Open-label, Clinical Study to Evaluate the Safety and Tolerability of TreT in Subjects With PAH Currently Using Tyvaso

Study Overview
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Brief Summary
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This is a Phase 1b safety and tolerability single-sequence study in which PAH subjects on a stable regimen of Tyvaso will switch to a corresponding dose of TreT.

Detailed Description
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United Therapeutics Corporation (UTC) is developing a combination drug-device product which is comprised of a dry powder formulation of Treprostinil Inhalation Powder (TreT) and a small, portable, dry powder inhaler. In this Phase 1b safety and tolerability study, patients with PAH on a stable dose of Tyvaso (6 to 12 breaths 4 times daily [QID]) will be evaluated after switching to a corresponding dose of TreT. Patients will undergo PK assessments, safety assessments, a 6-Minute Walk Test (6MWT), and questionnaires for satisfaction/preference for inhaled devices and patient-reported PAH symptoms and impact. Following 3 weeks of treatment with TreT, patients will be offered the opportunity to participate in the Optional Extension Phase until the study terminates or the drug/device becomes commercially available.

Official Title
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An Open-label, Clinical Study to Evaluate the Safety and Tolerability of Treprostinil Inhalation Powder (TreT) in Subjects With Pulmonary Arterial Hypertension Currently Using Tyvaso

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: Treprostinil Inhalation Powder


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject voluntarily gives informed consent to participate in the study. Subject is aged 18 years or older at the time of signing informed consent. Women of childbearing potential are those who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal (defined as amenorrhea for at least 12 consecutive months). WOCBP must be nonpregnant (as confirmed by a urine pregnancy test at Screening prior to initiating study medication), nonlactating, and will do 1 of the following: Abstain from intercourse (when it is in line with their preferred and usual lifestyle), or Use 2 medically acceptable, highly effective forms of contraception for the duration of study, and at least 30 days after discontinuing TreT. Medically acceptable, highly effective forms of contraception can include approved hormonal contraceptives (oral, injectable, and implantable), intrauterine devices or systems, and barrier methods (such as a condom or diaphragm) when used with a spermicide. Males with a partner of childbearing potential must use a condom for the duration of treatment and for at least 48 hours after discontinuing TreT. Subject is diagnosed with PAH as defined by the following World Health Organization (WHO) Group 1 categories: Idiopathic/familial Associated with unrepaired or repaired congenital systemic-to-pulmonary shunts (repaired ≥5 years prior to screening) Associated with collagen vascular disease Associated with human immunodeficiency virus Associated with appetite suppressant/other drug or toxin use Subject must have started Tyvaso ≥3 months prior to the Baseline Visit and must currently be on a stable regimen (no change in dose within 30 days of Baseline Visit) of Tyvaso (6 to 12 breaths QID). Baseline 6MWD ≥150 m. If currently receiving other approved background therapy (eg, endothelin receptor antagonist or phosphodiesterase type 5 inhibitor or both), the subject must be on a stable dose with no additions or discontinuations for a minimum of 30 days prior to Screening. The subject has had evidence of forced expiratory volume in 1 second (FEV1) ≥60% and FEV1/forced vital capacity ratio ≥60% during the 6 months prior to enrollment. In the opinion of the Investigator, the subject is able to communicate effectively with study personnel, and is considered reliable, willing, and likely to be cooperative with protocol requirements, including all study visits. Exclusion Criteria: Subject is pregnant or lactating. Subject has been diagnosed with pulmonary hypertension for reasons other than WHO Group 1 as outlined in Inclusion Criterion 5 (including but not limited to portal hypertension, chronic thromboembolic disease, pulmonary veno-occlusive disease, hemolytic anemia, sarcoidosis). Subject has a history of uncontrolled sleep apnea, parenchymal lung disease, or hemodynamically significant left-sided heart disease (including but not limited to aortic or mitral valve disease, pericardial constriction, restrictive or congestive cardiomyopathy, or coronary artery disease). Subject is currently taking any other prostacyclin analogue or agonist, including but not limited to selexipag, epoprostenol, iloprost, or beraprost; except for acute vasoreactivity testing. Subject experienced an acute exacerbation of disease or hospitalization for any reason within 30 days of the Screening Visit or between Screening and Baseline. Subject is WHO Functional Class IV at Screening. Subject has used any investigational drug/device or participated in any other investigational study with therapeutic intent within 30 days prior to the Screening Visit. Subject has a history of anaphylaxis, a documented hypersensitivity reaction, or a clinically significant idiosyncratic reaction to treprostinil or excipients in the investigational product. Subject has conditions that, in the opinion of the Investigator, would make the subject ineligible. Subject is not able to perform inhalation maneuvers that meet inspiratory training criteria. Subject has a musculoskeletal disorder (eg, arthritis affecting the lower limbs, recent hip or knee joint replacement) or any disease that would likely be the primary limit to ambulation, or is connected to a machine that is not portable enough to allow for a 6MWT. Subject has had a new type of chronic therapy (including but not limited to oxygen, a different class of vasodilator, diuretic, and digoxin) for pulmonary hypertension added within 30 days of the Screening Phase. Initiation of pulmonary rehabilitation within 12 weeks prior to the Baseline Visit.

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
Intervention Model: Single Group Assignment
Interventional Model Description: Single-sequence in which subjects on a stable regimen of Tyvaso will switch to a corresponding dose of TreT
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tyvaso to TreT<br>Each subject will receive a corresponding dose of TreT for 3 weeks during the Treatment Phase based on the subject's current stable Tyvaso dose. | Drug: Treprostinil Inhalation Powder<br>* Treprostinil inhalation powder single-use cartridges containing either 32 or 48 micrograms of treprostinil per cartridge (QID)<br>* Other names: TreT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with treatment-emergent adverse events [Safety and Tolerability] | The safety and tolerability of TreT in subjects with PAH currently treated with Tyvaso will be evaluated by the number of subjects with treatment-emergent adverse events | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Analysis of treprostinil plasma concentration (pharmacokinetics [PK]) | Systemic exposure of treprostinil will be evaluated in subjects with PAH when delivered as Tyvaso and TreT | Serial PK measurements at Baseline and Week 3 | 
| Change in 6-Minute Walk Distance (6MWD) from Baseline to Week 3 | 6MWD will be evaluated at study entry and after 3 weeks of treatment with TreT | After 3 weeks of treatment with TreT | 
| Number of subjects with treatment-emergent adverse events [Long-term Safety and Tolerability] during an Optional Extension Phase | The long-term safety and tolerability of TreT in subjects with PAH currently treated with Tyvaso will be evaluated by the number of subjects with treatment-emergent adverse events during an Optional Extension Phase of the study | Every 4 weeks beginning on Week 7 until study termination, an average of 1 year | 
| Subject satisfaction with and preference for inhaled treprostinil devices | Subject satisfaction with and preference for inhaled treprostinil devices will be evaluated with the Preference Questionnaire for Inhaled Treprostinil Devices (PQ-ITD) | At Baseline (Tyvaso Inhalation System) and after 3 weeks of treatment (TreT Inhaler) | 
| Patient-reported PAH symptoms and impact | Patient-reported PAH symptoms and impact will be evaluated with the PAH Symptoms and Impact (PAH-SYMPACT) Questionnaire | After 3 weeks and 11 weeks (for subjects participating in the Optional Extension Phase) of treatment with TreT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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prostacyclin