nOH, Symptomatic Neurogenic Orthostatic Hypertension
Conditions
Keywords
Symptomatic neurogenic orthostatic hypertension, hepatic impairment
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.
Interventions
DRUGAmpreloxetine
The study drug will be administered orally as a single Dose A tablet
Sponsors
Theravance Biopharma
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma AUC0-t | Plasma AUC0-t will be measured Day 1 to Day 15 | Estimation of Area under the concentration-time curve, from time zero to the last measured time point |
| Plasma AUC0-inf | Plasma AUC0-inf will be measured from Day 1 to Day 15 | Estimation of AUC from time zero extrapolated to infinity |
| Plasma Cmax | up to Day 21 | Estimation of maximum observed plasma concentration |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of subjects with clinically significant vital sign abnormalities | up to Day 21 | Clinically significant abnormalities in vital signs will be listed and described |
| Number of subjects with change in C-SSRS scores | up to Day 21 | Changes in Columbia suicide severity rating scale (C-SSRS) scores will be listed and described |
Countries
United States
Outcome results
None listed