Sarcoidosis-associated Pulmonary Hypertension
Conditions
Keywords
selexipag, sarcoidosis, pulmonary hypertension
Brief summary
Oral selexipag is commercially available in several countries for the treatment of a particular group of pulmonary hypertension (PH) called pulmonary arterial hypertension (PAH). The aim of the present study is to investigate whether selexipag could be helpful to treat patients with another form of PH called sarcoidosis-associated pulmonary hypertension (SAPH).
Detailed description
Pulmonary hypertension (PH) is a pathophysiological disorder that may involve multiple clinical conditions and can complicate several cardiovascular and respiratory diseases. Sarcoidosis is a multisystemic disorder that is characterized by non-caseating granulomas which are present in multiple tissues, particularly in the lung and lymphatic system. Severe untreated pulmonary hypertension (PH) carries a poor prognosis and is associated with higher mortality in participants with interstitial lung diseases and sarcoidosis. While there is no approved treatment for SAPH, PH-specific treatments are frequently used. Selexipag is a selective, orally available and long-acting non-prostanoid agonist of the prostacyclin receptor (prostacyclin \[IP\] receptor) for the treatment of patients with PAH. The rationale for this study is based on the unmet medical need for new therapeutic options for patients with SAPH and is supported by the established efficacy and safety of selexipag in the PAH indication, the shared pathomechanism between SAPH and PAH, and the available data on the efficacy and safety of PH-specific therapies in SAPH. This study consists of screening period, main observation period and double blind extension period and safety follow-up period. The duration of individual participation in the study will be different for each individual participant (between approximately 15 months and up to approximately 3.5 years) and will depend on the time of each participant's individual date of entering the study and the total recruitment time. The efficacy assessments include right heart catheterization (RHC), assessment of exercise capacity, dyspnea, pulmonary function tests, etc. Safety and tolerability will be evaluated throughout the study and includes review of concomitant medications and adverse events (AEs), clinical laboratory tests, 12-lead electrocardiogram (ECG), vital signs, physical examination, and pregnancy testing.
Interventions
DRUGSelexipag
Oral tablets containing 200 µg of selexipag. Depending on the iMTD, participants will receive 1 (200 µg) to 8 (1600 µg) tablets at each administration
DRUGPlacebo
Oral tablets without active compound. Participants can receive 1 to 8 tablets at each administration.
Sponsors
Actelion
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: * Confirmed diagnosis of sarcoidosis as per American Thoracic Society (ATS) criteria * Sarcoidosis-associated precapillary PH, confirmed by RHC (at rest) within 90 days prior to randomization. * PH severity according to modified WHO FC II-IV at Screening and randomization; participants in WHO FC IV must be in a stable condition and able to perform a 6MWT. * Either not receiving treatment with PH-specific treatment or oral PH-specific monotherapy (ie, riociguat or PDE5i or ERA); if on oral PH-specific monotherapy then treatment had to be stable (ie, no introduction of new therapies or changes in dose) for at least 90 days prior to both and the RHC qualifying for enrollment and randomization * Stable sarcoidosis treatment regimen, ie, no new specific anti-inflammatory treatment for sarcoidosis for at least 90 days, and stable dose(s) for at least 30 days prior to both the RHC qualifying for enrollment and randomization * 6-minute walk distance (6MWD) greater than or equal to (\>=) 50 meters both at Screening and at the time of randomization. Participants can use their usual walking aids during the test (example, cane, crutches). The same walking aid should be used for all 6-minute walk test (6MWTs). Walkers are not allowed * Forced Vital Capacity (FVC) greater than (\>) 50 percent (%) and Forced Expiratory Volume (in 1 second) (FEV1) \> 50% of predicted at Screening * Diffusing capacity of the lung for carbon monoxide (DLCO) \>= 40% of predicted. If DLCO less than (\<) 40% of predicted, the extent of emphysema should not be greater than that of fibrosis as assessed by high resolution computerized tomography (CT) scan * Women of childbearing potential must have a negative pregnancy test at screening and randomization, must agree to undertake monthly urine pregnancy tests, and to practice an acceptable method of contraception and agreeing to remain on an acceptable method while receiving study intervention and until 30 days after last dose of study intervention * A woman only using hormonal contraceptives must have been using this method for at least 30 days prior to randomization Main
Exclusion criteria
* PH due to left heart disease (PAWP \>15 mmHg). * History of left heart failure (LHF) as assessed by the investigator including cardiomyopathies, and cardiac sarcoidosis, with a left ventricular ejection fraction (LVEF) \<40%. * Treatment with prostacyclin, prostacyclin analogues or IP receptor agonists (ie, selexipag) within 90 days prior to randomization and/or prior to the RHC qualifying for enrollment, except those given at vasodilator testing during RHC. * SBP \<90 mmHg at Screening or at randomization. * Included on a lung transplant list or planned to be included until Visit 6 / Week 39. * Change in dose or initiation of new diuretics and/or calcium channel blockers within 1 week prior to RHC qualifying for enrollment. * Any condition for which, in the opinion of the investigator, participation would not be in the best interests of the participant (eg, compromise well-being), or that could prevent, limit, or confound the protocol-specified assessments. * Any acute or chronic impairment that may influence the ability to comply with study requirements such as to perform RHC, a reliable and reproducible 6MWT, or lung function tests. * Any other criteria as per selexipag Summary of Product Characteristics (SmPC)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pulmonary Vascular Resistance (PVR) up to Week 26 | Baseline up to Week 26 | PVR represents the resistance against which the right ventricle needs to pump. PVR was determined by right heart catheterization (RHC). It was measured as the ratio of the PVR value post-treatment initiation up to Week 26 (post) versus the PVR value pre-treatment initiation at baseline (pre), expressed as a percentage of baseline value. The baseline reference value for PVR was based on the last RHC performed prior to study intervention initiation. PVR was calculated as 80\*(mean pulmonary arterial pressure - pulmonary artery wedge pressure) divided by cardiac output. As specified in the statistical analysis plan, data was not planned to be summarized for this outcome measure and only individual participant wise data was collected. |
Countries
Belgium, Brazil, Canada, France, Germany, Italy, Netherlands, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Selexipag 200 Micrograms (mcg) Participants received a single oral tablet of selexipag 200 mcg on Day 1. The dose was up-titrated by the investigator/delegate at weekly intervals to allow each participant to reach their individual maximum tolerated dose (iMTD), in the range of 200 mcg to 1600 mcg (that is, 1 to 8 tablets) twice daily from Day 2 to Week 12 or until reaching iMTD. From Week 12 onwards, participants received their iMTD of selexipag orally twice daily till end of treatment (up to 456 days). For participants with moderate hepatic impairment (Child-Pugh Class B) or who were concomitantly taking moderate CYP2C8 inhibitor(s) the dosing frequency was once daily. | 6 |
| Placebo Participants received placebo matching to selexipag 1 to 8 tablets twice daily from Day 1 till end of treatment (up to 456 days). For participants with moderate hepatic impairment (Child-Pugh Class B) or who were concomitantly taking moderate CYP2C8 inhibitor(s) the dosing frequency was once daily. | 4 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Study terminated by sponsor | 5 | 3 |
Baseline characteristics
| Characteristic | Selexipag 200 Micrograms (mcg) | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 4 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 0 Participants | 4 Participants |
| Age, Continuous | 55 years STANDARD_DEVIATION 14.53 | 68.5 years STANDARD_DEVIATION 2.38 | 60.4 years STANDARD_DEVIATION 12.95 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 3 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 5 Participants | 3 Participants | 8 Participants |
| Region of Enrollment France | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Germany | 4 Participants | 0 Participants | 4 Participants |
| Region of Enrollment Spain | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment United Kingdom | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 6 | 0 / 4 |
| other Total, other adverse events | 6 / 6 | 3 / 4 |
| serious Total, serious adverse events | 2 / 6 | 3 / 4 |
Outcome results
Primary
Pulmonary Vascular Resistance (PVR) up to Week 26
PVR represents the resistance against which the right ventricle needs to pump. PVR was determined by right heart catheterization (RHC). It was measured as the ratio of the PVR value post-treatment initiation up to Week 26 (post) versus the PVR value pre-treatment initiation at baseline (pre), expressed as a percentage of baseline value. The baseline reference value for PVR was based on the last RHC performed prior to study intervention initiation. PVR was calculated as 80\*(mean pulmonary arterial pressure - pulmonary artery wedge pressure) divided by cardiac output. As specified in the statistical analysis plan, data was not planned to be summarized for this outcome measure and only individual participant wise data was collected.
Time frame: Baseline up to Week 26
Population: Randomized analysis set included all participants assigned to the study intervention. Here, 'N' (number of participants analyzed) signifies participants evaluable for this outcome measure and 'n' (number analyzed) signifies number of participants randomized and analyzed in respective treatment arm. Here, 'n' (number analyzed)=0 signifies that the participant was not randomized in that treatment arm.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Selexipag 200 Micrograms (mcg) | Pulmonary Vascular Resistance (PVR) up to Week 26 | Participant 8 | 86.0 percentage of baseline PVR |
| Selexipag 200 Micrograms (mcg) | Pulmonary Vascular Resistance (PVR) up to Week 26 | Participant 5 | 100 percentage of baseline PVR |
| Selexipag 200 Micrograms (mcg) | Pulmonary Vascular Resistance (PVR) up to Week 26 | Participant 6 | 47.0 percentage of baseline PVR |
| Selexipag 200 Micrograms (mcg) | Pulmonary Vascular Resistance (PVR) up to Week 26 | Participant 7 | 82.0 percentage of baseline PVR |
| Selexipag 200 Micrograms (mcg) | Pulmonary Vascular Resistance (PVR) up to Week 26 | Participant 4 | 88 percentage of baseline PVR |
| Placebo | Pulmonary Vascular Resistance (PVR) up to Week 26 | Participant 2 | 201 percentage of baseline PVR |
| Placebo | Pulmonary Vascular Resistance (PVR) up to Week 26 | Participant 3 | 56 percentage of baseline PVR |
| Placebo | Pulmonary Vascular Resistance (PVR) up to Week 26 | Participant 1 | 89.0 percentage of baseline PVR |