarbital will be tapered over 4 weeks upon discharge from the hospital. The standardized taper is based the patient specific dose at the time of discharge.	Clonidine 5 mcg/kg/day divided every 3 hours. Clonidine will be continued to achieve control of NAS symptoms. Clonidine may be weaned after successful discontinuation of oral morphine sulfate. Infants will not be discharged on clonidine. Clonidine: Clonidine 5 mcg/kg/day divided every 3 hours. Clonidine will be increased by 1.5 mcg/kg/day to achieve control of NAS symptoms based upon standardized scoring for neonatal abstinence syndrome. Clonidine will be weaned by 25% every 24 hours after successful discontinuation of oral morphine sulfate. Infants will not be discharged on clonidine.
Period Title: Overall Study
STARTED	11	14
COMPLETED	11	14
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Phenobarbital	Clonidine	Total
Arm/Group Description	Phenobarbital loading dose 20mg/kg in 2 divided doses, then 5 mg/kg/day divided every 12 hours. Phenobarbital continued throughout the infants hospitalization. Phenobarbital: Phenobarbital loading dose 20 mg/kg in 2 divided doses, then 5 mg/kg/day divided every 12 hours. Phenobarbital dose will be adjusted to obtain desired trough of 25 to 30 mcg/mL. Levels will be obtained on Day 6 then weekly thereafter. Phenobarbital will be tapered over 4 weeks upon discharge from the hospital. The standardized taper is based the patient specific dose at the time of discharge.	Clonidine 5 mcg/kg/day divided every 3 hours. Clonidine will be continued to achieve control of NAS symptoms. Clonidine may be weaned after successful discontinuation of oral morphine sulfate. Infants will not be discharged on clonidine. Clonidine: Clonidine 5 mcg/kg/day divided every 3 hours. Clonidine will be increased by 1.5 mcg/kg/day to achieve control of NAS symptoms based upon standardized scoring for neonatal abstinence syndrome. Clonidine will be weaned by 25% every 24 hours after successful discontinuation of oral morphine sulfate. Infants will not be discharged on clonidine.	Total of all reporting groups
Overall Participants	11	14	25
Age (Count of Participants)
<=18 years	11 100%	14 100%	25 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (Weeks) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Weeks]	38 (1)	38.6 (1.6)	38.3 (1.3)
Sex: Female, Male (Count of Participants)
Female	5 45.5%	7 50%	12 48%
Male	6 54.5%	7 50%	13 52%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	11 100%	14 100%	25 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	11 100%	14 100%	25 100%
Appearance, Pulse, Grimace, Activity, and Respiration - APGAR scale (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	6.7 (2.1)	7.8 (0.9)	7.3 (1.4)
Birth weight, grams (Grams) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Grams]	3173 (588)	3141 (519)	3155 (549)

Outcome Measures

1. Primary Outcome

Title	Time From Initiation of Adjunctive Therapy Until Hospital Discharge
Description	Number of days from initiation of adjunctive therapy until hospital discharge
Time Frame	From date of randomization until hospital discharge, up to 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phenobarbital	Clonidine
Arm/Group Description	Phenobarbital loading dose 20mg/kg in 2 divided doses, then 5 mg/kg/day divided every 12 hours. Phenobarbital continued throughout the infants hospitalization. Phenobarbital: Phenobarbital loading dose 20 mg/kg in 2 divided doses, then 5 mg/kg/day divided every 12 hours. Phenobarbital dose will be adjusted to obtain desired trough of 25 to 30 mcg/mL. Levels will be obtained on Day 6 then weekly thereafter. Phenobarbital will be tapered over 4 weeks upon discharge from the hospital. The standardized taper is based the patient specific dose at the time of discharge.	Clonidine 5 mcg/kg/day divided every 3 hours. Clonidine will be continued to achieve control of NAS symptoms. Clonidine may be weaned after successful discontinuation of oral morphine sulfate. Infants will not be discharged on clonidine. Clonidine: Clonidine 5 mcg/kg/day divided every 3 hours. Clonidine will be increased by 1.5 mcg/kg/day to achieve control of NAS symptoms based upon standardized scoring for neonatal abstinence syndrome. Clonidine will be weaned by 25% every 24 hours after successful discontinuation of oral morphine sulfate. Infants will not be discharged on clonidine.
Measure Participants	11	14
Mean (Standard Deviation) [Days]	20 (12.6)	33.8 (14.3)

2. Secondary Outcome

Title	Length of Stay
Description	Number of days of hospital admission
Time Frame	From date of randomization until hospital discharge, up to 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phenobarbital	Clonidine
Arm/Group Description	Phenobarbital loading dose 20mg/kg in 2 divided doses, then 5 mg/kg/day divided every 12 hours. Phenobarbital continued throughout the infants hospitalization. Phenobarbital: Phenobarbital loading dose 20 mg/kg in 2 divided doses, then 5 mg/kg/day divided every 12 hours. Phenobarbital dose will be adjusted to obtain desired trough of 25 to 30 mcg/mL. Levels will be obtained on Day 6 then weekly thereafter. Phenobarbital will be tapered over 4 weeks upon discharge from the hospital. The standardized taper is based the patient specific dose at the time of discharge.	Clonidine 5 mcg/kg/day divided every 3 hours. Clonidine will be continued to achieve control of NAS symptoms. Clonidine may be weaned after successful discontinuation of oral morphine sulfate. Infants will not be discharged on clonidine. Clonidine: Clonidine 5 mcg/kg/day divided every 3 hours. Clonidine will be increased by 1.5 mcg/kg/day to achieve control of NAS symptoms based upon standardized scoring for neonatal abstinence syndrome. Clonidine will be weaned by 25% every 24 hours after successful discontinuation of oral morphine sulfate. Infants will not be discharged on clonidine.
Measure Participants	11	14
Mean (Standard Deviation) [Days]	31 (9.96)	41.78 (10.94)

3. Secondary Outcome

Title	Length of Oral Morphine Sulfate Therapy
Description	Number of days of oral morphine sulfate therapy
Time Frame	From date of randomization until hospital discharge, up to 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phenobarbital	Clonidine
Arm/Group Description	Phenobarbital loading dose 20mg/kg in 2 divided doses, then 5 mg/kg/day divided every 12 hours. Phenobarbital continued throughout the infants hospitalization. Phenobarbital: Phenobarbital loading dose 20 mg/kg in 2 divided doses, then 5 mg/kg/day divided every 12 hours. Phenobarbital dose will be adjusted to obtain desired trough of 25 to 30 mcg/mL. Levels will be obtained on Day 6 then weekly thereafter. Phenobarbital will be tapered over 4 weeks upon discharge from the hospital. The standardized taper is based the patient specific dose at the time of discharge.	Clonidine 5 mcg/kg/day divided every 3 hours. Clonidine will be continued to achieve control of NAS symptoms. Clonidine may be weaned after successful discontinuation of oral morphine sulfate. Infants will not be discharged on clonidine. Clonidine: Clonidine 5 mcg/kg/day divided every 3 hours. Clonidine will be increased by 1.5 mcg/kg/day to achieve control of NAS symptoms based upon standardized scoring for neonatal abstinence syndrome. Clonidine will be weaned by 25% every 24 hours after successful discontinuation of oral morphine sulfate. Infants will not be discharged on clonidine.
Measure Participants	11	14
Mean (Standard Deviation) [Days]	25.45 (6.95)	34.36 (10.18)

4. Secondary Outcome

Title	Number of Patients Requiring Triple Therapy
Description	Number of patients requiring a third agent to control withdrawal symptoms
Time Frame	From date of randomization until hospital discharge, up to 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phenobarbital	Clonidine
Arm/Group Description	Phenobarbital loading dose 20mg/kg in 2 divided doses, then 5 mg/kg/day divided every 12 hours. Phenobarbital continued throughout the infants hospitalization. Phenobarbital: Phenobarbital loading dose 20 mg/kg in 2 divided doses, then 5 mg/kg/day divided every 12 hours. Phenobarbital dose will be adjusted to obtain desired trough of 25 to 30 mcg/mL. Levels will be obtained on Day 6 then weekly thereafter. Phenobarbital will be tapered over 4 weeks upon discharge from the hospital. The standardized taper is based the patient specific dose at the time of discharge.	Clonidine 5 mcg/kg/day divided every 3 hours. Clonidine will be continued to achieve control of NAS symptoms. Clonidine may be weaned after successful discontinuation of oral morphine sulfate. Infants will not be discharged on clonidine. Clonidine: Clonidine 5 mcg/kg/day divided every 3 hours. Clonidine will be increased by 1.5 mcg/kg/day to achieve control of NAS symptoms based upon standardized scoring for neonatal abstinence syndrome. Clonidine will be weaned by 25% every 24 hours after successful discontinuation of oral morphine sulfate. Infants will not be discharged on clonidine.
Measure Participants	11	14
Number [participants]	4 36.4%	10 71.4%

5. Secondary Outcome

Title	Readmission Rate
Description	Number of patients readmitted to the hospital within 30 days of hospital discharge or discontinuation of phenobarbital.
Time Frame	From date of randomization until 30 days after hospital discharge or discontinuation of phenobarbital, up to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phenobarbital	Clonidine
Arm/Group Description	Phenobarbital loading dose 20mg/kg in 2 divided doses, then 5 mg/kg/day divided every 12 hours. Phenobarbital continued throughout the infants hospitalization. Phenobarbital: Phenobarbital loading dose 20 mg/kg in 2 divided doses, then 5 mg/kg/day divided every 12 hours. Phenobarbital dose will be adjusted to obtain desired trough of 25 to 30 mcg/mL. Levels will be obtained on Day 6 then weekly thereafter. Phenobarbital will be tapered over 4 weeks upon discharge from the hospital. The standardized taper is based the patient specific dose at the time of discharge.	Clonidine 5 mcg/kg/day divided every 3 hours. Clonidine will be continued to achieve control of NAS symptoms. Clonidine may be weaned after successful discontinuation of oral morphine sulfate. Infants will not be discharged on clonidine. Clonidine: Clonidine 5 mcg/kg/day divided every 3 hours. Clonidine will be increased by 1.5 mcg/kg/day to achieve control of NAS symptoms based upon standardized scoring for neonatal abstinence syndrome. Clonidine will be weaned by 25% every 24 hours after successful discontinuation of oral morphine sulfate. Infants will not be discharged on clonidine.
Measure Participants	11	14
Count of Participants [Participants]	0 0%	0 0%

Adverse Events

Time Frame	6 months
Arm/Group Title	Phenobarbital		Clonidine
Arm/Group Description	Phenobarbital loading dose 20mg/kg in 2 divided doses, then 5 mg/kg/day divided every 12 hours. Phenobarbital continued throughout the infants hospitalization. Phenobarbital: Phenobarbital loading dose 20 mg/kg in 2 divided doses, then 5 mg/kg/day divided every 12 hours. Phenobarbital dose will be adjusted to obtain desired trough of 25 to 30 mcg/mL. Levels will be obtained on Day 6 then weekly thereafter. Phenobarbital will be tapered over 4 weeks upon discharge from the hospital. The standardized taper is based the patient specific dose at the time of discharge.		Clonidine 5 mcg/kg/day divided every 3 hours. Clonidine will be continued to achieve control of NAS symptoms. Clonidine may be weaned after successful discontinuation of oral morphine sulfate. Infants will not be discharged on clonidine. Clonidine: Clonidine 5 mcg/kg/day divided every 3 hours. Clonidine will be increased by 1.5 mcg/kg/day to achieve control of NAS symptoms based upon standardized scoring for neonatal abstinence syndrome. Clonidine will be weaned by 25% every 24 hours after successful discontinuation of oral morphine sulfate. Infants will not be discharged on clonidine.
All Cause Mortality
	Phenobarbital		Clonidine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/14 (0%)
Serious Adverse Events
	Phenobarbital		Clonidine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	Phenobarbital		Clonidine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		3/14 (21.4%)
Cardiac disorders
Hypotension	0/11 (0%)	0	2/14 (14.3%)	2
Hypertension	0/11 (0%)	0	1/14 (7.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.