A Study of Rodatristat Ethyl in Patients With Pulmonary Arterial Hypertension (ELEVATE 2)

Phase 2

Completed

• Conditions: Pulmonary Arterial Hypertension
• Interventions: Drug: Placebo; Drug: rodatristat ethyl 300 mg tablet BID; Drug: rodatristat ethyl 600 mg BID

• Registration Number: NCT04712669
• Lead Sponsor: Altavant Sciences GmbH

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.

Study Timeline

• Study First Submitted: 2021-01-12
• Study First Submitted QC: 2021-01-13
• Study First Posted: 2021-01-15
• Study Start: 2021-03-15
• Primary Completion: 2023-06-05
• Study Completion: 2023-08-28
• Status Verified: 2023-10
• Last Update Submitted: 2023-10-03
• Last Update Posted: 2023-10-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 108

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Matching placebo tablet + standard of care medication(s) taken for 24 weeks
Rodatristat Ethyl 300 mg BID	rodatristat ethyl 300 mg tablet BID	Rodatristat ethyl 300 mg tablet BID + standard of care medication(s) taken for 24 weeks
Rodatristat Ethyl 600 mg BID	rodatristat ethyl 600 mg BID	Rodatristat ethyl 600 mg tablet BID + standard of care medication(s) taken for 24 weeks

Primary Outcome Measures

Name	Time	Method
Percent change from baseline of pulmonary vascular resistance (PVR) as measured by right heart catheterization between active and placebo	From initiation of treatment to Week 24

Secondary Outcome Measures

Name	Time	Method
Proportion of patients who improve in WHO World Health Organization (WHO) Functional Class (FC)	From initiation of treatment to Week 24
Change from baseline in 6MWD	From initiation of treatment to Week 24
Change from baseline in N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) levels	From initiation of treatment to Week 24

Trial Locations

Locations (64)

George Washington University Medical Center; 🇺🇸 Washington, District of Columbia, United States

Mayo Clinic Florida; 🇺🇸 Jacksonville, Florida, United States

University of New Mexico Heath Science Center; 🇺🇸 Albuquerque, New Mexico, United States

NYU Langone Health; 🇺🇸 New York, New York, United States

University of Rochester; 🇺🇸 Rochester, New York, United States

Brown University - Rhode Island Hospital; 🇺🇸 Providence, Rhode Island, United States

Inova Fairfax Hospital; 🇺🇸 Falls Church, Virginia, United States

Ordensklinikum Linz GmbH Elisabethinen; 🇦🇹 Linz, Oberösterreich, Austria

AKH- Wien, Medizinische Univsersität Wien; 🇦🇹 Wien, Austria

UZ Leuven - Campus Gasthuisberg - Pneumologie; 🇧🇪 Leuven, Vlaams Brabant, Belgium

University Clinical Centre of the Republic of Srpska; 🇧🇦 Banja Luka, Bosnia and Herzegovina

London Health Sciences Centre - Victoria Hospital; 🇨🇦 London, Ontario, Canada

Sir Mortimer B. Davis Jewish General Hospital; 🇨🇦 Montréal, Quebec, Canada

Vseobecna fakultni nemocnice v Praze; 🇨🇿 Praha 2, Czechia

Groupement Hospitalier Est; 🇫🇷 Lyon, Rhône, France

P.Stradina Clinical University Hospital; 🇱🇻 Riga, Latvia

Spitalul Clinic Republican; 🇲🇩 Chisinau, Moldova, Republic of

Clinical Center of Serbia; 🇷🇸 Belgrade, Serbia

Ronald Reagan UCLA Medical Center; 🇺🇸 Los Angeles, California, United States

University Health Network, Toronto General Hospital; 🇨🇦 Toronto, Ontario, Canada

Jeffrey S. Sager, MD Medical Corporation; 🇺🇸 Santa Barbara, California, United States

Brigham and Women's Hospital (BWH), Harvard Medical School; 🇺🇸 Boston, Massachusetts, United States

Temple University Hospital; 🇺🇸 Philadelphia, Pennsylvania, United States

UT Southwestern; 🇺🇸 Dallas, Texas, United States

Houston Methodist Hospital; 🇺🇸 Houston, Texas, United States

Duke University Medical Center; 🇺🇸 Durham, North Carolina, United States

University of Cincinnati Physicians; 🇺🇸 Cincinnati, Ohio, United States

The University of Kansas Medical Center; 🇺🇸 Kansas City, Kansas, United States

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

IRCCS Policlinico San Matteo, Università degli studi di Pavi; 🇮🇹 Pavia, Italy

Arizona Pulmonary Specialists; 🇺🇸 Phoenix, Arizona, United States

VA Greater LA Healthcare System/UCLA; 🇺🇸 Los Angeles, California, United States

Tufts Medical Center; 🇺🇸 Boston, Massachusetts, United States

Hôpital Erasme; 🇧🇪 Brussels, Brussels Capital Region, Belgium

University Clinical Hospital Mostar; 🇧🇦 Mostar, Bosnia and Herzegovina

University MHAT "Sv. Anna"; 🇧🇬 Sofia, Sofia-Grad, Bulgaria

Peter Lougheed Centre; 🇨🇦 Calgary, Alberta, Canada

Fakultni nemocnice Olomouc; 🇨🇿 Olomouc, Czechia

Chu De Bicetre; 🇫🇷 Le Kremlin-Bicêtre, Val-de-Marne, France

Centre Hospitalier Universitaire (CHU) de Caen - Hopital Cote de Nacre; 🇫🇷 Caen Cedex, Calvados, France

Universitätsklinikum Giessen und Marburg; 🇩🇪 Gießen, Germany

Umberto I Policlinico di Roma, Università La Sapienza; 🇮🇹 Rome, Roma, Italy

CHU de Saint-Etienne - Hopital Nord; 🇫🇷 Saint-Étienne, France

AOU S.Martino, IRCCS, IST-Istituto Nazionale Ricerca Sul Can; 🇮🇹 Genova, Italy

Uniwersytecki Szpital Kliniczny w Bialymstoku; 🇵🇱 Bialystok, Poland

Europejskie Centrum Zdrowia Otwock Szpital im Fryderyka Chopina; 🇵🇱 Otwock, Poland

Wojewodzki Specjalistyczny Szpital im. dr Wl. Bieganskiego; 🇵🇱 Łódź, Lódzkie, Poland

Samodzielny Publiczny Szpital Kliniczny nr 4 w Lublinie; 🇵🇱 Lublin, Poland

Institute for Cardiovascular diseases of Vojvodina; 🇷🇸 Sremska Kamenica, Vojvodina, Serbia

Institute for Pulmonary Diseases of Vojvodina; 🇷🇸 Sremska Kamenica, Vojvodina, Serbia

Hospital Clinic de Barcelona; 🇪🇸 Barcelona, Spain

Hospital Universitario 12 de Octubre; 🇪🇸 Madrid, Spain

Dnipropetrovsk Regional Clinical Diagnostic Center; 🇺🇦 Dnipropetrovs'k, Dnipropetrovs'ka Oblast', Ukraine

Nats Naukovyi Tsentr Amn Ukrainy; 🇺🇦 Kyiv, Ukraine

University of North Carolina Medical Center - Chapel Hill; 🇺🇸 Chapel Hill, North Carolina, United States

UC Davis Medical Center; 🇺🇸 Sacramento, California, United States

Norton Pulmonary Specialists; 🇺🇸 Louisville, Kentucky, United States

University of Colorado; 🇺🇸 Aurora, Colorado, United States

University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States

University of California San Diego Health Sciences; 🇺🇸 La Jolla, California, United States

Royal Free London NHS Foundation Trust; 🇬🇧 London, United Kingdom

Royal Brompton Hospital; 🇬🇧 London, United Kingdom