Clinical trial NCT04200573: Effect of Hepatic Impairment on the Pharmacokinetics of a Single Dose of TD-9855
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Symptomatic Neurogenic Orthostatic Hypertension
nOH
Keywords: Symptomatic neurogenic orthostatic hypertension
hepatic impairment
Lead sponsor: Theravance Biopharma
Sponsor class: INDUSTRY
First posted: 2019-12-16
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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
* 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

Primary outcomes:
measure: Plasma AUC0-t
timeFrame: Plasma AUC0-t will be measured Day 1 to Day 15
measure: Plasma AUC0-inf
timeFrame: Plasma AUC0-inf will be measured from Day 1 to Day 15
measure: Plasma Cmax
timeFrame: up to Day 21
Secondary outcomes:
measure: Number of subjects with clinically significant vital sign abnormalities
timeFrame: up to Day 21
measure: Number of subjects with change in C-SSRS scores
timeFrame: up to Day 21
Other outcomes:
Locations:
city: Miami
country: United States
facility: Theravance Biopharma Investigational Site
state: Florida
city: Orlando
country: United States
facility: Theravance Biopharma Investigational Site
state: Florida
Study officials:
affiliation: Theravance Biopharma
name: Medical Monitor
role: STUDY_DIRECTOR
References: