Buprenorphine Pharmacometric Open Label Research Study of Drug Exposure (B-PHORE)

January 18, 2022 updated by: Thomas Jefferson University

Modeled Dose Exposure of Sublingual Buprenorphine in the Neonatal Opioid Abstinence Syndrome

Neonatal withdrawal syndrome is a series of signs and symptoms in infants exposed to opioids in utero. Buprenorphine has demonstrated a 40% reduction in length of pharmacologic treatment compared to oral morphine. These results were with an empirically derived dose. This study will use pharmacokinetic modeling-informed dosing to clarify the dose/response relationship and use a rational approach to define an optimal dose regimen. The clinical trial will be open label, single arm design with a goal of initial testing of a new dosing regimen.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The overall rationale for this study is to explore new dose regimens in a small number of patients. There is evidence from pharmacometric models with dose simulation that suggest there is room for improvement in buprenorphine dosing. This study will explore these doses. While the endpoint will be primarily pharmacokinetic, it is likely that the revised dose regimen will be more effective and thus holds the potential for benefit for those infants participating. This information will be used to feed back to the model and generate rationally derived, optimal doses to be tested in subsequent efficacy trials.

The neonatal abstinence syndrome (NAS) is a set of signs of withdrawal in an infant with in utero exposure to opioids. Cardinal manifestations include increased muscle tone, autonomic instability, irritability, poor sucking reflex, gastrointestinal symptoms, and impaired weight gain. All infants are treated with non-pharmacologic methods such as swaddling, rooming in with mother and minimization of stimuli. Despite these measures, ~50% of infants require pharmacologic treatment to ensure proper growth and development. While the optimal pharmacologic treatment for NAS has not been identified, expert review identifies an opioid as the primary therapy. In the US 80% of infants are treated with morphine and 20% with methadone. Sublingual buprenorphine has been demonstrated to be safe and effective in an open label phase 1 clinical trial conducted by the Thomas Jefferson University Team [NCT00521248]. These data were used to plan the BBORN (Blinded Buprenorphine OR Neonatal morphine solution) clinical trial [NCT01452789] comparing buprenorphine to morphine for NAS. BBORN demonstrated a 40% reduction in length of treatment compared to morphine in a double blind fashion (New England Journal of Medicine, June 2017). The external validity of this finding has been supported by retrospective examination of buprenorphine used in a treatment paradigm at the University of Cincinnati Medical Center, with a reduction in length of treatment of ~30% in >200 infants.

Dose selection for both the phase 1 trial and the efficacy trial (BBORN) were empirically derived. A population pharmacokinetic model for buprenorphine in NAS has been published by our group. In addition a pre-specified endpoint for the BBORN trial was a pharmacokinetic analysis of buprenorphine. A pharmacokinetic/pharmacodynamic model from the BBORN study has been published (Clinical Pharmacology and Therapeutics, March 2018). The time to control of symptoms was directly tied to buprenorphine exposure, which itself appeared to be driven primarily by clearance. Among the strengths of pharmacometric models is the ability to simulate in silico many potential dose regimens. In this manner, a dose regimen can be chosen that is more likely to be in the desired range of concentrations. This approach also allows for incorporation of covariates of drug exposure or response to treatment. This is much safer and efficient than the traditional approach of choosing an empiric dose that would need to be tested in clinical trial. An ideal dose would quickly reach this exposure while maintaining a good safety margin. There was no evidence of decline in respiratory rate in infants treated with higher doses of buprenorphine compared to lower doses, or those treated with buprenorphine compared to those treated with morphine. This may allow a higher initial dose to more quickly reach therapeutic buprenorphine concentrations. This ultimately could lead to shorter lengths of treatment and stay, though achieving this goal is outside of the scope of the current proposed project.

In summary, buprenorphine at the dose and schedule used in prior clinical trials has been demonstrated to be safe and effective. The goal of the proposed study is to simulate a dose of sublingual buprenorphine for NAS using pharmacometric modelling techniques. This dose will be tested in infants requiring treatment for NAS. Pharmacokinetic samples would be collected and used to confirm and refine the pharmacokinetic model. The proposed study would allow broad examination and refinement of the exposure/response relationship. This optimized dose could later be used in an efficacy trial.

Study Type

Interventional

Enrollment (Actual)

10

Phase

  • Phase 2
  • Phase 1

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

No older than 1 year (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. ≥ 36 weeks gestation
  2. Exposure to opioids in utero
  3. Demonstration of signs and symptoms of neonatal abstinence syndrome requiring pharmacologic treatment

Exclusion Criteria:

  1. Major congenital malformations and/or intrauterine growth retardation, defined as birth weight <2000 gm
  2. Medical illness requiring intensification of medical therapy. This includes but is not limited to suspected sepsis requiring antibiotic therapy.
  3. Hypoglycemia requiring treatment with intravenous dextrose
  4. Bilirubin >20 mg/dL (The need for phototherapy is not exclusionary)
  5. 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: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: buprenorphine

Buprenorphine 0.075 mg ml sublingual solution

Initial daily dose 24 mcg/kg/day Initial unit dose 8 mcg/kg q8 hours Maximum daily dose 75 mcg/kg/day Maximum unit dose 25 mcg/kg q8 hours Up-titration rate 33% Maximum # of up-titrations 4 Weaning rate 15% Cessation (bottom) dose < Initial dose Dosing interval until bottom dose (hrs) 8 Dose interval extension #1 at bottom dose (hrs) 12 Dose interval extension #2 at bottom dose (hrs) 24
Drug: Buprenorphine
buprenorphine 0.075 mg/ml solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Buprenorphine Pharmacokinetics
Time Frame: Duration of pharmacologic treatment for neonatal abstinence syndrome up to 70 days of age
Goal is to define buprenorphine pharmacokinetic exposure (Area under the plasma concentration versus time curve (AUC)) in infants treated with buprenorphine for neonatal abstinence syndrome (NAS) using a model-based optimized dose.
Duration of pharmacologic treatment for neonatal abstinence syndrome up to 70 days of age

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants With Treatment Related Adverse Events
Time Frame: Duration of pharmacologic treatment for neonatal abstinence syndrome, up to 70 days of age
The number of participants with treatment related adverse events
Duration of pharmacologic treatment for neonatal abstinence syndrome, up to 70 days of age
Length of Treatment
Time Frame: Duration of pharmacologic treatment for neonatal abstinence syndrome up to 70 days of age
Length of treatment with buprenrophine for NAS (hours) of a model-based optimized dose of buprenorphine for infants treated for NAS.
Duration of pharmacologic treatment for neonatal abstinence syndrome up to 70 days of age

Collaborators and Investigators

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

Sponsor

Thomas Jefferson University

Collaborators

Chiesi Farmaceutici S.p.A.

Investigators

  • Principal Investigator: Walter K Kraft, MD, Thomas Jefferson 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

Helpful Links

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 (Actual)

August 29, 2018

Primary Completion (Actual)

July 11, 2019

Study Completion (Actual)

July 11, 2019

Study Registration Dates

First Submitted

June 25, 2018

First Submitted That Met QC Criteria

July 23, 2018

First Posted (Actual)

August 1, 2018

Study Record Updates

Last Update Posted (Actual)

February 11, 2022

Last Update Submitted That Met QC Criteria

January 18, 2022

Last Verified

January 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 18C.272

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

The sharing plan has not yet been defined

IPD Sharing Time Frame

until 2024

IPD Sharing Access Criteria

Consent of principal investigator or designee, with data use agreement in place

IPD Sharing Supporting Information Type

  • Study Protocol
  • Statistical Analysis Plan (SAP)
  • Informed Consent Form (ICF)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

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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