Pulmonary Arterial Hypertension
Conditions
Keywords
SERAPHIN, Pulmonary Arterial Hypertension, ACT-064992
Brief summary
The main objective of the AC 055 303/SERAPHIN OL study, which will follow the AC 055 302/SERAPHIN study, will be to assess the long-term safety and tolerability of ACT 064992 in patients with symptomatic PAH.
Interventions
DRUGMacitentan
Tablet, oral administration, 10 mg dose once daily
Sponsors
Actelion
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed informed consent prior to initiation of any study-mandated procedure. * Patients with pulmonary arterial hypertension and having completed the event-driven study, AC 055 302/SERAPHIN, or Patients who have experienced a clinical worsening of PAH in AC 055 302/SERAPHIN and for whom a written approval to roll over into this study has been obtained from the Sponsor. * Women of childbearing potential must have a negative pre-treatment serum pregnancy test and must use a reliable method of contraception during study treatment and for at least 28 days after study treatment termination.
Exclusion criteria
* Any major violation of protocol AC 055 302/SERAPHIN. * Pregnancy or breast-feeding. * AST and/or ALT \> 3 times the upper limit of the normal range. * 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. * Known hypersensitivity to ACT 064992 or any of the excipients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) up to 28 Days After Study Treatment Discontinuation | Up to 28 days after study treatment discontinuation (Up to 12 years) | An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAE are defined as AEs with onset during the treatment period or that are a consequence of a pre-existing condition that has worsened since baseline. |
| Number of Participants With Death up to 28 Days After Study Treatment Discontinuation | Up to 28 days after study treatment discontinuation (Up to 12 years) | Number of participants with deaths up to 28 days after study treatment discontinuation were reported. |
| Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs) up to 28 Days After Study Treatment Discontinuation | Up to 28 days after study treatment discontinuation (Up to 12 years) | An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAE are defined as AEs with onset during the treatment period or that are a consequence of a pre-existing condition that has worsened since baseline. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; medically significant, or requires intervention to prevent at least one of the outcomes listed above. |
| Number of Participants With AEs Leading to Permanent Discontinuation of Study Treatment | Up to 28 days after study treatment discontinuation (Up to12 years) | Number of participants with AEs leading to permanent discontinuation of study treatment were reported. An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. |
| Number of Participants With Treatment Emergent Abnormal Liver Tests up to 28 Days After Study Treatment Discontinuation | Up to 28 days after study treatment discontinuation (Up to12 years) | Number of participants with treatment-emergent abnormal liver tests: Alanine aminotransferase (ALT) greater than (\>) 3\*upper limit of normal (ULN) or aspartate aminotransferase (AST) \>3\* ULN, ALT \>5\* ULN or AST \>5\*ULN, ALT \>8\*ULN or AST \>8\*ULN, total bilirubin (TBIL) \>2\*ULN, ALT \>3\*ULN or AST \>3\*ULN and TBIL \>2\*ULN at any time were reported. |
| Number of Participants With Treatment Emergent Hemoglobin Abnormality up to 28 Days After Study Treatment Discontinuation | Up to 28 days after treatment discontinuation (Up to 12 years) | Number of participants with treatment-emergent hemoglobin (HGB) abnormality up to 28 days after study treatment discontinuation were reported. Participants assessed for different categories of HGB were \<=80 grams/Liter (g/L), \<=100g/L, decrease from baseline \>=20 g/L, and decrease from baseline \>=50 g/L. |
Countries
Argentina, Australia, Austria, Belarus, Belgium, Bulgaria, Canada, Chile, China, Colombia, Croatia, Finland, France, Germany, Hong Kong, Hungary, India, Israel, Italy, Malaysia, Mexico, Netherlands, Peru, Poland, Romania, Russia, Serbia, Singapore, Slovakia, South Africa, Sweden, Taiwan, Thailand, Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
Participant flow reported below is up to study closure.
Participants by arm
| Arm | Count |
|---|---|
| Macitentan 10 mg Participants with symptomatic pulmonary arterial hypertension (PAH) who completed or have experienced a morbidity/clinical worsening of PAH in the study AC-055-302 (NCT00660179) and opted to continue this open label extension (OLE) study received macitentan oral tablet, 10 milligrams (mg) once daily from Day 1 up to end of study (up to 12 years) which depends on following a). transition to commercially available macitentan in the participant's country b). the sponsor decided to stop the OL study, and c). the participant's or investigators or sponsors decision to discontinue study treatment. | 550 |
| Total | 550 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 7 |
| Overall Study | Death | 182 |
| Overall Study | Lost to Follow-up | 5 |
| Overall Study | Missing (completion page missing) | 2 |
| Overall Study | Other | 8 |
| Overall Study | Withdrawal by Subject | 12 |
Baseline characteristics
| Characteristic | Macitentan 10 mg |
|---|---|
| Age, Continuous | 47.7 years STANDARD_DEVIATION 15.67 |
| Race/Ethnicity, Customized Asian | 165 Participants |
| Race/Ethnicity, Customized Other | 13 Participants |
| Race/Ethnicity, Customized White | 372 Participants |
| Region of Enrollment ARGENTINA | 32 Participants |
| Region of Enrollment AUSTRALIA | 6 Participants |
| Region of Enrollment AUSTRIA | 4 Participants |
| Region of Enrollment BELARUS | 21 Participants |
| Region of Enrollment BELGIUM | 2 Participants |
| Region of Enrollment BULGARIA | 4 Participants |
| Region of Enrollment CANADA | 12 Participants |
| Region of Enrollment CHILE | 24 Participants |
| Region of Enrollment CHINA | 74 Participants |
| Region of Enrollment COLOMBIA | 7 Participants |
| Region of Enrollment FRANCE | 8 Participants |
| Region of Enrollment GERMANY | 27 Participants |
| Region of Enrollment HONG KONG | 3 Participants |
| Region of Enrollment HUNGARY | 4 Participants |
| Region of Enrollment INDIA | 30 Participants |
| Region of Enrollment ISRAEL | 10 Participants |
| Region of Enrollment ITALY | 3 Participants |
| Region of Enrollment MALAYSIA | 6 Participants |
| Region of Enrollment MEXICO | 33 Participants |
| Region of Enrollment NETHERLANDS | 1 Participants |
| Region of Enrollment PERU | 4 Participants |
| Region of Enrollment POLAND | 19 Participants |
| Region of Enrollment ROMANIA | 12 Participants |
| Region of Enrollment RUSSIAN FEDERATION | 54 Participants |
| Region of Enrollment SERBIA | 13 Participants |
| Region of Enrollment SINGAPORE | 12 Participants |
| Region of Enrollment SLOVAKIA | 4 Participants |
| Region of Enrollment SOUTH AFRICA | 17 Participants |
| Region of Enrollment SWEDEN | 6 Participants |
| Region of Enrollment TAIWAN | 14 Participants |
| Region of Enrollment THAILAND | 19 Participants |
| Region of Enrollment UKRAINE | 12 Participants |
| Region of Enrollment UNITED KINGDOM | 4 Participants |
| Region of Enrollment UNITED STATES | 49 Participants |
| Sex: Female, Male Female | 440 Participants |
| Sex: Female, Male Male | 110 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 182 / 550 |
| other Total, other adverse events | 476 / 550 |
| serious Total, serious adverse events | 354 / 550 |
Outcome results
Primary
Number of Participants With AEs Leading to Permanent Discontinuation of Study Treatment
Number of participants with AEs leading to permanent discontinuation of study treatment were reported. An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.
Time frame: Up to 28 days after study treatment discontinuation (Up to12 years)
Population: The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 mg.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Macitentan 10 mg | Number of Participants With AEs Leading to Permanent Discontinuation of Study Treatment | 62 Participants |
Primary
Number of Participants With Death up to 28 Days After Study Treatment Discontinuation
Number of participants with deaths up to 28 days after study treatment discontinuation were reported.
Time frame: Up to 28 days after study treatment discontinuation (Up to 12 years)
Population: The SAF included all participants who received at least 1 dose of macitentan 10 mg.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Macitentan 10 mg | Number of Participants With Death up to 28 Days After Study Treatment Discontinuation | 175 Participants |
Primary
Number of Participants With Treatment Emergent Abnormal Liver Tests up to 28 Days After Study Treatment Discontinuation
Number of participants with treatment-emergent abnormal liver tests: Alanine aminotransferase (ALT) greater than (\>) 3\*upper limit of normal (ULN) or aspartate aminotransferase (AST) \>3\* ULN, ALT \>5\* ULN or AST \>5\*ULN, ALT \>8\*ULN or AST \>8\*ULN, total bilirubin (TBIL) \>2\*ULN, ALT \>3\*ULN or AST \>3\*ULN and TBIL \>2\*ULN at any time were reported.
Time frame: Up to 28 days after study treatment discontinuation (Up to12 years)
Population: The SAF included all participants who received at least 1 dose of macitentan 10 mg.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Macitentan 10 mg | Number of Participants With Treatment Emergent Abnormal Liver Tests up to 28 Days After Study Treatment Discontinuation | ALT or AST >3*ULN | 45 Participants |
| Macitentan 10 mg | Number of Participants With Treatment Emergent Abnormal Liver Tests up to 28 Days After Study Treatment Discontinuation | ALT or AST >5*ULN | 20 Participants |
| Macitentan 10 mg | Number of Participants With Treatment Emergent Abnormal Liver Tests up to 28 Days After Study Treatment Discontinuation | ALT or AST >8*ULN | 11 Participants |
| Macitentan 10 mg | Number of Participants With Treatment Emergent Abnormal Liver Tests up to 28 Days After Study Treatment Discontinuation | TBIL >2*ULN | 75 Participants |
| Macitentan 10 mg | Number of Participants With Treatment Emergent Abnormal Liver Tests up to 28 Days After Study Treatment Discontinuation | ALT or AST >3*ULN and (TBIL>2*ULN at any time) | 8 Participants |
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) up to 28 Days After Study Treatment Discontinuation
An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAE are defined as AEs with onset during the treatment period or that are a consequence of a pre-existing condition that has worsened since baseline.
Time frame: Up to 28 days after study treatment discontinuation (Up to 12 years)
Population: The safety analysis set (SAF) included all participants who received at least 1 dose of macitentan 10 milligrams (mg).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Macitentan 10 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) up to 28 Days After Study Treatment Discontinuation | 527 Participants |
Primary
Number of Participants With Treatment Emergent Hemoglobin Abnormality up to 28 Days After Study Treatment Discontinuation
Number of participants with treatment-emergent hemoglobin (HGB) abnormality up to 28 days after study treatment discontinuation were reported. Participants assessed for different categories of HGB were \<=80 grams/Liter (g/L), \<=100g/L, decrease from baseline \>=20 g/L, and decrease from baseline \>=50 g/L.
Time frame: Up to 28 days after treatment discontinuation (Up to 12 years)
Population: The SAF included all participants who received at least 1 dose of macitentan 10 mg.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Macitentan 10 mg | Number of Participants With Treatment Emergent Hemoglobin Abnormality up to 28 Days After Study Treatment Discontinuation | HGB <= 80 gram/Liter (g/L) | 33 Participants |
| Macitentan 10 mg | Number of Participants With Treatment Emergent Hemoglobin Abnormality up to 28 Days After Study Treatment Discontinuation | HGB <= 100 g/L | 98 Participants |
| Macitentan 10 mg | Number of Participants With Treatment Emergent Hemoglobin Abnormality up to 28 Days After Study Treatment Discontinuation | HGB decrease from baseline >= 20 g/L | 188 Participants |
| Macitentan 10 mg | Number of Participants With Treatment Emergent Hemoglobin Abnormality up to 28 Days After Study Treatment Discontinuation | HGB decrease from baseline >= 50 g/L | 29 Participants |
Primary
Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs) up to 28 Days After Study Treatment Discontinuation
An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAE are defined as AEs with onset during the treatment period or that are a consequence of a pre-existing condition that has worsened since baseline. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; medically significant, or requires intervention to prevent at least one of the outcomes listed above.
Time frame: Up to 28 days after study treatment discontinuation (Up to 12 years)
Population: The SAF included all participants who received at least 1 dose of macitentan 10 mg.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Macitentan 10 mg | Number of Participants With Treatment Emergent Serious Adverse Events (TESAEs) up to 28 Days After Study Treatment Discontinuation | 354 Participants |