Pulmonary Arterial Hypertension
Conditions
Keywords
Open-label, PAH, Pulmonary Arterial Hypertension
Brief summary
Long-term, single-arm, multicenter, open-label extension, Phase 3 study, to evaluate the safety and tolerability of ACT-293987 in patients with PAH who participated in the double-blind study AC-065A302 (GRIPHON)
Interventions
DRUGACT-293987
Tablets, twice daily
Sponsors
Actelion
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients who participated to the double-blind study AC-065A302 and either had a morbidity event or had completed the study as scheduled per protocol. * Signed informed consent.
Exclusion criteria
* Patients who have started receiving prostacyclin (epoprostenol) or prostacyclin analogs (i.e., treprostinil, iloprost, beraprost) since the last study drug intake in AC-065A302/GRIPHON. * Severe hepatic impairment (Child-Pugh C). * Females who are pregnant or who plan to become pregnant during the study, or are breastfeeding. * Any known factor or disease that might interfere with treatment compliance, study conduct or interpretation of the results, such as drug or alcohol dependence, or psychiatric disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) up to 3 Days After Study Intervention Discontinuation | Up to 3 days after study drug discontinuation (Up to 10.5 years) | An adverse event (AE) is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. A TEAE is any AE temporally associated with the use of study drug (from study drug initiation until 3 days after study drug discontinuation), whether or not considered related to the study drug. |
| Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) up to 3 Days After Study Intervention Discontinuation | Up to 3 days after study drug discontinuation (Up to 10.5 years) | An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience, is a congenital anomaly/birth defect and may jeopardize participant and/or may require medical or surgical intervention to prevent one of the outcomes listed above. Those SAEs occurring during study drug administration, that is, between study drug initiation and three days after study drug discontinuation, are defined as treatment-emergent SAEs. |
| Number of Participants With TEAEs Leading to Permanent Discontinuation of Study Intervention | Up to 10.5 years | An adverse event (AE) is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. A TEAE is any AE temporally associated with the use of study drug (from study drug initiation until 3 days after study drug discontinuation), whether or not considered related to the study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Alive Participants | Baseline (Day 1), Months 3, 6, 9, 12, 24, 36, 48, 60, 72, 84, 96, 108, and 120 | Percentage of alive participants were analyzed using Kaplan-Meier (KM) estimates. |
Countries
Argentina, Australia, Austria, Belarus, Belgium, Canada, Chile, China, Colombia, Czechia, Denmark, France, Germany, Greece, Hungary, India, Ireland, Israel, Malaysia, Mexico, Netherlands, Peru, Poland, Romania, Russia, Serbia, Singapore, Slovakia, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
Survival analysis was planned in subset of participants who received selexipag in main study (NCT01106014) and either entered or did not enter this open label (OL) study. Safety analysis including all-cause mortality was planned for OL safety set. Hence, all-cause mortality data is based on participants who received study drug (selexipag or placebo) in main study and entered this OL study. Participants who did not enter this OL study were not analyzed for all-cause mortality.
Participants by arm
| Arm | Count |
|---|---|
| Selexipag Participants with pulmonary arterial hypertension (PAH) who completed the double-blind AC-065A302 GRIPHON study (NCT01106014) or experienced a morbidity event in that study, entered in this open label (OL) study. Participants who received selexipag in GRIPHON continued to receive selexipag at the same dose (200 micrograms \[mcg\], twice daily \[bid\] up to 1600 mcg bid based on individual maximum tolerated dose) in this OL study. Participants who were on placebo or experienced a morbidity event in GRIPHON entered the titration period of this OL-study and received lowest dose of selexipag (200 mcg, bid) and dose was titrated up to 1600 mcg bid, based on the individual maximum tolerated dose. Each participant received study drug from Day 1 until the earliest of a) selexipag became commercially available in this indication in participant's country, b) sponsor decided to stop current study, or c) participant/investigator decided to discontinue study intervention (up to 10.5 years). | 709 |
| Total | 709 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 175 |
| Overall Study | Lost to Follow-up | 9 |
| Overall Study | Other | 70 |
| Overall Study | Withdrawal by Subject | 31 |
Baseline characteristics
| Characteristic | Selexipag |
|---|---|
| Age, Continuous | 47.9 years STANDARD_DEVIATION 15.19 |
| Race/Ethnicity, Customized ASIAN | 171 Participants |
| Race/Ethnicity, Customized BLACK OR AFRICAN AMERICAN | 15 Participants |
| Race/Ethnicity, Customized HISPANIC | 87 Participants |
| Race/Ethnicity, Customized OTHER | 8 Participants |
| Race/Ethnicity, Customized WHITE | 428 Participants |
| Region of Enrollment ARGENTINA | 20 Participants |
| Region of Enrollment AUSTRALIA | 37 Participants |
| Region of Enrollment AUSTRIA | 3 Participants |
| Region of Enrollment BELARUS | 34 Participants |
| Region of Enrollment BELGIUM | 17 Participants |
| Region of Enrollment CANADA | 13 Participants |
| Region of Enrollment CHILE | 31 Participants |
| Region of Enrollment CHINA | 113 Participants |
| Region of Enrollment COLOMBIA | 3 Participants |
| Region of Enrollment CZECH REPUBLIC | 11 Participants |
| Region of Enrollment DENMARK | 4 Participants |
| Region of Enrollment FRANCE | 21 Participants |
| Region of Enrollment GERMANY | 35 Participants |
| Region of Enrollment GREECE | 6 Participants |
| Region of Enrollment HUNGARY | 10 Participants |
| Region of Enrollment INDIA | 15 Participants |
| Region of Enrollment IRELAND | 4 Participants |
| Region of Enrollment ISRAEL | 11 Participants |
| Region of Enrollment ITALY | 4 Participants |
| Region of Enrollment MALAYSIA | 2 Participants |
| Region of Enrollment MEXICO | 20 Participants |
| Region of Enrollment NETHERLANDS | 4 Participants |
| Region of Enrollment PERU | 6 Participants |
| Region of Enrollment POLAND | 7 Participants |
| Region of Enrollment ROMANIA | 9 Participants |
| Region of Enrollment RUSSIAN FEDERATION | 72 Participants |
| Region of Enrollment SERBIA | 10 Participants |
| Region of Enrollment SINGAPORE | 8 Participants |
| Region of Enrollment SLOVAKIA | 1 Participants |
| Region of Enrollment SOUTH KOREA | 11 Participants |
| Region of Enrollment SPAIN | 8 Participants |
| Region of Enrollment SWEDEN | 10 Participants |
| Region of Enrollment SWITZERLAND | 2 Participants |
| Region of Enrollment TAIWAN | 11 Participants |
| Region of Enrollment THAILAND | 4 Participants |
| Region of Enrollment TURKEY | 8 Participants |
| Region of Enrollment UKRAINE | 35 Participants |
| Region of Enrollment UNITED KINGDOM | 9 Participants |
| Region of Enrollment UNITED STATES | 80 Participants |
| Sex: Female, Male Female | 590 Participants |
| Sex: Female, Male Male | 119 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 186 / 709 |
| other Total, other adverse events | 598 / 709 |
| serious Total, serious adverse events | 420 / 709 |
Outcome results
Primary
Number of Participants With TEAEs Leading to Permanent Discontinuation of Study Intervention
An adverse event (AE) is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. A TEAE is any AE temporally associated with the use of study drug (from study drug initiation until 3 days after study drug discontinuation), whether or not considered related to the study drug.
Time frame: Up to 10.5 years
Population: The OL safety analysis set included all randomized participants who received at least 1 dose of selexipag or placebo in main GRIPHON study (AC-065A302; NCT01106014) and entered to this current GRIPHON OL study (AC-065A303; NCT01112306). Participants who did not enter GRIPHON OL were not in the scope of the OL safety analysis set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Selexipag | Number of Participants With TEAEs Leading to Permanent Discontinuation of Study Intervention | 129 Participants |
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) up to 3 Days After Study Intervention Discontinuation
An adverse event (AE) is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. A TEAE is any AE temporally associated with the use of study drug (from study drug initiation until 3 days after study drug discontinuation), whether or not considered related to the study drug.
Time frame: Up to 3 days after study drug discontinuation (Up to 10.5 years)
Population: The open label (OL) safety analysis set included all randomized participants who received at least 1 dose of selexipag or placebo in main GRIPHON study (AC-065A302; NCT01106014) and entered to this current GRIPHON OL study (AC-065A303; NCT01112306). Participants who did not enter GRIPHON OL were not in the scope of the OL safety analysis set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Selexipag | Number of Participants With Treatment-emergent Adverse Events (TEAEs) up to 3 Days After Study Intervention Discontinuation | 684 Participants |
Primary
Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) up to 3 Days After Study Intervention Discontinuation
An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience, is a congenital anomaly/birth defect and may jeopardize participant and/or may require medical or surgical intervention to prevent one of the outcomes listed above. Those SAEs occurring during study drug administration, that is, between study drug initiation and three days after study drug discontinuation, are defined as treatment-emergent SAEs.
Time frame: Up to 3 days after study drug discontinuation (Up to 10.5 years)
Population: The OL safety analysis set included all randomized participants who received at least 1 dose of selexipag or placebo in main GRIPHON study (AC-065A302; NCT01106014) and entered to this current GRIPHON OL study (AC-065A303; NCT01112306). Participants who did not enter GRIPHON OL were not in the scope of the OL safety analysis set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Selexipag | Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) up to 3 Days After Study Intervention Discontinuation | 420 Participants |
Secondary
Percentage of Alive Participants
Percentage of alive participants were analyzed using Kaplan-Meier (KM) estimates.
Time frame: Baseline (Day 1), Months 3, 6, 9, 12, 24, 36, 48, 60, 72, 84, 96, 108, and 120
Population: Selexipag-treated set (STS): all participants who received at least 1 dose of selexipag in either main study (NCT01106014) or this OL study (NCT01112306). Survival analysis was planned in a subset of STS participants who received selexipag in main study, entered or did not enter this OL study. Here, n (number analyzed): participants at risk (alive and on study), analyzed at each specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Selexipag | Percentage of Alive Participants | KM estimate at Baseline (Day 1) | 100 Percentage of participants |
| Selexipag | Percentage of Alive Participants | KM estimate at Month 3 | 98.4 Percentage of participants |
| Selexipag | Percentage of Alive Participants | KM estimate at Month 6 | 96.3 Percentage of participants |
| Selexipag | Percentage of Alive Participants | KM estimate at Month 9 | 94.0 Percentage of participants |
| Selexipag | Percentage of Alive Participants | KM estimate at Month 72 | 66.8 Percentage of participants |
| Selexipag | Percentage of Alive Participants | KM estimate at Month 84 | 63.3 Percentage of participants |
| Selexipag | Percentage of Alive Participants | KM estimate at Month 96 | 60.3 Percentage of participants |
| Selexipag | Percentage of Alive Participants | KM estimate at Month 108 | 56.9 Percentage of participants |
| Selexipag | Percentage of Alive Participants | KM estimate at Month 12 | 92.0 Percentage of participants |
| Selexipag | Percentage of Alive Participants | KM estimate at Month 24 | 85.3 Percentage of participants |
| Selexipag | Percentage of Alive Participants | KM estimate at Month 36 | 79.3 Percentage of participants |
| Selexipag | Percentage of Alive Participants | KM estimate at Month 48 | 75.2 Percentage of participants |
| Selexipag | Percentage of Alive Participants | KM estimate at Month 60 | 71.2 Percentage of participants |
| Selexipag | Percentage of Alive Participants | KM estimate at Month 120 | 56.9 Percentage of participants |