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

Pulmonary Arterial Hypertension Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04712669
• Other study ID #: RVT-1201-2002 / ELEVATE 2
• Status: Completed
• Phase: Phase 2
• Start date: March 15, 2021
• Est. completion date: August 28, 2023

Study information

• Verified date: October 2023
• Source: Altavant Sciences GmbH
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 108
• Est. completion date: August 28, 2023
• Est. primary completion date: June 5, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Pulmonary Arterial Hypertension

Intervention

Drug:
• rodatristat ethyl 300 mg tablet BID
rodatristat ethyl 300 mg tablet + matching placebo tablet twice daily on top of standard of care
• rodatristat ethyl 600 mg BID
2 rodatristat ethyl 300 mg tablets twice daily on top of standard of care
• Placebo
2 matching placebo tablets on top of standard of care

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Altavant Sciences GmbH

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Bosnia and Herzegovina,  Bulgaria,  Canada,  Czechia,  France,  Germany,  Italy,  Latvia,  Moldova, Republic of,  Poland,  Serbia,  Spain,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Proportion of patients who improve in WHO World Health Organization (WHO) Functional Class (FC)		From initiation of treatment to Week 24
Secondary	Change from baseline in 6MWD		From initiation of treatment to Week 24
Secondary	Change from baseline in N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) levels		From initiation of treatment to Week 24