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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

United Therapeutics Corp.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

16 May 2019 → 3 Feb 2026

Decision date (initial)

2024-06-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

United Therapeutics Corporation

External identifiers

EU CT number

2023-509304-16-00

EudraCT number

2018-001187-33

ClinicalTrials.gov

NCT03626688

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenetic, Therapy, Efficacy, Pharmacokinetic, Safety, Others

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 objectives 5

1. 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 m 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
2. Time to first all-cause hospitalization
3. Time to all-cause mortality
4. Heart rate recovery (HRR) following completion of the 6MWT
5. To evaluate the safety and tolerability of ralinepag in subjects with PAH

Conditions and MedDRA coding

Pulmonary arterial hypertension (PAH)

Study design 3 periods

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

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 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 m.
9. If the subject is taking concomitant medications that may affect the clinical manifestations of PAH (e.g., calcium channel blockers, diuretics, digoxin, L-arginine supplementation, 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 impregnate, in vitro fertilization) during the study and for 30 days after the last dose of IMP. Eligible male subjects must agree not to participate in sperm donation for 90 days after the last dose of IMP.

Exclusion criteria 22

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) or activin signaling inhibitor 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. Subject tests positive for amphetamine, cocaine, methamphetamine, methylenedioxymethamphetamine or phencyclidine on thein urine drug screen performed at Screening, or has a recent history (6 months) of alcohol or drug abuse. A subject will not be excluded due to a positive drug screen caused by prescribed medications.
17. Initiation or discontinuation of a cardio-pulmonary rehabilitation program based upon exercise within 90 days prior to Screening and/or planned during study participation.
18. Prior participation in any study of ralinepag or participation in another interventional clinical study with medicinal products within 30 days prior to Screening. Concurrent participation in registry or observational studies is allowed, as long as the subject can fulfill all other entry criteria and comply with all study procedures.
19. Any reason that, in the opinion of the Investigator or Medical Monitor, precludes the subject from participating in the study (e.g., any previous or intercurrent medical condition) that may increase the risk associated with study participation or that would confound study analysis or impair study participation or cooperation.
20. Known hypersensitivity to ralinepag or any of the excipients.
21. Life expectancy <12 months based on the Investigator's opinion.
22. Women who are pregnant, lactating, or breast-feeding

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is the time 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.

Secondary endpoints 9

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. The proportion of subjects who achieve all three of the following: NT-proBNP <300 pg/mL, 6MWD >440 m, WHO/NYHA functional class I or II status or better will be analyzed using CMH method. The odds ratio will be presented together with 95% CIs and the p-value.
8. REVEAL score will be analyzed using MMRM analysis with treatment, the stratification factors, week, and treatment-by-week interaction as factors and baseline REVEAL 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.
9. HRQoL measures (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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

United Therapeutics Corp.

Sponsor organisation

United Therapeutics Corp.

Address

55 TW Alexander Drive

City

Durham

Postcode

27713-2847

Country

United States

Scientific contact point

Organisation

United Therapeutics Corp.

Contact name

Regulatory Department

Public contact point

Organisation

United Therapeutics Corp.

Contact name

Global Medical Information

Third parties 6

Locations

15 EU/EEA countries · 48 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 214 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications