Essential Hypertension
Conditions
Brief summary
The main objective will be to evaluate the dose-response of ACT-132577 (aprocitentan) on diastolic blood pressure (DBP) in participants with grade 1 or 2 essential hypertension. Secondary objectives will be to evaluate the dose-response of ACT-132577 on: systolic blood pressure (SBP); control and response rate of blood pressure; 24-hour ambulatory blood pressure monitoring (ABPM) and to evaluate the safety and tolerability of a once daily oral regimen of 4 doses of ACT-132577.
Detailed description
Participation in the study is planned to last up to 18 weeks. A single-blind placebo run-in period of 4 to 6 weeks after which participants will be randomized into a double-blind treatment period of 8 weeks and a washout and follow-up period ending with an end-of-study visit approximately 12 weeks after randomization.
Interventions
DRUGAprocitentan 5 mg
One capsule of 5 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.
DRUGAprocitentan 10 mg
Two capsules of 5 mg aprocitentan, orally, once daily in the morning for 8 weeks.
One capsule of 25 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.
DRUGAprocitentan 50 mg
One capsule of 50 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.
DRUGLisinopril 20 mg
One capsule of 20 mg lisinopril, orally, once daily in the morning for 8 weeks, along with placebo capsule matching aprocitentan
DRUGPlacebo
One capsule each of placebo matching aprocitentan and placebo matching lisinopril orally, once daily in the morning for 8 weeks.
Sponsors
Idorsia Pharmaceuticals Ltd.
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
* Signed informed consent prior to any study-mandated procedure * No contra-indication to stop (according to label) anti-hypertensive treatment(s) at screening * Mild-to-moderate essential hypertension with or without ongoing anti-hypertensive treatment(s): \-- Mean (of 5 measurements) sitting diastolic blood pressure (SiDBP) ≥ 90 to \< 110 mmHg measured by office blood pressure measurements (OBPM). * Women of childbearing potential must have a negative pregnancy test and use of reliable methods of contraception
Exclusion criteria
* Severe hypertension (grade 3): mean sitting systolic/diastolic BP (SiSBP/SiDBP; measured by OBPM) ≥ 180/110 mmHg, respectively. * Secondary hypertension * Known hypertensive retinopathy greater than Keith-Wagener Grade 2 * Myocardial infarction, percutaneous transluminal coronary angioplasty, or coronary artery bypass graft within 12 months prior to randomization * Unstable angina within 6 months prior to randomization * Heart failure New York Heart Association class III and IV * Valvular defects (such as severe aortic or mitral valve disease) and/or hemodynamically relevant rhythm disturbances * Clinical evidence of cerebrovascular insufficiency or a cerebrovascular accident within 6 months prior to randomization. * Subjects working night shifts * Body mass index \< 20 kg/m2 or \> 40 kg/m2 * Treatment with any medication which may affect BP (e.g., treatment of psychiatric diseases, ophthalmic preparations) * Treatment with strong cytochrome P450 3A4 (CYP3A4) isoenzyme inhibitors or inducers * Treatment with guanethidine and/or mineralocorticoid receptor antagonists within 1 month prior to Screening (Visit 1) * Treatment with another investigational treatment within 1 month prior to Screening (Visit 1) * Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Baseline (Day 1) and end of double-blind treatment (Day 56) | Participants had their blood pressure measured at the study site using the BpTRU® device. The BpTRU® is an automatic unattended office blood pressure measurement device. Six measurements, at rest, per participant per visit were performed. The mean of the last 5 measurements was used for the analysis. The absolute change in mean trough sitting diastolic blood pressure (SiDBP) measured by from baseline (i.e., at randomization) to week 8 (Day 56). A negative change indicates a decrease in the diastolic blood pressure from the start of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to End of Double-blind Treatment in Sitting Systolic Blood Pressure at Trough | Baseline (Day 1) and end of double-blind treatment (Day 56) | Participants had their blood pressure measured at the study site using the BpTRU® device. The BpTRU® is an automatic unattended office blood pressure measurement device. Six measurements, at rest, per participant per visit were performed. The mean of the last 5 measurements was used for the analysis. The absolute change in mean trough sitting systolic blood pressure (SiSBP) measured by from baseline (i.e., at randomization) to week 8 (Day 56). A negative change indicates a decrease in the systolic blood pressure from the start of treatment. |
| Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | End of double-blind treatment (Day 56) | Participants had their blood pressure measured at the study site using the BpTRU® device. The BpTRU® is an automatic unattended office blood pressure measurement device. Six measurements, at rest, per participant per visit were performed. The mean of the last 5 measurements was used for the analysis. The Canadian Hypertension Education Program (CHEP) issued guidelines proposing cut-offs of 85 mmHg for diastolic blood pressure and 135 mmHg for systolic blood pressure specifically focusing on measurement by automated office blood pressure measurement. The number of participants at the end of the 8-week treatment period that had values below the protocol and CHEP cut-off values are reported. The initial protocol control rates at Week 8 (Day 56) on trough SiDBP are also reported and were defined as a SiDBP of less than 90 mmHg and a SiSBP of less than 140 mmHg. |
| Response Rates at End of Double-blind Treatment Period Based on Trough Sitting Diastolic Blood Pressure | Baseline (Day 1) and end of double-blind treatment (Day 56) | Participants had their blood pressure measured at the study site using the BpTRU® device. The BpTRU® is an automatic unattended office blood pressure measurement device. Six measurements, at rest, per participant per visit were performed. The mean of the last 5 measurements was used for the analysis. A participant was a responder if the reduction from baseline in mean trough sitting diastolic blood pressure (SiDBP) was 10 mmHg or greater-than 10 mmHg. |
| Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Baseline (Day -1 to Day 1) and end of double-blind treatment (Day 55 and Day 56) | Diastolic and systolic ambulatory blood pressure monitoring was performed over a 24-hour period with the ABPM device (Mobil-o-Graph) set to record diastolic and systolic blood pressure at a pre-defined time. Over a 24-hour period 3 measurements per hour during the day and 2 per hour during the night were made. The blood pressure measurements were derived from the area under the diastolic and systolic blood pressure curves and divided by the time span and averaged. For ambulatory blood pressure monitoring the baseline was the period from the time of last run-in placebo intake up to the time of the first double-blind treatment intake. |
| Ratio of Group Mean at Trough to Group Mean at Peak for Diastolic Blood Pressure Based on Ambulatory Blood Pressure Monitoring (ABPM) | Baseline (Day -1 to Day 1) and end of double-blind treatment (Day 55 and Day 56) | Ratio of group mean at trough to group mean at peak was calculated from the diastolic ambulatory blood pressure monitoring performed over a 24-hour period with the ABPM device. The trough (the smallest blood pressure reduction) and the peak (the highest blood pressure reduction) ratio show the extent of blood pressure lowering throughout the 24-hour dosing interval in the group. The group mean trough (at 20-24 hours) to group mean (at 2-6 hours) peak of diastolic blood pressure were examined to evaluate the extent to which once-daily dosing criteria were met (trough-to-peak values greater than 0.5). The ratio is positive if there was a decrease in diastolic blood pressure at both the trough and peak times at the end of treatment (Day 55 to Day 56) when compared to baseline (Day -1 to Day 1). For ambulatory blood pressure monitoring the baseline was the period from the time of last run-in placebo intake up to the time of the first double-blind treatment intake. |
| Response Rates at End of Double-blind Treatment Period Based on Trough Sitting Systolic Blood Pressure | Baseline (Day 1) and end of double-blind treatment (Day 56) | Participants had their blood pressure measured at the study site using the BpTRU® device. The BpTRU® is an automatic unattended office blood pressure measurement device. Six measurements, at rest, per participant per visit were performed. The mean of the last 5 measurements was used for the analysis. A participant was a responder if the reduction from baseline in mean trough sitting systolic blood pressure (SiSBP) was 20 mmHg or greater-than 20 mmHg. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Supportive Analysis of Primary Endpoint: Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Baseline (Day -1 to Day 1) and end of double-blind treatment (Day 55 and Day 56) | Participants had their blood pressure measured at the study site using the BpTRU® device. The BpTRU® is an automatic unattended office blood pressure measurement device. Six measurements, at rest, per participant per visit were performed. The mean of the last 5 measurements was used for the analysis. The absolute change in mean trough sitting diastolic blood pressure (SiDBP) measured by from baseline (i.e., at randomization) to week 8 (Day 56). A negative change indicates a decrease in the diastolic blood pressure from the start of treatment. |
Countries
Canada, Israel, Puerto Rico, United States
Participant flow
Recruitment details
The study was conducted at 99 sites in 3 countries. Of the 1659 participants that signed the informed consent 996 entered the run-in period (i.e. 663 participants were screening failures: 651 failed to meet the eligibility criteria to enter the run-in period, 6 withdrew and 6 did not enter the run-in period for other reasons).
Pre-assignment details
Of the 996 participants enrolled into the run-in period, a total 992 participants received at least one dose of the single-blind placebo. Of these 992 participants 502 were considered run-in failures (390 failing to meet randomization criteria, 57 withdrew consent and 55 left for other reasons) and 490 participants were randomized into the study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants randomized to placebo treatment for 8 weeks. | 82 |
| Aprocitentan 5 mg Participants randomized to 5 mg aprocitentan treatment for 8 weeks. | 82 |
| Aprocitentan 10 mg Participants randomized to 10 mg aprocitentan treatment for 8 weeks. | 82 |
| Aprocitentan 25 mg Participants randomized to 25 mg aprocitentan treatment for 8 weeks. | 82 |
| Aprocitentan 50 mg Participants randomized to 50 mg aprocitentan treatment for 8 weeks. | 81 |
| Lisinopril 20 mg Participants randomized to 20 mg lisinopril treatment for 8 weeks. | 81 |
| Total | 490 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 0 | 2 | 2 | 1 | 1 |
| Overall Study | Lack of Efficacy | 0 | 1 | 0 | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 3 | 1 | 4 | 2 | 2 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 | 2 | 1 |
| Overall Study | Pre-specified discontinuation criteria | 3 | 3 | 2 | 2 | 3 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 1 | 2 | 3 | 3 | 4 |
Baseline characteristics
| Characteristic | Total | Aprocitentan 5 mg | Aprocitentan 10 mg | Aprocitentan 25 mg | Aprocitentan 50 mg | Placebo | Lisinopril 20 mg |
|---|---|---|---|---|---|---|---|
| Age, Continuous Full Analysis Set | 54.7 years STANDARD_DEVIATION 9.3 | 54.1 years STANDARD_DEVIATION 8.5 | 55.3 years STANDARD_DEVIATION 9.8 | 55.1 years STANDARD_DEVIATION 10 | 54.2 years STANDARD_DEVIATION 9.3 | 53.5 years STANDARD_DEVIATION 9.1 | 56.0 years STANDARD_DEVIATION 9 |
| Age, Continuous modified Per Protocol Set | 55.1 years STANDARD_DEVIATION 9.3 | 55.0 years STANDARD_DEVIATION 8.5 | 55.8 years STANDARD_DEVIATION 9.5 | 55.7 years STANDARD_DEVIATION 9.8 | 54.0 years STANDARD_DEVIATION 9.4 | 54.0 years STANDARD_DEVIATION 9.1 | 56.1 years STANDARD_DEVIATION 9.4 |
| Age, Continuous Per Protocol Set | 55.1 years STANDARD_DEVIATION 9.3 | 55.0 years STANDARD_DEVIATION 8.5 | 55.8 years STANDARD_DEVIATION 9.5 | 55.7 years STANDARD_DEVIATION 9.8 | 54.0 years STANDARD_DEVIATION 9.4 | 53.9 years STANDARD_DEVIATION 9.1 | 56.1 years STANDARD_DEVIATION 9.4 |
| Antihypertensive treatment at screening Full Analysis Set | 317 participants | 56 participants | 45 participants | 49 participants | 54 participants | 57 participants | 56 participants |
| Antihypertensive treatment at screening modified Per Protocol Set | 263 participants | 48 participants | 38 participants | 39 participants | 45 participants | 45 participants | 48 participants |
| Antihypertensive treatment at screening Per Protocol Set | 264 participants | 48 participants | 38 participants | 39 participants | 45 participants | 46 participants | 48 participants |
| Body Mass Index Full Analysis Set | 30.5 kilograms per square meter STANDARD_DEVIATION 4.57 | 30.1 kilograms per square meter STANDARD_DEVIATION 4.56 | 30.8 kilograms per square meter STANDARD_DEVIATION 4.52 | 31.0 kilograms per square meter STANDARD_DEVIATION 4.16 | 30.2 kilograms per square meter STANDARD_DEVIATION 4.55 | 30.6 kilograms per square meter STANDARD_DEVIATION 5.07 | 30.4 kilograms per square meter STANDARD_DEVIATION 4.59 |
| Body Mass Index modified Per Protocol Set | 30.3 kilograms per square meter STANDARD_DEVIATION 4.6 | 29.8 kilograms per square meter STANDARD_DEVIATION 4.5 | 30.4 kilograms per square meter STANDARD_DEVIATION 4.6 | 31.0 kilograms per square meter STANDARD_DEVIATION 4.3 | 30.3 kilograms per square meter STANDARD_DEVIATION 4.7 | 30.1 kilograms per square meter STANDARD_DEVIATION 5.1 | 30.4 kilograms per square meter STANDARD_DEVIATION 4.6 |
| Body Mass Index Per Protocol Set | 30.3 kilograms per square meter STANDARD_DEVIATION 4.6 | 29.8 kilograms per square meter STANDARD_DEVIATION 4.5 | 30.4 kilograms per square meter STANDARD_DEVIATION 4.6 | 31.0 kilograms per square meter STANDARD_DEVIATION 4.3 | 30.3 kilograms per square meter STANDARD_DEVIATION 4.7 | 30.1 kilograms per square meter STANDARD_DEVIATION 5.1 | 30.4 kilograms per square meter STANDARD_DEVIATION 4.6 |
| Duration of essential hypertension at screening Full Analysis Set | 9.94 years STANDARD_DEVIATION 9.48 | 8.12 years STANDARD_DEVIATION 8.25 | 10.48 years STANDARD_DEVIATION 10.18 | 9.56 years STANDARD_DEVIATION 8.97 | 10.60 years STANDARD_DEVIATION 9.95 | 9.13 years STANDARD_DEVIATION 8.72 | 11.79 years STANDARD_DEVIATION 10.47 |
| Duration of essential hypertension at screening Per Protocol Set | 10.06 years STANDARD_DEVIATION 9.7 | 8.38 years STANDARD_DEVIATION 8.62 | 10.6 years STANDARD_DEVIATION 10.51 | 9.19 years STANDARD_DEVIATION 8.61 | 10.35 years STANDARD_DEVIATION 10.07 | 9.24 years STANDARD_DEVIATION 8.93 | 12.53 years STANDARD_DEVIATION 10.88 |
| Ethnicity (NIH/OMB) Full Analysis Set Hispanic or Latino | 161 Participants | 26 Participants | 31 Participants | 27 Participants | 28 Participants | 23 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Full Analysis Set Not Hispanic or Latino | 329 Participants | 56 Participants | 51 Participants | 55 Participants | 53 Participants | 59 Participants | 55 Participants |
| Ethnicity (NIH/OMB) Full Analysis Set Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Per Protocol Set Hispanic or Latino | 141 Participants | 22 Participants | 28 Participants | 24 Participants | 25 Participants | 19 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Per Protocol Set Not Hispanic or Latino | 269 Participants | 46 Participants | 43 Participants | 43 Participants | 43 Participants | 48 Participants | 46 Participants |
| Ethnicity (NIH/OMB) Per Protocol Set Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Full Analysis Set American Indian or Alaska Native | 4 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Full Analysis Set Asian | 5 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Full Analysis Set Black or African American | 178 Participants | 28 Participants | 26 Participants | 35 Participants | 26 Participants | 31 Participants | 32 Participants |
| Race (NIH/OMB) Full Analysis Set More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Full Analysis Set Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Full Analysis Set Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Full Analysis Set White | 302 Participants | 54 Participants | 53 Participants | 46 Participants | 55 Participants | 48 Participants | 46 Participants |
| Race (NIH/OMB) Per Protocol Set American Indian or Alaska Native | 3 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Per Protocol Set Asian | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Per Protocol Set Black or African American | 140 Participants | 22 Participants | 19 Participants | 26 Participants | 21 Participants | 26 Participants | 26 Participants |
| Race (NIH/OMB) Per Protocol Set More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Per Protocol Set Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Per Protocol Set Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Per Protocol Set White | 263 Participants | 46 Participants | 49 Participants | 40 Participants | 47 Participants | 40 Participants | 41 Participants |
| Region of Enrollment Canada | 21 participants | 1 participants | 6 participants | 4 participants | 2 participants | 3 participants | 5 participants |
| Region of Enrollment Israel | 26 participants | 6 participants | 2 participants | 5 participants | 4 participants | 4 participants | 5 participants |
| Region of Enrollment United States | 443 participants | 75 participants | 74 participants | 73 participants | 75 participants | 75 participants | 71 participants |
| Sex: Female, Male Full Analysis Set Female | 193 Participants | 34 Participants | 31 Participants | 37 Participants | 28 Participants | 27 Participants | 36 Participants |
| Sex: Female, Male Full Analysis Set Male | 297 Participants | 48 Participants | 51 Participants | 45 Participants | 53 Participants | 55 Participants | 45 Participants |
| Sex: Female, Male modified Per Protocol Set Female | 160 Participants | 27 Participants | 26 Participants | 30 Participants | 24 Participants | 22 Participants | 31 Participants |
| Sex: Female, Male modified Per Protocol Set Male | 249 Participants | 41 Participants | 45 Participants | 37 Participants | 44 Participants | 44 Participants | 38 Participants |
| Sex: Female, Male Per Protocol Set Female | 160 Participants | 27 Participants | 26 Participants | 30 Participants | 24 Participants | 22 Participants | 31 Participants |
| Sex: Female, Male Per Protocol Set Male | 250 Participants | 41 Participants | 45 Participants | 37 Participants | 44 Participants | 45 Participants | 38 Participants |
| Weight Full Analysis Set | 89.4 kilograms STANDARD_DEVIATION 17.37 | 88.6 kilograms STANDARD_DEVIATION 16.9 | 90.1 kilograms STANDARD_DEVIATION 18.3 | 91.1 kilograms STANDARD_DEVIATION 16.9 | 87.6 kilograms STANDARD_DEVIATION 15.8 | 92.0 kilograms STANDARD_DEVIATION 18.9 | 87.0 kilograms STANDARD_DEVIATION 17.2 |
| Weight modified Per Protocol Set | 89.0 kilograms STANDARD_DEVIATION 17.7 | 88.3 kilograms STANDARD_DEVIATION 17.6 | 89.3 kilograms STANDARD_DEVIATION 19 | 91.7 kilograms STANDARD_DEVIATION 18.1 | 87.1 kilograms STANDARD_DEVIATION 15.8 | 90.6 kilograms STANDARD_DEVIATION 19 | 86.5 kilograms STANDARD_DEVIATION 16 |
| Weight Per Protocol Set | 89.0 kilograms STANDARD_DEVIATION 17.7 | 88.3 kilograms STANDARD_DEVIATION 17.6 | 89.3 kilograms STANDARD_DEVIATION 19 | 91.7 kilograms STANDARD_DEVIATION 18.1 | 87.1 kilograms STANDARD_DEVIATION 15.8 | 91.0 kilograms STANDARD_DEVIATION 19.2 | 86.5 kilograms STANDARD_DEVIATION 16 |
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 | 0 / 82 | 0 / 82 | 0 / 82 | 0 / 82 | 0 / 81 | 0 / 81 |
| other Total, other adverse events | 30 / 82 | 18 / 82 | 24 / 82 | 32 / 82 | 22 / 81 | 25 / 81 |
| serious Total, serious adverse events | 0 / 82 | 0 / 82 | 0 / 82 | 2 / 82 | 0 / 81 | 1 / 81 |
Outcome results
Primary
Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough
Participants had their blood pressure measured at the study site using the BpTRU® device. The BpTRU® is an automatic unattended office blood pressure measurement device. Six measurements, at rest, per participant per visit were performed. The mean of the last 5 measurements was used for the analysis. The absolute change in mean trough sitting diastolic blood pressure (SiDBP) measured by from baseline (i.e., at randomization) to week 8 (Day 56). A negative change indicates a decrease in the diastolic blood pressure from the start of treatment.
Time frame: Baseline (Day 1) and end of double-blind treatment (Day 56)
Population: Modified Per-protocol set (mPPS). All participants who had a mean trough sitting diastolic blood pressure (SiDBP) at Week-8 of the double-blind treatment period and that did not have any major protocol deviation were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Baseline | 97.5 mmHg | Standard Deviation 5.4 |
| Placebo | Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Absolute Change from Baseline to Week 8 | -4.9 mmHg | Standard Deviation 11.1 |
| Aprocitentan 5 mg | Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Baseline | 97.8 mmHg | Standard Deviation 5.5 |
| Aprocitentan 5 mg | Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Absolute Change from Baseline to Week 8 | -6.3 mmHg | Standard Deviation 8.9 |
| Aprocitentan 10 mg | Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Baseline | 97.7 mmHg | Standard Deviation 4.3 |
| Aprocitentan 10 mg | Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Absolute Change from Baseline to Week 8 | -9.9 mmHg | Standard Deviation 8.7 |
| Aprocitentan 25 mg | Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Baseline | 97.8 mmHg | Standard Deviation 4.8 |
| Aprocitentan 25 mg | Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Absolute Change from Baseline to Week 8 | -12.0 mmHg | Standard Deviation 8.2 |
| Aprocitentan 50 mg | Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Baseline | 98.2 mmHg | Standard Deviation 5.3 |
| Aprocitentan 50 mg | Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Absolute Change from Baseline to Week 8 | -10.0 mmHg | Standard Deviation 7.9 |
| Lisinopril 20 mg | Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Baseline | 96.8 mmHg | Standard Deviation 4.6 |
| Lisinopril 20 mg | Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Absolute Change from Baseline to Week 8 | -8.4 mmHg | Standard Deviation 9.6 |
Comparison: Multiple Comparison Procedure-Modeling (MCP-Mod) was used to assess a dose-response across placebo and all aprocitentan doses. The null hypothesis of no dose-response was rejected if at least one of the six Multiple Contrast Tests (MCTs) had a multiplicity adjusted p-value \<0.05. The analysis was performed using the R-package DoseFinding (Bornkamp B, Pinheiro J, Bretz F. Planning and analyzing dose finding experiments. 2016. Available from: cran.r-projects.org/web/packages/DoseFinding.)p-value: <0.001Multiple Comparison Procedure-Modeling
p-value: 0.811795% CI: [-5.1, 2.49]ANCOVA
p-value: 0.005395% CI: [-8.68, -1.17]ANCOVA
p-value: <0.000195% CI: [-10.8, -3.19]ANCOVA
p-value: 0.005795% CI: [-8.75, -1.15]ANCOVA
Secondary
Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM)
Diastolic and systolic ambulatory blood pressure monitoring was performed over a 24-hour period with the ABPM device (Mobil-o-Graph) set to record diastolic and systolic blood pressure at a pre-defined time. Over a 24-hour period 3 measurements per hour during the day and 2 per hour during the night were made. The blood pressure measurements were derived from the area under the diastolic and systolic blood pressure curves and divided by the time span and averaged. For ambulatory blood pressure monitoring the baseline was the period from the time of last run-in placebo intake up to the time of the first double-blind treatment intake.
Time frame: Baseline (Day -1 to Day 1) and end of double-blind treatment (Day 55 and Day 56)
Population: All participants in a treatment group with a full set of ABPM (Ambulatory Blood Pressure Monitoring) values over the 24-hour period at baseline and at Week 8.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Baseline 24-hour mean DBP | 90.46 mmHg | Standard Error 10.66 |
| Placebo | Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Absolute change in 24-hour mean DBP at Week 8 | -2.49 mmHg | Standard Error 5.52 |
| Placebo | Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Baseline 24-hour mean SBP | 140.28 mmHg | Standard Error 14.2 |
| Placebo | Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Absolute change in 24-hour mean SBP at Week 8 | -3.54 mmHg | Standard Error 7.46 |
| Aprocitentan 5 mg | Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Baseline 24-hour mean SBP | 139.90 mmHg | Standard Error 15.87 |
| Aprocitentan 5 mg | Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Absolute change in 24-hour mean DBP at Week 8 | -3.76 mmHg | Standard Error 6.36 |
| Aprocitentan 5 mg | Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Baseline 24-hour mean DBP | 90.60 mmHg | Standard Error 10.19 |
| Aprocitentan 5 mg | Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Absolute change in 24-hour mean SBP at Week 8 | -3.16 mmHg | Standard Error 10.54 |
| Aprocitentan 10 mg | Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Absolute change in 24-hour mean SBP at Week 8 | -7.72 mmHg | Standard Error 11.37 |
| Aprocitentan 10 mg | Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Baseline 24-hour mean SBP | 144.30 mmHg | Standard Error 15.68 |
| Aprocitentan 10 mg | Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Absolute change in 24-hour mean DBP at Week 8 | -6.55 mmHg | Standard Error 7.04 |
| Aprocitentan 10 mg | Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Baseline 24-hour mean DBP | 92.60 mmHg | Standard Error 10.92 |
| Aprocitentan 25 mg | Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Baseline 24-hour mean DBP | 89.28 mmHg | Standard Error 9.53 |
| Aprocitentan 25 mg | Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Absolute change in 24-hour mean SBP at Week 8 | -9.23 mmHg | Standard Error 9.92 |
| Aprocitentan 25 mg | Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Absolute change in 24-hour mean DBP at Week 8 | -8.86 mmHg | Standard Error 7.35 |
| Aprocitentan 25 mg | Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Baseline 24-hour mean SBP | 140.83 mmHg | Standard Error 11.23 |
| Aprocitentan 50 mg | Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Baseline 24-hour mean SBP | 141.28 mmHg | Standard Error 14.73 |
| Aprocitentan 50 mg | Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Absolute change in 24-hour mean SBP at Week 8 | -6.07 mmHg | Standard Error 8.93 |
| Aprocitentan 50 mg | Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Absolute change in 24-hour mean DBP at Week 8 | -5.98 mmHg | Standard Error 6.63 |
| Aprocitentan 50 mg | Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Baseline 24-hour mean DBP | 91.53 mmHg | Standard Error 10.54 |
| Lisinopril 20 mg | Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Absolute change in 24-hour mean DBP at Week 8 | -5.72 mmHg | Standard Error 9.12 |
| Lisinopril 20 mg | Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Baseline 24-hour mean SBP | 143.35 mmHg | Standard Error 17.53 |
| Lisinopril 20 mg | Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Absolute change in 24-hour mean SBP at Week 8 | -7.23 mmHg | Standard Error 14.33 |
| Lisinopril 20 mg | Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) | Baseline 24-hour mean DBP | 91.18 mmHg | Standard Error 9.48 |
Secondary
Change From Baseline to End of Double-blind Treatment in Sitting Systolic Blood Pressure at Trough
Participants had their blood pressure measured at the study site using the BpTRU® device. The BpTRU® is an automatic unattended office blood pressure measurement device. Six measurements, at rest, per participant per visit were performed. The mean of the last 5 measurements was used for the analysis. The absolute change in mean trough sitting systolic blood pressure (SiSBP) measured by from baseline (i.e., at randomization) to week 8 (Day 56). A negative change indicates a decrease in the systolic blood pressure from the start of treatment.
Time frame: Baseline (Day 1) and end of double-blind treatment (Day 56)
Population: Modified Per-protocol set (mPPS). All participants who had a mean trough sitting systolic blood pressure (SiSBP) at Week 8 of the double-blind treatment period and that did not have any major protocol deviation were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline to End of Double-blind Treatment in Sitting Systolic Blood Pressure at Trough | Baseline | 149.2 mmHg | Standard Deviation 13.1 |
| Placebo | Change From Baseline to End of Double-blind Treatment in Sitting Systolic Blood Pressure at Trough | Absolute Change from Baseline to Week 8 | -7.7 mmHg | Standard Deviation 18.8 |
| Aprocitentan 5 mg | Change From Baseline to End of Double-blind Treatment in Sitting Systolic Blood Pressure at Trough | Baseline | 149.4 mmHg | Standard Deviation 13.9 |
| Aprocitentan 5 mg | Change From Baseline to End of Double-blind Treatment in Sitting Systolic Blood Pressure at Trough | Absolute Change from Baseline to Week 8 | -10.3 mmHg | Standard Deviation 15.3 |
| Aprocitentan 10 mg | Change From Baseline to End of Double-blind Treatment in Sitting Systolic Blood Pressure at Trough | Baseline | 149.8 mmHg | Standard Deviation 12.7 |
| Aprocitentan 10 mg | Change From Baseline to End of Double-blind Treatment in Sitting Systolic Blood Pressure at Trough | Absolute Change from Baseline to Week 8 | -15.0 mmHg | Standard Deviation 14.5 |
| Aprocitentan 25 mg | Change From Baseline to End of Double-blind Treatment in Sitting Systolic Blood Pressure at Trough | Baseline | 151.2 mmHg | Standard Deviation 13.7 |
| Aprocitentan 25 mg | Change From Baseline to End of Double-blind Treatment in Sitting Systolic Blood Pressure at Trough | Absolute Change from Baseline to Week 8 | -18.5 mmHg | Standard Deviation 15 |
| Aprocitentan 50 mg | Change From Baseline to End of Double-blind Treatment in Sitting Systolic Blood Pressure at Trough | Baseline | 148.6 mmHg | Standard Deviation 12.8 |
| Aprocitentan 50 mg | Change From Baseline to End of Double-blind Treatment in Sitting Systolic Blood Pressure at Trough | Absolute Change from Baseline to Week 8 | -15.1 mmHg | Standard Deviation 11.8 |
| Lisinopril 20 mg | Change From Baseline to End of Double-blind Treatment in Sitting Systolic Blood Pressure at Trough | Baseline | 149.8 mmHg | Standard Deviation 14.2 |
| Lisinopril 20 mg | Change From Baseline to End of Double-blind Treatment in Sitting Systolic Blood Pressure at Trough | Absolute Change from Baseline to Week 8 | -12.8 mmHg | Standard Deviation 16 |
Comparison: Multiple Comparison Procedure-Modeling (MCP-Mod) was used to assess a dose-response across placebo and all aprocitentan doses. The null hypothesis of no dose-response was rejected if at least one of the six Multiple Contrasts Tests (MCTs) had a multiplicity adjusted p-value \<0.05. The analysis was performed using the R-package DoseFinding (Bornkamp B, Pinheiro J, Bretz F. Planning and analyzing dose finding experiments. 2016. Available from: cran-rprojects.org/web/packages/DoseFinding.)p-value: <0.001Multiple Comparison Procedure-Modeling
p-value: 0.707195% CI: [-8.44, 3.54]ANCOVA
p-value: 0.013895% CI: [-12.98, -1.12]ANCOVA
p-value: 0.000395% CI: [-15.92, -3.88]ANCOVA
p-value: 0.007795% CI: [-13.58, -1.59]ANCOVA
Secondary
Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure
Participants had their blood pressure measured at the study site using the BpTRU® device. The BpTRU® is an automatic unattended office blood pressure measurement device. Six measurements, at rest, per participant per visit were performed. The mean of the last 5 measurements was used for the analysis. The Canadian Hypertension Education Program (CHEP) issued guidelines proposing cut-offs of 85 mmHg for diastolic blood pressure and 135 mmHg for systolic blood pressure specifically focusing on measurement by automated office blood pressure measurement. The number of participants at the end of the 8-week treatment period that had values below the protocol and CHEP cut-off values are reported. The initial protocol control rates at Week 8 (Day 56) on trough SiDBP are also reported and were defined as a SiDBP of less than 90 mmHg and a SiSBP of less than 140 mmHg.
Time frame: End of double-blind treatment (Day 56)
Population: Modified Per Protocol Set (mPPS). All participants who had diastolic and systolic blood pressure measurements at Week 8 of the double-blind treatment period and that did not have any major protocol deviation were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | SiDBP less than 90 mmHg | 22 Participants |
| Placebo | Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | SiDBP less than 85 mmHg (CHEP) | 17 Participants |
| Placebo | Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | SiSBP less than 140 mmHg | 34 Participants |
| Placebo | Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | SiSBP less than 135 mmHg (CHEP) | 24 Participants |
| Aprocitentan 5 mg | Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | SiSBP less than 140 mmHg | 37 Participants |
| Aprocitentan 5 mg | Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | SiDBP less than 85 mmHg (CHEP) | 15 Participants |
| Aprocitentan 5 mg | Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | SiDBP less than 90 mmHg | 30 Participants |
| Aprocitentan 5 mg | Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | SiSBP less than 135 mmHg (CHEP) | 27 Participants |
| Aprocitentan 10 mg | Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | SiSBP less than 135 mmHg (CHEP) | 32 Participants |
| Aprocitentan 10 mg | Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | SiSBP less than 140 mmHg | 43 Participants |
| Aprocitentan 10 mg | Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | SiDBP less than 85 mmHg (CHEP) | 29 Participants |
| Aprocitentan 10 mg | Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | SiDBP less than 90 mmHg | 37 Participants |
| Aprocitentan 25 mg | Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | SiDBP less than 90 mmHg | 43 Participants |
| Aprocitentan 25 mg | Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | SiSBP less than 135 mmHg (CHEP) | 38 Participants |
| Aprocitentan 25 mg | Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | SiDBP less than 85 mmHg (CHEP) | 29 Participants |
| Aprocitentan 25 mg | Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | SiSBP less than 140 mmHg | 44 Participants |
| Aprocitentan 50 mg | Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | SiSBP less than 140 mmHg | 47 Participants |
| Aprocitentan 50 mg | Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | SiSBP less than 135 mmHg (CHEP) | 36 Participants |
| Aprocitentan 50 mg | Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | SiDBP less than 85 mmHg (CHEP) | 21 Participants |
| Aprocitentan 50 mg | Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | SiDBP less than 90 mmHg | 39 Participants |
| Lisinopril 20 mg | Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | SiDBP less than 85 mmHg (CHEP) | 23 Participants |
| Lisinopril 20 mg | Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | SiSBP less than 140 mmHg | 39 Participants |
| Lisinopril 20 mg | Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | SiSBP less than 135 mmHg (CHEP) | 31 Participants |
| Lisinopril 20 mg | Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure | SiDBP less than 90 mmHg | 38 Participants |
Secondary
Ratio of Group Mean at Trough to Group Mean at Peak for Diastolic Blood Pressure Based on Ambulatory Blood Pressure Monitoring (ABPM)
Ratio of group mean at trough to group mean at peak was calculated from the diastolic ambulatory blood pressure monitoring performed over a 24-hour period with the ABPM device. The trough (the smallest blood pressure reduction) and the peak (the highest blood pressure reduction) ratio show the extent of blood pressure lowering throughout the 24-hour dosing interval in the group. The group mean trough (at 20-24 hours) to group mean (at 2-6 hours) peak of diastolic blood pressure were examined to evaluate the extent to which once-daily dosing criteria were met (trough-to-peak values greater than 0.5). The ratio is positive if there was a decrease in diastolic blood pressure at both the trough and peak times at the end of treatment (Day 55 to Day 56) when compared to baseline (Day -1 to Day 1). For ambulatory blood pressure monitoring the baseline was the period from the time of last run-in placebo intake up to the time of the first double-blind treatment intake.
Time frame: Baseline (Day -1 to Day 1) and end of double-blind treatment (Day 55 and Day 56)
Population: All participants in a treatment group with a full set of ABPM (Ambulatory Blood Pressure Monitoring) values over the 24-hour period at baseline and at Week 8.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Ratio of Group Mean at Trough to Group Mean at Peak for Diastolic Blood Pressure Based on Ambulatory Blood Pressure Monitoring (ABPM) | -48.03 Ratio of mean at trough to mean at peak |
| Aprocitentan 5 mg | Ratio of Group Mean at Trough to Group Mean at Peak for Diastolic Blood Pressure Based on Ambulatory Blood Pressure Monitoring (ABPM) | 2.59 Ratio of mean at trough to mean at peak |
| Aprocitentan 10 mg | Ratio of Group Mean at Trough to Group Mean at Peak for Diastolic Blood Pressure Based on Ambulatory Blood Pressure Monitoring (ABPM) | 0.90 Ratio of mean at trough to mean at peak |
| Aprocitentan 25 mg | Ratio of Group Mean at Trough to Group Mean at Peak for Diastolic Blood Pressure Based on Ambulatory Blood Pressure Monitoring (ABPM) | 1.49 Ratio of mean at trough to mean at peak |
| Aprocitentan 50 mg | Ratio of Group Mean at Trough to Group Mean at Peak for Diastolic Blood Pressure Based on Ambulatory Blood Pressure Monitoring (ABPM) | 1.25 Ratio of mean at trough to mean at peak |
| Lisinopril 20 mg | Ratio of Group Mean at Trough to Group Mean at Peak for Diastolic Blood Pressure Based on Ambulatory Blood Pressure Monitoring (ABPM) | 0.65 Ratio of mean at trough to mean at peak |
Secondary
Response Rates at End of Double-blind Treatment Period Based on Trough Sitting Diastolic Blood Pressure
Participants had their blood pressure measured at the study site using the BpTRU® device. The BpTRU® is an automatic unattended office blood pressure measurement device. Six measurements, at rest, per participant per visit were performed. The mean of the last 5 measurements was used for the analysis. A participant was a responder if the reduction from baseline in mean trough sitting diastolic blood pressure (SiDBP) was 10 mmHg or greater-than 10 mmHg.
Time frame: Baseline (Day 1) and end of double-blind treatment (Day 56)
Population: Modified Per Protocol Set (mPPS).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Response Rates at End of Double-blind Treatment Period Based on Trough Sitting Diastolic Blood Pressure | 21 Participants |
| Aprocitentan 5 mg | Response Rates at End of Double-blind Treatment Period Based on Trough Sitting Diastolic Blood Pressure | 21 Participants |
| Aprocitentan 10 mg | Response Rates at End of Double-blind Treatment Period Based on Trough Sitting Diastolic Blood Pressure | 34 Participants |
| Aprocitentan 25 mg | Response Rates at End of Double-blind Treatment Period Based on Trough Sitting Diastolic Blood Pressure | 40 Participants |
| Aprocitentan 50 mg | Response Rates at End of Double-blind Treatment Period Based on Trough Sitting Diastolic Blood Pressure | 38 Participants |
| Lisinopril 20 mg | Response Rates at End of Double-blind Treatment Period Based on Trough Sitting Diastolic Blood Pressure | 31 Participants |
Secondary
Response Rates at End of Double-blind Treatment Period Based on Trough Sitting Systolic Blood Pressure
Participants had their blood pressure measured at the study site using the BpTRU® device. The BpTRU® is an automatic unattended office blood pressure measurement device. Six measurements, at rest, per participant per visit were performed. The mean of the last 5 measurements was used for the analysis. A participant was a responder if the reduction from baseline in mean trough sitting systolic blood pressure (SiSBP) was 20 mmHg or greater-than 20 mmHg.
Time frame: Baseline (Day 1) and end of double-blind treatment (Day 56)
Population: Modified Per Protocol Set (mPPS).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Response Rates at End of Double-blind Treatment Period Based on Trough Sitting Systolic Blood Pressure | 16 Participants |
| Aprocitentan 5 mg | Response Rates at End of Double-blind Treatment Period Based on Trough Sitting Systolic Blood Pressure | 16 Participants |
| Aprocitentan 10 mg | Response Rates at End of Double-blind Treatment Period Based on Trough Sitting Systolic Blood Pressure | 22 Participants |
| Aprocitentan 25 mg | Response Rates at End of Double-blind Treatment Period Based on Trough Sitting Systolic Blood Pressure | 28 Participants |
| Aprocitentan 50 mg | Response Rates at End of Double-blind Treatment Period Based on Trough Sitting Systolic Blood Pressure | 22 Participants |
| Lisinopril 20 mg | Response Rates at End of Double-blind Treatment Period Based on Trough Sitting Systolic Blood Pressure | 20 Participants |
Other Pre-specified
Supportive Analysis of Primary Endpoint: Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough
Participants had their blood pressure measured at the study site using the BpTRU® device. The BpTRU® is an automatic unattended office blood pressure measurement device. Six measurements, at rest, per participant per visit were performed. The mean of the last 5 measurements was used for the analysis. The absolute change in mean trough sitting diastolic blood pressure (SiDBP) measured by from baseline (i.e., at randomization) to week 8 (Day 56). A negative change indicates a decrease in the diastolic blood pressure from the start of treatment.
Time frame: Baseline (Day -1 to Day 1) and end of double-blind treatment (Day 55 and Day 56)
Population: The Full Analysis Set (FAS) includes all participants randomized who had a baseline mean trough SiDBP. Participants were evaluated according to the study treatment they have been assigned to. Missing data was analyzed by LOCF (Last Observation Carried Forward).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Supportive Analysis of Primary Endpoint: Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Baseline | 98.0 mmHg | Standard Deviation 5.5 |
| Placebo | Supportive Analysis of Primary Endpoint: Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Absolute Change from Baseline to Week 8 | -4.2 mmHg | Standard Deviation 11.1 |
| Aprocitentan 5 mg | Supportive Analysis of Primary Endpoint: Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Baseline | 97.5 mmHg | Standard Deviation 5.3 |
| Aprocitentan 5 mg | Supportive Analysis of Primary Endpoint: Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Absolute Change from Baseline to Week 8 | -5.8 mmHg | Standard Deviation 8.9 |
| Aprocitentan 10 mg | Supportive Analysis of Primary Endpoint: Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Baseline | 97.7 mmHg | Standard Deviation 4.2 |
| Aprocitentan 10 mg | Supportive Analysis of Primary Endpoint: Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Absolute Change from Baseline to Week 8 | -9.9 mmHg | Standard Deviation 8.4 |
| Aprocitentan 25 mg | Supportive Analysis of Primary Endpoint: Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Baseline | 98.2 mmHg | Standard Deviation 5 |
| Aprocitentan 25 mg | Supportive Analysis of Primary Endpoint: Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Absolute Change from Baseline to Week 8 | -11.7 mmHg | Standard Deviation 7.8 |
| Aprocitentan 50 mg | Supportive Analysis of Primary Endpoint: Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Baseline | 98.4 mmHg | Standard Deviation 5.3 |
| Aprocitentan 50 mg | Supportive Analysis of Primary Endpoint: Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Absolute Change from Baseline to Week 8 | -9.9 mmHg | Standard Deviation 7.8 |
| Lisinopril 20 mg | Supportive Analysis of Primary Endpoint: Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Baseline | 96.9 mmHg | Standard Deviation 4.4 |
| Lisinopril 20 mg | Supportive Analysis of Primary Endpoint: Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough | Absolute Change from Baseline to Week 8 | -8.2 mmHg | Standard Deviation 9.7 |
Comparison: Multiple Comparison Procedure-Modeling (MCP-Mod) was used to assess a dose-response across placebo and all aprocitentan doses. The null hypothesis of no dose-response was rejected if at least one of the six Multiple Contrast Tests (MCTs) had a multiplicity adjusted p-value \<0.05. The analysis was performed using the R-package DoseFinding (Bornkamp B, Pinheiro J, Bretz F. Planning and analyzing dose finding experiments. 2016. Available from: cran.r-projects.org/web/packages/DoseFinding.)p-value: <0.001Multiple Comparison Procedure-Modeling
p-value: 0.535695% CI: [-5.19, 1.69]ANCOVA
p-value: 0.000195% CI: [-9.25, -2.4]ANCOVA
p-value: <0.000195% CI: [-10.96, -4.04]ANCOVA
p-value: 0.000395% CI: [-9.11, -2.19]ANCOVA