Effect of Hepatic Impairment on the Pharmacokinetics of a Single Dose of TD-9855

NCT ID: NCT04200573

Last Updated: 2021-09-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 31 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-01-13
• Study Completion Date: 2021-08-19

Brief Summary

An open-label study to characterize the effects of mild, moderate, and severe Hepatic Impairment (HI) on the pharmacokinetics (PK) of ampreloxetine following a single oral dose in comparison with healthy volunteers with normal hepatic function.

Detailed Description

This is a multicenter, non-randomized, open label, parallel group, single dose, 2-part study being conducted in adult subjects with mild, moderate, or severe HI (Child-Pugh Class A, B, and C), and in matching healthy subjects. The healthy matching group will be comparable to the corresponding hepatic impairment groups by matching subjects by weight (±20% of group mean), age (±10 years of group mean), and sex (equal ratios across groups).

The study will be conducted in two sequential parts:

In Part A, following a 28-day screening period, 6 subjects each with mild or moderate HI and 6 matching healthy subjects who meet eligibility criteria will be enrolled and administered a single Dose A (Day 1).

In Part B, following a 28-day screening period, 6 subjects with severe hepatic impairment will receive a single Dose A (Day 1). Furthermore, the Sponsor may choose to enroll up to 6 additional healthy subjects in Part B to ensure matching of subjects across all groups for weight, age, and sex is maintained.

Conditions

Symptomatic Neurogenic Orthostatic Hypertension; nOH

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Normal Hepatic Function

Ampreloxetine Dose A single dose administration to subjects with normal hepatic function

Group Type: EXPERIMENTAL

Ampreloxetine

Intervention Type: DRUG

The study drug will be administered orally as a single Dose A tablet

Mild Hepatic Function

Ampreloxetine Dose A single dose administration to subjects with mild hepatic impairment

Group Type: EXPERIMENTAL

Ampreloxetine

Intervention Type: DRUG

The study drug will be administered orally as a single Dose A tablet

Moderate Hepatic Function

Ampreloxetine Dose A single dose administration to subjects with moderate hepatic impairment

Group Type: EXPERIMENTAL

Ampreloxetine

Intervention Type: DRUG

The study drug will be administered orally as a single Dose A tablet

Severe Hepatic Function

Ampreloxetine Dose A single dose administration to subjects with severe hepatic impairment

Group Type: EXPERIMENTAL

Ampreloxetine

Intervention Type: DRUG

The study drug will be administered orally as a single Dose A tablet

Interventions

Ampreloxetine

The study drug will be administered orally as a single Dose A tablet

Intervention Type: DRUG

Other Intervention Names

TD-9855

Eligibility Criteria

Inclusion Criteria

All Subjects:

• has a body mass index (BMI) of 19 to 40 kg/m2, inclusive, and weight of at least 55 kg.
• clinical labs within normal ranges
• creatinine clearance of >70 mL/min
• women must be non-pregnant and non-lactating, male and females must agree to highly effective methods of contraception
• additional criteria apply

Subjects with Impaired Hepatic Function additional criteria:

• Subject has mild (Child-Pugh Class A [5 to 6 points]), moderate (Child-Pugh Class B [7 to 9 points]), or severe (Child-Pugh Class C [10-15 points]) liver disease
• has stable hepatic impairment defined as no clinically significant change in disease status within the last 30 days
• must be on a stable dose of medication and/or treatment regimen at least 30 days before dosing

Exclusion Criteria

Subjects with normal hepatic function:

• history of reactions or hypersensitivity to ampreloxetine or known intolerance to other norepinephrine reuptake inhibitors (NRI) or serotonin norepinephrine reuptake inhibitors (SNRI).
• personal or family history of congenital long QT syndrome
• history of untreated closed angle glaucoma
• history of orthostatic hypotension or orthostatic tachycardia or a history of dizziness, lightheadedness or fainting, or a feeling of blacking out upon standing
• has used nephrotoxic or hepatotoxic medications 30 days before Day-2
• routinely uses more than 2 grams of acetaminophen daily
• has used tobacco-containing products (e.g., cigarettes, cigars, chewing tobacco, snuff, e cigarettes, vaporizers) within 3 months before Screening or has a positive cotinine result at Screening or Day -2
• used any CYP1A2 inhibitor or inducer within 7 days or 5 half lives, whichever is longer, prior to ampreloxetine dosing or requires concomitant use
• has used monoamine oxidase inhibitors (MAO-I) within 7 days or 5 half lives, whichever is longer, prior to ampreloxetine dosing or requires concomitant use

Subjects with impaired hepatic function additional criteria:

• has severe ascites that could potentially interfere with respiratory function
• current severe hepatic encephalopathy
• history of liver transplantation, hepatocellular carcinoma, or acute liver disease
• has biliary liver cirrhosis
• has uncontrolled hypertension (SBP >180 mm Hg and DBP (Diastolic blood pressure) >110 mm Hg)
• has an abnormal ECG at Screening or Day -2, including QTcF (Fridericia's corrected QT Interval) >470 msec

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Theravance Biopharma

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Monitor

Role: STUDY_DIRECTOR

Theravance Biopharma

Locations

Theravance Biopharma Investigational Site

Miami, Florida, United States

Theravance Biopharma Investigational Site

Orlando, Florida, United States

Countries

United States

References

Kanodia J, Giovinazzo H, Yates W, Bourdet DL, McRae MP, Helmke SM, Everson GT. Hepatic Dysfunction Quantified by HepQuant DuO Outperforms Child-Pugh Classification in Predicting the Pharmacokinetics of Ampreloxetine. Clin Pharmacol Ther. 2024 Jul;116(1):186-193. doi: 10.1002/cpt.3265. Epub 2024 Apr 23.

Reference Type: DERIVED

PMID: 38654484 (View on PubMed)

Other Identifiers

0179

Identifier Type: -

Identifier Source: org_study_id