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

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

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.

Study Overview

• Status: Completed
• Conditions: Systemic Sclerosis
• Intervention / Treatment: Drug: treprostinil diethanolamine; Drug: treprostinil diethanolamine

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins Scleroderma Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston University School of Medicine Rheumatology Arthritis Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48016
      • University of Michigan Scleroderma Program

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: treprostinil diethanolamine	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: United Therapeutics
• Investigators: Study Director: Kristan Rollins, PharmD, United Therapeutics

Publications and helpful links

General Publications

• Shah AA, Schiopu E, Hummers LK, Wade M, Phillips K, Anderson C, Wise R, Boin F, Seibold JR, Wigley F, Rollins KD. Open label study of escalating doses of oral treprostinil diethanolamine in patients with systemic sclerosis and digital ischemia: pharmacokinetics and correlation with digital perfusion. Arthritis Res Ther. 2013 Apr 18;15(2):R54. doi: 10.1186/ar4216.

Study record dates

Study Major Dates

• Study Start: December 1, 2008
• Primary Completion (Actual): January 1, 2010
• Study Completion (Actual): April 1, 2010

Study Registration Dates

• First Submitted: February 19, 2009
• First Submitted That Met QC Criteria: February 19, 2009
• First Posted (Estimate): February 20, 2009

Study Record Updates

• Last Update Posted (Estimate): October 23, 2012
• Last Update Submitted That Met QC Criteria: October 19, 2012
• Last Verified: October 1, 2012

More Information

Terms related to this study

• Keywords: pharmacokinetics; systemic sclerosis; scleroderma; treprostinil diethanolamine
• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Connective Tissue Diseases; Sclerosis; Scleroderma, Systemic; Scleroderma, Diffuse; Antihypertensive Agents; Treprostinil
• Other Study ID Numbers: TDE-DU-101

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No