Pulmonary Arterial Hypertension
Conditions
Keywords
PAH
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.
Interventions
DRUGrodatristat ethyl 300 mg tablet BID
rodatristat ethyl 300 mg tablet + matching placebo tablet twice daily on top of standard of care
2 rodatristat ethyl 300 mg tablets twice daily on top of standard of care
DRUGPlacebo
2 matching placebo tablets on top of standard of care
Sponsors
Altavant Sciences GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Austria, Belgium, Bosnia and Herzegovina, Bulgaria, Canada, Czechia, France, Germany, Italy, Latvia, Moldova, Poland, Serbia, Spain, Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
Out of 108 subjects who are dosed in Double Blind phase 76 Subjects have enrolled in Open Label extension phase.
Participants by arm
| Arm | Count |
|---|---|
| Rodatristat Ethyl 300 mg BID MAIN study: Rodatristat ethyl 300 mg and placebo tablet BID + standard of care medication(s) taken for 24 weeks | 36 |
| Rodatristat Ethyl 600 mg BID MAIN study:Rodatristat ethyl two 300 mg tablets BID + standard of care medication(s) taken for 24 weeks | 36 |
| Placebo MAIN study: Matching two placebo tablets BID+ standard of care medication(s) taken for 24 weeks | 36 |
| Placebo-Rodatristat Ethyl 300 mg 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 | 15 |
| Placebo-Rodatristat Ethyl 600 mg 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 | 16 |
| Rodatristat Ethyl 300 Mg-Rodatristat Ethyl 300 mg 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 | 22 |
| Rodatristat Ethyl 300 Mg-Rodatristat Ethyl 600 mg 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 | 2 |
| Rodatristat Ethyl 600 Mg-Rodatristat Ethyl 600 mg 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 | 21 |
| Total | 184 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Double Blind Phase | Adverse Event | 4 | 4 | 3 | 0 | 0 | 0 | 0 | 0 |
| Double Blind Phase | Physician Decision | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Double Blind Phase | Termination by Sponsor | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Double Blind Phase | Withdrawal by Subject | 3 | 6 | 0 | 0 | 0 | 0 | 0 | 0 |
| Open Label Phase | Adverse Event | 0 | 0 | 0 | 1 | 1 | 3 | 1 | 2 |
| Open Label Phase | Death | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Open Label Phase | Lack of Efficacy | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Open Label Phase | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Open Label Phase | Physician Decision | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Open Label Phase | Termination by Sponsor | 0 | 0 | 0 | 11 | 9 | 14 | 0 | 14 |
| Open Label Phase | Withdrawal by Subject | 0 | 0 | 0 | 1 | 5 | 5 | 0 | 4 |
Baseline characteristics
| Characteristic | Total | Rodatristat Ethyl 600 Mg-Rodatristat Ethyl 600 mg | Rodatristat Ethyl 300 Mg-Rodatristat Ethyl 600 mg | Rodatristat Ethyl 300 Mg-Rodatristat Ethyl 300 mg | Placebo-Rodatristat Ethyl 600 mg | Placebo-Rodatristat Ethyl 300 mg | Rodatristat Ethyl 600 mg BID | Rodatristat Ethyl 300 mg BID | Placebo |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical Double Blind Phase <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Double Blind Phase >=65 years | 30 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 7 Participants | 14 Participants | 9 Participants |
| Age, Categorical Double Blind Phase Between 18 and 65 years | 78 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 29 Participants | 22 Participants | 27 Participants |
| Age, Categorical Open Label Phase <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Open Label Phase >=65 years | 25 Participants | 5 Participants | 0 Participants | 12 Participants | 3 Participants | 5 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Open Label Phase Between 18 and 65 years | 51 Participants | 16 Participants | 2 Participants | 10 Participants | 13 Participants | 10 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous Double Blind Phase | 52.83 Years STANDARD_DEVIATION 14.84 | — | — | — | — | — | 48.4 Years STANDARD_DEVIATION 15.31 | 56.4 Years STANDARD_DEVIATION 14.3 | 53.7 Years STANDARD_DEVIATION 13.76 |
| Age, Continuous Open Label Phase | 54.68 Years STANDARD_DEVIATION 14.65 | 51.1 Years STANDARD_DEVIATION 13.3 | 53.0 Years STANDARD_DEVIATION 5.65 | 59.8 Years STANDARD_DEVIATION 15.84 | 53.4 Years STANDARD_DEVIATION 14.19 | 53.8 Years STANDARD_DEVIATION 13.96 | — | — | — |
| Baseline use of endothelin receptor antagonist Double Blind Phase No | 19 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 6 Participants | 6 Participants | 7 Participants |
| Baseline use of endothelin receptor antagonist Double Blind Phase Yes | 89 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 30 Participants | 30 Participants | 29 Participants |
| Baseline use of endothelin receptor antagonist Open Label Phase No | 17 Participants | 5 Participants | 0 Participants | 5 Participants | 3 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants |
| Baseline use of endothelin receptor antagonist Open Label Phase Yes | 59 Participants | 16 Participants | 2 Participants | 17 Participants | 13 Participants | 11 Participants | 0 Participants | 0 Participants | 0 Participants |
| Baseline use of parenteral prostacyclin Double Blind Phase No | 70 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 25 Participants | 23 Participants | 22 Participants |
| Baseline use of parenteral prostacyclin Double Blind Phase Yes | 38 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 11 Participants | 13 Participants | 14 Participants |
| Baseline use of parenteral prostacyclin Open Label Phase No | 45 Participants | 14 Participants | 1 Participants | 13 Participants | 10 Participants | 7 Participants | 0 Participants | 0 Participants | 0 Participants |
| Baseline use of parenteral prostacyclin Open Label Phase Yes | 31 Participants | 7 Participants | 1 Participants | 9 Participants | 6 Participants | 8 Participants | 0 Participants | 0 Participants | 0 Participants |
| Baseline use of selexipag Double Blind Phase No | 83 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 27 Participants | 28 Participants | 28 Participants |
| Baseline use of selexipag Double Blind Phase Yes | 25 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 9 Participants | 8 Participants | 8 Participants |
| Baseline use of selexipag Open Label Phase No | 64 Participants | 16 Participants | 2 Participants | 20 Participants | 13 Participants | 13 Participants | 0 Participants | 0 Participants | 0 Participants |
| Baseline use of selexipag Open Label Phase Yes | 12 Participants | 5 Participants | 0 Participants | 2 Participants | 3 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Duration since PAH diagnosis Double Blind Phase | 7.17 Year STANDARD_DEVIATION 5.4 | — | — | — | — | — | 6.69 Year STANDARD_DEVIATION 4.913 | 6.18 Year STANDARD_DEVIATION 4.268 | 8.65 Year STANDARD_DEVIATION 6.486 |
| Duration since PAH diagnosis Open Label Phase | 7.22 Year STANDARD_DEVIATION 5.8 | 6.14 Year STANDARD_DEVIATION 4.85 | 8.05 Year STANDARD_DEVIATION 3.18 | 5.82 Year STANDARD_DEVIATION 4.86 | 7.39 Year STANDARD_DEVIATION 6.98 | 10.54 Year STANDARD_DEVIATION 5.97 | — | — | — |
| Duration since PAH diagnosis category Double Blind Phase <=5 years | 48 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 17 Participants | 18 Participants | 13 Participants |
| Duration since PAH diagnosis category Double Blind Phase >5 years | 60 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 19 Participants | 18 Participants | 23 Participants |
| Duration since PAH diagnosis category Open Label Phase <=5 years | 34 Participants | 10 Participants | 0 Participants | 14 Participants | 8 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Duration since PAH diagnosis category Open Label Phase >5 years | 42 Participants | 11 Participants | 2 Participants | 8 Participants | 8 Participants | 13 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Double Blind Phase Hispanic or Latino | 11 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants | 4 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Double Blind Phase Not Hispanic or Latino | 94 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 29 Participants | 32 Participants | 33 Participants |
| Ethnicity (NIH/OMB) Double Blind Phase Unknown or Not Reported | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Open Label Phase Hispanic or Latino | 6 Participants | 2 Participants | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Open Label Phase Not Hispanic or Latino | 68 Participants | 18 Participants | 2 Participants | 20 Participants | 14 Participants | 14 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Open Label Phase Unknown or Not Reported | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Number of PAH therapies category Double Blind Phase 1 PAH therapy | 17 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 6 Participants | 5 Participants | 6 Participants |
| Number of PAH therapies category Double Blind Phase 2 PAH therapies | 35 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 12 Participants | 12 Participants | 11 Participants |
| Number of PAH therapies category Double Blind Phase 3 PAH therapies | 56 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 18 Participants | 19 Participants | 19 Participants |
| Number of PAH therapies category Open Label Phase 1 PAH therapy | 14 Participants | 4 Participants | 1 Participants | 3 Participants | 3 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants |
| Number of PAH therapies category Open Label Phase 2 PAH therapies | 25 Participants | 6 Participants | 0 Participants | 10 Participants | 5 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants |
| Number of PAH therapies category Open Label Phase 3 PAH therapies | 37 Participants | 11 Participants | 1 Participants | 9 Participants | 8 Participants | 8 Participants | 0 Participants | 0 Participants | 0 Participants |
| PAH classification Double Blind Phase Drug or toxin | 8 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 3 Participants | 2 Participants |
| PAH classification Double Blind Phase HPAH | 14 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants | 5 Participants | 4 Participants |
| PAH classification Double Blind Phase IPAH | 58 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 19 Participants | 13 Participants | 26 Participants |
| PAH classification Double Blind Phase PAH associated with congenital systemic pulmonary shunt | 13 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 6 Participants | 4 Participants | 3 Participants |
| PAH classification Double Blind Phase PAH associated with connective tissue disease | 15 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 11 Participants | 1 Participants |
| PAH classification Open Label Phase Drug or toxin | 5 Participants | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| PAH classification Open Label Phase HPAH | 9 Participants | 3 Participants | 1 Participants | 2 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| PAH classification Open Label Phase IPAH | 41 Participants | 8 Participants | 0 Participants | 10 Participants | 12 Participants | 11 Participants | 0 Participants | 0 Participants | 0 Participants |
| PAH classification Open Label Phase PAH associated with congenital systemic pulmonary shunt | 10 Participants | 5 Participants | 0 Participants | 2 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| PAH classification Open Label Phase PAH associated with connective tissue disease | 11 Participants | 2 Participants | 1 Participants | 7 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Double Blind Phase American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Double Blind Phase Asian | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Double Blind Phase Black or African American | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Double Blind Phase More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Double Blind Phase Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Double Blind Phase Unknown or Not Reported | 17 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants | 5 Participants | 7 Participants |
| Race (NIH/OMB) Double Blind Phase White | 83 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 29 Participants | 29 Participants | 25 Participants |
| Race (NIH/OMB) Open Label Phase American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Open Label Phase Asian | 4 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Open Label Phase Black or African American | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Open Label Phase More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Open Label Phase Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Open Label Phase Unknown or Not Reported | 12 Participants | 3 Participants | 0 Participants | 3 Participants | 3 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Open Label Phase White | 57 Participants | 17 Participants | 2 Participants | 17 Participants | 10 Participants | 11 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Austria | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Belgium | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Bosnia and Herzegovina | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Bulgaria | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Canada | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Czechia | 3 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment France | 12 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 3 Participants | 5 Participants |
| Region of Enrollment Germany | 3 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Region of Enrollment Italy | 6 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Latvia | 7 Participants | 1 Participants | 0 Participants | 4 Participants | 1 Participants | 0 Participants | 4 Participants | 6 Participants | 2 Participants |
| Region of Enrollment Moldova | 12 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants |
| Region of Enrollment Poland | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Spain | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United Kingdom | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants |
| Region of Enrollment United States | 44 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 13 Participants |
| Sex: Female, Male Double Blind Phase Female | 85 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 31 Participants | 28 Participants | 26 Participants |
| Sex: Female, Male Double Blind Phase Male | 23 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants | 8 Participants | 10 Participants |
| Sex: Female, Male Open Label Phase Female | 62 Participants | 19 Participants | 1 Participants | 17 Participants | 12 Participants | 13 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Open Label Phase Male | 14 Participants | 2 Participants | 1 Participants | 5 Participants | 4 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 36 | 0 / 36 | 0 / 36 | 2 / 15 | 0 / 16 | 0 / 22 | 0 / 2 | 0 / 21 |
| other Total, other adverse events | 32 / 36 | 34 / 36 | 27 / 36 | 12 / 15 | 15 / 16 | 12 / 22 | 2 / 2 | 17 / 21 |
| serious Total, serious adverse events | 9 / 36 | 6 / 36 | 1 / 36 | 2 / 15 | 4 / 16 | 6 / 22 | 0 / 2 | 3 / 21 |
Outcome results
Primary
Percent Change From Baseline of Pulmonary Vascular Resistance (PVR) at Week 24
Pulmonary vascular resistance (PVR) was measured by right heart catheterization (RHC)
Time frame: 24 Weeks
Population: ITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Rodatristat Ethyl 300 mg BID | Percent Change From Baseline of Pulmonary Vascular Resistance (PVR) at Week 24 | 63.083 percent | Standard Error 18.529 |
| Rodatristat Ethyl 600 mg BID | Percent Change From Baseline of Pulmonary Vascular Resistance (PVR) at Week 24 | 64.219 percent | Standard Error 18.013 |
| Placebo | Percent Change From Baseline of Pulmonary Vascular Resistance (PVR) at Week 24 | 5.813 percent | Standard Error 18.052 |
p-value: 0.020895% CI: [8.716, 105.824]ANCOVA
p-value: 0.017495% CI: [10.272, 106.54]ANCOVA
Secondary
Change From Baseline in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) Levels
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.
Time frame: 24 Weeks
Population: ITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Rodatristat Ethyl 300 mg BID | Change From Baseline in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) Levels | 1145.7 pg/mL | Standard Error 325.93 |
| Rodatristat Ethyl 600 mg BID | Change From Baseline in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) Levels | 886.1 pg/mL | Standard Error 275.7 |
| Placebo | Change From Baseline in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) Levels | 19.8 pg/mL | Standard Error 143.86 |
p-value: 0.001495% CI: [437.39, 1814.39]Mixed Models Analysis
p-value: 0.004795% CI: [265.41, 1467.16]Mixed Models Analysis
Secondary
Change From Baseline in Six-minute Walk Distance (6MWD)
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.
Time frame: 24 Weeks
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rodatristat Ethyl 300 mg BID | Change From Baseline in Six-minute Walk Distance (6MWD) | -14.5 six-minute walk distance (6MWD) (meters) |
| Rodatristat Ethyl 600 mg BID | Change From Baseline in Six-minute Walk Distance (6MWD) | 0 six-minute walk distance (6MWD) (meters) |
| Placebo | Change From Baseline in Six-minute Walk Distance (6MWD) | 2.5 six-minute walk distance (6MWD) (meters) |
p-value: 0.063695% CI: [-69.13, 1.91]Wilcoxon (Mann-Whitney)
p-value: 0.157395% CI: [-45.45, 7.35]Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline in World Health Organization (WHO) Functional Class (FC)
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
Time frame: 24 Weeks
Population: ITT population
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Rodatristat Ethyl 300 mg BID | Change From Baseline in World Health Organization (WHO) Functional Class (FC) | I | 4 Participants |
| Rodatristat Ethyl 300 mg BID | Change From Baseline in World Health Organization (WHO) Functional Class (FC) | No Change | 30 Participants |
| Rodatristat Ethyl 300 mg BID | Change From Baseline in World Health Organization (WHO) Functional Class (FC) | -II | 0 Participants |
| Rodatristat Ethyl 300 mg BID | Change From Baseline in World Health Organization (WHO) Functional Class (FC) | -I | 2 Participants |
| Rodatristat Ethyl 300 mg BID | Change From Baseline in World Health Organization (WHO) Functional Class (FC) | II | 0 Participants |
| Rodatristat Ethyl 600 mg BID | Change From Baseline in World Health Organization (WHO) Functional Class (FC) | No Change | 30 Participants |
| Rodatristat Ethyl 600 mg BID | Change From Baseline in World Health Organization (WHO) Functional Class (FC) | -II | 0 Participants |
| Rodatristat Ethyl 600 mg BID | Change From Baseline in World Health Organization (WHO) Functional Class (FC) | -I | 3 Participants |
| Rodatristat Ethyl 600 mg BID | Change From Baseline in World Health Organization (WHO) Functional Class (FC) | I | 3 Participants |
| Rodatristat Ethyl 600 mg BID | Change From Baseline in World Health Organization (WHO) Functional Class (FC) | II | 0 Participants |
| Placebo | Change From Baseline in World Health Organization (WHO) Functional Class (FC) | II | 0 Participants |
| Placebo | Change From Baseline in World Health Organization (WHO) Functional Class (FC) | I | 3 Participants |
| Placebo | Change From Baseline in World Health Organization (WHO) Functional Class (FC) | -II | 0 Participants |
| Placebo | Change From Baseline in World Health Organization (WHO) Functional Class (FC) | No Change | 30 Participants |
| Placebo | Change From Baseline in World Health Organization (WHO) Functional Class (FC) | -I | 3 Participants |
p-value: 0.573Regression, Logistic
p-value: 0.9911Regression, Logistic