Hepatic FailurePhase 4NCT01846455

Single Dose Pharmacokinetics of Suboxone Study in Hepatic Impaired Subjects

A Phase 4 study testing 2.0mg Buprenorphine/0.5mg Naloxone and Promethazine in people with Hepatic Failure and Hepatic Impairment, run by Indivior Inc. at 3 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

Search all trials

Trial summary

The objective was to determine if hepatitis C virus (HCV) infection or mild to severe hepatic impairment (Child-Pugh Classes A, B, and C) altered the PK of buprenorphine, norbuprenorphine, or naloxone. Read more about this study

Who is it for?: Ages 18 to 65 yearsHealthy volunteers can take part
Conditions the study is for: Hepatic Failure, Hepatic Impairment, Chronic Hepatitis C Infection With Hepatic Coma
What is being tested?: 2.0mg Buprenorphine/0.5mg Naloxone and Promethazine
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 43 participants
Where: 3 sitesUnited States
Study dates: Sep 2012to May 2013
Phase: Phase 4
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 65 years
All sexes
Healthy volunteers accepted
Adult, Older adult

Who may be able to join

Males or females between the ages of 18 and 65 years, inclusive
Females should be surgically sterile, 2 years post-menopausal or have a negative plasma β-human chorionic gonadotropin (β-hCG) pregnancy test. Subjects of child-bearing potential must take reasonable precautions during the study to avoid pregnancy by agreeing to remain abstinent or to practice double-barrier forms of birth control from the time of informed consent through the last study visit. A negative plasma pregnancy (β-hCG) test at Screening and upon admission to the investigational site. Testing for β-hCG will need to be timed to ensure a negative pregnancy result at Day 1.
Male subject agrees to use barrier contraception and spermicide when engaging in sexual activity with a female of child-bearing potential for at least 28 days after the study medication dose.
Male subject agrees to refrain from sperm donations for the entire duration of the study and for at least 90 days after the study drug dose.
Body mass index (BMI) of ≥ 18 to ≤ 33 kg^m2.
Subject agrees to the conditions of the study and signs the informed consent form

Who cannot join

Medical conditions: (a) pregnancy; and (b) breastfeeding
Psychiatric conditions: (a) current treatment for opioid addiction with substitution therapies; (b) active history of bipolar I, bipolar II, schizophrenia, schizophreniform; schizoaffective; mania, hypomania, or severe post-traumatic stress disorder; and (c) presence of suicidal behavior within the year before informed consent or suicidal intent within the 30 days before informed consent as documented by the Columbia Suicide Severity Rating Scale
Hypersensitivity to opioids, defined as intractable vomiting, severe constipation, or severe pruritus after opioid treatment
Subject has a known intolerance or hypersensitivity to buprenorphine or naloxone or any excipients in the Suboxone tablet formulation
In the judgment of the investigator, any other condition that would preclude safe, useful, or consistent participation in the study
Use of any investigational medication or investigational medical device in the 30 days before informed consent

Show all 18Show fewer

Hepatic encephalopathy greater than West Haven Grade 2
Donation of > 250 ml of blood within previous 30 days
Systolic BP ≤ 90 or ≥ 160 mmHg and/or Diastolic BP < 60 mmHg or > 100 mmHg
History of cholecystectomy
History or current acquired immunodeficiency syndrome (AIDS) or human immunodeficiency virus (HIV) antibodies
Estimated creatinine clearance rate (eC Cr) using Cockcroft-Gault formula < 60 mL/min
More than 1 missed appointment during Screening
Currently under mandate by the criminal justice system or Child and Family Services to participate in drug abuse treatment
Participation in drug or alcohol dependence treatment in the 30 days before informed consent
Positive urine drug screen result for amphetamines, methamphetamine, barbiturates, benzodiazepines, buprenorphine, cannabinoids, cocaine, methadone, opioids, oxycodone, or phencyclidine which, in the judgment of the investigator, is indicative of non-prescribed drug use; and/or positive urine alcohol screen result in which, in the judgment of the investigator, is indicative of alcohol abuse or alcoholism
Consumption of prohibited medications within 1 week of informed consent, including buprenorphine
Consumption of grapefruit and grapefruit juice for at least one week before the study dose and until the end of the study

Trial locations and contacts

3 sites in 1 country.

United States3 sites

Clinical Pharmacology of Miami, Inc.
Hialeah, Florida, 33014-3616
Orlando Clinical Research Center
Orlando, Florida, 32809
American Research Corporation (ARC)
San Antonio, Texas, 78215

Other trials in United States

About this study

Official title: Pharmacokinetics of Buprenorphine and Naloxone in Subjects With Mild to Severe Hepatic Impairment (Child-Pugh Classes, A, B, and C), in HCV-Seropositive Subjects, and in Healthy Volunteers

Read the detailed description

This will be a multi-center, open-label study. After providing informed consent, subjects will undergo an outpatient screening period of up to 21 days. Screening procedures will include an assessment of mental status which will be repeated before dosing. Eligible subjects will then undergo hospital intake procedures and reside at the investigational site until Day 5. Subjects will be enrolled in 5-treatment groups as follows: (1) Group 1: Subjects with hepatic impairment classified as Child-Pugh A; (2) Group 2: Subjects with hepatic impairment classified as Child-Pugh B; (3) Group 3: Subjects with hepatic impairment classified as Child-Pugh C; (4) Group 4: Subjects with Hepatitis C Virus (HCV) infection but without hepatic impairment; and (5) Group 5: Subjects without hepatic disease or impairment. Group 5 is used as a control group

Conditions: Hepatic Failure, Hepatic Impairment, Chronic Hepatitis C Infection With Hepatic Coma
Being tested: 2.0mg Buprenorphine/0.5mg Naloxone, Promethazine
Keywords: Hepatic, Hepatitis C Virus, Suboxone, Buprenorphine, Naloxone
Medical subject headings: Liver Failure, Hepatitis C

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

2.0mg Buprenorphine/0.5mg NaloxoneDrug
Also called Suboxone®
Each participant received a single sublingual dose of Suboxone® on Day 1 following a fast of at least 8 hours prior to dosing and 2 hours after dosing.
PromethazineDrug
Each participant received a 25-mg or 50-mg promethazine oral dose 30 minutes before Suboxone® administration and then 25-mg promethazine orally or by rectal suppositories every 4 hours as needed for nausea and vomiting during the first 48 hours after Suboxone® administration.

Study groups in NCT01846455
Study group	Role	What they receive
Hepatic Impairment: Child-Pugh A	Experimental	Participants with chronic liver disease and classified as Child-Pugh Grade A had a score of 5-6 (out of 15) which correlates with a good prognosis. Each participant received one sublingual tablet of Suboxone® (2mg buprenorphine with 0.5 mg naloxone) on Day 1. Receives: Drug: 2.0mg Buprenorphine/0.5mg Naloxone; Drug: Promethazine
Hepatic Impairment: Child-Pugh B	Experimental	Participants with chronic liver disease and classified as Child-Pugh Grade B had a score of 7-9 (out of 15) which correlates with significant functional liver compromise. Each participant received one sublingual tablet of Suboxone® (2mg buprenorphine with 0.5 mg naloxone) on Day 1. Receives: Drug: 2.0mg Buprenorphine/0.5mg Naloxone; Drug: Promethazine
Hepatic Impairment: Child-Pugh C	Experimental	Participants with chronic liver disease and classified as Child-Pugh Grade C had a score of 10-15 (out of 15) which correlates with decompensated liver disease. Each participant received one sublingual tablet of Suboxone® (2mg buprenorphine with 0.5 mg naloxone) on Day 1. Receives: Drug: 2.0mg Buprenorphine/0.5mg Naloxone; Drug: Promethazine
HCV Without Hepatic Impairment	Experimental	Participants with hepatitis C virus (HCV) without hepatic impairment received one sublingual tablet of Suboxone® (2mg buprenorphine with 0.5 mg naloxone) on Day 1. Receives: Drug: 2.0mg Buprenorphine/0.5mg Naloxone; Drug: Promethazine
No Hepatic Disease or Impairment	Active comparator	Participants with no hepatic disease or impairment received one sublingual tablet of Suboxone® (2mg buprenorphine with 0.5 mg naloxone) on Day 1. Receives: Drug: 2.0mg Buprenorphine/0.5mg Naloxone; Drug: Promethazine

What is being measured

The primary outcome is the main question the study is designed to answer.

Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide
AUC0-last was calculated for buprenorphine, norbuprenorphine, naloxone, and naloxone-3-β-D-glucuronide using non-compartmental analysis:
AUC0-last = AUC from time 0 to the time of the last measurable plasma concentration, calculated using the linear trapezoidal rule.
Measured: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide
Measured: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide
The extrapolation to infinity was done using the terminal phase.
AUC0-inf = AUC0-last + Ct/λz
Where Ct was the last observed quantifiable concentration and λz was the apparent terminal phase elimination rate constant.
Measured: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide
Measured: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Time of the Last Measureable Plasma Concentration (Tlast) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide
Measured: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Percentage of Area Under the Concentration-time Curve From Time Zero to Infinity Due to Extrapolation (%AUCextrap) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide
Calculated as:
(AUC0-inf - AUC0-last)/AUC0-inf * 100
AUC0-inf, apparent body clearance (CL/F), and apparent volume of distribution during terminal phase (Vz/F) would not have been reported if %AUCextrap was > 20%.
Measured: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Terminal Phase Elimination Rate-Constant (λz) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide
For the determination of λz, only those data points judged to describe the terminal log-linear decline resulting in an adjusted coefficient of determination value (R2) > 0.7 were used in the regression. A minimum of 3 data points were used in calculating λz.
Measured: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Terminal Elimination Half-life (t1/2) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide
Terminal elimination half-life, calculated as ln(2)/λz. The terminal phase elimination half-life was calculated over a period of at least 2 half-lives.
Measured: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Apparent Body Clearance (CL/F) of Buprenorphine and Naloxone
Apparent body clearance (only for buprenorphine and naloxone), calculated as Dose/AUC0-inf.
Measured: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Apparent Volume of Distribution During Terminal Phase (Vz/F) of Buprenorphine and Naloxone
Apparent volume of distribution during terminal phase (only for buprenorphine and naloxone), calculated as Dose/(λz • AUC0-inf).
Measured: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Sep 2012May 2013

First posted3 May 2013 (estimated)
Study startSep 2012
Primary completionApr 2013
Study completionMay 2013

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Hepatic FailureStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 4
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 43 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01846455
Sponsor's protocol ID: RB-US-08-0003
Status last verified: Sep 2016
First submitted: 1 May 2013
Last updated: 24 Oct 2016
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
Individual data sharing: No

Publications

Nasser AF, Heidbreder C, Liu Y, Fudala PJ. Pharmacokinetics of Sublingual Buprenorphine and Naloxone in Subjects with Mild to Severe Hepatic Impairment (Child-Pugh Classes A, B, and C), in Hepatitis C Virus-Seropositive Subjects, and in Healthy Volunteers. Clin Pharmacokinet. 2015 Aug;54(8):837-49. doi: 10.1007/s40262-015-0238-6.
PubMed 25603822

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

Not yet recruiting
Double Plasma Separation and Adsorption in Acute-on-Chronic Liver Failure (DPMAS-ACLF Trial)
Acute-on-Chronic Liver Failure (ACLF)
Not yet recruiting
Vitamin C for Acute Kidney Injury in ACLF With Septic Shock: A Randomized Controlled Trial
Acute-on-Chronic Liver Failure (ACLF)
Active, not recruiting
LiverPAL: A Trial of Inpatient Palliative Care for Patients With Advanced Liver Disease
Liver Disease Chronic, End Stage Liver DIsease
RecruitingObservational study
Establishing a Reference Framework for Outcomes After Machine-Preserved Liver Transplantation in Europe
End-stage Liver Disease (ESLD), Acute Liver Failure
Not yet recruiting
Effect of Mini-Program Monitoring on Hepatic Encephalopathy in Post-TIPS Patients
Hepatic Encephalopathy, Liver Cirrhosis

All Hepatic Failure trials

Study at a glance

From the registry record, last updated by the sponsor on 24 Oct 2016. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Pharmacokinetics of Buprenorphine and Naloxone in Subjects With Mild to Severe Hepatic Impairment (Child-Pugh Classes, A, B, and C), in HCV-Seropositive Subjects, and in Healthy Volunteers
ClinicalTrials.gov ID: NCT01846455
Acronym / sponsor ID: RB-US-08-0003
Conditions: Hepatic Failure, Hepatic Impairment, Chronic Hepatitis C Infection With Hepatic Coma
Keywords: Hepatic, Hepatitis C Virus, Suboxone, Buprenorphine, Naloxone
Phase: Phase 4
Study type: Interventional
Recruitment status: Completed
Enrolment: 43 participants (actual)
Lead sponsor: Indivior Inc.Industry (pharma, biotech, devices)
Study start: Sep 2012
Primary completion: Apr 2013 (actual)
Study completion: May 2013 (actual)
First posted: 3 May 2013 (estimated)
Results: Posted 24 Oct 2016

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 5

Arm	Type	Receives
Hepatic Impairment: Child-Pugh A	Experimental	Drug: 2.0mg Buprenorphine/0.5mg Naloxone, Drug: PromethazineParticipants with chronic liver disease and classified as Child-Pugh Grade A had a score of 5-6 (out of 15) which correlates with a good prognosis. Each participant received one sublingual tablet of Suboxone® (2mg buprenorphine with 0.5 mg naloxone) on Day 1.
Hepatic Impairment: Child-Pugh B	Experimental	Drug: 2.0mg Buprenorphine/0.5mg Naloxone, Drug: PromethazineParticipants with chronic liver disease and classified as Child-Pugh Grade B had a score of 7-9 (out of 15) which correlates with significant functional liver compromise. Each participant received one sublingual tablet of Suboxone® (2mg buprenorphine with 0.5 mg naloxone) on Day 1.
Hepatic Impairment: Child-Pugh C	Experimental	Drug: 2.0mg Buprenorphine/0.5mg Naloxone, Drug: PromethazineParticipants with chronic liver disease and classified as Child-Pugh Grade C had a score of 10-15 (out of 15) which correlates with decompensated liver disease. Each participant received one sublingual tablet of Suboxone® (2mg buprenorphine with 0.5 mg naloxone) on Day 1.
HCV Without Hepatic Impairment	Experimental	Drug: 2.0mg Buprenorphine/0.5mg Naloxone, Drug: PromethazineParticipants with hepatitis C virus (HCV) without hepatic impairment received one sublingual tablet of Suboxone® (2mg buprenorphine with 0.5 mg naloxone) on Day 1.
No Hepatic Disease or Impairment	Active comparator	Drug: 2.0mg Buprenorphine/0.5mg Naloxone, Drug: PromethazineParticipants with no hepatic disease or impairment received one sublingual tablet of Suboxone® (2mg buprenorphine with 0.5 mg naloxone) on Day 1.

Who may qualify

Ages: 18 to 65 years
Sex: All
Healthy volunteers: Accepted
Age groups: Adult, Older adult

Key inclusion criteria (6 listed)

Males or females between the ages of 18 and 65 years, inclusive
Females should be surgically sterile, 2 years post-menopausal or have a negative plasma β-human chorionic gonadotropin (β-hCG) pregnancy test. Subjects of child-bearing potential must take reasonable precautions during the study to avoid pregnancy by agreeing to remain abstinent or to practice double-barrier forms of birth control from the time of informed consent through the last study visit. A negative plasma pregnancy (β-hCG) test at Screening and upon admission to the investigational site. Testing for β-hCG will need to be timed to ensure a negative pregnancy result at Day 1.
Male subject agrees to use barrier contraception and spermicide when engaging in sexual activity with a female of child-bearing potential for at least 28 days after the study medication dose.
Male subject agrees to refrain from sperm donations for the entire duration of the study and for at least 90 days after the study drug dose.
Body mass index (BMI) of ≥ 18 to ≤ 33 kg^m2.

Key exclusion criteria (18 listed)

Medical conditions: (a) pregnancy; and (b) breastfeeding
Psychiatric conditions: (a) current treatment for opioid addiction with substitution therapies; (b) active history of bipolar I, bipolar II, schizophrenia, schizophreniform; schizoaffective; mania, hypomania, or severe post-traumatic stress disorder; and (c) presence of suicidal behavior within the year before informed consent or suicidal intent within the 30 days before informed consent as documented by the Columbia Suicide Severity Rating Scale
Hypersensitivity to opioids, defined as intractable vomiting, severe constipation, or severe pruritus after opioid treatment
Subject has a known intolerance or hypersensitivity to buprenorphine or naloxone or any excipients in the Suboxone tablet formulation
In the judgment of the investigator, any other condition that would preclude safe, useful, or consistent participation in the study

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
2.0mg Buprenorphine/0.5mg NaloxoneAlso: Suboxone®Each participant received a single sublingual dose of Suboxone® on Day 1 following a fast of at least 8 hours prior to dosing and 2 hours after dosing.	Drug	HCV Without Hepatic Impairment, Hepatic Impairment: Child-Pugh A, Hepatic Impairment: Child-Pugh B, Hepatic Impairment: Child-Pugh C, No Hepatic Disease or Impairment
PromethazineEach participant received a 25-mg or 50-mg promethazine oral dose 30 minutes before Suboxone® administration and then 25-mg promethazine orally or by rectal suppositories every 4 hours as needed for nausea and vomiting during the first 48 hours after Suboxone® administration.	Drug	HCV Without Hepatic Impairment, Hepatic Impairment: Child-Pugh A, Hepatic Impairment: Child-Pugh B, Hepatic Impairment: Child-Pugh C, No Hepatic Disease or Impairment

Primary outcome

Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide
Time frame: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
AUC0-last was calculated for buprenorphine, norbuprenorphine, naloxone, and naloxone-3-β-D-glucuronide using non-compartmental analysis: AUC0-last = AUC from time 0 to the time of the last measurable plasma concentration, calculated using the linear trapezoidal rule.
Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide
Time frame: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide
Time frame: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
The extrapolation to infinity was done using the terminal phase. AUC0-inf = AUC0-last + Ct/λz Where Ct was the last observed quantifiable concentration and λz was the apparent terminal phase elimination rate constant.
Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide
Time frame: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Time of the Last Measureable Plasma Concentration (Tlast) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide
Time frame: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Percentage of Area Under the Concentration-time Curve From Time Zero to Infinity Due to Extrapolation (%AUCextrap) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide
Time frame: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Calculated as: (AUC0-inf - AUC0-last)/AUC0-inf * 100 AUC0-inf, apparent body clearance (CL/F), and apparent volume of distribution during terminal phase (Vz/F) would not have been reported if %AUCextrap was > 20%.
Terminal Phase Elimination Rate-Constant (λz) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide
Time frame: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
For the determination of λz, only those data points judged to describe the terminal log-linear decline resulting in an adjusted coefficient of determination value (R2) > 0.7 were used in the regression. A minimum of 3 data points were used in calculating λz.
Terminal Elimination Half-life (t1/2) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide
Time frame: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Terminal elimination half-life, calculated as ln(2)/λz. The terminal phase elimination half-life was calculated over a period of at least 2 half-lives.
Apparent Body Clearance (CL/F) of Buprenorphine and Naloxone
Time frame: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Apparent body clearance (only for buprenorphine and naloxone), calculated as Dose/AUC0-inf.
Apparent Volume of Distribution During Terminal Phase (Vz/F) of Buprenorphine and Naloxone
Time frame: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing
Apparent volume of distribution during terminal phase (only for buprenorphine and naloxone), calculated as Dose/(λz • AUC0-inf).

Results and safety

Results posted to the registry on 24 Oct 2016, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Hepatic Impairment: Child-Pugh A	9	9
Hepatic Impairment: Child-Pugh B	8	8
Hepatic Impairment: Child-Pugh C	8	8
HCV Without Hepatic Impairment	10	10
No Hepatic Disease or Impairment	8	8

Primary outcome: Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide

Time frame: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing. Geometric mean (Geometric Coefficient of Variation). Unit: ng*hr/mL

Measure	Hepatic Impairment: Child-Pugh A n = 6	Hepatic Impairment: Child-Pugh B n = 7	Hepatic Impairment: Child-Pugh C n = 6	HCV Without Hepatic Impairment n = 6	No Hepatic Disease or Impairment n = 8
Buprenorphine	8.89 (33.3)	14.7 (55.0)	25.2 (53.7)	7.02 (36.5)	8.95 (49.4)
Norbuprenorphine	12.5 (119)	9.51 (71.4)	2.25 (118)	9.91 (43.4)	15.0 (51.8)
Naloxone	0.0726 (41.8)	0.291 (195)	1.28 (60.2)	0.0968 (73.0)	0.0915 (50.9)
Naloxone-3-β-D-Glucuronide	19.3 (31.9)	27.9 (33.6)	20.6 (40.2)	19.1 (21.8)	22.5 (15.8)

Hepatic Impairment: Child-Pugh A vs No Hepatic Disease or Impairment: ratio of parameter means, %: 99.34 (90% CI 66.05 to 149.43)
Hepatic Impairment: Child-Pugh B vs No Hepatic Disease or Impairment: ratio of parameter means, %: 163.88 (90% CI 110.82 to 242.34)
Hepatic Impairment: Child-Pugh C vs No Hepatic Disease or Impairment: ratio of parameter means, %: 281.43 (90% CI 187.10 to 423.33)

Population analysed: The PK population included participants without any major protocol deviations who contributed PK samples and had sufficient evaluable data for the calculation of PK parameters. Eight enrolled participants were excluded due to emesis observed within 4 hours postdose, and two due to protocol violations.

Primary outcome: Maximum Observed Plasma Concentration (Cmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide

Measure	Hepatic Impairment: Child-Pugh A n = 6	Hepatic Impairment: Child-Pugh B n = 7	Hepatic Impairment: Child-Pugh C n = 6	HCV Without Hepatic Impairment n = 6	No Hepatic Disease or Impairment n = 8
Buprenorphine	1.10 (52.2)	1.04 (46.5)	1.40 (27.4)	0.933 (30.5)	0.913 (53.2)
Norbuprenorphine	0.358 (99.0)	0.180 (73.2)	0.128 (60.6)	0.203 (61.0)	0.265 (59.8)
Naloxone	0.0287 (62.7)	0.0773 (159)	0.323 (28.7)	0.0361 (83.8)	0.0286 (68.1)
Naloxone-3-β-D-Glucuronide	9.02 (29.8)	9.03 (21.8)	6.75 (40.0)	6.80 (14.7)	8.12 (30.5)

Hepatic Impairment: Child-Pugh A vs No Hepatic Disease or Impairment: ratio of parameter means, %: 120.02 (90% CI 83.35 to 172.82)
Hepatic Impairment: Child-Pugh B vs No Hepatic Disease or Impairment: ratio of parameter means, %: 107.85 (90% CI 75.85 to 153.36)
Hepatic Impairment: Child-Pugh C vs No Hepatic Disease or Impairment: ratio of parameter means, %: 171.76 (90% CI 117.93 to 250.15)

Primary outcome: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide

Measure	Hepatic Impairment: Child-Pugh A n = 6	Hepatic Impairment: Child-Pugh B n = 7	Hepatic Impairment: Child-Pugh C n = 6	HCV Without Hepatic Impairment n = 6	No Hepatic Disease or Impairment n = 8
Buprenorphine (5,4,5,3,6)	11.0 (30.8)	18.9 (58.4)	25.5 (44.6)	8.61 (22.6)	10.3 (56.0)
Norbuprenorphine (3,3,1,3,3)	25.4 (25.5)	17.1 (77.4)	6.67 (NA)	13.9 (58.6)	16.0 (23.0)
Naloxone (5,6,5,4,7)	0.0671 (18.7)	0.274 (195)	1.45 (57.0)	0.0851 (57.0)	0.0971 (53.4)
Naloxone-3-β-D-Glucuronide (5,7,6,5,4)	21.9 (28.0)	28.9 (32.7)	21.3 (38.5)	21.5 (15.0)	26.0 (12.4)

Hepatic Impairment: Child-Pugh A vs No Hepatic Disease or Impairment: ratio of parameter means, %: 125.19 (90% CI 79.46 to 197.24)
Hepatic Impairment: Child-Pugh B vs No Hepatic Disease or Impairment: ratio of parameter means, %: 220.97 (90% CI 135.33 to 360.81)
Hepatic Impairment: Child-Pugh C vs No Hepatic Disease or Impairment: ratio of parameter means, %: 249.28 (90% CI 162.19 to 383.14)

Primary outcome: Time to Reach the Maximum Plasma Concentration (Tmax) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide

Time frame: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing. Median (Full Range). Unit: hours

Measure	Hepatic Impairment: Child-Pugh A n = 6	Hepatic Impairment: Child-Pugh B n = 7	Hepatic Impairment: Child-Pugh C n = 6	HCV Without Hepatic Impairment n = 6	No Hepatic Disease or Impairment n = 8
Buprenorphine	1.25 (1.00 to 2.00)	1.50 (0.500 to 2.00)	1.00 (0.500 to 2.00)	1.38 (1.00 to 1.50)	1.75 (1.00 to 3.00)
Norbuprenorphine	1.25 (1.00 to 1.25)	1.25 (1.00 to 36.0)	0.875 (0.500 to 6.00)	1.00 (1.00 to 36.0)	1.00 (1.00 to 2.00)
Naloxone	0.875 (0.500 to 1.25)	0.750 (0.500 to 1.50)	0.750 (0.250 to 1.25)	1.00 (0.500 to 1.00)	1.13 (0.500 to 2.00)
Naloxone-3-β-D-Glucuronide	0.500 (0.500 to 1.00)	0.750 (0.500 to 0.750)	0.500 (0.500 to 0.767)	0.750 (0.750 to 1.00)	0.500 (0.500 to 1.50)

Adverse events

Time frame: Days 1 - 21. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Hepatic Impairment: Child-Pugh A	0 of 9 (0%)	8 of 9 (88.9%)	Not reported
Hepatic Impairment: Child-Pugh B	0 of 8 (0%)	7 of 8 (87.5%)	Not reported
Hepatic Impairment: Child-Pugh C	0 of 8 (0%)	6 of 8 (75%)	Not reported
HCV Without Hepatic Impairment	0 of 10 (0%)	10 of 10 (100%)	Not reported
No Hepatic Disease or Impairment	0 of 8 (0%)	8 of 8 (100%)	Not reported

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 24 Oct 2016.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Results publication: PubMed 25603822Nasser AF, Heidbreder C, Liu Y, Fudala PJ. Pharmacokinetics of Sublingual Buprenorphine and Naloxone in Subjects with Mild to Severe Hepatic Impairment (Child-Pugh Classes A, B, and C), in Hepatitis C Virus-Seropositive Subjects, and in Healthy Volunteers. Clin Pharmacokinet. 2015 Aug;54(8):837-49. doi: 10.1007/s40262-015-0238-6.
Individual participant dataSharing planned: No

Related trials for Hepatic Failure

Not yet recruiting
Double Plasma Separation and Adsorption in Acute-on-Chronic Liver Failure (DPMAS-ACLF Trial)
Acute-on-Chronic Liver Failure (ACLF)
Not yet recruiting
Vitamin C for Acute Kidney Injury in ACLF With Septic Shock: A Randomized Controlled Trial
Acute-on-Chronic Liver Failure (ACLF)
Active, not recruiting
LiverPAL: A Trial of Inpatient Palliative Care for Patients With Advanced Liver Disease
Liver Disease Chronic, End Stage Liver DIsease
RecruitingObservational study
Establishing a Reference Framework for Outcomes After Machine-Preserved Liver Transplantation in Europe
End-stage Liver Disease (ESLD), Acute Liver Failure
Not yet recruiting
Effect of Mini-Program Monitoring on Hepatic Encephalopathy in Post-TIPS Patients
Hepatic Encephalopathy, Liver Cirrhosis

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Thomas Lasseter, MD principal investigator

Clinical Pharmacology of Miami, Inc.

Thomas Marabury, MD principal investigator

Orlando Clinical Research Center

Eric J. Lawitz, MD principal investigator

American Research Corporation (ARC)

3 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing 2.0mg Buprenorphine/0.5mg Naloxone and Promethazine in people with Hepatic Failure and Hepatic Impairment, run by Indivior Inc. at 3 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 24 Oct 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 24 Oct 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) of Buprenorphine, Norbuprenorphine, Naloxone and Naloxone-3-β-D-Glucuronide (time frame: before dosing (time 0; Baseline) and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours after dosing). The study lists 10 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01846455, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Oct 2016.