Resistant Hypertension
Conditions
Brief summary
The goal of this clinical trial is to show the blood pressure lowering effect of aprocitentan, a new drug, when added to other anti-hypertensive drugs of patients with difficult to control (resistant) high blood pressure (hypertension), and to show that blood pressure reduction is kept for long period of time.
Detailed description
Participation in the study will be up to 68 weeks. The study has 4 periods: 1. Screening period 2. Placebo run-in period 3. Randomized treatment period 4. Safety follow-up period The screening period lasts between 4 and 12 weeks. It starts at the screening visit with the signing of the informed consent form (ICF) and ends the day before the participant enters the run-in period. At least 4 weeks before the start of the run-in period, the background antihypertensive medication (except beta-blockers) of participants with a diagnosis of true resistant hypertension and having a mean trough sitting systolic blood pressure of equal to or greater than 140 mmHg measured by automated AOBPM will be standardized by switching to a fixed combination of a calcium channel blocker (amlodipine), an angiotensin receptor blocker (valsartan) and a diuretic (hydrochlorothiazide). In case a beta-blocker is used as one of the background antihypertensive medications or for any other indication, this can be kept, with the provision that it has been initiated and the dose kept stable for at least 4 weeks prior to the screening visit and the dose kept stable until the end-of-treatment. Following the screening period this study has a run-in period of 4 weeks. During this period, placebo will be administered in order to exclude potential placebo responders. Following the run-in period eligible participants will enter the randomized treatment period. This period lasts for 48 weeks. It starts at randomization (i.e., Day 1 of the double-blind part) and ends at the end-of-treatment visit (i.e., at the end of the double-blind withdrawal part). The randomized treatment period consists of 3 parts: Part 1 is double-blind, randomized, parallel-group and placebo-controlled and lasts 4 weeks. Part 2 is single-blind and single-arm and lasts for 32 weeks. Part 3 is a double-blind withdrawal, randomized, parallel-group and placebo-controlled and lasts for 12 weeks. End-of treatment is at Week 48 (i.e., end of the double-blind withdrawal part). The safety follow-up starts on the day after the last dose of study treatment and ends 30 to 33 days after the last dose of study treatment.
Interventions
DRUGAprocitentan 12.5 mg
Tablet, oral use
Tablet, oral use
DRUGPlacebo
Matching placebo tablet
Sponsors
Janssen Biotech, Inc.
Idorsia Pharmaceuticals Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
Study with multiple periods and parts. Once eligibility is confirmed during screening and the run-in period, the individuals entered the randomized treatment period consisting of 3 parts: Part 1: double-blind (DB), randomized to aprocitentan 12.5 mg, aprocitentan 25 mg or placebo; Part 2 single-blind (SB) aprocitentan 25 mg; Part 3: double-blind withdrawal (DB-WD) re-randomized to aprocitentan 25 mg or placebo.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Screening period: * Signed and dated informed consent form (ICF) prior to any study-mandated procedure; * Male and female participants; 18 years (or year of country specific majority) or older; * Historical documentation in the participant's medical records on uncontrolled blood pressure despite at least 3 background antihypertensive medications within 1 year before screening visit; * Treated with at least 3 antihypertensive therapies of different pharmacological classes for at least 4 weeks before the screening visit (Visit 1); * Mean Sitting Systolic Blood Pressure (SiSBP) greater or equal to 140 mmHg measured by Automated Office Blood Pressure Measurement (AOBPM); * Women of childbearing potential are eligible only if the following applies: * Negative pregnancy test at screening and at baseline (i.e., before randomization); * Agreement to undertake pregnancy tests during the study and up to 30 days after randomized study treatment discontinuation; * Agreement to use methods of birth control from Screening up to at least 30 days after randomized study treatment discontinuation. Run-in period (RI): * Switched to the standardized background antihypertensive therapy at least 4 weeks before the first RI visit; * Mean trough SiSBP greater than or equal to140 mmHg as measured by AOBPM. Randomization period: * Stable dose of the standardized background antihypertensive therapy for at least 1 week before the end of the RI period; * Mean trough SiSBP greater than or equal to 140 mmHg measured by AOBPM.
Exclusion criteria
* Apparent/pseudo Resistant Hypertension (RHT) due to white coat effect, medical inertia, poor therapeutic adherence, or secondary causes of hypertension (except sleep apnea); * Confirmed severe hypertension (grade 3) defined as SiSBP greater than or equal to 180 mmHg and/or Sitting Diastolic Blood Pressure (SiDBP) greater than or equal to 110 mmHg as measured by AOBPM at two different timepoints; * Pregnant or lactating participants; * Clinically significant unstable cardiac disease at screening or in the past in the opinion of the investigator (exclusion of participants with significant or potential unstable cardiac disease); * Severe renal insufficiency; * Any known factor, disease or clinically relevant medical or surgical conditions that, in the opinion of the investigator, might put the participant at risk, interfere with treatment compliance, study conduct or interpretation of the results. * Treatment with any medication which may affect blood pressure (BP) and/or treatment with high dose of loop diuretics (i.e., furosemide greater than 80 mg/day, or equivalent dosage of other loop diuretics).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 4 of Double-blind Treatment in Mean Trough Sitting Systolic Blood Pressure (SiSBP) Measured by Automated Office Blood Pressure Measurement | Pre-dose Day 1 (Part 1 double-blind randomized baseline) up to Week 4 (End of double-blind randomized part 1) | Changes from baseline to Week 4 in mean trough SiSBP were analyzed using a mixed model. Participants had their blood pressure (BP) measured at the study site using the automated oscillometric sphygmomanometer (Microlife WatchBP® Office) which was provided to each site. BP was to be measured at trough (before taking the study treatment and SBAT). The BP assessment, participant preparation (e.g., arm selection, arm position, cuff size) was standardized and followed the American Heart Association guidelines / Canadian Education Program on Hypertension. The participant was resting undisturbed, alone (unattended) in a quiet place for 5 minutes at each visit. BP was measured at each visit with the same device, which recorded five sitting blood pressure readings (one per minute, the first value was excluded from the average). A negative change indicates a decrease in SiSBP from baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Double-blind Withdrawal Baseline (Week 36) to Week 40 in Mean Trough Sitting Systolic Blood Pressure (SiSBP) Measured by Unattended Automated Office Blood Pressure Measurement | Pre-dose Week 36 (Part 3 double-blind-withdrawal baseline) up to Week 40 | Changes from double-blind withdrawal baseline (Week 36) to Week 40 in mean trough SiSBP were analyzed using a mixed model. Participants had their blood pressure (BP) measured at the study site using the automated oscillometric sphygmomanometer (Microlife WatchBP® Office) which was provided to each site. BP was to be measured at trough (before taking the study treatment and SBAT). The BP assessment, participant preparation (e.g., arm selection, arm position, cuff size) was standardized and followed the American Heart Association guidelines / Canadian Education Program on Hypertension. The participant was resting undisturbed, alone (unattended) in a quiet place for 5 minutes at each visit. BP was measured at each visit with the same device, which recorded five sitting blood pressure readings (one per minute, the first value was excluded from the average). A negative change indicates a decrease in SiSBP from baseline. |
| Change From Baseline to Week 4 of Double-blind Treatment in Mean Trough Sitting Diastolic Blood Pressure (SiDBP) Measured by Unattended Automated Office Blood Pressure Measurement | Pre-dose Day 1 (Part 1 double-blind randomized baseline) up to Week 4 (End of double-blind randomized part 1) | Changes from baseline to Week 4 in mean trough SiDBP were analyzed using a mixed model. Participants had their blood pressure (BP) measured at the study site using the automated oscillometric sphygmomanometer (Microlife WatchBP® Office) which was provided to each site. BP was to be measured at trough (before taking the study treatment and SBAT). The BP assessment, participant preparation (e.g., arm selection, arm position, cuff size) was standardized and followed the American Heart Association guidelines / Canadian Education Program on Hypertension. BP was measured at each visit with the same device, which recorded five sitting blood pressure readings (one per minute, the first value was excluded from the average). The participant was resting undisturbed, alone (unattended) in a quiet place for 5 minutes at each visit. A negative change indicates a decrease in SiDBP from baseline. |
| Changes From Baseline to Week 4 of Double-blind Treatment in 24-hour Mean Systolic (SBP) and Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring | Pre-dose Day 1 (Part 1 double-blind randomized baseline) and Week 4 (End of double-blind randomized part 1) | ABPM devices were provided to each site by the central blood pressure laboratory. On the first day after all visit assessments were performed, the ABPM device (Mobil-O-Graph NG) was fitted to the participant. The following day (i.e., second day), the participant came back to site to have the ABPM device removed. ABPM data collected over the 24-hours was electronically transferred to the central BP laboratory. Systolic blood pressure and diastolic blood pressure were measured at predetermined times every 20 minutes from 06:00 to 21:59, and every 30 minutes from 22:00 to 05:59. For each participant and at each visit (baseline and Week 4) the 24-hour mean SBP (or DBP) was calculated from the area under the SBP (or DBP) time curve and divided by the time span. A negative change indicates a decrease in 24-hour mean systolic / diastolic blood pressure from baseline. |
| Change From Double-blind Withdrawal Baseline (Week 36) to Week 40 of Double-blind-withdrawal (DB-WD) Treatment in Trough Sitting Diastolic Blood Pressure (SiDBP) Measured by Unattended Automated Office Blood Pressure | Pre-dose Week 36 (Part 3 double-blind-withdrawal baseline) up to Week 40 | Changes from double-blind withdrawal (Week 36) to Week 40 in mean trough SiDBP were analyzed using a mixed model. Participants had their blood pressure (BP) measured at the study site using the automated oscillometric sphygmomanometer (Microlife WatchBP® Office) which was provided to each site. BP was to be measured at trough (before taking the study treatment and SBAT). The BP assessment, participant preparation (e.g., arm selection, arm position, cuff size) was standardized and followed the American Heart Association guidelines / Canadian Education Program on Hypertension. The participant was resting undisturbed, alone (unattended) in a quiet place for 5 minutes at each visit. BP was measured at each visit with the same device, which recorded five sitting blood pressure readings (one per minute, the first value was excluded from the average). A negative change indicates a decrease in SiDBP from baseline. |
| Changes From Double-blind Withdrawal Baseline (Week 36) to Week 40 of Double-blind-withdrawal (DB-WD) Treatment in 24-hour Mean Systolic (SBP) and Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring | From Week 36 (Part 3 double-blind-withdrawal baseline) and Week 40 | ABPM devices were provided to each site by the central blood pressure laboratory. On the first day after all visit assessments were performed, the ABPM device (Mobil-O-Graph NG) was fitted to the participant. The following day (i.e., second day), the participant came back to site to have the ABPM device removed. ABPM data collected over the 24-hours was electronically transferred to the central BP laboratory. Systolic blood pressure and diastolic blood pressure were measured at predetermined times every 20 minutes from 06:00 to 21:59, and every 30 minutes from 22:00 to 05:59. For each participant and at each visit (the double-blind withdrawal baseline \[Week 36\] and the week 40) the 24-hour mean SBP (or DBP) was calculated from the area under the SBP (or DBP) time curve. A negative change indicates a decrease in 24-hour mean systolic / diastolic blood pressure from baseline. |
Countries
Australia, Belgium, Canada, China, Czechia, Finland, France, Germany, Greece, Hungary, Israel, Italy, Lithuania, Netherlands, Poland, Russia, Spain, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
The study was done from 18 June 2018 to 25 April 2022.
Pre-assignment details
730 participants are considered to be enrolled in the study and were randomized to study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Aprocitentan 12.5 mg in Part 1 (Double-blind) Participants randomized to aprocitentan 12.5 mg, orally, once daily in the morning for 4 weeks. | 243 |
| Aprocitentan 25 mg in Part 1 (Double-blind) Participants randomized to aprocitentan 25 mg, orally, once daily in the morning for 4 weeks. | 243 |
| Placebo in Part 1 (Double-blind) Participants randomized to placebo (matching aprocitentan), orally, once daily in the morning for 4 weeks. | 244 |
| Total | 730 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Part 1 Double-Blind | Adverse Event | 6 | 5 | 2 | 0 | 0 | 0 |
| Part 1 Double-Blind | Other reasons | 3 | 2 | 3 | 0 | 0 | 0 |
| Part 1 Double-Blind | Withdrawal by Subject | 2 | 2 | 1 | 0 | 0 | 0 |
| Part 2 Single-Blind | Adverse Event | 0 | 0 | 0 | 25 | 0 | 0 |
| Part 2 Single-Blind | Death | 0 | 0 | 0 | 5 | 0 | 0 |
| Part 2 Single-Blind | Lack of Efficacy | 0 | 0 | 0 | 1 | 0 | 0 |
| Part 2 Single-Blind | Lost to Follow-up | 0 | 0 | 0 | 8 | 0 | 0 |
| Part 2 Single-Blind | Other reasons | 0 | 0 | 0 | 32 | 0 | 0 |
| Part 2 Single-Blind | Pregnancy | 0 | 0 | 0 | 1 | 0 | 0 |
| Part 2 Single-Blind | Withdrawal by Subject | 0 | 0 | 0 | 19 | 0 | 0 |
| Part 3 Double-Blind Withdrawal | Adverse Event | 0 | 0 | 0 | 0 | 8 | 7 |
| Part 3 Double-Blind Withdrawal | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 1 |
| Part 3 Double-Blind Withdrawal | Other reasons | 0 | 0 | 0 | 0 | 9 | 6 |
| Part 3 Double-Blind Withdrawal | Re-randomized in part 3, however no drug dispensed | 0 | 0 | 0 | 0 | 1 | 0 |
| Part 3 Double-Blind Withdrawal | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 4 |
Baseline characteristics
| Characteristic | Aprocitentan 12.5 mg in Part 1 (Double-blind) | Total | Placebo in Part 1 (Double-blind) | Aprocitentan 25 mg in Part 1 (Double-blind) |
|---|---|---|---|---|
| Age, Continuous | 61.2 years STANDARD_DEVIATION 10.3 | 61.7 years STANDARD_DEVIATION 10.6 | 62.2 years STANDARD_DEVIATION 11.2 | 61.7 years STANDARD_DEVIATION 10.4 |
| Body Mass Index at Screening Visit | 33.6 kg/m^2 STANDARD_DEVIATION 6.2 | 33.7 kg/m^2 STANDARD_DEVIATION 6.2 | 33.3 kg/m^2 STANDARD_DEVIATION 5.6 | 34.3 kg/m^2 STANDARD_DEVIATION 6.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 28 Participants | 73 Participants | 23 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 213 Participants | 650 Participants | 218 Participants | 219 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 7 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 11 Participants | 38 Participants | 13 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 28 Participants | 82 Participants | 26 Participants | 28 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 4 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) White | 203 Participants | 605 Participants | 202 Participants | 200 Participants |
| Region of Enrollment Australia | 8 participants | 23 participants | 7 participants | 8 participants |
| Region of Enrollment Belgium | 1 participants | 8 participants | 4 participants | 3 participants |
| Region of Enrollment Canada | 8 participants | 21 participants | 6 participants | 7 participants |
| Region of Enrollment China | 6 participants | 27 participants | 10 participants | 11 participants |
| Region of Enrollment Czechia | 10 participants | 28 participants | 15 participants | 3 participants |
| Region of Enrollment Finland | 9 participants | 16 participants | 2 participants | 5 participants |
| Region of Enrollment France | 0 participants | 7 participants | 3 participants | 4 participants |
| Region of Enrollment Germany | 3 participants | 18 participants | 9 participants | 6 participants |
| Region of Enrollment Greece | 5 participants | 8 participants | 2 participants | 1 participants |
| Region of Enrollment Hungary | 1 participants | 6 participants | 1 participants | 4 participants |
| Region of Enrollment Israel | 5 participants | 10 participants | 3 participants | 2 participants |
| Region of Enrollment Italy | 3 participants | 5 participants | 0 participants | 2 participants |
| Region of Enrollment Lithuania | 2 participants | 10 participants | 4 participants | 4 participants |
| Region of Enrollment Netherlands | 2 participants | 8 participants | 3 participants | 3 participants |
| Region of Enrollment Poland | 15 participants | 51 participants | 20 participants | 16 participants |
| Region of Enrollment Russia | 61 participants | 166 participants | 49 participants | 56 participants |
| Region of Enrollment Spain | 4 participants | 18 participants | 6 participants | 8 participants |
| Region of Enrollment Ukraine | 30 participants | 86 participants | 30 participants | 26 participants |
| Region of Enrollment United Kingdom | 2 participants | 3 participants | 1 participants | 0 participants |
| Region of Enrollment United States | 68 participants | 211 participants | 69 participants | 74 participants |
| Sex: Female, Male Female | 99 Participants | 296 Participants | 99 Participants | 98 Participants |
| Sex: Female, Male Male | 144 Participants | 434 Participants | 145 Participants | 145 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 243 | 0 / 245 | 0 / 242 | 9 / 704 | 1 / 310 | 0 / 303 |
| other Total, other adverse events | 16 / 243 | 34 / 245 | 5 / 242 | 95 / 704 | 6 / 310 | 4 / 303 |
| serious Total, serious adverse events | 8 / 243 | 8 / 245 | 3 / 242 | 82 / 704 | 18 / 310 | 9 / 303 |
Outcome results
Primary
Change From Baseline to Week 4 of Double-blind Treatment in Mean Trough Sitting Systolic Blood Pressure (SiSBP) Measured by Automated Office Blood Pressure Measurement
Changes from baseline to Week 4 in mean trough SiSBP were analyzed using a mixed model. Participants had their blood pressure (BP) measured at the study site using the automated oscillometric sphygmomanometer (Microlife WatchBP® Office) which was provided to each site. BP was to be measured at trough (before taking the study treatment and SBAT). The BP assessment, participant preparation (e.g., arm selection, arm position, cuff size) was standardized and followed the American Heart Association guidelines / Canadian Education Program on Hypertension. The participant was resting undisturbed, alone (unattended) in a quiet place for 5 minutes at each visit. BP was measured at each visit with the same device, which recorded five sitting blood pressure readings (one per minute, the first value was excluded from the average). A negative change indicates a decrease in SiSBP from baseline.
Time frame: Pre-dose Day 1 (Part 1 double-blind randomized baseline) up to Week 4 (End of double-blind randomized part 1)
Population: The Full Analysis Set (FAS) includes all participants who were randomized and had a baseline sitting systolic blood pressure, measured by automated office blood pressure measurement. Baseline was defined as the last measurement before randomization.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Aprocitentan 12.5 mg in Part 1 (Double-blind) | Change From Baseline to Week 4 of Double-blind Treatment in Mean Trough Sitting Systolic Blood Pressure (SiSBP) Measured by Automated Office Blood Pressure Measurement | -15.26 mmHg |
| Aprocitentan 25 mg in Part 1 (Double-blind) | Change From Baseline to Week 4 of Double-blind Treatment in Mean Trough Sitting Systolic Blood Pressure (SiSBP) Measured by Automated Office Blood Pressure Measurement | -15.20 mmHg |
| Placebo in Part 1 (Double-blind) | Change From Baseline to Week 4 of Double-blind Treatment in Mean Trough Sitting Systolic Blood Pressure (SiSBP) Measured by Automated Office Blood Pressure Measurement | -11.47 mmHg |
p-value: 0.004297.5% CI: [-6.76, -0.82]Mixed Models Analysis
p-value: 0.004697.5% CI: [-6.67, -0.78]Mixed Models Analysis
Secondary
Change From Baseline to Week 4 of Double-blind Treatment in Mean Trough Sitting Diastolic Blood Pressure (SiDBP) Measured by Unattended Automated Office Blood Pressure Measurement
Changes from baseline to Week 4 in mean trough SiDBP were analyzed using a mixed model. Participants had their blood pressure (BP) measured at the study site using the automated oscillometric sphygmomanometer (Microlife WatchBP® Office) which was provided to each site. BP was to be measured at trough (before taking the study treatment and SBAT). The BP assessment, participant preparation (e.g., arm selection, arm position, cuff size) was standardized and followed the American Heart Association guidelines / Canadian Education Program on Hypertension. BP was measured at each visit with the same device, which recorded five sitting blood pressure readings (one per minute, the first value was excluded from the average). The participant was resting undisturbed, alone (unattended) in a quiet place for 5 minutes at each visit. A negative change indicates a decrease in SiDBP from baseline.
Time frame: Pre-dose Day 1 (Part 1 double-blind randomized baseline) up to Week 4 (End of double-blind randomized part 1)
Population: The Full Analysis Set (FAS) includes all participants who were randomized and had a baseline sitting systolic blood pressure, measured by automated office blood pressure measurement. Baseline was defined as the last measurement before randomization.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Aprocitentan 12.5 mg in Part 1 (Double-blind) | Change From Baseline to Week 4 of Double-blind Treatment in Mean Trough Sitting Diastolic Blood Pressure (SiDBP) Measured by Unattended Automated Office Blood Pressure Measurement | -10.43 mmHg |
| Aprocitentan 25 mg in Part 1 (Double-blind) | Change From Baseline to Week 4 of Double-blind Treatment in Mean Trough Sitting Diastolic Blood Pressure (SiDBP) Measured by Unattended Automated Office Blood Pressure Measurement | -10.95 mmHg |
| Placebo in Part 1 (Double-blind) | Change From Baseline to Week 4 of Double-blind Treatment in Mean Trough Sitting Diastolic Blood Pressure (SiDBP) Measured by Unattended Automated Office Blood Pressure Measurement | -6.48 mmHg |
p-value: <0.000195% CI: [-5.57, -2.31]Mixed Models Analysis
p-value: <0.000195% CI: [-6.09, -2.85]Mixed Models Analysis
Secondary
Change From Double-blind Withdrawal Baseline (Week 36) to Week 40 in Mean Trough Sitting Systolic Blood Pressure (SiSBP) Measured by Unattended Automated Office Blood Pressure Measurement
Changes from double-blind withdrawal baseline (Week 36) to Week 40 in mean trough SiSBP were analyzed using a mixed model. Participants had their blood pressure (BP) measured at the study site using the automated oscillometric sphygmomanometer (Microlife WatchBP® Office) which was provided to each site. BP was to be measured at trough (before taking the study treatment and SBAT). The BP assessment, participant preparation (e.g., arm selection, arm position, cuff size) was standardized and followed the American Heart Association guidelines / Canadian Education Program on Hypertension. The participant was resting undisturbed, alone (unattended) in a quiet place for 5 minutes at each visit. BP was measured at each visit with the same device, which recorded five sitting blood pressure readings (one per minute, the first value was excluded from the average). A negative change indicates a decrease in SiSBP from baseline.
Time frame: Pre-dose Week 36 (Part 3 double-blind-withdrawal baseline) up to Week 40
Population: The modified FAS (mFAS) includes all participants from the FAS who were re-randomized in the double-blind-withdrawal part (DB-WD) of the study and who have a DB-WD baseline sitting systolic blood pressure, measured by automatic office blood pressure measurement device at trough. Baseline was defined as the last measurement before re-randomization.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Aprocitentan 12.5 mg in Part 1 (Double-blind) | Change From Double-blind Withdrawal Baseline (Week 36) to Week 40 in Mean Trough Sitting Systolic Blood Pressure (SiSBP) Measured by Unattended Automated Office Blood Pressure Measurement | -1.47 mmHg |
| Aprocitentan 25 mg in Part 1 (Double-blind) | Change From Double-blind Withdrawal Baseline (Week 36) to Week 40 in Mean Trough Sitting Systolic Blood Pressure (SiSBP) Measured by Unattended Automated Office Blood Pressure Measurement | 4.36 mmHg |
p-value: <0.000195% CI: [-7.94, -3.71]Mixed Models Analysis
Secondary
Change From Double-blind Withdrawal Baseline (Week 36) to Week 40 of Double-blind-withdrawal (DB-WD) Treatment in Trough Sitting Diastolic Blood Pressure (SiDBP) Measured by Unattended Automated Office Blood Pressure
Changes from double-blind withdrawal (Week 36) to Week 40 in mean trough SiDBP were analyzed using a mixed model. Participants had their blood pressure (BP) measured at the study site using the automated oscillometric sphygmomanometer (Microlife WatchBP® Office) which was provided to each site. BP was to be measured at trough (before taking the study treatment and SBAT). The BP assessment, participant preparation (e.g., arm selection, arm position, cuff size) was standardized and followed the American Heart Association guidelines / Canadian Education Program on Hypertension. The participant was resting undisturbed, alone (unattended) in a quiet place for 5 minutes at each visit. BP was measured at each visit with the same device, which recorded five sitting blood pressure readings (one per minute, the first value was excluded from the average). A negative change indicates a decrease in SiDBP from baseline.
Time frame: Pre-dose Week 36 (Part 3 double-blind-withdrawal baseline) up to Week 40
Population: The modified FAS (mFAS) includes all participants in the FAS who were re-randomized in the double-blind-withdraw part of the study and who had a week 36 sitting systolic blood pressure, measured by automated office blood pressure measurement. Baseline was defined as the last measurement before re-randomization into part 3 of the double-blind withdrawal part of the study.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Aprocitentan 12.5 mg in Part 1 (Double-blind) | Change From Double-blind Withdrawal Baseline (Week 36) to Week 40 of Double-blind-withdrawal (DB-WD) Treatment in Trough Sitting Diastolic Blood Pressure (SiDBP) Measured by Unattended Automated Office Blood Pressure | -0.52 mmHg |
| Aprocitentan 25 mg in Part 1 (Double-blind) | Change From Double-blind Withdrawal Baseline (Week 36) to Week 40 of Double-blind-withdrawal (DB-WD) Treatment in Trough Sitting Diastolic Blood Pressure (SiDBP) Measured by Unattended Automated Office Blood Pressure | 4.67 mmHg |
p-value: <0.000195% CI: [-6.62, -3.76]Mixed Models Analysis
Secondary
Changes From Baseline to Week 4 of Double-blind Treatment in 24-hour Mean Systolic (SBP) and Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring
ABPM devices were provided to each site by the central blood pressure laboratory. On the first day after all visit assessments were performed, the ABPM device (Mobil-O-Graph NG) was fitted to the participant. The following day (i.e., second day), the participant came back to site to have the ABPM device removed. ABPM data collected over the 24-hours was electronically transferred to the central BP laboratory. Systolic blood pressure and diastolic blood pressure were measured at predetermined times every 20 minutes from 06:00 to 21:59, and every 30 minutes from 22:00 to 05:59. For each participant and at each visit (baseline and Week 4) the 24-hour mean SBP (or DBP) was calculated from the area under the SBP (or DBP) time curve and divided by the time span. A negative change indicates a decrease in 24-hour mean systolic / diastolic blood pressure from baseline.
Time frame: Pre-dose Day 1 (Part 1 double-blind randomized baseline) and Week 4 (End of double-blind randomized part 1)
Population: The ambulatory blood pressure monitoring full analysis set (aFAS) includes all participants from the FAS who have a baseline 24-hour mean systolic and diastolic blood pressure measured by ambulatory blood pressure monitoring with a total duration of at least 21 hours and at least 70% valid readings.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Aprocitentan 12.5 mg in Part 1 (Double-blind) | Changes From Baseline to Week 4 of Double-blind Treatment in 24-hour Mean Systolic (SBP) and Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring | 24-hour mean systolic blood pressure | -6.73 mmHg |
| Aprocitentan 12.5 mg in Part 1 (Double-blind) | Changes From Baseline to Week 4 of Double-blind Treatment in 24-hour Mean Systolic (SBP) and Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring | 24-hour mean diastolic blood pressure | -6.25 mmHg |
| Aprocitentan 25 mg in Part 1 (Double-blind) | Changes From Baseline to Week 4 of Double-blind Treatment in 24-hour Mean Systolic (SBP) and Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring | 24-hour mean systolic blood pressure | -8.44 mmHg |
| Aprocitentan 25 mg in Part 1 (Double-blind) | Changes From Baseline to Week 4 of Double-blind Treatment in 24-hour Mean Systolic (SBP) and Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring | 24-hour mean diastolic blood pressure | -7.74 mmHg |
| Placebo in Part 1 (Double-blind) | Changes From Baseline to Week 4 of Double-blind Treatment in 24-hour Mean Systolic (SBP) and Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring | 24-hour mean systolic blood pressure | -2.55 mmHg |
| Placebo in Part 1 (Double-blind) | Changes From Baseline to Week 4 of Double-blind Treatment in 24-hour Mean Systolic (SBP) and Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring | 24-hour mean diastolic blood pressure | -1.92 mmHg |
Comparison: 24-hour mean systolic (SBP)p-value: <0.000195% CI: [-6.25, -2.12]ANCOVA
Comparison: 24-hour mean systolic (SBP)p-value: <0.000195% CI: [-7.94, -3.85]ANCOVA
Comparison: 24-hour mean diastolic (DBP)p-value: <0.000195% CI: [-5.66, -2.98]ANCOVA
Comparison: 24-hour mean diastolic (DBP)p-value: <0.000195% CI: [-7.14, -4.49]ANCOVA
Secondary
Changes From Double-blind Withdrawal Baseline (Week 36) to Week 40 of Double-blind-withdrawal (DB-WD) Treatment in 24-hour Mean Systolic (SBP) and Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring
ABPM devices were provided to each site by the central blood pressure laboratory. On the first day after all visit assessments were performed, the ABPM device (Mobil-O-Graph NG) was fitted to the participant. The following day (i.e., second day), the participant came back to site to have the ABPM device removed. ABPM data collected over the 24-hours was electronically transferred to the central BP laboratory. Systolic blood pressure and diastolic blood pressure were measured at predetermined times every 20 minutes from 06:00 to 21:59, and every 30 minutes from 22:00 to 05:59. For each participant and at each visit (the double-blind withdrawal baseline \[Week 36\] and the week 40) the 24-hour mean SBP (or DBP) was calculated from the area under the SBP (or DBP) time curve. A negative change indicates a decrease in 24-hour mean systolic / diastolic blood pressure from baseline.
Time frame: From Week 36 (Part 3 double-blind-withdrawal baseline) and Week 40
Population: The modified ambulatory blood pressure monitoring full analysis set (maFAS) includes all participants from the modified Full Analysis Set (mFAS) who had a double-blind withdrawal (DB-WD) baseline 24-hour mean systolic and diastolic blood pressure, measured by ambulatory blood Pressure monitoring (ABPM) with a total duration of at least 21 hours and at least 70% valid readings.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Aprocitentan 12.5 mg in Part 1 (Double-blind) | Changes From Double-blind Withdrawal Baseline (Week 36) to Week 40 of Double-blind-withdrawal (DB-WD) Treatment in 24-hour Mean Systolic (SBP) and Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring | 24-hour mean systolic blood pressure | -0.07 mmHg |
| Aprocitentan 12.5 mg in Part 1 (Double-blind) | Changes From Double-blind Withdrawal Baseline (Week 36) to Week 40 of Double-blind-withdrawal (DB-WD) Treatment in 24-hour Mean Systolic (SBP) and Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring | 24-hour mean diastolic blood pressure | -0.47 mmHg |
| Aprocitentan 25 mg in Part 1 (Double-blind) | Changes From Double-blind Withdrawal Baseline (Week 36) to Week 40 of Double-blind-withdrawal (DB-WD) Treatment in 24-hour Mean Systolic (SBP) and Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring | 24-hour mean systolic blood pressure | 6.46 mmHg |
| Aprocitentan 25 mg in Part 1 (Double-blind) | Changes From Double-blind Withdrawal Baseline (Week 36) to Week 40 of Double-blind-withdrawal (DB-WD) Treatment in 24-hour Mean Systolic (SBP) and Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring | 24-hour mean diastolic blood pressure | 6.28 mmHg |
Comparison: 24-hour mean systolic (SBP)p-value: <0.000195% CI: [-8.5, -4.56]ANCOVA
Comparison: 24-hour mean diastolic (DBP)p-value: <0.000195% CI: [-7.98, -5.52]ANCOVA