Study of Nalbuphine ER in Participants With Hepatic Impairment

A Phase 1, Open-Label, Non-Randomized, Parallel-Group, Multiple-Escalating-Dose Pharmacokinetic Study of Nalbuphine Extended-Release Oral Tablets in Subjects With Impaired Hepatic Function Compared to Healthy Subjects and Exploratory Effect on Itch

This research study will evaluate the effect of hepatic impairment on the pharmacokinetics (the breakdown of the drug in the body) of parallel-group, multiple oral doses nalbuphine extended release (NAL ER), tablets in people with hepatic impairment (mild, moderate and severe), compared to people with normal liver function. The study will also test the safety and tolerability of the NAL ER, when it is given to participants with mild, moderate and severe hepatic impairment, compared to participants with normal liver function. This protocol will also study the effects of this drug on itching in hepatic impairment participants if they report some itching prior to taking part in this study.

Study Overview

• Status: Completed
• Conditions: Hepatic Impairment
• Intervention / Treatment: Drug: Nalbuphine ER

Detailed Description

The study is a three-center study that will include both a single-ascending-dose (SAD) portion and a multiple-ascending dose (MAD) portion. The PK, safety, and tolerability of single ascending doses (SAD) of NAL ER (4 dose levels) will be evaluated in subjects with mild, moderate and severe hepatic impairment.

The purpose of the SAD will be to assess the safety and PK parameters of the given dose levels in hepatic impaired subjects relative to a selected healthy subject control population as part of the overall NAL ER development program. The SAD will also allow a better understanding of the safety, tolerability and expected steady state PK characteristics in mild and moderate hepatic impairment prior to undertaking safety and itch suppression efficacy studies in this patient population.

In the MAD portion of this study, PK assessment will be carried out at steady state at each respective dose level at steady state during the titration over 13 days up to the highest planned therapeutic dose of 162 mg. It is well documented, in clinical practice and the opiate literature, that gradually increasing the dose of drug with a structured titration can reduce the frequency and severity of the expected AEs associated with initiation of therapy. The NAL ER clinical program utilizes this type of structured titration strategy, starting with once per day dosing at the 27 mg dose of NAL ER, and increasing the dose in a stepwise manner over the next 13 days to the target investigational dose of 162 mg twice daily. Pharmacokinetic steady state is reached

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • 01
    • Miami, Florida, United States, 33146
      • 02
    • Orlando, Florida, United States, 32809
      • 03

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

For participants with Hepatic Impairment (Cohort 1 to 4 and Cohort 6):

• Male or female with stable hepatic impairment, non-smoker and/or light smoker.
• Clinical diagnosis of liver cirrhosis
• Stable for study participation based upon medical history, physical examination, vital signs, ECGs, and screening clinical laboratory evaluations

For Healthy participants (Cohort 5):

• Male or female, non-smoker and/or light smoker (up to 5 cigarettes or equivalent/day)

• Healthy as defined by:

  • Normal hepatic function
  • The absence of clinically significant illness and surgery within 4 weeks prior to dosing.

Exclusion Criteria:

For participants with Hepatic Impairment (Cohort 1 to 4 and Cohort 6):

• Clinically significant unstable medical conditions
• Clinically significant abnormalities of laboratory, ECG, pulse oximetry, or clinical data that would preclude participation in the study.
• History of any illness that might confound the results of the study or pose an additional risk to the participant by participation in the study.

For Healthy participants (Cohort 5):

• Diagnosis of liver disease
• History of heart problems.
• History of significant alcohol abuse or drug abuse

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Part 1 Single Ascending Dose; Participants with mild (group 1), moderate (group 2) and severe (group 3) hepatic impairment received single dose ranging from 27 mg up to 162 mg of NAL ER tablet under fasting conditions. There was a washout period of at least 7 days between the drug administration between each dose level. Participants with no hepatic impairment (group 4) received a single dose of NAL ER of up to 162 mg under fasting conditions.

Drug: Nalbuphine ER; Oral tablet; Other Names: NAL ER

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Maximum Observed Plasma Concentration (Cmax) of NAL ER		Pre-dose and 1.5, 3, 5, 7, 9, 12, 24, 36, 48, and 72 hours post-dose at Day 1 in each dose level
Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of NAL ER		Pre-dose and 1.5, 3, 5, 7, 9, 12, 24, 36, 48, and 72 hours post-dose at Day 1 in each dose level
Part 1: Terminal Elimination Half-Life (T1/2 el) of NAL ER		Pre-dose and 1.5, 3, 5, 7, 9, 12, 24, 36, 48, and 72 hours post-dose at Day 1 in each dose level
Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of NAL ER		Pre-dose and 1.5, 3, 5, 7, 9, 12, 24, 36, 48, and 72 hours post-dose at Day 1 in each dose level
Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of NAL ER		Pre-dose and 1.5, 3, 5, 7, 9, 12, 24, 36, 48, and 72 hours post-dose at Day 1 in each dose level
Part 1: Number of Participants Who Experienced at Least One Treatment Emergent Adverse Event (TEAE)	An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A TEAE was defined as any AE that occurs after the first dose of study drug. TEAEs included both serious and non-serious TEAEs.	From signing the informed consent form up to Day 4
Part 1: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters	The clinical laboratory parameters included the clinical chemistry, hematology, coagulation, and urinalysis. Clinical significance was determined by the investigator.	From signing the informed consent form up to Day 4
Part 1: Number of Participants With Clinically Significant Findings in Vital Sign Parameters	Vital signs measurements included diastolic and systolic blood pressure, heart rate, respiratory rate, and body temperature. Clinical significance was determined by the investigator.	From signing the informed consent form up to Day 4
Part 1: Number of Participants With Clinically Significant Findings in Physical Examination Parameters	Physical examination included examination of at least the following components: head, eyes, ears, nose, throat (HEENT), neck, lungs, abdomen, skin, cardiovascular and musculoskeletal evaluation, and general neurological examination. Clinical significance was determined by the investigator.	From signing the informed consent form up to Day 4
Part 1: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECG)	ECG data included the measurement of heart rate and aggregate PR interval, QRS duration, QT interval, QTcB interval, and QTcF interval.	From signing the informed consent form up to Day 4
Part 1: Number of Participants With Clinically Significant Findings in Pulse Oximetry	Oxygen saturation was measured via pulse oximetry. Pulse oximetry measurements were to be collected within 10 min before or after the specified time point. Clinical significance was determined by the investigator.	Pre-dose and 1.5, 4, 5, and 8 hours post-dose in each dose level

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 2: Change From Baseline in Worst Itch Numerical Rating Scale (WI-NRS)	WI-NRS measure was used determine the severity of itch experienced by participants with hepatic impairment (for Cohort 6 only) at screening. Participants were to complete the two forms (the "Night-time Itch" and the "Daytime Itch") at the same time during the screening visit and the average was taken to determine the baseline severity. The scale was a 0 to 10 rating scale with 10 being the most severe itch experienced and 0 being no itching experienced. Higher score indicated greater severity of itching.	Baseline, Day 16

Collaborators and Investigators

• Sponsor: Trevi Therapeutics
• Collaborators: Syneos Health
• Investigators: Study Director: Chief Development Officer, Trevi Therapeutics, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): June 12, 2019
• Primary Completion (Actual): February 5, 2020
• Study Completion (Actual): February 5, 2020

Study Registration Dates

• First Submitted: May 30, 2019
• First Submitted That Met QC Criteria: July 11, 2019
• First Posted (Actual): July 15, 2019

Study Record Updates

• Last Update Posted (Actual): March 19, 2026
• Last Update Submitted That Met QC Criteria: February 26, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Pharmacokinetic; hepatic impairment; nalbuphine
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Nalbuphine
• Other Study ID Numbers: Protocol 182018 (TR10)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No