Investigation of the Safety and Pharmacology of Dry Powder Inhalation of Treprostinil

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the long-term safety and tolerability of LIQ861, a dry powder formulation of treprostinil, in patients with Pulmonary Arterial Hypertension (PAH). A secondary objective of this study is to evaluate the comparative bioavailability of treprostinil between two formulations of inhaled therapy.

Detailed Description
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One of the greatest impediments to patient treatment satisfaction with current inhaled treprostinil therapy is inconvenience. Currently, PAH patients using inhaled treprostinil may require more than 36 breaths per day using a nebulizer requiring daily set up and cleaning. The use of a discrete, hand-held dry powder inhaler to deliver treprostinil to the lungs could represent a major improvement in convenience and patient satisfaction, thereby improving the quality of life for PAH patients. Liquidia is pursuing approval of LIQ861, an inhalation dry powder formulation of treprostinil that is produced using Liquidia's PRINT® Technology (Particle Replication in Nonwetting Templates), as an alternative to current inhaled treprostinil therapy for the treatment of patients with PAH (WHO Group 1).

Official Title
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A Phase 3 Open-label, Multicenter Study to Evaluate the Long-term Safety and Tolerability of Inhaled LIQ861(Treprostinil) in Pulmonary Arterial Hypertension (WHO Group 1) Patients

Conditions
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Primary Pulmonary Hypertension

Intervention / Treatment
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* Drug: LIQ861 Inhaled Treprostinil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: signed informed consent by patient prior to study enrollment 18 years of age or older If female of childbearing potential, a negative pregnancy test at the Baseline Visit and agrees to practice adequate birth control throughout the duration of the study. If the patient is postmenopausal or has documented surgical sterilization, a pregnancy test and birth control is not necessary. The patient has been diagnosed with PAH belonging to the following subgroups of the updated Nice Clinical Classification Group 1 (Simonneau, Gatzoulis et al. 2013), which include: Idiopathic PAH (1.1), or Heritable PAH (1.2), or Drug and toxin induced PAH (1.3), or PAH associated with connective tissue disease (1.4.1), HIV infection (1.4.2), or congenital heart disease (1.4.4) with simple systemic-to-pulmonary shunt at least 1 year after surgical repair The patient has been diagnosed with PAH and is NYHA Functional Class II - IV at Screening. has documented stable doses of approved inhaled therapy for at least 3 months prior to screening and is willing and able to transition from their prescribed dose of inhaled therapy to study drug, or has documented stable doses of no more than two approved oral therapies for at least 3 months prior to screening and is willing and able to add LIQ861 to their treatment regimen. The patient can complete a baseline six-minute walk distance (6MWD) ≥ 150 m. The patient has had evidence of FEV1 ≥ 60% and FEV1/FVC ratio ≥ 60% during the 6-month period prior to enrollment. Exclusion Criteria: The patient's clinical condition is such that, in the opinion of the Investigator, they are not expected to remain clinically stable for the duration of the study. Patients with PH in the Updated Nice Classification Groups 2-5, or PAH Group 1 subgroups not covered by the inclusion criteria (e.g., associated with portal hypertension [1.4.3] or with schistosomiasis [1.4.5]). The patient is currently taking oral prostacyclin analogues or agonists, including treprostinil and selexipag. The patient has had any PAH medication (except for anticoagulants) discontinued within 14 days of Baseline. The patient has had a new type of chronic therapy (including but not limited to oxygen, a different class of vasodilator, diuretic, digoxin, and digitalis) for pulmonary hypertension added within 30 days of Baseline. The patient has uncontrolled systemic hypertension as evidenced by persistent systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 100 mmHg. The patient has a history of 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 (CAD). The patient has had an atrial septostomy. The patient has any serious or life-threatening disease other than conditions associated with PAH (e.g. malignancy requiring aggressive chemotherapy, end stage renal disease, etc.). The patient is taking any excluded medications listed in the Investigator's Brochure, namely inhibitors and inducers of CYP2C8 The patient has a hypersensitivity or allergy to any of the ingredients of LIQ861 or other clinically relevant allergies (clinical relevance per Investigator judgment). The patient has had a pulmonary infarction (defined as infarction in more than one lung segment documented by V/Q scan or pulmonary angiography) within two weeks of Screening. The patient has had a stroke or transient ischemic attack (TIA) within six months of Screening. The patient has evidence of an active uncontrolled sepsis or systemic infection during Screening. The patient is pregnant or lactating. The patient has any musculoskeletal disease or any other disease that would limit ambulation. The patient has participated in an investigational product or device study within the 30 days prior to Screening. The patient has current evidence of drug abuse in the opinion of the Investigator. The patient has severe hepatic impairment as evidenced by any history of ascites AND encephalopathy. The patient has severe renal impairment (eGFR < 35). The patient is taking inhaled treprostinil doses of greater than 90 μg (more than 15 breaths). Additional Exclusion Criteria for PK Sub-Study: The patient meets any of Primary Exclusion Criteria #1 - 19. The patient has moderate or severe renal impairment (eGFR < 60). The patient is taking inhaled treprostinil doses of greater than 72 μg (more than 12 breaths).

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: The study will evaluate the long term safety and tolerability of LIQ861 in PAH patients transitioning from stable doses of inhaled treprostinil therapy, or who are taking no more than 2 approved, non-prostacylcin, oral PAH therapies. Patients transitioning from inhaled treprostinil will be initiated at a comparable dose of LIQ861, and then titrate in 25ug incremental doses to tolerance and symptom relief. Patients adding LIQ861 to current oral therapies will start at a 25ug dose, and increase in 25ug increments on a weekly basis to tolerance and symptom relief. A subset of the patients transitioning from inhaled treprostinil will be enrolled in a one-directional crossover to compare the bioavailability and pharmacokinetics of treprostinil as they transition to LIQ861. Serial PK sample collections will be taken on back to back days for transitioning and LIQ861 treprostinil formulations. These patients will then continue to be followed as all other patients enrolled in the study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LIQ861 Inhaled Treprostinil<br>LIQ861 inhaled treprostinil at capsule strengths of 25 μg, 50 μg, 75 μg and 100 μg. LIQ861 will be administered using the RS00 Model 8 dry powder inhalation (DPI) device (Plastiape S.p.A.; Osnago, Italy) at dose levels of 25 μg to 150 μg treprostinil QID in individual patients. | Drug: LIQ861 Inhaled Treprostinil<br>* LIQ861 bulk powder is generated from a treprostinil/excipient matrix from which particles of precise size and shape are created and filled into a hydroxypropyl methylcellulose (HPMC) capsule (size 3). LIQ861 capsules are provided in capsule strengths of 25 μg, 50 μg, 75 μg and 100 μg treprostinil.<br>* Other names: inhaled prostacyclin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events and Serious Adverse Events | Treatment-Emergent Adverse Events and Serious Adverse Events will be grouped by MedDRA System Organ Class, dose level, time on drug, and relationship to dose titration | Baseline, Week 2, Month 1, Month 2 Visits, with bimonthly follow up for up to 30 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Arterial Hypertension, Idiopathic Pulmonary Arterial Hypertension, Heritable Pulmonary Arterial Hypertension, Drug Induced Pulmonary Arterial Hypertension, Toxin Induced Pulmonary Arterial Hypertension, Connective tissue disease