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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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nOH, Symptomatic Neurogenic Orthostatic Hypertension

Intervention / Treatment
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* Drug: Ampreloxetine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Symptomatic neurogenic orthostatic hypertension, hepatic impairment