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

A Phase 2, Dose-Ranging, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Rodatristat Ethyl in Patients With Pulmonary Arterial Hypertension

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

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: rodatristat ethyl 300 mg tablet BID; Drug: rodatristat ethyl 600 mg BID; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 108
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Watiri Kamau-Kelley; Phone Number: +1-408-300-3316; Email: watiri@enzyvant.com
• Study Contact Backup: Name: Howard Lazarus, MD, FCCP; Phone Number: +1-203-297-5374; Email: howard.lazarus@enzyvant.com

Study Locations

• Austria
  • Wien, Austria, 1090
    • AKH- Wien, Medizinische Univsersität Wien
  • Oberösterreich
    • Linz, Oberösterreich, Austria, 4020
      • Ordensklinikum Linz GmbH Elisabethinen
• Belgium
  • Brussels Capital Region
    • Brussels, Brussels Capital Region, Belgium, 1070
      • Hôpital Erasme
  • Vlaams Brabant
    • Leuven, Vlaams Brabant, Belgium, 3000
      • UZ Leuven - Campus Gasthuisberg - Pneumologie
• Bosnia and Herzegovina
  • Banja Luka, Bosnia and Herzegovina, 78 000
    • University Clinical Centre of the Republic of Srpska
  • Mostar, Bosnia and Herzegovina, 88000
    • University Clinical Hospital Mostar
• Bulgaria
  • Sofia-Grad
    • Sofia, Sofia-Grad, Bulgaria, 1750
      • University MHAT "Sv. Anna"
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T1Y6J4
      • Peter Lougheed Centre
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • London Health Sciences Centre - Victoria Hospital
    • Toronto, Ontario, Canada, M5G 2N2
      • University Health Network, Toronto General Hospital
  • Quebec
    • Montréal, Quebec, Canada, H3T 1E2
      • Sir Mortimer B. Davis Jewish General Hospital
• Czechia
  • Olomouc, Czechia, 779 00
    • Fakultni Nemocnice Olomouc
  • Praha 2, Czechia, 128 08
    • Všeobecná fakultní nemocnice v Praze
• France
  • Saint-Étienne, France, 42270
    • CHU de Saint-Etienne - Hôpital Nord
  • Calvados
    • Caen Cedex, Calvados, France, 14033
      • Centre Hospitalier Universitaire (CHU) de Caen - Hopital Cote de Nacre
  • Rhône
    • Lyon, Rhône, France, 69677
      • Groupement Hospitalier Est
  • Val-de-Marne
    • Le Kremlin-Bicêtre, Val-de-Marne, France, 94275
      • CHU de Bicêtre
• Germany
  • Gießen, Germany, 35392
    • Universitätsklinikum Gießen und Marburg
• Italy
  • Genova, Italy, 16132
    • AOU S.Martino, IRCCS, IST-Istituto Nazionale Ricerca Sul Can
  • Pavia, Italy, 27100
    • IRCCS Policlinico San Matteo, Università degli studi di Pavi
  • Roma
    • Rome, Roma, Italy, 00161
      • Umberto I Policlinico di Roma, Università La Sapienza
• Latvia
  • Riga, Latvia, LV-1002
    • P.Stradina Clinical University Hospital
• Moldova, Republic of
  • Chisinau, Moldova, Republic of, MD2025
    • Spitalul Clinic Republican
• Poland
  • Bialystok, Poland, 15-276
    • Uniwersytecki Szpital Kliniczny w Bialymstoku
  • Lublin, Poland, 20-954
    • Samodzielny Publiczny Szpital Kliniczny nr 4 w Lublinie
  • Otwock, Poland, 05-400
    • Europejskie Centrum Zdrowia Otwock Szpital im Fryderyka Chopina
  • Lódzkie
    • Łódź, Lódzkie, Poland, 91-347
      • Wojewodzki Specjalistyczny Szpital im. dr Wl. Bieganskiego
• Serbia
  • Belgrade, Serbia, 11000
    • Clinical Center of Serbia
  • Vojvodina
    • Sremska Kamenica, Vojvodina, Serbia, 21204
      • Institute For Pulmonary Diseases of Vojvodina
    • Sremska Kamenica, Vojvodina, Serbia, 21204
      • Institute for Cardiovascular Diseases of Vojvodina
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clínic de Barcelona
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
• Ukraine
  • Kyiv, Ukraine, 03680
    • Nats Naukovyi Tsentr Amn Ukrainy
  • Dnipropetrovs'ka Oblast'
    • Dnipropetrovs'k, Dnipropetrovs'ka Oblast', Ukraine, 49070
      • Dnipropetrovsk Regional Clinical Diagnostic Center
• United Kingdom
  • London, United Kingdom, NW3 2QG
    • Royal Free London NHS Foundation Trust
  • London, United Kingdom, SW3 6NP
    • Royal Brompton Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85012
      • Arizona Pulmonary Specialists
  • California
    • La Jolla, California, United States, 92093
      • University of California San Diego Health Sciences
    • Los Angeles, California, United States, 90095
      • Ronald Reagan UCLA Medical Center
    • Los Angeles, California, United States, 90073
      • VA Greater LA Healthcare System/UCLA
    • Sacramento, California, United States, 95816
      • UC Davis Medical Center
    • Santa Barbara, California, United States, 93105
      • Jeffrey S. Sager, MD Medical Corporation
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • George Washington University Medical Center
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Florida
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • The University of Kansas Medical Center
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Norton Pulmonary Specialists
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital (BWH), Harvard Medical School
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico Heath Science Center
  • New York
    • New York, New York, United States, 10016
      • NYU Langone Health
    • Rochester, New York, United States, 14623
      • University of Rochester
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • University of North Carolina Medical Center - Chapel Hill
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Physicians
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Brown University - Rhode Island Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern
    • Houston, Texas, United States, 77030
      • Houston Methodist Hospital
  • Virginia
    • Falls Church, Virginia, United States, 22042-3307
      • Inova Fairfax Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rodatristat Ethyl 300 mg BID; Rodatristat ethyl 300 mg tablet BID + standard of care medication(s) taken for 24 weeks	Drug: rodatristat ethyl 300 mg tablet BID; rodatristat ethyl 300 mg tablet + matching placebo tablet twice daily on top of standard of care
Experimental: Rodatristat Ethyl 600 mg BID; Rodatristat ethyl 600 mg tablet BID + standard of care medication(s) taken for 24 weeks	Drug: rodatristat ethyl 600 mg BID; 2 rodatristat ethyl 300 mg tablets twice daily on top of standard of care
Placebo Comparator: Placebo; Matching placebo tablet + standard of care medication(s) taken for 24 weeks	Drug: Placebo; 2 matching placebo tablets on top of standard of care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Outcome Measure	Time Frame
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

Collaborators and Investigators

• Sponsor: Altavant Sciences GmbH
• Investigators: Study Director: Howard M Lazarus, MD, FCCP, Altavant Sciences GmbH

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2021
• Primary Completion (Actual): June 5, 2023
• Study Completion (Actual): August 28, 2023

Study Registration Dates

• First Submitted: January 12, 2021
• First Submitted That Met QC Criteria: January 13, 2021
• First Posted (Actual): January 15, 2021

Study Record Updates

• Last Update Posted (Actual): October 5, 2023
• Last Update Submitted That Met QC Criteria: October 3, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: PAH
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension
• Other Study ID Numbers: RVT-1201-2002 / ELEVATE 2

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No