Pharmacokinetics of Oral Treprostinil in Patients With Systemic Sclerosis

Study Overview
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Brief Summary
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This study will assess the pharmacokinetic and safety profile of treprostinil following fixed and escalating doses of treprostinil diethanolamine SR tablets. Open-label, two-part study assessing the pharmacokinetics, safety, and tolerability of oral treprostinil diethanolamine SR. Cohort 1: single 1 mg treprostinil diethanolamine SR dose. Cohort 2: escalating doses of treprostinil diethanolamine SR up to a target dose of 4 mg BID.

Official Title
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An Evaluation of the Pharmacokinetics and Safety of Fixed and Escalating Doses of Oral Treprostinil Diethanolamine (UT-15C) Sustained Release Tablets in Patients With Systemic Sclerosis

Conditions
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Systemic Sclerosis

Intervention / Treatment
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* Drug: treprostinil diethanolamine
* Drug: treprostinil diethanolamine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject gives voluntary written informed consent to participate in the study. Subject has been diagnosed with systemic sclerosis (SSc) as defined by American College of Rheumatology (ACR) criteria. Males and females age greater than 18 years at time of Screening. Presence of active digital ulcer OR history of digital ulcer occurring within past 6 months at time of Screening and poorly controlled Raynaud's phenomenon (as documented by patient report of 6-10 episodes per week). Females of childbearing potential must be willing to use two forms of medically acceptable contraception (at least one barrier method) and have a negative pregnancy test at Screening, confirmed at Baseline if separate visits. Women who are surgically sterile or have been post-menopausal for at least 2 years are not considered to be of child-bearing potential. Subject agrees to abstain from consuming grapefruit containing food or beverages for 3 days prior to Baseline and until discharge from the study. Subject is able to communicate effectively with study personnel and be considered reliable, willing and cooperative in terms of compliance with the protocol requirements. Exclusion Criteria: Has diagnosis of pulmonary arterial hypertension and receiving approved or investigational therapies for PAH, including endothelin receptor antagonists, phosphodiesterase inhibitors, or prostacyclin analogues. Body weight less than 40 kg at time of Screening, confirmed at Baseline. The subject has a history of postural hypotension, unexplained syncope, a blood pressure that is less than 85 mmHg systolic or 50 mmHg diastolic at Screening or Baseline. Hemoglobin concentration less than 75% of the lower limit of the normal range at time of Screening. AST and/or ALT concentrations greater than 3 times upper limit of normal (ULN) at time of Screening. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C. Intractable diarrhea, severe malabsorption, defined as greater than 15% unintentional loss of body weight in the last 6 months prior to Screening, or any severe organ failure (e.g., lung, kidney) or any life-threatening condition. Pregnancy or breast-feeding. Overlap with another connective tissue disease that could affect rest pain and hand function (e.g. diabetes mellitus, rheumatoid arthritis). Sympathectomy of the upper limb performed within 12 months of Baseline. Receipt of parenteral prostanoid treatment (epoprostenol, treprostinil sodium, or other prostacyclin analog) within the previous 3 months for conditions including PAH, rest pain and / or digital ulcers. Treatment with gemfibrozil, glitazones, or cyclophosphamide within 1 week prior to Baseline. Treatment with rifampin within 4 weeks prior to Baseline. Local injection of botulinum toxin in an affected finger within 1 month prior to Baseline. Received systemic antibiotics to treat infection of digital ulcers within 2 weeks prior to Baseline. Treatment with phosphodiesterase inhibitors such as sildenafil, except for intermittent treatment of male erectile dysfunction. Received an investigational product within 1 month preceding Screening. Known hypersensitivity to oral treprostinil or any of the excipients. Cigarette smoking at any level within the past 6 months prior to Screening. Any condition that could prevent compliance with the protocol or adherence to therapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: treprostinil diethanolamine<br> | Drug: treprostinil diethanolamine<br>* Cohort 1: Single 1 mg treprostinil diethanolamine sustained release tablet dose<br>Drug: treprostinil diethanolamine<br>* Cohort 2: treprostinil diethanolamine sustained release doses will be escalated up to a target dose of 4 mg BID<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort 1: treprostinil pharmacokinetics in patients with systemic sclerosis following single oral administration of a 1 mg treprostinil diethanolamine SR dose. |  | pre-24hrs post dose | 
| Cohort 2: treprostinil pharmacokinetics at dose levels of 2 mg BID and 4 mg BID, respectively, in patients with systemic sclerosis following repeated oral administration of treprostinil diethanolamine SR tablets |  | 0-12 hrs post-dose | 
| adverse event monitoring |  | Cohort 1:Day 0 to Day 2; Cohort 2: Day 0 to Day 47 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| clinical laboratories |  | Cohort 1: Day 0 and Day 2; Cohort 2: Day 0 and Day 47 | 
| Cohort 2: Raynauds Phenomenon Visual Analoge Scale |  | 7 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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systemic sclerosis, scleroderma, pharmacokinetics, treprostinil diethanolamine