| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| pulmonary arterial hypertension (PAH) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10077731 |
| E.1.2 | Term | Pulmonary hypertension WHO functional class I |
| E.1.2 | System Organ Class | 100000004855 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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 |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the effects of ralinepag on:
1. NT-proBNP
2. VE/VCO2 slope
3. WHO/NYHA FC
4. Health-related quality of life measured by the Short Form Health
Survey (SF-36)
5. Time to first all-cause nonelective hospitalization
6. Safety and tolerability
Note: Other protocol defined exploratory objectives may apply. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Optional evaluation of proteomics, metabolomics, transcriptomics, and pharmacogenetic analysis:
For subjects who agree to participate in the optional proteomics, metabolomics, and transcriptomics analyses, blood samples will be collected at Baseline, the Week 28 Visit, or the Study Drug Termination Visit; for subjects who agree to participate in the optional genetic analysis, a blood sample will be collected at Baseline. |
|
| E.3 | Principal inclusion criteria |
Each subject must meet ALL 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 1 of the following subgroups:
a. Idiopathic pulmonary arterial hypertension
b. Heritable pulmonary arterial hypertension
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
ii. Human immunodeficiency virus (HIV) infection
iii. 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)
4. Has had a diagnostic RHC performed at or within 3 years before
Screening (or during Screening if one is not available) that is consistent
with the diagnosis of PAH, meeting all the following criteria:
a) Pulmonary artery pressure mean >20 mmHg (at rest)
b) PAWP ≤15 mmHg (If PAWP cannot be reliably attained, then left
ventricular end diastolic pressure ≤15 mmHg)
c) PVR ≥3 Wood units or ≥240 dynes/sec/cm5
If more than 1 RHC was performed within 3 years 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 II to III symptoms at Baseline.
6) Must be on a stable dose(s) of PAH-specific oral therapy, defined as
no change in dose or regimen for at least 120 days prior to
randomization. Allowable PAH-specific therapy is an ERA and/or PDE5-I
or a sGC stimulator. 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 a PDE5-I for erectile dysfunction, 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 ≥150 meters during Screening.
8) Has a VE/VCO2 slope ≥38 during the Screening CPET, as assessed by
the CPET core laboratory.
9) Has a peak VO2 of ≥10 to <18 mL·kg-1·min-1 during the Screening
CPET, as assessed by the CPET core laboratory.
10) If the subject is taking concomitant medications that may affect the
clinical manifestations of PAH (ie, calcium channel blockers, digoxin,
diuretics, beta blockers, angiotensin-converting enzyme inhibitors,
angiotensin II receptor blockers, or L-arginine suplements), the subject
must be on a stable dose for at least 30 days prior to the randomization
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 randomization.
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 a conception process (ie, actively
attempt to become pregnant or to impregnate, sperm donation, in vitro
fertilization) during the study and for 30 days after the final dose of
study drug.
Eligible male subjects must agree not to participate in sperm donation
for 90 days after the final dose of study drug.
Women who are surgically sterile or postmenopausal (defined as 12
consecutive months with no menses without an alternative medical
cause) are not considered to be of childbearing potential. If of
childbearing potential, female partners of male study participants should
agree to utilize medically acceptable methods of contraception for the duration of study participation.
|
|
| E.4 | Principal 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 of
differentiation 4 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 ≥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) myocardial infarction, percutaneous coronary intervention or
angiographic evidence of coronary artery disease (>50% stenosis in at
least 1 coronary artery)
ii) Positive stress test for cardiac ischemia with imaging
iii) Previous coronary artery bypass graft
iv) Angina
e) Recurrent or persistent atrial fibrillation
3) Not applicable.
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 PFTs performed
within 1 year prior to, or during, Screening. Subjects with any of the
following criteria will be excluded (BOTH measurements must be
performed):
a. Forced expiratory volume in 1 second <60% predicted;
b. 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 ongoing and clinically significant sleep apnea as
defined by 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 QTcF >450 msec and female subjects with QTcF
>470 msec on electrocardiogram (ECG) recorded at Screening. Subjects
with evidence of intraventricular conduction delay (defined as a QRS
interval >110msec) 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 HCV.
15) Subjects with alanine aminotransferase or aspartate
aminotransferase ≥3 times the upper limit of normal or total bilirubin ≥
2 times the upper limit of normal at Screening.
16) Chronic renal insufficiency as defined by estimated glomerular
filtration rate <30 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 (use in vasoreactive testing is permitted).
19) Subjects currently on or who have been treated with an inhaled or
oral prostacyclin pathway agent (iloprost, treprostinil, beraprost, or
selexipag) withinn 120 days prior to randomization.
20) Subject has pulmonary veno-occlusive disease.
21) Malignancy diagnosed and/or treated within 3 years of 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.
22. Subject tests positive for amphetamine, cocaine, methamphetamine,
methylenedioxymethamphetamine, or phencyclidine in urine drug screen
performed at Screening or has a recent history (6 months) of alcohol or
drug abuse. Subjects will not be excluded due to a positive drug screen
caused by prescribed medications.
23) Initiation or discontinuation of a cardio-pulmonary rehabilitation
program based upon exercise within 90 days prior to Screening and/or
planned during study participation.
24) 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.
25) Any reason that, in the opinion of the Investigator, precludes the
subject from participating in the study (eg, any previous or intercurrent
medical condition) that may increase the risk associated with study
participation or that would confound study analysis (eg, right-to-left
shunt detected during CPET) or impair study participation or
cooperation.
26) Known hypersensitivity to ralinepag or any of the excipients.
27) Life expectancy <12 months.
28. Women who are pregnant, lactating, or breast-feeding. |
|
| E.5 End points |
| E.5.1 | 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | 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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Optional evaluation of proteomics, metabolomics, transcriptomics, and genetics |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Brazil |
| United States |
| Austria |
| Belgium |
| Germany |
| Italy |
| Poland |
| Spain |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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