Study to Evaluate Efficacy and Safety of Oral Treprostinil in Subjects With Pulmonary Hypertension (PH) Associated With Sickle Cell Disease (SCD)

A Phase 3, Multicenter, Randomized, Placebo-controlled Study to Evaluate Efficacy and Safety of Oral Treprostinil in Subjects With Pulmonary Hypertension Associated With Sickle Cell Disease

This is a multicenter, randomized (2:1; oral treprostinil:placebo), double-blind, placebo-controlled event-driven (time to pulmonary hypertension [PH] clinical worsening) study in subjects with PH associated with sickle cell disease (SCD). Once enrolled, subjects will be evaluated at Weeks 6, 12, 24, and then every 12 weeks for the duration of the study. Subjects will be permitted to enter a 48-week open-label extension period if they experience a PH clinical worsening event.

Study Overview

• Status: Withdrawn
• Conditions: Pulmonary Hypertension Associated With Sickle Cell Disease
• Intervention / Treatment: Drug: Oral Treprostinil; Drug: Placebo

• Study Type: Interventional
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. The subject must have a diagnosis of SCD confirmed by hemoglobin electrophoresis.
2. The subject has a diagnosis of symptomatic World Health Organization (WHO) Group 5.1 chronic hemolytic anemia PH.
3. The subject must have a Baseline 6MWD greater than 150 meters, in the absence of a concurrent injury, illness, or other confounding factor.
4. The subject has pulmonary function tests conducted within 6 months of Screening or during the Screening period.
5. The subject must be on stable doses of other medical therapy for at least 30 days prior to randomization with no dose adjustments, additions, or discontinuations.
6. The subject must be optimally treated with conventional PH therapy for at least 10 days prior to randomization with no additions, discontinuations, or dose changes.
7. Subjects receiving an endothelin receptor antagonist (ERA) must have been receiving therapy for greater than 90 days, and have reached and maintained a stable dose for a minimum of 30 days prior to randomization.
8. Subjects receiving calcium channel blockers must have been on a stable dose for a minimum of 3 months prior to randomization.

Exclusion Criteria:

1. The subject is pregnant or lactating.
2. The subject has previously received oral treprostinil or is receiving a phosphodiesterase type 5 inhibitor (PDE5-I).
3. The subject has received a prostacyclin within 30 days prior to start of the study, or had previous intolerance or significant lack of efficacy to any prostacyclin or prostacyclin analogue that resulted in discontinuation or inability to titrate that therapy effectively.
4. The subject has had any other background conventional therapies for PH added, removed, or doses adjusted within 10 days prior to randomization.
5. The subject has any disease associated with pulmonary arterial hypertension (PAH).
6. The subject has had a vaso-occlusive crisis, acute chest syndrome event, or unscheduled transfusion within 30 days of randomization.
7. The subject has a history of ischemic heart disease, including a previous myocardial infarction or symptomatic coronary artery disease, within 6 months prior to Screening or a left ventricular ejection fraction less than 40% assessed by either multigated angiogram (MUGA), angiography, or echocardiogram.
8. The subject has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels 3 times or greater than the upper limit of normal, clinically significant liver disease/dysfunction, or known Child-Pugh Class B or C hepatic disease at Screening.
9. The subject has chronic renal insufficiency, as defined by the requirement for dialysis.
10. The subject has a musculoskeletal disorder, any disease that is likely to limit ambulation, or is connected to a machine that is not portable.
11. The subject has an unstable psychiatric condition or is mentally incapable of understanding the objectives, nature, or consequences of the study, or has any condition which in the Investigator's opinion would constitute an unacceptable risk to the subject's safety.
12. The subject is receiving an investigational drug, has an investigational device in place, or has participated in an investigational drug or device study within 30 days prior to Screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oral Treprostinil; Extended-release oral tablet for three times daily (TID) administration	Drug: Oral Treprostinil; Extended-release oral tablet for TID administration
Placebo Comparator: Placebo; Placebo (sugar pill) for TID administration	Drug: Placebo; Matching placebo for TID administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of oral treprostinil compared with placebo on time to first adjudicated PH clinical worsening (morbidity or mortality) event in subjects with PH associated with SCD	Clinical worsening is defined as the occurrence of any 1 of the following events: hospitalization related to PH and/or right heart failure, initiation of an infused prostacyclin to treat worsening PH, decrease in 6-Minute Walk Distance (6MWD) >15% from Baseline directly related to disease under study.	Baseline until the first adjudicated PH clinical worsening event, assessed up to approximately 4 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Effect of oral treprostinil compared with placebo on exercise capacity as assessed by 6-Minute Walk Distance (6MWD)	Baseline to Week 24
Effect of oral treprostinil compared with placebo on combined 6MWD/Borg dyspnea score	Baseline to Week 24
Effect of oral treprostinil compared with placebo on Borg dyspnea score	Baseline to Week 24
Effect of oral treprostinil compared with placebo on N-Terminal pro-brain natriuretic peptide (NT-proBNP) levels	Baseline to Week 24
Effect of oral treprostinil compared with placebo on maximal tricuspid regurgitant velocity (TRV) assessed by transthoracic Doppler echocardiography	Baseline to Week 24

Collaborators and Investigators

• Sponsor: United Therapeutics

Study record dates

Study Major Dates

• Study Start (Anticipated): June 1, 2017
• Primary Completion (Anticipated): December 1, 2021
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: January 27, 2017
• First Submitted That Met QC Criteria: February 13, 2017
• First Posted (Actual): February 16, 2017

Study Record Updates

• Last Update Posted (Actual): April 11, 2017
• Last Update Submitted That Met QC Criteria: April 7, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: PH; sickle cell; Oral treprostinil; 6-Minute Walk Distance
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Hypertension; Anemia, Sickle Cell; Hypertension, Pulmonary; Antihypertensive Agents; Treprostinil
• Other Study ID Numbers: TDE-SC-301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No