Pharmacokinetics of Oral Treprostinil in Patients With Systemic Sclerosis (DISTOL-PK)

• Cohort 1: treprostinil pharmacokinetics in patients with systemic sclerosis following single oral administration of a 1 mg treprostinil diethanolamine SR dose. [ Time Frame: pre-24hrs post dose ] [ Designated as safety issue: No ]
• 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 [ Time Frame: 0-12 hrs post-dose ] [ Designated as safety issue: No ]
• adverse event monitoring [ Time Frame: Cohort 1:Day 0 to Day 2; Cohort 2: Day 0 to Day 47 ] [ Designated as safety issue: Yes ]

• clinical laboratories [ Time Frame: Cohort 1: Day 0 and Day 2; Cohort 2: Day 0 and Day 47 ] [ Designated as safety issue: Yes ]
• Cohort 2: Raynauds Phenomenon Visual Analoge Scale [ Time Frame: 7 weeks ] [ Designated as safety issue: No ]

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.

• Drug: treprostinil diethanolamine
  Cohort 1: Single 1 mg treprostinil diethanolamine sustained release tablet dose
• Drug: treprostinil diethanolamine
  Cohort 2: treprostinil diethanolamine sustained release doses will be escalated up to a target dose of 4 mg BID

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.