Clinical trial NCT03399604: Investigation of the Safety and Pharmacology of Dry Powder Inhalation of Treprostinil
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Primary Pulmonary Hypertension
Keywords: Pulmonary Arterial Hypertension
Idiopathic Pulmonary Arterial Hypertension
Heritable Pulmonary Arterial Hypertension
Drug Induced Pulmonary Arterial Hypertension
Toxin Induced Pulmonary Arterial Hypertension
Connective tissue disease
Lead sponsor: Liquidia Technologies, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Nuventra, Inc.
First posted: 2018-01-16
Enrollment: 121
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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).

Detailed description: 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).

Eligibility criteria: 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:

  1. Idiopathic PAH (1.1), or
  2. Heritable PAH (1.2), or
  3. Drug and toxin induced PAH (1.3), or
  4. 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.

  1. 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
  2. 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).

Primary outcomes:
measure: Incidence of Treatment-Emergent Adverse Events and Serious Adverse Events
timeFrame: Baseline, Week 2, Month 1, Month 2 Visits, with bimonthly follow up for up to 16 months.
Secondary outcomes:
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Banner University Medical Center
state: Arizona
city: Phoenix
country: United States
facility: Arizona Pulmonary Specialists, Ltd.
state: Arizona
city: Los Angeles
country: United States
facility: West Los Angeles VA Healthcare Center
state: California
city: Sacramento
country: United States
facility: UC Davis Medical Center
state: California
city: Torrance
country: United States
facility: Los Angeles Biomedical Research Center
state: California
city: Aurora
country: United States
facility: University of Colorado Anschutz Medical Campus
state: Colorado
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic-Jacksonville
state: Florida
city: Orlando
country: United States
facility: AdventHealth
state: Florida
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Marietta
country: United States
facility: Wellstar Research Institute
state: Georgia
city: Chicago
country: United States
facility: Northwestern Medicine, Feinberg School of Medicine
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Medicine
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Louisville
country: United States
facility: Kentuckiana Pulmonary Research Center
state: Kentucky
city: New Orleans
country: United States
facility: Ochsner Medical Center
state: Louisiana
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic-Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Albuquerque
country: United States
facility: University of New Mexico Health Science Center
state: New Mexico
city: Mineola
country: United States
facility: NYU Winthrop University Hospital
state: New York
city: New York
country: United States
facility: NYU Langone Health
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina School of Medicine
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals of Cleveland Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: the Ohio State University Wexner Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science Center
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania Health System
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Alleghany General Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Presbyterian Hospital
state: Pennsylvania
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Houston Methodist Lung Center
state: Texas
city: Houston
country: United States
facility: University of Texas - Health Science Center
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Falls Church
country: United States
facility: INOVA Fairfax Medical Campus
state: Virginia
city: Milwaukee
country: United States
facility: The Medical College of Wisconsin/Froedtert Hospital
state: Wisconsin
Study officials:
affiliation: Tufts Medical Center
name: Nicholas S Hill, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Roscigno R, Vaughn T, Anderson S, Wargin W, Hunt T, Hill NS. Pharmacokinetics and tolerability of LIQ861, a novel dry-powder formulation of treprostinil. Pulm Circ. 2020 Nov 19;10(4):2045894020971509. doi: 10.1177/2045894020971509. eCollection 2020 Oct-Dec.