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

March 10, 2020 updated by: Thomas Jefferson University

A Randomized, Active-Control, Double-Blind, Double-Dummy Clinical Trial Comparing Sublingual Buprenorphine And Morphine Solution For The Treatment Of Neonatal Opioid Abstinence Syndrome

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

63

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19107
        • Thomas Jefferson University Hosptial

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Length of Treatment
Time Frame: 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.
Patients will be followed for the duration of hospital stay, an expected average of 5 weeks.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Length of Hospitalization
Time Frame: 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.
Duration of hospital stay is an expected average of 5 weeks.
Number of Patients Requiring Supplemental Phenobarbital Treatment.
Time Frame: 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.
Patients will be followed for the duration of hospital stay, an expected average of 5 weeks.
Number of Participants With Adverse Events as a Measure of Safety and Tolerability
Time Frame: 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.
Patients will be followed for the duration of hospital stay, an expected average of 5 weeks.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Thomas Jefferson University

Collaborators

National Institute on Drug Abuse (NIDA)

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2011

Primary Completion (Actual)

June 1, 2016

Study Completion (Actual)

June 1, 2016

Study Registration Dates

First Submitted

October 4, 2011

First Submitted That Met QC Criteria

October 14, 2011

First Posted (Estimate)

October 17, 2011

Study Record Updates

Last Update Posted (Actual)

March 24, 2020

Last Update Submitted That Met QC Criteria

March 10, 2020

Last Verified

March 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 11F.193
  • R01DA029076-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Interested investigators should contact the PI listed on clinicaltrials.gov. Study protocol, statistical action plan and informed consent are available in the public domain as a supplement to the publication https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662132/

IPD Sharing Time Frame

Available after Jan. 1, 2020

IPD Sharing Access Criteria

PI and co-investigators will have discretion to share data with potential collaborators.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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