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

A Phase 1, Open-Label, Single Dose Study to Evaluate the Pharmacokinetics of Ampreloxetine Following a Single-dose in Subjects With Mild, Moderate, and Severe Hepatic Impairment and in Matching Healthy Subjects

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.

Study Overview

• Status: Completed
• Conditions: Symptomatic Neurogenic Orthostatic Hypertension; nOH
• Intervention / Treatment: Drug: Ampreloxetine

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.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33014
      • Theravance Biopharma Investigational Site
    • Orlando, Florida, United States, 32809
      • Theravance Biopharma Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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
• Additional inclusion criteria apply

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
• additional exclusion criteria apply

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
• additional exclusion criteria apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Normal Hepatic Function; Ampreloxetine Dose A single dose administration to subjects with normal hepatic function	Drug: Ampreloxetine; The study drug will be administered orally as a single Dose A tablet; Other Names: TD-9855
Experimental: Mild Hepatic Function; Ampreloxetine Dose A single dose administration to subjects with mild hepatic impairment	Drug: Ampreloxetine; The study drug will be administered orally as a single Dose A tablet; Other Names: TD-9855
Experimental: Moderate Hepatic Function; Ampreloxetine Dose A single dose administration to subjects with moderate hepatic impairment	Drug: Ampreloxetine; The study drug will be administered orally as a single Dose A tablet; Other Names: TD-9855
Experimental: Severe Hepatic Function; Ampreloxetine Dose A single dose administration to subjects with severe hepatic impairment	Drug: Ampreloxetine; The study drug will be administered orally as a single Dose A tablet; Other Names: TD-9855

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma AUC0-t	Estimation of Area under the concentration-time curve, from time zero to the last measured time point	Plasma AUC0-t will be measured Day 1 to Day 15
Plasma AUC0-inf	Estimation of AUC from time zero extrapolated to infinity	Plasma AUC0-inf will be measured from Day 1 to Day 15
Plasma Cmax	Estimation of maximum observed plasma concentration	up to Day 21

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of subjects with clinically significant vital sign abnormalities	Clinically significant abnormalities in vital signs will be listed and described	up to Day 21
Number of subjects with change in C-SSRS scores	Changes in Columbia suicide severity rating scale (C-SSRS) scores will be listed and described	up to Day 21

Collaborators and Investigators

• Sponsor: Theravance Biopharma

Study record dates

Study Major Dates

• Study Start (Actual): January 13, 2020
• Primary Completion (Actual): August 19, 2021
• Study Completion (Actual): August 19, 2021

Study Registration Dates

• First Submitted: December 13, 2019
• First Submitted That Met QC Criteria: December 13, 2019
• First Posted (Actual): December 16, 2019

Study Record Updates

• Last Update Posted (Actual): September 8, 2021
• Last Update Submitted That Met QC Criteria: September 7, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: hepatic impairment; Symptomatic neurogenic orthostatic hypertension
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension
• Other Study ID Numbers: 0179

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Theravance Biopharma, Inc. will not be sharing individual de-identified participant data or other relevant study documents.

Drug and device information, study documents

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