| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | The primary objective of this study is:
To evaluate the long-term safety and tolerability of ralinepag in subjects who participated in a Phase 2 or Phase 3 study of ralinepag. | |
| E.2.2 | Secondary objectives of the trial | The secondary objectives of the study are to evaluate the long-term effects of ralinepag on the following parameters:
• N-terminal pro b-type natriuretic peptide (NT-proBNP)
• 6-minute walk distance (6MWD)
• Heart rate recovery (HRR) following completion of the 6-minute walk test (6MWT)
• WHO/ New York Heart Association (NYHA) functional class
• Health-related quality of life (HRQoL) measures
• Proportion of subjects who achieve all three of the following:
o NT-proBNP <300 pg/mL
o 6MWD >440 meters
o WHO/NYHA functional class II status or better
• Time to all-cause hospitalization
• Time to all-cause mortality
• Time to protocol-defined clinical failure events | |
| 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 | | A pharmacokinetic (PK) substudy is planned at selected sites. Approximately 20 subjects who consented to participate, have completed the Dose Titration Period of the study (if applicable), and have received a stable dose of ralinepag for at least 7 days will participate in the PK Substudy. Collected plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation purposes, stability assessments, metabolite assessments, or to assess other actions of ralinepag with plasma constituents. | |
| E.3 | Principal 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 document indicating that the subject has been informed of all pertinent aspects of the study prior to initiation of any study-related procedures.
2. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Completed the protocol-defined EOS procedures and EOS Visit in the original ralinepag study.
4. 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 (i.e., actively attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization) during the study and for 30 days after the last dose of IMP. Highly effective birth control methods include the following:
• oral, implantable, or injectable contraceptives associated with the inhibition of ovulation (starting ≥60 days before dosing) in combination with a diaphragm with vaginal spermicide, cervical cap with vaginal spermicide, or male condom;
• standard intrauterine device (IUD; e.g., Copper T 380A IUD), intrauterine system (IUS; e.g., LNg 20 IUS - progesterone IUD), progesterone implant, or tubal sterilization (≥180 days after surgery);
• post vasectomy and male condom, partner using diaphragm with spermicide, cervical cap with spermicide, estrogen and progesterone oral contraceptives (“the pill”), estrogen and progesterone transdermal patch, vaginal ring, or progesterone injection.
• Complete sexual abstinence defined as refraining from heterosexual intercourse for the entire period of risk associated with study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the usual lifestyle of the subject. Periodic abstinence (calendar, symptothermal, post-ovulation methods) is not acceptable.
Women who surgically sterile or are 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.
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| E.4 | Principal exclusion criteria | Eligible subjects must not meet ANY of the following exclusion criteria to be eligible for enrollment into the study:
1. Subjects who prematurely discontinued investigational medicinal product (IMP) due to a drug-related AE/SAE or tolerability issue in the original ralinepag study in which they were enrolled, or subjects who did not complete all protocol defined study procedures at an EOS Visit (not Early Termination Visit) in the original ralinepag study.
2. Subjects who withdrew consent during participation in another ralinepag study.
3. Female subjects who wish to become pregnant or who have a positive pregnancy test on Day 1 (OLE Entry Visit).
4. Women who are pregnant, lactating or breast-feeding
5. Subjects who have undergone lung or heart/lung transplant or the initiation of parenteral (intravenous [i.v.] infusion or subcutaneous injection) therapy with a prostacyclin or oral therapy with another IP receptor agonist (selexipag) during the time since participation in their original ralinepag study.
6. Male subjects with a corrected QT interval using Fridericia’s formula (QTcF) >450 msec and female subjects with QTcF >470 msec on electrocardiogram (ECG) measured on Day 1 (OLE Entry Visit).
7. Subjects who had an emergency unblinding procedure in a prior Phase 2 or 3 study or subjects who developed withdrawal criteria in their original study but were not withdrawn.
8. Known hypersensitivity to ralinepag or any of the excipients.
9. Any reason that, in the opinion of the investigator or medical monitor, precludes the subject from participating in the study, e.g., non-compliance concerns, 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.
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| E.5 End points |
| E.5.1 | Primary end point(s) | Efficacy will be assessed by an evaluation of NT-proBNP; measurement of 6MWD and HRR after completion of the 6MWT; WHO/NYHA functional class assessments; evaluation of HRQoL measures using the Short Form (36) Health Survey (SF-36) and the PAH-Symptoms and Impact (PAH-SYMPACT®) Questionnaires (where validated); time to all-cause hospitalization; time to all-cause mortality, and time to protocol-defined clinical failure events.
Efficacy endpoints will include an evaluation of:
• NT-proBNP
• 6MWD
• HRR measurements following assessment of 6MWD
• WHO/NYHA functional class
• The proportion of subjects who achieve all 3 the following (at specified time points):
o NT-proBNP level <300 pg/mL
o 6MWD >440 meters
o WHO/NYHA functional class II status or better
• HRQoL measures (where validated)
• Time to all-cause hospitalization during the study period
• Time to all-cause mortality during the study period
• Time to events of protocol-defined clinical failure during the study period
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| E.5.1.1 | Timepoint(s) of evaluation of this end point | Continuous endpoints and changes from baseline will be summarized by visit.
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| E.5.2 | Secondary end point(s) | |
| 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 | No |
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description | |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 90 |
| 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 | | Canada | | Chile | | China | | European Union | | Israel | | Korea, Republic of | | Mexico | | Serbia | | Singapore | | Taiwan | | Turkey | | Ukraine | | United States | |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
