A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Ralinepag to Evaluate Safety and Effects on Exercise Capacity Assessed by Cardiopulmonary Exercise Testing in Subjects with World Health Organization Group 1 Pulmonary Hypertension Who Recently Initiated Therapy

• Register: EUCTR
• Last refreshed on: 19 October 2020
• Main ID: EUCTR2019-003309-88-GB
• Date of registration: 11/02/2020
• Prospective Registration: Yes
• Primary sponsor: United Therapeutics Corporation
• Public title: A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Ralinepag to Evaluate Safety and Effects on Exercise Capacity Assessed by Cardiopulmonary Exercise Testing in Subjects with World Health Organization Group 1 Pulmonary Hypertension Who Recently Initiated Therapy
• Scientific title: A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Ralinepag to Evaluate Safety and Effects on Exercise Capacity Assessed by Cardiopulmonary Exercise Testing in Subjects with World Health Organization Group 1 Pulmonary Hypertension Who Recently Initiated Therapy - ADVANCE Capacity
• Date of first enrolment: 02/06/2020
• Target sample size: 193
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2019-003309-88
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Austria, Belgium, Brazil, Czech Republic, Germany, Italy, Poland, Spain, United Kingdom, United States

Contacts

• Name: Regulatory Department
• Affiliation: United Therapeutics Corporation

• Name: Regulatory Department
• Affiliation: United Therapeutics Corporation

Key inclusion & exclusion criteria

Inclusion criteria:
Each subject must meet ALL of the following inclusion criteria to be eligible for enrollment into the study:
1) Evidence of a personally signed and dated Informed Consent Form (ICF) indicating that the subject has been informed of all pertinent aspects of the study prior to initiation of any study-related procedures.
2) At least 18 years of age at the time of consent.
3) Primary diagnosis of PAH classified by one of the following subgroups:
a. Idiopathic pulmonary arterial hypertension (IPAH)
b. Heritable pulmonary arterial hypertension (HPAH)
c. Drugs or toxins induced based on prior exposure to drugs, chemicals, or toxins, such as fenfluramine derivatives, other anorexigens, toxic rapeseed oil, or L-tryptophan
d. PAH associated with:
i. Connective tissue disease (CTD)
ii. Human immunodeficiency virus (HIV) infection
iii. Congenital systemic-pulmonary shunt (must have undergone surgical correction at least 1 year prior to Screening) and have no, or a clinically insignificant, shunt fraction (1.0=pulmonary-systemic flow ratio [QP/QS] =1.5)
4. Has had a diagnostic right heart catheterization (RHC) performed within 1 year of Screening (or during Screening if one is not available) that is consistent with the diagnosis of PAH, meeting all of the following criteria:
a) Pulmonary artery pressure mean (PAPm) >20 mmHg (at rest)
b) Pulmonary artery wedge pressure (PAWP) =15 mmHg (If PAWP cannot be reliably attained, then left ventricular end diastolic pressure [LVEDP] =15 mmHg)
c) Pulmonary vascular resistance (PVR) =3 Wood units or =240 dynes/sec/cm5
If more than 1 RHC was performed within 1 year of Screening, the most recent RHC that includes parameters sufficient to evaluate the above criteria must be used for this assessment.
5) Has WHO/NYHA FC 2 to 3 symptoms at Baseline.
6) Must have initiated first PAH-specific oral therapy with an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 inhibitor (PDE5-I) or a soluble guanylate cyclase (sGC) stimulator within 9 months prior to Screening, and be on a stable dose(s), defined as no change in dose or regimen for at least 30 days prior to Screening. Subjects may be on a stable dose of either a PDE5-I or a sGC stimulator, not both.
a) If the subject’s disease-specific PAH therapy does not include a PDE5-I, the use of PDE5-I as needed for erectile dysfunction (ED), up to 3 doses per week, is permitted. The subject should not have taken a dose within 48 hours of Baseline.
7) Has a 6MWD of =150 meters during Screening.
8) Has a VE/VCO2 slope =38 during the Screening CPET, as assessed by the CPET core lab.
9) Has a peak VO2 of =10 to <18 mL·kg-1·min-1 during the Screening CPET, as assessed by the CPET core lab.
10) If the subject is taking concomitant medications that may affect PAH (ie, calcium channel blockers, digoxin, diuretics, beta blockers, Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, or L-arginine), the subject must be on a stable dose for at least 30 days prior to the Baseline Visit and the dosage maintained throughout the study. The exception is that the dose of diuretics should remain stable for at least the 10 days prior to Baseline.
11. Both male and female subjects agree to use a highly effective method of birth control throughout the entire study period from informed consent through to the Week 28 Visit/28-day Follow-up Visit, if the possibility of conception exists. Eligible male and female subjects must also agree not to participate in
Exclusion criteria:
Subjects must not meet ANY of the following exclusion criteria to be eligible for enrollment into the study:
1) For subjects with known HIV-associated PAH, a cluster designation 4 (CD4+) T-cell count <200/mm3 at Screening.
]2) Has 3 or more of the following left ventricular disease/dysfunction risk factors:
a) Body mass index (BMI) =30 kg/m2
b) History of systemic hypertension
c) Diabetes mellitus - any type
d) Historical evidence of significant coronary artery disease established by any 1 of the following:
i) History of myocardial infarction or percutaneous coronary intervention or angiographic evidence of coronary artery disease (>50% stenosis in at least 1 coronary artery)
ii) Positive stress test with imaging
iii) Previous coronary artery bypass graft
iv) Angina
e) Chronic atrial fibrillation
3) Current unstable angina.
4) Symptomatic coronary disease and/or myocardial infarction within past 6 months.
5) Current symptomatic aortic or mitral valve disease.
6) Has evidence of more than mild lung disease on pulmonary function tests (PFTs) performed within 1 year prior to, or during, Screening. Subjects with any of the following criteria will be excluded:
a. Forced expiratory volume in 1 second (FEV1) <60% predicted; or
b. Total lung capacity (TLC) <60% predicted
7) Has evidence of thromboembolic disease as determined by ventilation-perfusion (V/Q) lung scan or local standard of care diagnostic evaluation at or after diagnosis of PAH.
8) Current diagnosis of uncontrolled sleep apnea in the clinical opinion of the Investigator.
9) Requires use of supplemental oxygen during CPET procedures.
10) Respiratory exchange ratio (RER) <1.0 at Screening CPET, as determined by the CPET core laboratory.
11) Acute non-cardiac disorder that may affect exercise performance or be aggravated by exercise (eg, infection, renal failure, thyrotoxicosis).
12) Male subjects with a corrected QT interval using Fridericia’s formula (QTcF) >450 msec and female subjects with QTcF >470 msec on electrocardiogram (ECG) recorded in triplicate at Screening in subjects without evidence of intraventricular conduction delay (IVCD). In presence of IVCD, subjects will be excluded if QTcF is >500 msec for both males and females.
13) Severe chronic liver disease (ie, Child-Pugh C), portal hypertension, cirrhosis, or complications of cirrhosis/portal hypertension (eg, history of variceal hemorrhage, encephalopathy).
14) Confirmed active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV).
15) Subjects with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =3 times the upper limit of normal (ULN) or total bilirubin =2 × ULN at Screening.
16) Chronic renal insufficiency as defined by serum creatinine >2.5 mg/dL or requiring dialysis at Screening.
17) Hemoglobin concentration <9 g/dL at Screening.
18) Subjects treated with an intravenous (IV) or subcutaneous (SC) prostacyclin pathway agent (eg, epoprostenol, treprostinil, or iloprost) at any time prior to Baseline (use in vasoreactive testing is permitted).
19) Subjects treated with an inhaled or oral prostacyclin pathway agent (iloprost, treprostinil, beraprost, or selexipag) that was stopped for a safety or tolerability issue.
• If a subject discontinued for other reasons, the subject is eligible if the subject has been off therapy and stable (ie, no change in WHO/NYHA FC or change in PAH-specific background therapy) for 90 days prior to Baseline.
20) Subject has pulmonary veno-occlusive disease.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

pulmonary arterial hypertension (PAH)
MedDRA version: 20.0 Level: LLT Classification code 10077731 Term: Pulmonary hypertension WHO functional class I System Organ Class: 100000004855

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Intervention(s)

Product Name: Ralinepag
Product Code: APD811
Pharmaceutical Form: Prolonged-release tablet
INN or Proposed INN: RALINEPAG
CAS Number: 1187856-49-0
Current Sponsor code: APD811
Other descriptive name: AR392830
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: Ralinepag
Product Code: APD811
Pharmaceutical Form: Prolonged-release tablet
INN or Proposed INN: RALINEPAG
CAS Number: 1187856-49-0
Current Sponsor code: APD811
Other descriptive name: AR392830
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 250-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: Ralinepag
Product Code: APD811
Pharmaceutical Form: Prolonged-release tablet
INN or Proposed INN: RALINEPAG
CAS Number: 1187856-49-0
Current Sponsor code: APD811
Other descriptive name: AR392830
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 400-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: To evaluate the effects of ralinepag therapy on exercise capacity as assessed by change in peak oxygen consumption (VO2) derived from cardiopulmonary exercise testing (CPET) after 28 weeks of treatment

Secondary Objective: To evaluate the effects of ralinepag on:
1. N-terminal pro b-type natriuretic peptide (NT-proBNP)
2. Minute ventilation (VE)/carbon dioxide output (VCO2) slope
3. WHO/New York Heart Association (NYHA) Functional Class (FC)
4. Health-related quality of life (HRQoL) measured by the Short Form (36) Health Survey (SF-36)
5. Time to first all-cause nonelective hospitalization
6. Safety and tolerability
Note: Other protocol defined exploratory objectives may apply.

Primary end point(s): The primary endpoint of the study is the change from Baseline in peak VO2 after 28 weeks of treatment with study drug.

Timepoint(s) of evaluation of this end point: Through the study.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Throughout the study.

Secondary end point(s): The following secondary endpoints will be analyzed in hierarchical order:
• Change from Baseline at Week 28 in NT-proBNP: NT-proBNP with log transformation will be analyzed in the ITT population using mixed-effect model repeated measures (MMRM) analysis with treatment, the stratification factors, week, and treatment-by-week interaction as factors and baseline NT-proBNP as a covariate
• Change from Baseline at Week 28 in VE/VCO2 slope: VE/VCO2 slope will be analyzed in the mITT population and repeated in the ITT population using ANCOVA with a model that includes treatment and the stratification factors as factors and Baseline VE/VCO2 slope as a covariate.
• Change in SF-36 scores from Baseline to Week 28: the component and domain scores will be analyzed in the ITT population using MMRM analysis with treatment, the stratification factors, week, and treatment-by-week interaction as factors and baseline component/domain score as a covariate.
• Time to first all-cause nonelective hospitalization in randomized subjects during the study period will be analyzed in the ITT population using Cox proportional hazard regression model that includes treatment and the stratification factors.

Secondary ID(s)

109021

ROR-PH-302

Source(s) of Monetary Support

United Therapeutics Corporation

Ethics review

Status: Approved
Approval date: 02/06/2020
Contact: