Blinded Trial of Buprenorphine or Morphine in the Treatment of the Neonatal Abstinence Syndrome

• Sponsor: Thomas Jefferson University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01452789
• Collaborator: National Institute on Drug Abuse (NIDA) (NIH)
• Enrollment: 63
• Location: 1
• Arms: 2
• Duration (Months): 55
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

The opioid neonatal abstinence syndrome (NAS) is a condition of withdrawal symptoms after utero exposure to opioids. In an open label Phase 1 trial sublingual buprenorphine was associated with a ~30% reduction length of treatment compared to standard of care morphine. Due to the subjective nature of the scoring instrument, efficacy in a blinded trial is needed to unequivocally establish the superiority of buprenorphine over morphine. The primary objective of the trial is to compare length of treatment using sublingual buprenorphine or oral morphine solution in the pharmacologic treatment of the NAS.

Condition or Disease	Intervention/Treatment	Phase
Neonatal Abstinence Syndrome	Drug: sublingual buprenorphine; Drug: oral morphine	Phase 3

Detailed Description

This was a single-site, randomized, double-blind, double-dummy, parallel-group clinical trial. Potential patients were identified in the pre-natal period by staff of the Thomas Jefferson University Family center. Mothers who provided consent were contacted upon admission to TJUH. Inclusion and exclusion criteria were reassessed during the peri-partum period and study details reviewed again with the mother, and where possible, the father of the child. Women admitted to TJUH with in utero exposure to opioids who are not in the Family Center present were screened and approached for consent during their inpatient stay.

Infants at risk for NAS had abstinence assessed using the MOTHER scoring instrument, which is based upon Finnegan Score and will hereafter be called the "NAS score". This is the standard instrument used at TJUH. A need for initiation of treatment was defined as any consecutive 3 scores adding up to ≥ 24 or any single score ≥12, and the clinical decision of the attending physician that the infant requires pharmacologic therapy. Randomization took place following reaching of the threshold for initiation of treatment and a re-review of inclusion and exclusion criteria. Patients were randomized to treatment groups of 1) oral morphine/sublingual placebo for buprenorphine or 2) oral placebo for morphine/sublingual buprenorphine. Randomization was stratified according to in utero exposure to methadone or buprenorphine. Oral morphine or placebo for morphine was administered by mouth every 4 hours, while buprenorphine or placebo for buprenorphine was administered every 8 hours. NAS scores were obtained every 4 hours. Dose assessment took place on a daily basis. If the three previous NAS scores are greater than 24, a dose advancement took place (at the discretion of the neonatologist). Morphine/placebo will be increased by 20% and buprenorphine/placebo will be increased by 25%. NNNS scoring took place for all infants who provide consent at day 2-3 of life, or earlier if pharmacologic treatment is required before this time, on day 10 of life, and in the post therapy period (but no later than corrected post gestational age of 46 weeks).

Study Design

• Study Type: Interventional
• Actual Enrollment: 63 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Active-Control, Double-Blind, Double-Dummy Clinical Trial Comparing Sublingual Buprenorphine And Morphine Solution For The Treatment Of Neonatal Opioid Abstinence Syndrome
• Study Start Date: Nov 1, 2011
• Actual Primary Completion Date: Jun 1, 2016
• Actual Study Completion Date: Jun 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: sublingual buprenorphine This is the group that received active sublingual buprenorphine and placebo for oral morphine	Drug: sublingual buprenorphine; Initial daily dose: 15.9 mcg/kg/day; Initial unit dose: 5.3 mcg/kg q8 hours; Maximum daily dose: 60 mcg/kg/day; Up-titration rate: 25%; Weaning rate: 10%; Cessation Dose: Within 10 or 20% of starting dose; Other Names: Buprenex
Active Comparator: oral morphine This is the group that received active oral morphine and placebo for sublingual buprenorphine	Drug: oral morphine; Initial daily dose: 0.4 mg/kg/day; Initial unit dose: 0.07 mg/kg q 4 hours; Maximum daily dose: 1.25 mg/kg/day; Up-titration rate: 20%; Weaning rate: 10%; Cessation Dose: 0.025 mg/kg q 4 hours

Outcome Measures

Primary Outcome Measures

1. Length of Treatment [Patients will be followed for the duration of hospital stay, an expected average of 5 weeks.]

   This endpoint will compare length of treatment (in days) using sublingual buprenorphine or oral morphine solution.

Secondary Outcome Measures

1. Length of Hospitalization [Duration of hospital stay is an expected average of 5 weeks.]

   This endpoint will compare length of stay in the hospital (in days) using sublingual buprenorphine or morphine solution.

2. Number of Patients Requiring Supplemental Phenobarbital Treatment. [Patients will be followed for the duration of hospital stay, an expected average of 5 weeks.]

   This endpoint will compare requirement number of patients who require use of supplemental phenobarbital.

3. Number of Participants With Adverse Events as a Measure of Safety and Tolerability [Patients will be followed for the duration of hospital stay, an expected average of 5 weeks.]

   Adverse events will be collected, graded by severity, and assessed for causality referent to study drug.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• ≥ 37 weeks gestation

• Exposure to opiates in utero

• Demonstration of signs and symptoms of neonatal abstinence syndrome requiring treatment

Exclusion Criteria:

• Major congenital malformations and/or intrauterine growth retardation

• Medical illness requiring intensification of medical therapy. This includes, but is not limited to suspected sepsis requiring antibiotic therapy.

• Hypoglycemia requiring treatment with intravenous dextrose.

• Bilirubin >20 mg/dL (The need for phototherapy is not exclusionary)

• Concomitant benzodiazepine or severe alcohol abuse , self-report of regular use of alcohol or of benzodiazepines use in the past 30 days, and/or receipt of benzodiazepines by prescription (as determined by self-report or intake urine) by the mother 30 days prior to birth,

• Concomitant use of Cytrochrom (CYP) 3A inhibitors (erythromycin, clarithromycin, ketoconazole, itraconazole, HIV protease inhibitors) or inducers (rifampin, carbamazepine, phenobarbital) prior to initiation of NAS treatment

• Seizure activity or other neurologic abnormality

• Breast feeding

• Inability of mother to give informed consent due to co-morbid psychiatric diagnosis

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Thomas Jefferson University Hosptial	Philadelphia	Pennsylvania	United States	19107

Sponsors and Collaborators

• Thomas Jefferson University
• National Institute on Drug Abuse (NIDA)

Investigators

• Principal Investigator: Walter K Kraft, MD, Thomas Jeffeson University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Kraft WK, Dysart K, Greenspan JS, Gibson E, Kaltenbach K, Ehrlich ME. Revised dose schema of sublingual buprenorphine in the treatment of the neonatal opioid abstinence syndrome. Addiction. 2011 Mar;106(3):574-80. doi: 10.1111/j.1360-0443.2010.03170.x. Epub 2010 Oct 6.
• Kraft WK, Gibson E, Dysart K, Damle VS, Larusso JL, Greenspan JS, Moody DE, Kaltenbach K, Ehrlich ME. Sublingual buprenorphine for treatment of neonatal abstinence syndrome: a randomized trial. Pediatrics. 2008 Sep;122(3):e601-7. doi: 10.1542/peds.2008-0571. Epub 2008 Aug 11.

• Responsible Party: Thomas Jefferson University
• ClinicalTrials.gov Identifier: NCT01452789
• Other Study ID Numbers: 11F.193; R01DA029076-01A1
• First Posted: Oct 17, 2011
• Last Update Posted: Mar 24, 2020
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Thomas Jefferson University: neonatal abstinence syndrome; buprenorphine; morphine; pharmacokinetics
• Additional relevant MeSH terms: Neonatal Abstinence Syndrome; Syndrome; Morphine; Buprenorphine

Study Results

Participant Flow

Recruitment Details	From November 1, 2011, to May 29, 2016, we enrolled term infants (≥37 weeks of gestation) who had been exposed to opioids in utero and had signs and symptoms of the neonatal abstinence syndrome.

Arm/Group Title	Sublingual Buprenorphine	Oral Morphine
Arm/Group Description	sublingual buprenorphine: Initial daily dose: 15.9 mcg/kg/day; Initial unit dose: 5.3 mcg/kg q8 hours; Maximum daily dose: 60 mcg/kg/day; Up-titration rate: 25%; Weaning rate: 10%; Cessation Dose: Within 10 or 20% of starting dose	oral morphine: Initial daily dose: 0.4 mg/kg/day; Initial unit dose: 0.07 mg/kg q 4 hours; Maximum daily dose: 1.25 mg/kg/day; Up-titration rate: 20%; Weaning rate: 10%; Cessation Dose: 0.025 mg/kg q 4 hours
Period Title: Overall Study
STARTED	33	30
COMPLETED	30	28
NOT COMPLETED	3	2

Baseline Characteristics

Arm/Group Title	Sublingual Buprenorphine	Oral Morphine	Total
Arm/Group Description	sublingual buprenorphine: Initial daily dose: 15.9 mcg/kg/day; Initial unit dose: 5.3 mcg/kg q8 hours; Maximum daily dose: 60 mcg/kg/day; Up-titration rate: 25%; Weaning rate: 10%; Cessation Dose: Within 10 or 20% of starting dose	oral morphine: Initial daily dose: 0.4 mg/kg/day; Initial unit dose: 0.07 mg/kg q 4 hours; Maximum daily dose: 1.25 mg/kg/day; Up-titration rate: 20%; Weaning rate: 10%; Cessation Dose: 0.025 mg/kg q 4 hours	Total of all reporting groups
Overall Participants	33	30	63
Age (Count of Participants)
<=18 years	33 100%	30 100%	63 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (gestational age months) [Median (Full Range) ]
Median (Full Range) [gestational age months]	38.5	39	38.7
Sex: Female, Male (Count of Participants)
Female	16 48.5%	12 40%	28 44.4%
Male	17 51.5%	18 60%	35 55.6%
Region of Enrollment (participants) [Number]
United States	33 100%	30 100%	63 100%

Outcome Measures

1. Primary Outcome

Title	Length of Treatment
Description	This endpoint will compare length of treatment (in days) using sublingual buprenorphine or oral morphine solution.
Time Frame	Patients will be followed for the duration of hospital stay, an expected average of 5 weeks.

Outcome Measure Data

Analysis Population Description

Intention to treat

Arm/Group Title	Sublingual Buprenorphine	Oral Morphine
Arm/Group Description	sublingual buprenorphine: Initial daily dose: 15.9 mcg/kg/day; Initial unit dose: 5.3 mcg/kg q8 hours; Maximum daily dose: 60 mcg/kg/day; Up-titration rate: 25%; Weaning rate: 10%; Cessation Dose: Within 10 or 20% of starting dose	oral morphine: Initial daily dose: 0.4 mg/kg/day; Initial unit dose: 0.07 mg/kg q 4 hours; Maximum daily dose: 1.25 mg/kg/day; Up-titration rate: 20%; Weaning rate: 10%; Cessation Dose: 0.025 mg/kg q 4 hours
Measure Participants	33	30
Median (Full Range) [days]	15	28

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oral Morphine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	van Elteren
	Comments

2. Secondary Outcome

Title	Length of Hospitalization
Description	This endpoint will compare length of stay in the hospital (in days) using sublingual buprenorphine or morphine solution.
Time Frame	Duration of hospital stay is an expected average of 5 weeks.

Outcome Measure Data

Analysis Population Description

Intention to treat

Arm/Group Title	Sublingual Buprenorphine	Oral Morphine
Arm/Group Description	sublingual buprenorphine: Initial daily dose: 15.9 mcg/kg/day; Initial unit dose: 5.3 mcg/kg q8 hours; Maximum daily dose: 60 mcg/kg/day; Up-titration rate: 25%; Weaning rate: 10%; Cessation Dose: Within 10 or 20% of starting dose	oral morphine: Initial daily dose: 0.4 mg/kg/day; Initial unit dose: 0.07 mg/kg q 4 hours; Maximum daily dose: 1.25 mg/kg/day; Up-titration rate: 20%; Weaning rate: 10%; Cessation Dose: 0.025 mg/kg q 4 hours
Measure Participants	33	30
Median (Full Range) [days]	21	33

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oral Morphine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	van Elteren
	Comments

3. Secondary Outcome

Title	Number of Patients Requiring Supplemental Phenobarbital Treatment.
Description	This endpoint will compare requirement number of patients who require use of supplemental phenobarbital.
Time Frame	Patients will be followed for the duration of hospital stay, an expected average of 5 weeks.

Outcome Measure Data

Analysis Population Description

Intention to treat

Arm/Group Title	Sublingual Buprenorphine	Oral Morphine
Arm/Group Description	sublingual buprenorphine: Initial daily dose: 15.9 mcg/kg/day; Initial unit dose: 5.3 mcg/kg q8 hours; Maximum daily dose: 60 mcg/kg/day; Up-titration rate: 25%; Weaning rate: 10%; Cessation Dose: Within 10 or 20% of starting dose	oral morphine: Initial daily dose: 0.4 mg/kg/day; Initial unit dose: 0.07 mg/kg q 4 hours; Maximum daily dose: 1.25 mg/kg/day; Up-titration rate: 20%; Weaning rate: 10%; Cessation Dose: 0.025 mg/kg q 4 hours
Measure Participants	33	30
Number [participants]	5 15.2%	7 23.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oral Morphine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

4. Secondary Outcome

Title	Number of Participants With Adverse Events as a Measure of Safety and Tolerability
Description	Adverse events will be collected, graded by severity, and assessed for causality referent to study drug.
Time Frame	Patients will be followed for the duration of hospital stay, an expected average of 5 weeks.

Outcome Measure Data

Analysis Population Description

Intention to treat

Arm/Group Title	Sublingual Buprenorphine	Oral Morphine
Arm/Group Description	sublingual buprenorphine: Initial daily dose: 15.9 mcg/kg/day; Initial unit dose: 5.3 mcg/kg q8 hours; Maximum daily dose: 60 mcg/kg/day; Up-titration rate: 25%; Weaning rate: 10%; Cessation Dose: Within 10 or 20% of starting dose	oral morphine: Initial daily dose: 0.4 mg/kg/day; Initial unit dose: 0.07 mg/kg q 4 hours; Maximum daily dose: 1.25 mg/kg/day; Up-titration rate: 20%; Weaning rate: 10%; Cessation Dose: 0.025 mg/kg q 4 hours
Measure Participants	33	30
Count of Participants [Participants]	7 21.2%	8 26.7%

Adverse Events

Time Frame	Adverse events were collected from allocation through discharge from hospital, up to a maximum of 71 days
Arm/Group Title	Sublingual Buprenorphine		Oral Morphine
Arm/Group Description	sublingual buprenorphine: Initial daily dose: 15.9 mcg/kg/day; Initial unit dose: 5.3 mcg/kg q8 hours; Maximum daily dose: 60 mcg/kg/day; Up-titration rate: 25%; Weaning rate: 10%; Cessation Dose: Within 10 or 20% of starting dose		oral morphine: Initial daily dose: 0.4 mg/kg/day; Initial unit dose: 0.07 mg/kg q 4 hours; Maximum daily dose: 1.25 mg/kg/day; Up-titration rate: 20%; Weaning rate: 10%; Cessation Dose: 0.025 mg/kg q 4 hours
All Cause Mortality
	Sublingual Buprenorphine		Oral Morphine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/33 (0%)		0/30 (0%)
Serious Adverse Events
	Sublingual Buprenorphine		Oral Morphine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/33 (3%)		1/30 (3.3%)
Ear and labyrinth disorders
supraglottoplasty	1/33 (3%)	1	0/30 (0%)	0
Gastrointestinal disorders
Inguinal hernia repair	0/33 (0%)	0	1/30 (3.3%)	1
Other (Not Including Serious) Adverse Events
	Sublingual Buprenorphine		Oral Morphine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/33 (39.4%)		10/30 (33.3%)
Blood and lymphatic system disorders
anemia	1/33 (3%)	1	0/30 (0%)	0
Cardiac disorders
Tachycardia	1/33 (3%)	1	0/30 (0%)	0
Gastrointestinal disorders
Gastrointestinal	3/33 (9.1%)	3	2/30 (6.7%)	3
Infections and infestations
Urinary Tract Infection	0/33 (0%)	0	1/30 (3.3%)	1
Respiratory Infection	0/33 (0%)	0	2/30 (6.7%)	2
Respiratory, thoracic and mediastinal disorders
cough	1/33 (3%)	1	0/30 (0%)	0
Skin and subcutaneous tissue disorders
diaper rash	5/33 (15.2%)	5	3/30 (10%)	3
Rash	4/33 (12.1%)	5	3/30 (10%)	3
Umbilical granuloma	1/33 (3%)	1	0/30 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.