An open-label extension (OLE) study to evaluate the long-term safety and efficacy of ralinepag in patients with pulmonary arterial hypertension

• Register: EUCTR
• Last refreshed on: 30 April 2019
• Main ID: EUCTR2018-001189-40-FR
• Date of registration: 16/11/2018
• Prospective Registration: Yes
• Primary sponsor: Arena Pharmaceuticals, Inc.
• Public title: An open-label extension (OLE) study to evaluate the long-term safety and efficacy of ralinepag in patients with pulmonary arterial hypertension
• Scientific title: A StuDy EVAluatiNg the Long-Term EffiCacy and Safety of RalinEpag in Subjects with PAH via an Open-Label EXTENSION - ADVANCE-extension
• Date of first enrolment: 15/02/2019
• Target sample size: 1000
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-001189-40
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: yes; Other trial design description: extension; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no; Number of treatment arms in the trial: 1
• 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, Denmark, European Union, France, Greece, Hungary, Israel, Japan, Korea, Republic of, Mexico, Serbia, Singapore, Sweden, Switzerland, Taiwan, Thailand, Turkey, Ukraine, United Kingdom, United States

Contacts

• Name: Sonia Villegas
• Affiliation: Arena Pharmaceuticals Inc.

• Name: Sonia Villegas
• Affiliation: Arena Pharmaceuticals Inc.

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 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.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 800
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 200

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.



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: Film-coated tablet
INN or Proposed INN: ralinepag
CAS Number: 1187856-49-0
Current Sponsor code: APD811
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: Film-coated tablet
INN or Proposed INN: ralinepag
CAS Number: 1187856-49-0
Current Sponsor code: APD811
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: Film-coated tablet
INN or Proposed INN: ralinepag
CAS Number: 1187856-49-0
Current Sponsor code: APD811
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)

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

Timepoint(s) of evaluation of this end point: Continuous endpoints and changes from baseline will be summarized by visit.

Main Objective: 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.

Secondary Objective: 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

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: No

Secondary end point(s): No

Secondary ID(s)

APD811-303

109021

Source(s) of Monetary Support

Arena Pharmaceuticals, Inc.

Ethics review

Status: Approved
Approval date:
Contact: