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

This was a Phase 1b safety and tolerability single-sequence study in which PAH subjects on a stable regimen of Tyvaso switched to a corresponding dose of TreT.

United Therapeutics Corporation (UTC) developed a combination drug-device product 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 \[QID\]) were evaluated after switching to a corresponding dose of TreT. Patients underwent 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 were offered the opportunity to participate in the Optional Extension Phase until the drug/device became commercially available.

Eligibility Criteria:
Inclusion Criteria:

1. Subject voluntarily gave informed consent to participate in the study.
2. Subject was aged 18 years or older at the time of signing informed consent.
3. Women of childbearing potential were those who had experienced menarche and who had not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or were not postmenopausal (defined as amenorrhea for at least 12 consecutive months). WOCBP must have been nonpregnant (as confirmed by a urine pregnancy test at Screening prior to initiating study medication), nonlactating, and did 1 of the following:

   1. Abstained from intercourse (when it was in line with their preferred and usual lifestyle), or
   2. Used 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 included 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.
4. Males with a partner of childbearing potential must have used a condom for the duration of treatment and for at least 48 hours after discontinuing TreT.
5. Subject was diagnosed with PAH as defined by the following World Health Organization (WHO) Group 1 categories:

   1. Idiopathic/familial
   2. Associated with unrepaired or repaired congenital systemic-to-pulmonary shunts (repaired ≥5 years prior to Screening)
   3. Associated with collagen vascular disease
   4. Associated with human immunodeficiency virus
   5. Associated with appetite suppressant/other drug or toxin use
6. Subject must have started Tyvaso ≥3 months prior to the Baseline Visit and was currently on a stable regimen (no change in dose within 30 days of Baseline Visit) of Tyvaso (6 to 12 breaths QID).
7. Baseline 6MWD ≥150 m.
8. If the subject was currently receiving other approved background therapy (eg, endothelin receptor antagonist or phosphodiesterase type 5 inhibitor or both), the subject must have been on a stable dose with no additions or discontinuations for a minimum of 30 days prior to Screening.
9. The subject 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.
10. In the opinion of the Investigator, the subject was able to communicate effectively with study personnel, and was considered reliable, willing, and likely to be cooperative with protocol requirements, including all study visits.

Exclusion Criteria:

1. Subject was pregnant or lactating.
2. Subject was 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).
3. Subject had 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).
4. Subject was currently taking any other prostacyclin analogue or agonist, including but not limited to selexipag, epoprostenol, iloprost, or beraprost; except for acute vasoreactivity testing.
5. Subject experienced an acute exacerbation of disease or hospitalization for any reason within 30 days of the Screening Visit or between Screening and Baseline.
6. Subject was WHO Functional Class IV at Screening.
7. Subject had used any investigational drug/device or participated in any other investigational study with therapeutic intent within 30 days prior to the Screening Visit.
8. Subject had a history of anaphylaxis, a documented hypersensitivity reaction, or a clinically significant idiosyncratic reaction to treprostinil or excipients in the investigational product.
9. Subject had conditions that, in the opinion of the Investigator, would make the subject ineligible.
10. Subject was not able to perform inhalation maneuvers that met inspiratory training criteria.
11. Subject had 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 was connected to a machine that was not portable enough to allow for a 6MWT.
12. Subject 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.
13. Initiation of pulmonary rehabilitation within 12 weeks prior to the Baseline Visit.