A study evaluating the efficacy and safety of ralinepag in treatment of patients with pulmonary hypertension.

• Register: EUCTR
• Last refreshed on: 29 July 2024
• Main ID: EUCTR2018-001187-33-GR
• Date of registration: 20/03/2019
• Prospective Registration: Yes
• Primary sponsor: United Therapeutics Corporation
• Public title: A study evaluating the efficacy and safety of ralinepag in treatment of patients with pulmonary hypertension.
• Scientific title: A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients - ADVANCE-Outcomes
• Date of first enrolment: 03/04/2019
• Target sample size: 1000
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-001187-33
• 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, Belgium, Brazil, Bulgaria, Canada, Chile, China, Croatia, Czech Republic, Denmark, European Union, France, Germany, Greece, Hungary, Israel, Italy, Japan, Korea, Republic of, Mexico, Netherlands, Poland, Portugal, Romania, Serbia, Singapore, Sweden, Taiwan, Turkey, Ukraine, 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. At least 18 years of age
2. Evidence of a personally signed and dated Informed Consent Form
indicating that the subject has been informed of all pertinent aspects of
the study prior to initiation of any study-related procedures.
3. Subjects who are willing and able to comply with scheduled visits,
treatment plan, laboratory tests, and other study procedures.
4. Primary diagnosis of symptomatic PAH classified by one of the
following subgroups:
a. Idiopathic pulmonary arterial hypertension;
b. Heritable pulmonary arterial hypertension;
c. Drug or toxin 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: Connective tissue disease (CTD), HIV infection;
Congenital systemic-pulmonary intracardiac shunt (must have
undergone surgical correction or repair with a closure device at least 1
year prior to Screening and have no, or a clinically
insignificant, shunt fraction [1.0 =pulmonary-systemic flow ratio =1.5]
in the opinion of the Investigator.
5. Has had a right heart catheterization (RHC) performed at or within 3
years prior to Screening (RHC will be performed during Screening if not
available) that is consistent with the diagnosis of PAH, meeting all of the
following criteria:
a. Mean pulmonary arterial pressure (mPAP) =20 mmHg (at rest)
b. PAWP =15 mmHg (if PAWP cannot be reliably attained, then left
ventricular end diastolic pressure =15 mmHg)
c. PVR >2.00 Wood units (>160 dynes/sec/cm5).
6. Has WHO/NYHA functional class II to IV symptoms.
7. If on PAH-specific background oral therapy, subject is on stable
therapy with either an endothelin receptor antagonist (ERA) and/or a
PDE5-I or a soluble guanylate cyclase (sGC) stimulator. Subjects must
have access to locally available standard of care treatment in accordance
with national guidelines
a. Stable is defined as no change in dose or regimen within 30 days prior
to Baseline and for the duration of the study.
b. Subjects may be on either a PDE5 inhibitor or an sGC at stable dose
(but not both).
c. If the subject's disease-specific PAH therapy does not include a PDE-5
inhibitor, the use of PDE5-I for erectile dysfunction, up to 3 doses per
week, is permitted.
8. Has a 6MWD of =150 meters.
9. If the subject is taking concomitant medications that may affect the
clinical manifestations of PAH (e.g., calcium channel blockers, diuretics,
digoxin, or L-arginine supplementation, beta blockers, angiotensinconverting
enzyme inhibitors, or angiotensin II receptor blockers), the
subject must be on a stable dose for at least 30 days prior to the Baseline Visit and the dosage mainta, beta
blockers, angiotensin-converting enzyme inhibitors, or angiotensin II
receptor blockers), 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 must be stable for
at least the 10 days prior to Baseline.
10. Both male and female subjects agree to use a highly effective
method of birth control throughout the entire study period from
informed consent through the 30-Day Follow-up Visit, if the possibility of
conception exists. Eligible male and female subjects must also agree not
to participate in a conception process (ie, actively attempt to become
pregnant or to imp
Exclusion criteria:
Subjects must not meet ANY of the following exclusion criteria to be
eligible for enrollment into the study, unless otherwise indicated:
1. For subjects with known HIV-associated PAH, a cluster designation 4
T-cell count <200/mm3 within 90 days of Baseline.
2. Subjects must not have 3 or more of the following left ventricular
dysfunction risk factors:
a. Body mass index =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: History of myocardial infarction or
percutaneous coronary intervention or angiographic evidence of
coronary artery disease (>50% stenosis in at least 1 coronary artery);
Positive stress test with imaging; Previous coronary artery bypass graft;
angina
e. Recurrent or persistent atrial fibrillation.
3. Has evidence of more than mild lung disease on PFTs performed
within 180 days prior to, or during Screening. Subjects with any of the
following criteria will be excluded:
a. Forced expiratory volume in 1 second <60% (predicted); or
b. Total lung capacity (TLC) <60% (predicted)
4. Has evidence of thromboembolic disease as determined by a V/Q lung
scan or other local standard of care diagnostic evaluation at or after
diagnosis of PAH.
5. Current diagnosis of ongoing and clinically significant sleep apnea as
defined by the Investigator.
6. Male subjects with a corrected QT interval using Fridericia's formula
(QTcF) >450 msec and female subjects with a QTcF >470 msec on ECG
recorded at Screening and analyzed by the central ECG laboratory.
Subjects with evidence of intraventricular conduction delay (IVCD). In
the presence of IVCD, subjects, defined as a QRS interval greater than
110 msec, will be excluded if the QTcF is
>500 msec for both males and females.
7. Severe chronic liver disease (i.e., Child-Pugh Class C), portal
hypertension, cirrhosis or complications of cirrhosis/portal hypertension
(e.g., history of variceal hemorrhage, encephalopathy).
8. Confirmed active infection with hepatitis B virus (HBV) or hepatitis C
virus (HCV).
9. Subjects with alanine aminotransferase or aspartate aminotransferase
=3 times the upper limit of normal (ULN) or total bilirubin =2 × ULN at
Screening.
10. Chronic renal insufficiency as defined by serum creatinine >2.5
mg/dL or requiring dialysis at Screening.
11. Hemoglobin concentration <9 g/dL at Screening.
12. Subjects treated with an IV or SC prostacyclin pathway agent (e.g.,
epoprostenol, treprostinil, or iloprost) for PAH at any time prior to Baseline (use in vasoreactive testing is permitted).
13. Subjects currently on or who were treated with an inhaled or oral
prostacyclin pathway agent (iloprost, treprostinil, beraprost, or
selexipag) for >6 months or within 90 days prior to Baseline.
Subject is not eligible if treatment was stopped for a safety or
tolerability issue related
to systemic prostacyclin adverse effects at any time. If a subject
discontinued for other reasons, the subject may be eligible if the subject
has been off therapy and stable (i.e., no change in WHO/NYHA FC or
change in PAHspecific background oral therapy) for at least 90 days
prior to Baseline.
14. Subject has pulmonary veno-occlusive disease.
15. Malignancy diagnosed and/or treated within 5 years prior to
Screening, with the exception of localized non-metastatic basal cell or
squamous cell carcinoma of the skin or in-situ carcinoma of the cervix
excised with curative intent.
16. Subjec

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

Health Condition(s) or Problem(s) studied

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

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

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: NA
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: NA
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: NA
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)

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

Primary end point(s): The primary endpoint is the time (in days) from randomization to the first adjudicated protocol-defined worsening event. Subjects without a protocol-defined clinical worsening event will be censored at date of last contact, 7 days after last study dose, or end of study date, whichever is the earliest.

Main Objective: The primary objective of this study is:
To demonstrate the effect of ralinepag on the time to first adjudicated
protocol-defined clinical worsening event in subjects with PAH.

Secondary Objective: The secondary objectives of the study are:
To evaluate the effects of ralinepag from Baseline to Week 28 on:
• N-terminal pro b-type natriuretic peptide (NT-proBNP)
• 6 minute walk distance (6MWD)
• WHO/ New York Heart Association (NYHA) functional class
• Shift and proportion of subjects who attain all three of the following:
o NT-proBNP <300 pg/mL
o 6MWD >440 meters
o WHO/NYHA functional class I or II
• REVEAL risk score
• Clinical improvement as defined by the absence of clinical worsening
and fulfillment of at least 2 of the 3 following criteria:
o Increase in 6MWD by =10% or =30 m
o Improvement to or maintenance of WHO FC I or II
o Decrease in NT-proBNP by at least 30%
• Health-related quality of life (HRQoL) measures
• Time to first all-cause hospitalization
• Time to all-cause mortality
• Heart rate recovery (HRR) following completion of the 6MWT
• To evaluate the safety and tolerability of ralinepag in subjects with
PAH

Secondary Outcome(s)

Secondary end point(s): • NT-proBNP with log transformation will be analyzed using MMRM analysis with treatment, the stratification factors, week, and treatment-by-week interaction as factors and baseline NT-proBNP as a covariate. Least squares means, standard errors (SE), and 95% CIs for the treatments and their difference will be presented together with the p-value.
• 6MWD will be analyzed using MMRM analysis with treatment measured>12 hours post dose, the stratification factors (less 6MWD stratum), week, and treatment-by-week interaction as factors and baseline 6MWD as a covariate. Least squares means, SEs, and 95% CIs for the treatments and their difference will be presented together with the p-value.
• WHO/NYHA functional class will be analyzed using using CMH method adjusted for baseline WHO/NYHA functional class and using modified ridit scores to compute the test statistic and p-value for the between treatment comparison.
• Time to first all-cause hospitalization will be analyzed using Cox regression with a model that includes treatment and the stratification factors. The hazard ratio for treatment together with its 95% CI and p-value will be presented.
• Time to all-cause mortality will be analyzed using Cox regression with a model that includes treatment and the stratification factors. The hazard ratio for treatment together with its 95% CI and p-value will be presented.
• HRR following completion of 6MWT will be analyzed using MMRM analysis with treatment, the stratification factors, week, and treatment-by-week interaction as factors and baseline HRR as a covariate. Least squares means, SEs, and 95% CIs for the treatments and their difference will be presented together with the p-value.
• The proportion of subjects who achieve all three of the following: NT-proBNP <300 pg/mL, 6MWD >440 meters, WHO/NYHA functional class II status or better will be analyzed using CMH method. The odds ratio will be presented together with 95% CIs and the p-value.
• HRQoL measures (PAH-SYMPACT Questionnaire and SF-36) will be analyzed using MMRM analysis with treatment, the stratification factors, week, and treatment-by-week interaction as factors and baseline domain score as a covariate. Least squares means, SEs, and 95% CIs for the treatments and their difference will be presented together with the p-value.

Timepoint(s) of evaluation of this end point: Throughout the study; secondary endpoints will be assessed as the change from baseline to Week 28, except for time to all-cause hospitalization and time to all-cause mortality.

Secondary ID(s)

109021

2018-001187-33-FR

ROR-PH-301(APD811-301)

Source(s) of Monetary Support

United Therapeutics Corporation

Ethics review

Status: Approved
Approval date: 29/03/2019
Contact: