Clinical trial NCT04712669: A Study of Rodatristat Ethyl in Patients With Pulmonary Arterial Hypertension (Core OLE)
Official title: A Phase 2, Dose-Ranging, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Rodatristat Ethyl in Patients With Pulmonary Arterial Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Arterial Hypertension
Keywords: PAH
Lead sponsor: Altavant Sciences GmbH
Sponsor class: INDUSTRY
First posted: 2021-01-15
Enrollment: 108
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Following screening assessments, Patients will be enrolled into 1 of 3 treatment arms in a core double blind phase in 1:1:1 randomization. Subjects are allowed to participant into open label extension phase upon completion of double blind phase.
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess the safety and efficacy of Rodatristat Ethyl in pulmonary arterial hypertension (PAH) patients.

Detailed description: Rodatristat Ethyl is a peripherally restricted TPH inhibitor being studied as a potential treatment for PAH. This dose-ranging, randomized, double-blind, placebo-controlled, multicenter study will evaluate the effect of Rodatristat Ethyl from baseline on pulmonary vascular resistance as measured at right heart catheterization.

Patients will be enrolled into a main study with an option to enroll into an open label extension.

The study is expected to enroll patients in the USA, Canada and Europe.

Eligibility criteria: Inclusion Criteria:

1. Male and female 18 years or older 2. Body Mass Index (BMI) \>18kg/m2 to \<=40kg/m2 3. Symptomatic PAH belonging to one of the following 2018 WHO Clinical Group 1 subtypes:

a. Idiopathic PAH b. Heritable PAH c. Drug- or toxin-induced d. PAH associated with:

1. Connective tissue disease
2. Congenital systemic to pulmonary shunt (atrial septal defect, ventricular septal defect, patent ductus arteriosus) repaired at least one year prior to Screening
3. Human immunodeficiency virus (HIV) infection - if diagnosed with HIV, must have stable disease status defined as follows:

   1. stable treatment with HIV medications for at least 8 weeks prior to Screening
   2. no active opportunistic infection during the Screening Period
   3. no hospitalizations due to HIV for at least 4 weeks prior to Screening
4. WHO FC II or III
5. Confirmed diagnosis of PAH and meet all the following hemodynamic criteria by means of a screening RHC completed prior to randomization:

   1. mPAP of \>20 mmHg
   2. PVR ≥ 350 dyne•sec/cm5
   3. Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) of ≤ 12 mmHg if PVR ≥ 350 and \< 500 dyne•sec/cm5, or PCWP/LVEDP ≤ 15 mmHg if PVR ≥ 500 dyne•sec/cm5
6. 6MWD of 100 to 550 meters at Screening
7. Currently on a stable treatment regimen with one or more treatments approved for PAH. Stable therapy is defined as receiving the same medication(s) for ≥ 12 weeks prior to the screening RHC and at a stable dose level for each for ≥ 8 weeks prior to the screening RHC (see Protocol Section 6.6.2 for approved PAH medications). Any instances where doses of a medication have been missed prior to RHC must be discussed with the Medical Monitor prior to performing the RHC.
8. Meet all of the following criteria determined by pulmonary function tests completed no more than 24 weeks prior to Screening (performed with or without bronchodilation):

   1. Forced expiratory volume in one second (FEV1) ≥ 60% of predicted normal, and
   2. Total lung capacity (TLC) ≥ 70% of predicted normal or FVC ≥ 70% predicted if TLC is not available; For subjects with CTD associated PAH, if TLC is ≥ 60% of predicted but \< 70% of predicted of if FVC ≥ 60% or predicted but \< 70% of predicted, high resolution computed tomography \[HRCT\] obtained within 6 months of screening may be utilized to demonstrate limited interstitial lung disease
9. If participating in an exercise program for pulmonary rehabilitation, the program must have been initiated ≥ 12 weeks prior to Screening, and patient must agree to maintain the current level of rehabilitation for the first 24 weeks of receiving IP. If not participating in an exercise training program for pulmonary rehabilitation, patient must agree not to enroll in an exercise training program for pulmonary rehabilitation during the Screening Period and the first 24 weeks of receiving IP.

Exclusion Criteria:

1. Women of childbearing potential who are pregnant, planning to become pregnant, or lactating or female/male patients unwilling to use effective contraception
2. WHO pulmonary hypertension (PH) Group 1 PAH associated with portal hypertension or schistosomiasis; PH due to left heart disease (WHO PH Group 2), lung diseases and/or hypoxia (WHO PH Group 3), chronic thromboembolic PH (WHO PH Group 4), or PH with unclear multifactorial mechanisms (WHO PH Group 5)
3. PH associated with significant venous or capillary involvement (PCWP \> 15 mmHg), pulmonary capillary hemangiomatosis, portal hypertension, or unrepaired congenital heart defects (CHD)
4. Three or more of the following risk factors for left ventricular disease:

   1. BMI \> 30 kg/m2
   2. Diagnosis of essential hypertension that is actively treated
   3. Diabetes mellitus
   4. History of significant coronary artery disease (e.g., chronic stable angina, history of coronary intervention within the last 3 months, or a stenosis \> 70% at coronary angiography)
   5. Atrial fibrillation
   6. Left atrial volume index \> 41 mL/m2 \[or left atrial diameter (LA) \> 4 cm if LAVi unavailable\]
5. Known genetic hypertrophic cardiomyopathy
6. Known cardiac sarcoidosis or amyloidosis
7. The patient has a history of, or currently has, a constrictive cardiomyopathy.
8. Known history of any left ventricular ejection fraction (LVEF) \< 40% by echocardiogram within 3 years of randomization (Note: a transient decline in LVEF below 40% that occurred and recovered more than 6 months before the start of Screening and was associated with an acute intercurrent condition \[e.g., atrial fibrillation\] is allowed).
9. Hemodynamically significant valvular heart disease as determined by the Investigator, including:

   1. greater than mild aortic and/or mitral stenosis and/or
   2. severe mitral and/or aortic regurgitation (\> Grade 3)
10. Severe arthritis, musculoskeletal problems, or morbid obesity that, in the opinion of the Investigator, is the cause of the patient's functional limitation and would affect the patient's ability to perform or complete the 6MWT.

Primary outcomes:
measure: Percent Change From Baseline of Pulmonary Vascular Resistance (PVR) at Week 24
timeFrame: 24 Weeks
Secondary outcomes:
measure: Change From Baseline in World Health Organization (WHO) Functional Class (FC)
timeFrame: 24 Weeks
measure: Change From Baseline in Six-minute Walk Distance (6MWD)
timeFrame: 24 Weeks
measure: Change From Baseline in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) Levels
timeFrame: 24 Weeks
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Arizona Pulmonary Specialists
state: Arizona
city: La Jolla
country: United States
facility: University of California San Diego Health Sciences
state: California
city: Los Angeles
country: United States
facility: VA Greater LA Healthcare System/UCLA
state: California
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA Medical Center
state: California
city: Sacramento
country: United States
facility: UC Davis Medical Center
state: California
city: Santa Barbara
country: United States
facility: Jeffrey S. Sager, MD Medical Corporation
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Washington
country: United States
facility: George Washington University Medical Center
state: District of Columbia
city: Jacksonville
country: United States
facility: Mayo Clinic Florida
state: Florida
city: Kansas City
country: United States
facility: The University of Kansas Medical Center
state: Kansas
city: Louisville
country: United States
facility: Norton Pulmonary Specialists
state: Kentucky
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital (BWH), Harvard Medical School
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
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 Heath Science Center
state: New Mexico
city: New York
country: United States
facility: NYU Langone Health
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina Medical Center - Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Physicians
state: Ohio
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Providence
country: United States
facility: Brown University - Rhode Island Hospital
state: Rhode Island
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Falls Church
country: United States
facility: Inova Fairfax Hospital
state: Virginia
city: Linz
country: Austria
facility: Ordensklinikum Linz GmbH Elisabethinen
state: Oberösterreich
city: Wien
country: Austria
facility: AKH- Wien, Medizinische Univsersität Wien
city: Brussels
country: Belgium
facility: Hôpital Erasme
state: Brussels Capital Region
city: Leuven
country: Belgium
facility: UZ Leuven - Campus Gasthuisberg - Pneumologie
state: Vlaams Brabant
city: Banja Luka
country: Bosnia and Herzegovina
facility: University Clinical Centre of the Republic of Srpska
city: Mostar
country: Bosnia and Herzegovina
facility: University Clinical Hospital Mostar
city: Sofia
country: Bulgaria
facility: University MHAT "Sv. Anna"
state: Sofia-Grad
city: Calgary
country: Canada
facility: Peter Lougheed Centre
state: Alberta
city: London
country: Canada
facility: London Health Sciences Centre - Victoria Hospital
state: Ontario
city: Toronto
country: Canada
facility: University Health Network, Toronto General Hospital
state: Ontario
city: Montréal
country: Canada
facility: Sir Mortimer B. Davis Jewish General Hospital
state: Quebec
city: Olomouc
country: Czechia
facility: Fakultni nemocnice Olomouc
city: Praha 2
country: Czechia
facility: Vseobecna fakultni nemocnice v Praze
city: Caen Cedex
country: France
facility: Centre Hospitalier Universitaire (CHU) de Caen - Hopital Cote de Nacre
state: Calvados
city: Lyon
country: France
facility: Groupement Hospitalier Est
state: Rhône
city: Le Kremlin-Bicêtre
country: France
facility: Chu De Bicetre
state: Val-de-Marne
city: Saint-Étienne
country: France
facility: CHU de Saint-Etienne - Hopital Nord
city: Gießen
country: Germany
facility: Universitätsklinikum Giessen und Marburg
city: Rome
country: Italy
facility: Umberto I Policlinico di Roma, Università La Sapienza
state: Roma
city: Genova
country: Italy
facility: AOU S.Martino, IRCCS, IST-Istituto Nazionale Ricerca Sul Can
city: Pavia
country: Italy
facility: IRCCS Policlinico San Matteo, Università degli studi di Pavi
city: Riga
country: Latvia
facility: P.Stradina Clinical University Hospital
city: Chisinau
country: Moldova, Republic of
facility: Spitalul Clinic Republican
city: Łódź
country: Poland
facility: Wojewodzki Specjalistyczny Szpital im. dr Wl. Bieganskiego
state: Lódzkie
city: Bialystok
country: Poland
facility: Uniwersytecki Szpital Kliniczny w Bialymstoku
city: Lublin
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny nr 4 w Lublinie
city: Otwock
country: Poland
facility: Europejskie Centrum Zdrowia Otwock Szpital im Fryderyka Chopina
city: Sremska Kamenica
country: Serbia
facility: Institute for Cardiovascular diseases of Vojvodina
state: Vojvodina
city: Sremska Kamenica
country: Serbia
facility: Institute for Pulmonary Diseases of Vojvodina
state: Vojvodina
city: Belgrade
country: Serbia
facility: Clinical Center of Serbia
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Dnipropetrovs'k
country: Ukraine
facility: Dnipropetrovsk Regional Clinical Diagnostic Center
state: Dnipropetrovs'ka Oblast'
city: Kyiv
country: Ukraine
facility: Nats Naukovyi Tsentr Amn Ukrainy
city: London
country: United Kingdom
facility: Royal Free London NHS Foundation Trust
city: London
country: United Kingdom
facility: Royal Brompton Hospital
Study officials:
affiliation: Altavant Sciences GmbH
name: Howard M Lazarus, MD, FCCP
role: STUDY_DIRECTOR
References: