A Study of Rodatristat Ethyl in Patients With Pulmonary Arterial Hypertension (Core OLE)

Phase 2

Completed

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

• 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
• Results First Submitted: 2024-09-30
• Status Verified: 2025-06
• Results First Submitted QC: 2025-06-02
• Last Update Submitted: 2025-06-02
• Results First Posted: 2025-06-04
• Last Update Posted: 2025-06-04

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
Rodatristat Ethyl 300 mg BID	rodatristat ethyl 300 mg tablet BID	MAIN study: Rodatristat ethyl 300 mg and placebo tablet BID + standard of care medication(s) taken for 24 weeks
Rodatristat Ethyl 600 mg BID	rodatristat ethyl 600 mg BID	MAIN study:Rodatristat ethyl two 300 mg tablets BID + standard of care medication(s) taken for 24 weeks
Placebo	Placebo	MAIN study: Matching two placebo tablets BID+ standard of care medication(s) taken for 24 weeks
Placebo-Rodatristat Ethyl 300 mg	rodatristat ethyl 300 mg tablet BID	Subjects whose actual treatment group is Placebo in the double-blind phase (Main Study) and received Rodatristat ethyl two 300 mg tablets BID in the open-label phase
Placebo-Rodatristat Ethyl 600 mg	rodatristat ethyl 600 mg BID	Subjects whose actual treatment group is Placebo in the double-blind phase (Main Study) and received Rodatristat ethyl two 600 mg tablets BID in the open-label phase
Rodatristat Ethyl 300 mg-Rodatristat Ethyl 300 mg	rodatristat ethyl 300 mg tablet BID	Subjects whose actual treatment group is Rodatristat ethyl two 300 mg in the double-blind phase (Main Study) and received Rodatristat ethyl two 300 mg tablets BID in the open-label phase
Rodatristat Ethyl 300 mg-Rodatristat Ethyl 600 mg	rodatristat ethyl 600 mg BID	Subjects whose actual treatment group is Rodatristat ethyl two 300 mg in the double-blind phase (Main Study) and received Rodatristat ethyl two 600 mg tablets BID in the open-label phase
Rodatristat Ethyl 600 mg-Rodatristat Ethyl 600 mg	rodatristat ethyl 600 mg BID	Subjects whose actual treatment group is Rodatristat ethyl two 600 mg in the double-blind phase (Main Study) and received Rodatristat ethyl two 600 mg tablets BID in the open-label phase

Primary Outcome Measures

Name	Time	Method
Percent Change From Baseline of Pulmonary Vascular Resistance (PVR) at Week 24	24 Weeks	Pulmonary vascular resistance (PVR) was measured by right heart catheterization (RHC)

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in World Health Organization (WHO) Functional Class (FC)	24 Weeks	PAH functional disease severity is classified in 4 classes (I to IV) according to World Health Organization (WHO).; I:Patients with pulmonary hypertension (PH) but without resulting limitation of physical act.Ordinary physical act does not cause undue dyspnea,fatigue,chest pain,near syncope.; II:Patients with PH with slight limitation of physical act.Ordinary physical act causes undue dyspnea or fatigue, chest pain,or near syncope.; III:Patients with PH with marked limitation of physical act.Less than ordinary act causes undue dyspnea or fatigue,chest pain,or near syncope.; IV:Patients with PH with inability to carry out any physical act without symptoms,manifest signs of right-heart failure.Dyspnea and/or fatigue may even be present at rest.Discomfort is increased by physical act; -II, -I:Patients condition improved at WK24 compared with baseline II, I:Patients condition worsened at WK24 compared with baseline No change:Patients condition not changes at WK24 compare with baseline
Change From Baseline in Six-minute Walk Distance (6MWD)	24 Weeks	The six-minute walk distance (6MWD) is a simple, commonly used, standardized measure of functional exercise capacity and endurance. It is a commonly used measure of efficacy in PAH clinical studies.
Change From Baseline in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) Levels	24 Weeks	N-terminal prohormone of brain natriuretic peptide (NT-proBNP) is a strong predictor of disease progression and mortality in PAH patients. Current PAH treatment guidelines recommend measurement of NT-proBNP levels for both risk assessment and longitudinal follow up. NT-proBNP levels are also a good marker of response to treatment.

Trial Locations

Locations (64)

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

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

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

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

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

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

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

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

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

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

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