A Research Study to Show the Effect of Aprocitentan in the Treatment of Difficult to Control (Resistant) High Blood Pressure (Hypertension) and Find Out More About Its Safety (PRECISION)

• ClinicalTrials.gov Identifier: NCT03541174
• Recruitment Status: Completed
• First Posted: May 30, 2018
• Results First Posted: March 21, 2023
• Last Update Posted: March 21, 2023
• Sponsor: Idorsia Pharmaceuticals Ltd.
• Collaborator: Janssen Biotech, Inc.
• Information provided by (Responsible Party): Idorsia Pharmaceuticals Ltd.

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Resistant Hypertension
• Interventions: Drug: Aprocitentan 12.5 mg; Drug: Aprocitentan 25 mg; Drug: Placebo
• Enrollment: 730

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.

Arm/Group Title	Aprocitentan 12.5 mg in Part 1 (Double-blind)	Aprocitentan 25 mg in Part 1 (Double-blind)	Placebo in Part 1 (Double-blind)	Aprocitentan 25 mg in Part 2 (Single-blind)	Aprocitentan 25 mg in Part 3 (Double-blind Withdrawal)	Placebo in Part 3 (Double-blind Withdrawal)
Arm/Group Description	Participants were randomized and received aprocitentan 12.5 mg, orally, once daily in the morning for 4 weeks.	Participants were randomized and received aprocitentan 25 mg, orally, once daily in the morning for 4 weeks.	Participants were randomized and received placebo (matching aprocitentan), orally, once daily in the morning for 4 weeks.	Participants that completed the double-blind part received aprocitentan 25 mg, orally, once daily in the morning for 32 weeks.	After the 32-week single-blind, single-arm aprocitentan 25 mg (Part 2), participants were re-randomized and received aprocitentan 25 mg, orally, once daily in the morning for 12 weeks.	After the 32-week single-blind, single-arm aprocitentan 25 mg (Part 2), participants were re-randomized and received placebo (matching aprocitentan), orally, once daily in the morning for 12 weeks.
Period Title: Part 1 Double-Blind
Started	243	243	244	0	0	0
Safety Set [1]	243	245	242	0	0	0
Completed	232	234	238	0	0	0
Not Completed	11	9	6	0	0	0
Reason Not Completed
Adverse Event	6	5	2	0	0	0
Withdrawal by Subject	2	2	1	0	0	0
Other reasons	3	2	3	0	0	0
[1] Two participants randomized to placebo received at least one dose of aprocitentan 25 mg during double-blind part 1.
Period Title: Part 2 Single-Blind
Started	0 [1]	0 [2]	0 [3]	704 [4]	0	0
Completed	0	0	0	613	0	0
Not Completed	0	0	0	91	0	0
Reason Not Completed
Adverse Event	0	0	0	25	0	0
Lack of Efficacy	0	0	0	1	0	0
Withdrawal by Subject	0	0	0	19	0	0
Lost to Follow-up	0	0	0	8	0	0
Death	0	0	0	5	0	0
Pregnancy	0	0	0	1	0	0
Other reasons	0	0	0	32	0	0
[1] The 232 participants that completed 12.5 mg aprocitentan study treatment in part 1 entered the single-blind 25 mg aprocitentan arm in part 2.; [2] The 236 participants that completed 25 mg aprocitentan study treatment in part 1 entered the single-blind 25 mg aprocitentan arm in part 2.; [3] The 236 participants that completed placebo study treatment in part 1 entered the single-blind 25 mg aprocitentan arm in part 2.; [4] Total number of participants that completed the double-blind part 1 who entered the single-blind, single-arm part 2.
Period Title: Part 3 Double-Blind Withdrawal
Started	0	0	0	0	307	307
Safety Set [1]	0	0	0	0	310	303
Completed	0	0	0	0	288	289
Not Completed	0	0	0	0	19	18
Reason Not Completed
Adverse Event	0	0	0	0	8	7
Withdrawal by Subject	0	0	0	0	1	4
Lost to Follow-up	0	0	0	0	0	1
Other reasons	0	0	0	0	9	6
Re-randomized in part 3, however no drug dispensed	0	0	0	0	1	0
[1] 613 participants started study treatment in Part 3. Four participants re-randomised to placebo received at least one dose of aprocitentan 25 mg during part 3.

Baseline Characteristics

Arm/Group Title		Aprocitentan 12.5 mg in Part 1 (Double-blind)	Aprocitentan 25 mg in Part 1 (Double-blind)	Placebo in Part 1 (Double-blind)	Total
Arm/Group Description		Participants randomized to aprocitentan 12.5 mg, orally, once daily in the morning for 4 weeks.	Participants randomized to aprocitentan 25 mg, orally, once daily in the morning for 4 weeks.	Participants randomized to placebo (matching aprocitentan), orally, once daily in the morning for 4 weeks.	Total of all reporting groups
Overall Number of Baseline Participants		243	243	244	730
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	243 participants	243 participants	244 participants	730 participants
		61.2 (10.3)	61.7 (10.4)	62.2 (11.2)	61.7 (10.6)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	243 participants	243 participants	244 participants	730 participants
	Female	99	98	99	296
	Male	144	145	145	434
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	243 participants	243 participants	244 participants	730 participants
	Hispanic or Latino	28	22	23	73
	Not Hispanic or Latino	213	219	218	650
	Unknown or Not Reported	2	2	3	7
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	243 participants	243 participants	244 participants	730 participants
	American Indian or Alaska Native	0	0	0	0
	Asian	11	14	13	38
	Native Hawaiian or Other Pacific Islander	1	0	0	1
	Black or African American	28	28	26	82
	White	203	200	202	605
	More than one race	0	0	0	0
	Unknown or Not Reported	0	1	3	4
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	243 participants	243 participants	244 participants	730 participants
Australia		8	8	7	23
Belgium		1	3	4	8
Canada		8	7	6	21
China		6	11	10	27
Czechia		10	3	15	28
Finland		9	5	2	16
France		0	4	3	7
Germany		3	6	9	18
Greece		5	1	2	8
Hungary		1	4	1	6
Israel		5	2	3	10
Italy		3	2	0	5
Lithuania		2	4	4	10
Netherlands		2	3	3	8
Poland		15	16	20	51
Russia		61	56	49	166
Spain		4	8	6	18
Ukraine		30	26	30	86
United Kingdom		2	0	1	3
United States		68	74	69	211
Body Mass Index at Screening Visit; Mean (Standard Deviation); Unit of measure: Kg/m^2
	Number Analyzed	243 participants	243 participants	244 participants	730 participants
		33.6 (6.2)	34.3 (6.8)	33.3 (5.6)	33.7 (6.2)

Outcome Measures

1. Primary Outcome

Title	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
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Aprocitentan 12.5 mg in Part 1 (Double-blind)	Aprocitentan 25 mg in Part 1 (Double-blind)	Placebo in Part 1 (Double-blind)
Arm/Group Description:	Participants randomized to aprocitentan 12.5 mg, orally, once daily in the morning for 4 weeks.	Participants randomized to aprocitentan 25 mg, orally, once daily in the morning for 4 weeks.	Participants randomized to placebo (matching aprocitentan), orally, once daily in the morning for 4 weeks.
Overall Number of Participants Analyzed	243	243	244
Least Squares Mean (97.5% Confidence Interval); Unit of Measure: mmHg
	-15.26; (-17.36 to -13.17)	-15.20; (-17.27 to -13.13)	-11.47; (-13.57 to -9.38)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aprocitentan 12.5 mg in Part 1 (Double-blind), Placebo in Part 1 (Double-blind)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0042
	Comments	Mixed effects model for Repeated Measures: Change from baseline in SiSBP = baseline SiSBP + treatment + visit + treatment x visit + baseline x visit.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean difference to placebo
	Estimated Value	-3.79
	Confidence Interval	(2-Sided) 97.5%; -6.76 to -0.82
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Aprocitentan 25 mg in Part 1 (Double-blind), Placebo in Part 1 (Double-blind)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0046
	Comments	Mixed effects model for Repeated Measures: Change from baseline in SiSBP = baseline SiSBP + treatment + visit + treatment x visit + baseline x visit.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean difference to placebo
	Estimated Value	-3.73
	Confidence Interval	(2-Sided) 97.5%; -6.67 to -0.78
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Aprocitentan 25 mg in Part 3 (Double-blind Withdrawal)	Placebo in Part 3 (Double-blind Withdrawal)
Arm/Group Description:	After 32-weeks in the single-blind, single-arm part, participants were re-randomized to aprocitentan 25 mg, orally, once daily in the morning for 12 weeks.	After 32-weeks in the single-blind, single-arm part, participants were re-randomized to placebo (matching aprocitentan), orally, once daily in the morning for 12 weeks.
Overall Number of Participants Analyzed	307	307
Least Squares Mean (95% Confidence Interval); Unit of Measure: mmHg
	-1.47; (-2.97 to 0.04)	4.36; (2.87 to 5.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aprocitentan 25 mg in Part 3 (Double-blind Withdrawal), Placebo in Part 3 (Double-blind Withdrawal)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effects model for Repeated Measures: Change from DB-WD baseline in SiSBP = DB-WD baseline SiSBP + stratum (randomized treatment in DB part) + treatment + visit + treatment x visit + DB-WD baseline x visit.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS mean difference to placebo.
	Estimated Value	-5.82
	Confidence Interval	(2-Sided) 95%; -7.94 to -3.71
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	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
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Aprocitentan 12.5 mg in Part 1 (Double-blind)	Aprocitentan 25 mg in Part 1 (Double-blind)	Placebo in Part 1 (Double-blind)
Arm/Group Description:	Participants randomized to aprocitentan 12.5 mg, orally, once daily in the morning for 4 weeks.	Participants randomized to aprocitentan 25 mg, orally, once daily in the morning for 4 weeks.	Participants randomized to placebo (matching aprocitentan), orally, once daily in the morning for 4 weeks.
Overall Number of Participants Analyzed	243	243	244
Least Squares Mean (95% Confidence Interval); Unit of Measure: mmHg
	-10.43; (-11.58 to -9.27)	-10.95; (-12.09 to -9.82)	-6.48; (-7.63 to -5.33)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aprocitentan 12.5 mg in Part 1 (Double-blind), Placebo in Part 1 (Double-blind)
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effects model for Repeated Measures: Change from baseline in SiDBP = baseline SiDBP + treatment + visit + treatment x visit + baseline x visit.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean difference to placebo
	Estimated Value	-3.94
	Confidence Interval	(2-Sided) 95%; -5.57 to -2.31
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Aprocitentan 25 mg in Part 1 (Double-blind), Placebo in Part 1 (Double-blind)
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effects model for Repeated Measures: Change from baseline in SiDBP = baseline SiDBP + treatment + visit + treatment x visit + baseline x visit.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean difference to placebo
	Estimated Value	-4.47
	Confidence Interval	(2-Sided) 95%; -6.09 to -2.85
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	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
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Aprocitentan 12.5 mg in Part 1 (Double-blind)	Aprocitentan 25 mg in Part 1 (Double-blind)	Placebo in Part 1 (Double-blind)
Arm/Group Description:	Participants randomized to aprocitentan 12.5 mg, orally, once daily in the morning for 4 weeks.	Participants randomized to aprocitentan 25 mg, orally, once daily in the morning for 4 weeks.	Participants randomized to placebo (matching aprocitentan), orally, once daily in the morning for 4 weeks.
Overall Number of Participants Analyzed	206	207	220
Least Squares Mean (95% Confidence Interval); Unit of Measure: mmHg
24-hour mean systolic blood pressure	-6.73; (-8.20 to -5.26)	-8.44; (-9.88 to -7.00)	-2.55; (-4.00 to -1.10)
24-hour mean diastolic blood pressure	-6.25; (-7.20 to -5.29)	-7.74; (-8.67 to -6.80)	-1.92; (-2.87 to -0.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aprocitentan 12.5 mg in Part 1 (Double-blind), Placebo in Part 1 (Double-blind)
	Comments	24-hour mean systolic (SBP)
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean difference to placebo
	Estimated Value	-4.18
	Confidence Interval	(2-Sided) 95%; -6.25 to -2.12
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Aprocitentan 25 mg in Part 1 (Double-blind), Placebo in Part 1 (Double-blind)
	Comments	24-hour mean systolic (SBP)
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean difference to placebo
	Estimated Value	-5.90
	Confidence Interval	(2-Sided) 95%; -7.94 to -3.85
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Aprocitentan 12.5 mg in Part 1 (Double-blind), Placebo in Part 1 (Double-blind)
	Comments	24-hour mean diastolic (DBP)
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean difference to placebo
	Estimated Value	-4.32
	Confidence Interval	(2-Sided) 95%; -5.66 to -2.98
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Aprocitentan 25 mg in Part 1 (Double-blind), Placebo in Part 1 (Double-blind)
	Comments	24-hour mean diastolic (DBP)
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-5.81
	Confidence Interval	(2-Sided) 95%; -7.14 to -4.49
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Aprocitentan 25 mg in Part 3 (Double-blind Withdrawal)	Placebo in Part 3 (Double-blind Withdrawal)
Arm/Group Description:	After 32-weeks in the single-blind, single-arm part, participants were re-randomized to aprocitentan 25 mg, orally, once daily in the morning for 12 weeks.	After 32-weeks in the single-blind, single-arm part, participants were re-randomized to placebo (matching aprocitentan), orally, once daily in the morning for 12 weeks.
Overall Number of Participants Analyzed	307	307
Least Squares Mean (95% Confidence Interval); Unit of Measure: mmHg
	-0.52; (-1.54 to 0.50)	4.67; (3.66 to 5.68)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aprocitentan 25 mg in Part 3 (Double-blind Withdrawal), Placebo in Part 3 (Double-blind Withdrawal)
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Mixed effects model for Repeated Measures: Change from DB-WD baseline in SiDBP = Double-blind withdrawal baseline SiDBP + stratum (randomized treatment in DB part) + treatment + visit + treatment x visit + Double-blind withdrawal baseline x visit.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean difference to placebo
	Estimated Value	-5.19
	Confidence Interval	(2-Sided) 95%; -6.62 to -3.76
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Aprocitentan 25 mg in Part 3 (Double-blind Withdrawal)	Placebo in Part 3 (Double-blind Withdrawal)
Arm/Group Description:	After 32-weeks in the single-blind, single-arm part, participants were re-randomized to aprocitentan 25 mg, orally, once daily in the morning for 12 weeks.	After 32-weeks in the single-blind, single-arm part, participants were re-randomized to placebo (matching aprocitentan), orally, once daily in the morning for 12 weeks.
Overall Number of Participants Analyzed	237	241
Least Squares Mean (95% Confidence Interval); Unit of Measure: mmHg
24-hour mean systolic blood pressure	-0.07; (-1.46 to 1.32)	6.46; (5.06 to 7.85)
24-hour mean diastolic blood pressure	-0.47; (-1.34 to 0.40)	6.28; (5.40 to 7.15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Aprocitentan 25 mg in Part 3 (Double-blind Withdrawal), Placebo in Part 3 (Double-blind Withdrawal)
	Comments	24-hour mean systolic (SBP)
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean difference to placebo
	Estimated Value	-6.53
	Confidence Interval	(2-Sided) 95%; -8.50 to -4.56
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Aprocitentan 25 mg in Part 3 (Double-blind Withdrawal), Placebo in Part 3 (Double-blind Withdrawal)
	Comments	24-hour mean diastolic (DBP)
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LSM Mean difference to placebo
	Estimated Value	-6.75
	Confidence Interval	(2-Sided) 95%; -7.98 to -5.52
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	Adverse events (AEs) were considered treatment-emergent, if the onset date is between the first intake of treatment up to 30 days after the stop of study treatment. Study treatment was for up to 48 weeks. In Part 1 double-blind (DB) treatment was for 4 weeks. Part 2 single-blind (SB) study treatment was for 32 weeks. In Part 3 double-blind withdrawal (DB-WD) study treatment was for 12 weeks.
Adverse Event Reporting Description	Only participants entering the randomized treatment period were considered enrolled for the study and are included in AE analysis. The Run-in period was designed to exclude potential placebo responders and is not part of statistical analysis of this study.
Arm/Group Title	Aprocitentan 12.5 mg in Part 1 (Double-blind)		Aprocitentan 25 mg in Part 1 (Double-blind)		Placebo in Part 1 (Double-blind)		Aprocitentan 25 mg in Part 2 (Single-blind)		Aprocitentan 25 mg in Part 3 (Double-blind Withdrawal)		Placebo in Part 3 (Double-blind Withdrawal)
Arm/Group Description	Participants received aprocitentan 12.5 mg, orally, once daily in the morning for 4 weeks.		Participants received aprocitentan 25 mg, orally, once daily in the morning for 4 weeks.		Participants received placebo, orally, once daily in the morning for 4 weeks.		All participants received aprocitentan 25 mg, orally, once daily in the morning for 32 weeks.		After 32-weeks in the single-blind, single-arm part, participants received aprocitentan 25 mg, orally, once daily in the morning for 12 weeks.		After 32-weeks in the single-blind, single-arm part, participants received placebo (matching aprocitentan), orally, once daily in the morning for 12 weeks.
All-Cause Mortality
	Aprocitentan 12.5 mg in Part 1 (Double-blind)		Aprocitentan 25 mg in Part 1 (Double-blind)		Placebo in Part 1 (Double-blind)		Aprocitentan 25 mg in Part 2 (Single-blind)		Aprocitentan 25 mg in Part 3 (Double-blind Withdrawal)		Placebo in Part 3 (Double-blind Withdrawal)
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	1/243 (0.41%)		0/245 (0.00%)		0/242 (0.00%)		9/704 (1.28%)		1/310 (0.32%)		0/303 (0.00%)
Serious Adverse Events
	Aprocitentan 12.5 mg in Part 1 (Double-blind)		Aprocitentan 25 mg in Part 1 (Double-blind)		Placebo in Part 1 (Double-blind)		Aprocitentan 25 mg in Part 2 (Single-blind)		Aprocitentan 25 mg in Part 3 (Double-blind Withdrawal)		Placebo in Part 3 (Double-blind Withdrawal)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/243 (3.29%)		8/245 (3.27%)		3/242 (1.24%)		82/704 (11.65%)		18/310 (5.81%)		9/303 (2.97%)
Blood and lymphatic system disorders
Anaemia † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Cardiac disorders
Acute left ventricular failure † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	0/704 (0.00%)	0	1/310 (0.32%)	1	0/303 (0.00%)	0
Acute myocardial infarction † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	2/704 (0.28%)	2	0/310 (0.00%)	0	0/303 (0.00%)	0
Angina unstable † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	5/704 (0.71%)	5	1/310 (0.32%)	1	0/303 (0.00%)	0
Atrial fibrillation † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	3/704 (0.43%)	3	3/310 (0.97%)	3	0/303 (0.00%)	0
Atrioventricular block † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Atrioventricular block second degree † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Cardiac failure † 1	0/243 (0.00%)	0	1/245 (0.41%)	1	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Cardiac failure acute † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	0/704 (0.00%)	0	0/310 (0.00%)	0	1/303 (0.33%)	1
Cardiac failure chronic † 1	0/243 (0.00%)	0	1/245 (0.41%)	1	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Cardiac failure congestive † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	3/704 (0.43%)	3	0/310 (0.00%)	0	0/303 (0.00%)	0
Cardiogenic shock † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	0/704 (0.00%)	0	1/310 (0.32%)	1	0/303 (0.00%)	0
Coronary artery disease † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	2/704 (0.28%)	2	0/310 (0.00%)	0	0/303 (0.00%)	0
Coronary artery dissection † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	0/704 (0.00%)	0	0/310 (0.00%)	0	1/303 (0.33%)	1
Left ventricular dysfunction † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Myocardial infarction † 1	1/243 (0.41%)	1	0/245 (0.00%)	0	0/242 (0.00%)	0	2/704 (0.28%)	2	1/310 (0.32%)	1	0/303 (0.00%)	0
Ear and labyrinth disorders
Meniere's disease † 1	0/243 (0.00%)	0	1/245 (0.41%)	1	0/242 (0.00%)	0	0/704 (0.00%)	0	0/310 (0.00%)	0	0/303 (0.00%)	0
Vestibular ataxia † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Gastrointestinal disorders
Gastrointestinal haemorrhage † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Pancreatitis chronic † 1	0/243 (0.00%)	0	1/245 (0.41%)	1	0/242 (0.00%)	0	0/704 (0.00%)	0	1/310 (0.32%)	1	0/303 (0.00%)	0
Rectal fissure † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Umbilical hernia, obstructive † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Upper gastrointestinal haemorrhage † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
General disorders
Chest pain † 1	0/243 (0.00%)	0	1/245 (0.41%)	1	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Death † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Multiple organ dysfunction syndrome † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	0/704 (0.00%)	0	1/310 (0.32%)	1	0/303 (0.00%)	0
Oedema peripheral † 1	0/243 (0.00%)	0	1/245 (0.41%)	1	0/242 (0.00%)	0	0/704 (0.00%)	0	0/310 (0.00%)	0	0/303 (0.00%)	0
Pyrexia † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Sudden cardiac death † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Hepatobiliary disorders
Cholecystitis acute † 1	1/243 (0.41%)	1	0/245 (0.00%)	0	0/242 (0.00%)	0	0/704 (0.00%)	0	0/310 (0.00%)	0	0/303 (0.00%)	0
Infections and infestations
Abscess jaw † 1	0/243 (0.00%)	0	1/245 (0.41%)	1	0/242 (0.00%)	0	0/704 (0.00%)	0	0/310 (0.00%)	0	0/303 (0.00%)	0
COVID-19 † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	0/704 (0.00%)	0	1/310 (0.32%)	1	0/303 (0.00%)	0
COVID-19 pneumonia † 1	2/243 (0.82%)	2	0/245 (0.00%)	0	1/242 (0.41%)	1	14/704 (1.99%)	14	4/310 (1.29%)	4	2/303 (0.66%)	2
Cellulitis † 1	0/243 (0.00%)	0	2/245 (0.82%)	2	0/242 (0.00%)	0	0/704 (0.00%)	0	0/310 (0.00%)	0	0/303 (0.00%)	0
Cholecystitis infective † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	0/704 (0.00%)	0	1/310 (0.32%)	1	0/303 (0.00%)	0
Diabetic gangrene † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Diverticulitis † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Erysipelas † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Gastroenteritis † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Peritonsillar abscess † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	1/242 (0.41%)	1	0/704 (0.00%)	0	0/310 (0.00%)	0	0/303 (0.00%)	0
Pneumonia † 1	1/243 (0.41%)	1	1/245 (0.41%)	1	0/242 (0.00%)	0	2/704 (0.28%)	2	2/310 (0.65%)	2	0/303 (0.00%)	0
Pneumonia bacterial † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Pyelonephritis acute † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	1/242 (0.41%)	1	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Sepsis † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	1/242 (0.41%)	1	0/704 (0.00%)	0	0/310 (0.00%)	0	0/303 (0.00%)	0
Ureteritis † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Urinary tract infection † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Wound infection † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Injury, poisoning and procedural complications
Chest injury † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Procedural intestinal perforation † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Road traffic accident † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Subdural haemorrhage † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Tibia fracture † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Traumatic intracranial haemorrhage † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Investigations
Blood creatinine increased † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Blood pressure increased † 1	0/243 (0.00%)	0	1/245 (0.41%)	1	0/242 (0.00%)	0	0/704 (0.00%)	0	0/310 (0.00%)	0	0/303 (0.00%)	0
Metabolism and nutrition disorders
Hyperkalaemia † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	2/704 (0.28%)	2	0/310 (0.00%)	0	0/303 (0.00%)	0
Hypoglycaemia † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Osteoarthritis † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Osteochondrosis † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Rotator cuff syndrome † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Invasive breast carcinoma † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Lung neoplasm malignant † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Mantle cell lymphoma † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Metastatic neoplasm † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Renal cancer † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	0/704 (0.00%)	0	0/310 (0.00%)	0	1/303 (0.33%)	1
Renal cell carcinoma † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Nervous system disorders
Brain oedema † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Cerebral infarction † 1	1/243 (0.41%)	1	0/245 (0.00%)	0	0/242 (0.00%)	0	0/704 (0.00%)	0	0/310 (0.00%)	0	0/303 (0.00%)	0
Cerebrovascular accident † 1	0/243 (0.00%)	0	1/245 (0.41%)	1	0/242 (0.00%)	0	2/704 (0.28%)	2	0/310 (0.00%)	0	0/303 (0.00%)	0
Facial paresis † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	0/704 (0.00%)	0	1/310 (0.32%)	1	0/303 (0.00%)	0
Haemorrhage intracranial † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	0/704 (0.00%)	0	0/310 (0.00%)	0	1/303 (0.33%)	1
Ischaemic stroke † 1	1/243 (0.41%)	1	0/245 (0.00%)	0	1/242 (0.41%)	1	0/704 (0.00%)	0	0/310 (0.00%)	0	1/303 (0.33%)	1
Seizure † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Syncope † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	2/704 (0.28%)	2	0/310 (0.00%)	0	0/303 (0.00%)	0
Transient ischaemic attack † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	1/310 (0.32%)	1	0/303 (0.00%)	0
Renal and urinary disorders
Acute kidney injury † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Calculus urinary † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	2/704 (0.28%)	2	0/310 (0.00%)	0	0/303 (0.00%)	0
Nephropathy toxic † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Ureteric stenosis † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	2	0/310 (0.00%)	0	0/303 (0.00%)	0
Reproductive system and breast disorders
Endometrial hyperplasia † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	0/704 (0.00%)	0	0/310 (0.00%)	0	1/303 (0.33%)	1
Uterine polyp † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Asthma † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Dyspnoea † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	1/310 (0.32%)	1	0/303 (0.00%)	0
Pulmonary embolism † 1	1/243 (0.41%)	1	0/245 (0.00%)	0	0/242 (0.00%)	0	0/704 (0.00%)	0	0/310 (0.00%)	0	0/303 (0.00%)	0
Pulmonary oedema † 1	0/243 (0.00%)	0	1/245 (0.41%)	1	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Respiratory failure † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Skin and subcutaneous tissue disorders
Angioedema † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	0/704 (0.00%)	0	0/310 (0.00%)	0	1/303 (0.33%)	1
Dermatitis allergic † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Skin ulcer † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	0/704 (0.00%)	0	1/310 (0.32%)	1	0/303 (0.00%)	0
Surgical and medical procedures
Coronary artery bypass † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Hip arthroplasty † 1	1/243 (0.41%)	1	0/245 (0.00%)	0	0/242 (0.00%)	0	0/704 (0.00%)	0	0/310 (0.00%)	0	0/303 (0.00%)	0
Peripheral artery bypass † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Toe amputation † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Vascular disorders
Aortic stenosis † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	0/704 (0.00%)	0	1/310 (0.32%)	1	0/303 (0.00%)	0
Deep vein thrombosis † 1	1/243 (0.41%)	1	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Distributive shock † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Hypertension † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	0/704 (0.00%)	0	1/310 (0.32%)	1	0/303 (0.00%)	0
Hypertensive crisis † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Hypertensive urgency † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Hypotension † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Intermittent claudication † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
Peripheral artery stenosis † 1	0/243 (0.00%)	0	0/245 (0.00%)	0	0/242 (0.00%)	0	1/704 (0.14%)	1	0/310 (0.00%)	0	0/303 (0.00%)	0
1 Term from vocabulary, MedDRA (24.1); † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Aprocitentan 12.5 mg in Part 1 (Double-blind)		Aprocitentan 25 mg in Part 1 (Double-blind)		Placebo in Part 1 (Double-blind)		Aprocitentan 25 mg in Part 2 (Single-blind)		Aprocitentan 25 mg in Part 3 (Double-blind Withdrawal)		Placebo in Part 3 (Double-blind Withdrawal)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/243 (6.58%)		34/245 (13.88%)		5/242 (2.07%)		95/704 (13.49%)		6/310 (1.94%)		4/303 (1.32%)
General disorders
Oedema peripheral † 1	16/243 (6.58%)	16	34/245 (13.88%)	34	5/242 (2.07%)	5	95/704 (13.49%)	102	6/310 (1.94%)	7	4/303 (1.32%)	4
1 Term from vocabulary, MedDRA (24.1); † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Any study-related publication written independently by investigators must be submitted to the sponsor for review at least 30 days prior to submission for publication or presentation at a congress. Upon review, the sponsor may provide comments, and may also request alterations and/or deletions for the sole purpose of protecting its confidential information and/or patent rights. Neither the institution nor the investigator should permit publication during such a review period.

Results Point of Contact

• Name/Title: Clinical Trial Disclosure Desk
• Organization: Idorsia Pharmaceuticals Ltd
• Phone: +41 58844 1977
• EMail: idorsiaclinicaltrials@idorsia.com

Publications of Results:

Danaietash P, Verweij P, Wang JG, Dresser G, Kantola I, Lawrence MK, Narkiewicz K, Schlaich M, Bellet M; PRECISION investigators. Identifying and treating resistant hypertension in PRECISION: A randomized long-term clinical trial with aprocitentan. J Clin Hypertens (Greenwich). 2022 Jul;24(7):804-813. doi: 10.1111/jch.14517. Epub 2022 Jun 9.

Other Publications:

Daskalopoulou SS, Khan NA, Quinn RR, Ruzicka M, McKay DW, Hackam DG, Rabkin SW, Rabi DM, Gilbert RE, Padwal RS, Dawes M, Touyz RM, Campbell TS, Cloutier L, Grover S, Honos G, Herman RJ, Schiffrin EL, Bolli P, Wilson T, Feldman RD, Lindsay MP, Hemmelgarn BR, Hill MD, Gelfer M, Burns KD, Vallee M, Prasad GV, Lebel M, McLean D, Arnold JM, Moe GW, Howlett JG, Boulanger JM, Larochelle P, Leiter LA, Jones C, Ogilvie RI, Woo V, Kaczorowski J, Trudeau L, Bacon SL, Petrella RJ, Milot A, Stone JA, Drouin D, Lamarre-Cliche M, Godwin M, Tremblay G, Hamet P, Fodor G, Carruthers SG, Pylypchuk G, Burgess E, Lewanczuk R, Dresser GK, Penner B, Hegele RA, McFarlane PA, Sharma M, Campbell NR, Reid D, Poirier L, Tobe SW; Canadian Hypertension Education Program. The 2012 Canadian hypertension education program recommendations for the management of hypertension: blood pressure measurement, diagnosis, assessment of risk, and therapy. Can J Cardiol. 2012 May;28(3):270-87. doi: 10.1016/j.cjca.2012.02.018.

Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill MN, Jones DW, Kurtz T, Sheps SG, Roccella EJ. Recommendations for blood pressure measurement in humans and experimental animals: part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Circulation. 2005 Feb 8;111(5):697-716. doi: 10.1161/01.CIR.0000154900.76284.F6.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Schlaich MP, Bellet M, Weber MA, Danaietash P, Bakris GL, Flack JM, Dreier RF, Sassi-Sayadi M, Haskell LP, Narkiewicz K, Wang JG; PRECISION investigators. Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial. Lancet. 2022 Dec 3;400(10367):1927-1937. doi: 10.1016/S0140-6736(22)02034-7. Epub 2022 Nov 7. Erratum In: Lancet. 2023 Jan 28;401(10373):268.

• Responsible Party: Idorsia Pharmaceuticals Ltd.
• ClinicalTrials.gov Identifier: NCT03541174
• Other Study ID Numbers: ID-080A301; 2017-004393-33 ( EudraCT Number )
• First Submitted: May 17, 2018
• First Posted: May 30, 2018
• Results First Submitted: November 8, 2022
• Results First Posted: March 21, 2023
• Last Update Posted: March 21, 2023