Hepatic Impairment
Conditions
Keywords
nalbuphine, Pharmacokinetic, hepatic impairment
Brief summary
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.
Interventions
DRUGNalbuphine ER
Oral tablet
Sponsors
Trevi Therapeutics
Syneos Health
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | From signing the informed consent form up to Day 4 | 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. |
| Part 1: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters | From signing the informed consent form up to Day 4 | The clinical laboratory parameters included the clinical chemistry, hematology, coagulation, and urinalysis. Clinical significance was determined by the investigator. |
| Part 1: Number of Participants With Clinically Significant Findings in Vital Sign Parameters | From signing the informed consent form up to Day 4 | Vital signs measurements included diastolic and systolic blood pressure, heart rate, respiratory rate, and body temperature. Clinical significance was determined by the investigator. |
| Part 1: Number of Participants With Clinically Significant Findings in Physical Examination Parameters | From signing the informed consent form up to Day 4 | 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. |
| Part 1: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECG) | From signing the informed consent form up to Day 4 | ECG data included the measurement of heart rate and aggregate PR interval, QRS duration, QT interval, QTcB interval, and QTcF interval. |
| Part 1: Number of Participants With Clinically Significant Findings in Pulse Oximetry | Pre-dose and 1.5, 4, 5, and 8 hours post-dose in each dose level | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Change From Baseline in Worst Itch Numerical Rating Scale (WI-NRS) | Baseline, Day 16 | 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. |
Countries
United States
Contacts
STUDY_DIRECTORChief Development Officer
Trevi Therapeutics, Inc.
Participant flow
Recruitment details
Participants were enrolled at 3 sites in the United States from 12 June 2019 to 05 February 2020.
Pre-assignment details
A total of 66 participants were screened and 28 participants were enrolled. The study was planned to be conducted in 2 parts: Part 1 (Single Ascending Dose \[SAD\]) followed by Part 2 (Multiple Ascending Dose \[MAD\]). As per the judgement of the safety committee, Part 2 was not conducted based on protocol defined criteria. In Part 1, each cohort was dosed sequentially from lowest dose for mild and moderate impaired participants. Participants in Cohort 1 could also take part in Cohorts 2, 3, and 4.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous Cohort 1 (NAL ER 27 mg): Group 1 | 59.2 years STANDARD_DEVIATION 5.6 |
| Age, Continuous Cohort 1 (NAL ER 27 mg): Group 2 | 62.5 years STANDARD_DEVIATION 5.1 |
| Age, Continuous Cohort 1 (NAL ER 27 mg): Group 3 | 60.3 years STANDARD_DEVIATION 9 |
| Age, Continuous Cohort 2 (NAL ER 54 mg): Group 1 | 59.5 years STANDARD_DEVIATION 4.9 |
| Age, Continuous Cohort 2 (NAL ER 54 mg): Group 2 | 61.3 years STANDARD_DEVIATION 5.6 |
| Age, Continuous Cohort 3 (NAL ER 108 mg): Group 1 | 59.5 years STANDARD_DEVIATION 4.9 |
| Age, Continuous Cohort 3 (NAL ER 108 mg): Group 2 | 60.3 years STANDARD_DEVIATION 6.1 |
| Age, Continuous Cohort 4 (NAL ER 162 mg): Group 1 | 59.3 years STANDARD_DEVIATION 5.3 |
| Age, Continuous Cohort 4 (NAL ER 162 mg): Group 2 | 58.8 years STANDARD_DEVIATION 5.2 |
| Age, Continuous Cohort 5 (NAL ER 162 mg): Group 4 | 55.9 years STANDARD_DEVIATION 5.7 |
| Ethnicity (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 1 Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 1 Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 1 Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 2 Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 2 Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 2 Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 3 Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 3 Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 3 Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Cohort 2 (NAL ER 54 mg): Group 1 Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Cohort 2 (NAL ER 54 mg): Group 1 Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Cohort 2 (NAL ER 54 mg): Group 1 Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Cohort 2 (NAL ER 54 mg): Group 2 Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Cohort 2 (NAL ER 54 mg): Group 2 Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Cohort 2 (NAL ER 54 mg): Group 2 Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Cohort 3 (NAL ER 108 mg): Group 1 Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Cohort 3 (NAL ER 108 mg): Group 1 Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Cohort 3 (NAL ER 108 mg): Group 1 Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Cohort 3 (NAL ER 108 mg): Group 2 Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Cohort 3 (NAL ER 108 mg): Group 2 Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Cohort 3 (NAL ER 108 mg): Group 2 Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Cohort 4 (NAL ER 162 mg): Group 1 Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Cohort 4 (NAL ER 162 mg): Group 1 Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Cohort 4 (NAL ER 162 mg): Group 1 Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Cohort 4 (NAL ER 162 mg): Group 2 Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Cohort 4 (NAL ER 162 mg): Group 2 Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Cohort 4 (NAL ER 162 mg): Group 2 Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Cohort 5 (NAL ER 162 mg): Group 4 Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Cohort 5 (NAL ER 162 mg): Group 4 Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Cohort 5 (NAL ER 162 mg): Group 4 Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 1 American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 1 Asian | 1 Participants |
| Race (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 1 Black or African American | 3 Participants |
| Race (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 1 More than one race | 0 Participants |
| Race (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 1 Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 1 Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 1 White | 2 Participants |
| Race (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 2 American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 2 Asian | 0 Participants |
| Race (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 2 Black or African American | 2 Participants |
| Race (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 2 More than one race | 0 Participants |
| Race (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 2 Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 2 Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 2 White | 4 Participants |
| Race (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 3 American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 3 Asian | 0 Participants |
| Race (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 3 Black or African American | 1 Participants |
| Race (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 3 More than one race | 0 Participants |
| Race (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 3 Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 3 Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Cohort 1 (NAL ER 27 mg): Group 3 White | 3 Participants |
| Race (NIH/OMB) Cohort 2 (NAL ER 54 mg): Group 1 American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Cohort 2 (NAL ER 54 mg): Group 1 Asian | 1 Participants |
| Race (NIH/OMB) Cohort 2 (NAL ER 54 mg): Group 1 Black or African American | 3 Participants |
| Race (NIH/OMB) Cohort 2 (NAL ER 54 mg): Group 1 More than one race | 0 Participants |
| Race (NIH/OMB) Cohort 2 (NAL ER 54 mg): Group 1 Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Cohort 2 (NAL ER 54 mg): Group 1 Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Cohort 2 (NAL ER 54 mg): Group 1 White | 4 Participants |
| Race (NIH/OMB) Cohort 2 (NAL ER 54 mg): Group 2 American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Cohort 2 (NAL ER 54 mg): Group 2 Asian | 0 Participants |
| Race (NIH/OMB) Cohort 2 (NAL ER 54 mg): Group 2 Black or African American | 2 Participants |
| Race (NIH/OMB) Cohort 2 (NAL ER 54 mg): Group 2 More than one race | 0 Participants |
| Race (NIH/OMB) Cohort 2 (NAL ER 54 mg): Group 2 Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Cohort 2 (NAL ER 54 mg): Group 2 Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Cohort 2 (NAL ER 54 mg): Group 2 White | 5 Participants |
| Race (NIH/OMB) Cohort 3 (NAL ER 108 mg): Group 1 American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Cohort 3 (NAL ER 108 mg): Group 1 Asian | 1 Participants |
| Race (NIH/OMB) Cohort 3 (NAL ER 108 mg): Group 1 Black or African American | 3 Participants |
| Race (NIH/OMB) Cohort 3 (NAL ER 108 mg): Group 1 More than one race | 0 Participants |
| Race (NIH/OMB) Cohort 3 (NAL ER 108 mg): Group 1 Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Cohort 3 (NAL ER 108 mg): Group 1 Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Cohort 3 (NAL ER 108 mg): Group 1 White | 4 Participants |
| Race (NIH/OMB) Cohort 3 (NAL ER 108 mg): Group 2 American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Cohort 3 (NAL ER 108 mg): Group 2 Asian | 0 Participants |
| Race (NIH/OMB) Cohort 3 (NAL ER 108 mg): Group 2 Black or African American | 1 Participants |
| Race (NIH/OMB) Cohort 3 (NAL ER 108 mg): Group 2 More than one race | 0 Participants |
| Race (NIH/OMB) Cohort 3 (NAL ER 108 mg): Group 2 Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Cohort 3 (NAL ER 108 mg): Group 2 Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Cohort 3 (NAL ER 108 mg): Group 2 White | 6 Participants |
| Race (NIH/OMB) Cohort 4 (NAL ER 162 mg): Group 1 American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Cohort 4 (NAL ER 162 mg): Group 1 Asian | 0 Participants |
| Race (NIH/OMB) Cohort 4 (NAL ER 162 mg): Group 1 Black or African American | 3 Participants |
| Race (NIH/OMB) Cohort 4 (NAL ER 162 mg): Group 1 More than one race | 0 Participants |
| Race (NIH/OMB) Cohort 4 (NAL ER 162 mg): Group 1 Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Cohort 4 (NAL ER 162 mg): Group 1 Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Cohort 4 (NAL ER 162 mg): Group 1 White | 4 Participants |
| Race (NIH/OMB) Cohort 4 (NAL ER 162 mg): Group 2 American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Cohort 4 (NAL ER 162 mg): Group 2 Asian | 0 Participants |
| Race (NIH/OMB) Cohort 4 (NAL ER 162 mg): Group 2 Black or African American | 1 Participants |
| Race (NIH/OMB) Cohort 4 (NAL ER 162 mg): Group 2 More than one race | 0 Participants |
| Race (NIH/OMB) Cohort 4 (NAL ER 162 mg): Group 2 Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Cohort 4 (NAL ER 162 mg): Group 2 Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Cohort 4 (NAL ER 162 mg): Group 2 White | 5 Participants |
| Race (NIH/OMB) Cohort 5 (NAL ER 162 mg): Group 4 American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Cohort 5 (NAL ER 162 mg): Group 4 Asian | 0 Participants |
| Race (NIH/OMB) Cohort 5 (NAL ER 162 mg): Group 4 Black or African American | 2 Participants |
| Race (NIH/OMB) Cohort 5 (NAL ER 162 mg): Group 4 More than one race | 0 Participants |
| Race (NIH/OMB) Cohort 5 (NAL ER 162 mg): Group 4 Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Cohort 5 (NAL ER 162 mg): Group 4 Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Cohort 5 (NAL ER 162 mg): Group 4 White | 6 Participants |
| Sex: Female, Male Cohort 1 (NAL ER 27 mg): Group 1 Female | 3 Participants |
| Sex: Female, Male Cohort 1 (NAL ER 27 mg): Group 1 Male | 3 Participants |
| Sex: Female, Male Cohort 1 (NAL ER 27 mg): Group 2 Female | 1 Participants |
| Sex: Female, Male Cohort 1 (NAL ER 27 mg): Group 2 Male | 5 Participants |
| Sex: Female, Male Cohort 1 (NAL ER 27 mg): Group 3 Female | 2 Participants |
| Sex: Female, Male Cohort 1 (NAL ER 27 mg): Group 3 Male | 2 Participants |
| Sex: Female, Male Cohort 2 (NAL ER 54 mg): Group 1 Female | 4 Participants |
| Sex: Female, Male Cohort 2 (NAL ER 54 mg): Group 1 Male | 4 Participants |
| Sex: Female, Male Cohort 2 (NAL ER 54 mg): Group 2 Female | 1 Participants |
| Sex: Female, Male Cohort 2 (NAL ER 54 mg): Group 2 Male | 6 Participants |
| Sex: Female, Male Cohort 3 (NAL ER 108 mg): Group 1 Female | 4 Participants |
| Sex: Female, Male Cohort 3 (NAL ER 108 mg): Group 1 Male | 4 Participants |
| Sex: Female, Male Cohort 3 (NAL ER 108 mg): Group 2 Female | 0 Participants |
| Sex: Female, Male Cohort 3 (NAL ER 108 mg): Group 2 Male | 7 Participants |
| Sex: Female, Male Cohort 4 (NAL ER 162 mg): Group 1 Female | 3 Participants |
| Sex: Female, Male Cohort 4 (NAL ER 162 mg): Group 1 Male | 4 Participants |
| Sex: Female, Male Cohort 4 (NAL ER 162 mg): Group 2 Female | 0 Participants |
| Sex: Female, Male Cohort 4 (NAL ER 162 mg): Group 2 Male | 6 Participants |
| Sex: Female, Male Cohort 5 (NAL ER 162 mg): Group 4 Female | 3 Participants |
| Sex: Female, Male Cohort 5 (NAL ER 162 mg): Group 4 Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 15 | 0 / 15 | 0 / 13 | 0 / 8 |
| other Total, other adverse events | 3 / 16 | 5 / 15 | 9 / 15 | 12 / 13 | 5 / 8 |
| serious Total, serious adverse events | 0 / 16 | 0 / 15 | 0 / 15 | 0 / 13 | 0 / 8 |
Outcome results
None listed