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

• ClinicalTrials.gov Identifier: NCT04712669
• Recruitment Status: Recruiting
• First Posted: January 15, 2021
• Last Update Posted: January 5, 2023
• Sponsor: Altavant Sciences GmbH
• Information provided by (Responsible Party): Altavant Sciences GmbH

Tracking Information

• First Submitted Date: January 12, 2021
• First Posted Date: January 15, 2021
• Last Update Posted Date: January 5, 2023
• Actual Study Start Date: March 15, 2021
• Estimated Primary Completion Date: February 2023 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: January 3, 2022): Percent change from baseline of pulmonary vascular resistance (PVR) as measured by right heart catheterization between active and placebo [ Time Frame: From initiation of treatment to Week 24 ]
• Original Primary Outcome Measures (submitted: January 13, 2021): Change from baseline of pulmonary vascular resistance as measured by right heart catherization [ Time Frame: From initiation to Week 24 ]

Current Secondary Outcome Measures (submitted: January 3, 2022)

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

Original Secondary Outcome Measures (submitted: January 13, 2021)

• Change from baseline of cardiac index (CI) [ Time Frame: From initiation to Week 24 ]
• Change from baseline of mean pulmonary artery pressure (mPAP) [ Time Frame: From initiation to Week 24 ]
• Change from baseline of mean mixed venous oxygen saturation (SvO2) [ Time Frame: From initiation to Week 24 ]
• Change from baseline of pulmonary artery compliance (PAC) [ Time Frame: From initiation to Week 24 ]
• Time to the first occurrence of a clinical worsening event (TTCW) [ Time Frame: From initiation to Week 24 ]
  Time to Clinical Worsening (TTCW) defined as the first occurrence of: 1. Death from any cause, 2. Hospitalization for worsening PAH (any hospitalization for worsening PAH, lung or heart and lung transplantation, atrial septostomy, or initiation of parenteral prostanoid therapy), 3. Disease progression defined as a decrease of more than 15% from Baseline in the 6-minute walk distance (6MWD) combined with World Health Organization (WHO) Functional Class (FC) III or IV symptoms at 2 consecutive visits separated by at least 14 days (adjudicated)
• Change in baseline in WHO FC World Health Organization (WHO) Functional Class (FC) [ Time Frame: From initiation to Week 24 ]
• Change from baseline in 6MWD [ Time Frame: From initiation to Week 24 ]
• Change from baseline in N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) levels [ Time Frame: From initiation to Week 24 ]
• Change from baseline in of right atrial size by echocardiogram [ Time Frame: From initiation to Week 24 ]
• Change from baseline in the tricuspid annular systolic velocity by echocardiogram [ Time Frame: From initiation to Week 24 ]
• Change from baseline in the tricuspid annular plane systolic excursion (TAPSE) by echocardiogram [ Time Frame: From initiation to Week 24 ]
• Change from baseline in the RV fractional area change by echocardiogram [ Time Frame: From initiation to Week 24 ]
• Change in baseline in the Pulmonary Arterial Hypertension Symptoms and Impact Questionnaire (PAH SYMPACT) Score [ Time Frame: From initiation to Week 24 ]
• Change in baseline in the Registry to Evaluate Early and Long Term PAH Disease Management (REVEAL) Lite 2 score [ Time Frame: From initiation to Week 24 ]
• Change from baseline in plasma and urine 5-hydroxyindoleacetic acid (5-HIAA) [ Time Frame: From initiation to Week 24 ]

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: January 13, 2021)

• Time to Clinical Improvement (TTCI) [ Time Frame: From initiation to Week 24 ]
  A > 10% increase in 6MWD or 30 meters AND an improvement to or maintenance of WHO FC II symptomatology, in the absence of a deterioration in clinical condition or death during the 24 weeks of the Main Study
• Change from baseline on the following actigraphy endpoints: [ Time Frame: From initiation to Week 24 ]
  1. Light to vigorous activity/day, 2. Moderate to vigorous activity/day, 3.Total movement/day, 4.Best 6-minute walk effort

Descriptive Information

• Brief Title: A Study of Rodatristat Ethyl in Patients With Pulmonary Arterial Hypertension (ELEVATE 2)
• Official Title: A Phase 2, Dose-Ranging, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Rodatristat Ethyl in Patients With Pulmonary Arterial Hypertension
• 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 Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Following screening assessments, Patients will be enrolled into 1 of 3 treatment arms in a 1:1:1 randomization.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment

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

Study Arms

• Experimental: Rodatristat Ethyl 300 mg BID
  Rodatristat ethyl 300 mg tablet BID + standard of care medication(s) taken for 24 weeks
  Intervention: Drug: rodatristat ethyl 300 mg tablet BID
• Experimental: Rodatristat Ethyl 600 mg BID
  Rodatristat ethyl 600 mg tablet BID + standard of care medication(s) taken for 24 weeks
  Intervention: Drug: rodatristat ethyl 600 mg BID
• Placebo Comparator: Placebo
  Matching placebo tablet + standard of care medication(s) taken for 24 weeks
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 13, 2021): 90
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: February 2023
• Estimated Primary Completion Date: February 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Watiri Kamau-Kelley; +1-408-300-3316; watiri@enzyvant.com

Contact: Howard Lazarus, MD, FCCP; +1-203-297-5374; howard.lazarus@enzyvant.com

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

Administrative Information

• NCT Number: NCT04712669
• Other Study ID Numbers: RVT-1201-2002 / ELEVATE 2
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Altavant Sciences GmbH
• Original Responsible Party: Same as current
• Current Study Sponsor: Altavant Sciences GmbH
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Altavant Sciences GmbH
• Verification Date: July 2022