Dose-finding Study With ACT-132577 (Aprocitentan) in Participants With Essential Hypertension

• Sponsor: Idorsia Pharmaceuticals Ltd. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02603809
• Collaborator: (none)
• Enrollment: 1,659
• Locations: 91
• Arms: 6
• Actual Duration (Months): 15.8
• Patients Per Site: 18.2
• Patients Per Site Per Month: 1.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Essential Hypertension	Drug: Aprocitentan 5 mg; Drug: Aprocitentan 10 mg; Drug: Aprocitentan 25 mg; Drug: Aprocitentan 50 mg; Drug: Lisinopril 20 mg; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1659 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multi-center, Double-blind, Double-dummy, Randomized, Placebo- and Active-reference, Parallel Group, Phase 2, Dose-finding Study With ACT-132577 in Subjects With Essential Hypertension (Grade 1 and 2).
• Actual Study Start Date: Dec 14, 2015
• Actual Primary Completion Date: Feb 28, 2017
• Actual Study Completion Date: Apr 7, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo After a 4 to 6-week single-blind placebo run-in period, participants will be randomized to received placebo orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.	Drug: Placebo; One capsule each of placebo matching aprocitentan and placebo matching lisinopril orally, once daily in the morning for 8 weeks.
Experimental: Aprocitentan 5 mg After a 4 to 6-week single-blind placebo run-in period, participants will be randomized to received aprocitentan orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.	Drug: Aprocitentan 5 mg; One capsule of 5 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.; Other Names: ACT-132577
Experimental: Aprocitentan 10 mg After a 4 to 6-week single-blind placebo run-in period, participants will be randomized to received aprocitentan 10 mg orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.	Drug: Aprocitentan 10 mg; Two capsules of 5 mg aprocitentan, orally, once daily in the morning for 8 weeks.; Other Names: ACT-132577
Experimental: Aprocitentan 25 mg After a 4 to 6-week single-blind placebo run-in period, participants will be randomized to received aprocitentan 25 mg orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.	Drug: Aprocitentan 25 mg; One capsule of 25 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.; Other Names: ACT-132577
Experimental: Aprocitentan 50 mg After a 4 to 6-week single-blind placebo run-in period, participants will be randomized to received aprocitentan 50 mg orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.	Drug: Aprocitentan 50 mg; One capsule of 50 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.; Other Names: ACT-132577
Active Comparator: Lisinopril 20 mg After a 4 to 6-week single-blind placebo run-in period, participants will be randomized to received lisinopril 20 mg orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.	Drug: Lisinopril 20 mg; One capsule of 20 mg lisinopril, orally, once daily in the morning for 8 weeks, along with placebo capsule matching aprocitentan

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

Other Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Appalachian Cardiovascular Associates	Fort Payne	Alabama	United States	35967
2	Radiant Research Inc	Chandler	Arizona	United States	85224
3	Warner Family Practice / Radiant Research Inc	Chandler	Arizona	United States	85224
4	Phoenix Medical Research Institute LLC	Peoria	Arizona	United States	85381
5	Advanced Arizona Clinical Research	Tucson	Arizona	United States	85704
6	Noble Clinical Research LLC	Tucson	Arizona	United States	85704
7	Desert Sun Clinical Research LLc	Tucson	Arizona	United States	85710
8	Advanced Research Center Inc	Anaheim	California	United States	92805
9	Med Center	Carmichael	California	United States	95608
10	John Muir Physician Network Clinical Research Center	Concord	California	United States	94520
11	Clinical Trials Research	Lincoln	California	United States	95648
12	Long Beach Center for Clinical Research	Long Beach	California	United States	90807
13	Entertainment Medical Group Inc	Los Angeles	California	United States	90036
14	Artemis institute for Clinical Research	San Diego	California	United States	92103
15	Memorial Research Medical Clinic / Orange County Research Center	Tustin	California	United States	92780
16	Empire Clinical Research	Upland	California	United States	91786
17	Clinical Research Consulting LLC	Milford	Connecticut	United States	06460
18	Chase Medical Research LLC	Waterbury	Connecticut	United States	06708
19	Alfieri Cardiology	Wilmington	Delaware	United States	19803
20	ACRC - Cardiology	Atlantis	Florida	United States	33462
21	Innovative Research of West Florida INC	Clearwater	Florida	United States	33756
22	Avail Clinical Research LLC	DeLand	Florida	United States	32720
23	Alan Graff, MD, PA	Fort Lauderdale	Florida	United States	33308
24	Gulfcoast Clinical Research Center	Fort Myers	Florida	United States	33912
25	AGA Clinical Trials	Hialeah	Florida	United States	33012
26	Canvas Clinical Research, LLC	Lake Worth	Florida	United States	33467
27	LCC Medical Research Institute	Miami	Florida	United States	33126
28	Allied Biomedical Research Institute, INC	Miami	Florida	United States	33155
29	Southeast Regional Research Group	Savannah	Georgia	United States	31401
30	Community Clin Res CTR	Anderson	Indiana	United States	46011
31	Midwest Institute for Clinical Research	Indianapolis	Indiana	United States	46260
32	Heartland Research Associated LLC	Newton	Kansas	United States	67114
33	Heartland Research Associates LLC	Wichita	Kansas	United States	67205
34	Heartland Research Associates LLC	Wichita	Kansas	United States	67207
35	Avant Research Associates, LLC	Crowley	Louisiana	United States	70526
36	Best Clinical Trials LLC	New Orleans	Louisiana	United States	70115
37	New Orleans Center for Clinical Research - Nola	New Orleans	Louisiana	United States	70119
38	Clinsite LLC	Ann Arbor	Michigan	United States	48106
39	Primecare Research Associates, LLC	Florissant	Missouri	United States	63031
40	Clinical Research Advantage, Inc. / Diagnostic Center Of Medicine - Durango	Las Vegas	Nevada	United States	89117
41	Premier Research	Trenton	New Jersey	United States	08611
42	Rochester Clinical Research Inc.	Rochester	New York	United States	14609
43	Metrolina Internal Medicine/Internal Medicine Research	Charlotte	North Carolina	United States	28204
44	Pharmquest LLC	Greensboro	North Carolina	United States	27408
45	Peters Medical Research	High Point	North Carolina	United States	27262
46	Wake Research Associates	Raleigh	North Carolina	United States	27604-1547
47	Lillestol Research LLC	Fargo	North Dakota	United States	58103
48	Sterling Research Group Ltd.	Cincinnati	Ohio	United States	45219
49	Aventiv Research Inc.	Columbus	Ohio	United States	43213
50	Dayton Clinical Research	Dayton	Ohio	United States	45406
51	Aventiv Research Inc.	Dublin	Ohio	United States	43016
52	Oklahoma City Clinic - Edmond / Radiant Research Inc	Edmond	Oklahoma	United States	73034
53	Clinical Research Advantage, Inc. / Oklahoma City Clinic - Midwest City	Midwest City	Oklahoma	United States	73110
54	Willamette Valley Clinical Studies	Eugene	Oregon	United States	97404
55	Detweiler Family Medicine and Associates PC	Lansdale	Pennsylvania	United States	19446
56	Suburban Research Center	Media	Pennsylvania	United States	19063
57	Degarmo Institute of Medical Research	Greer	South Carolina	United States	29651
58	Volunteer Research Group	Knoxville	Tennessee	United States	37920
59	Tekton Research Inc	Austin	Texas	United States	78745
60	Texas Diabetes & Endocrinology	Austin	Texas	United States	78749
61	Trinity Hypertension & Metabolic Research Institute	Carrollton	Texas	United States	75006
62	Family Medicine Associates of Texas - ACRC Trials	Carrollton	Texas	United States	75010
63	Coastal Bend Clinical Research	Corpus Christi	Texas	United States	78413
64	TR - Global Medical Research	DeSoto	Texas	United States	75115
65	Ventavia Research Group, LLC	Fort Worth	Texas	United States	76104
66	Clinical Investigations of Texas	Plano	Texas	United States	75075
67	Avant Research Associates LLC	Port Arthur	Texas	United States	77640
68	Texas Diabetes & Endocrinology	Round Rock	Texas	United States	78681
69	Radiant Research Inc	San Antonio	Texas	United States	78229
70	Bandera Family Health Care	San Antonio	Texas	United States	78249
71	Wasatch Clinical Research LLC	Salt Lake City	Utah	United States	84107
72	Health Research of Hampton Roads	Newport News	Virginia	United States	23606
73	National Clinical Research Inc	Richmond	Virginia	United States	23294
74	Northwest Clinical Research Center	Bellevue	Washington	United States	98007
75	Manna Research - Vancouver	Vancouver	British Columbia	Canada	V6J 1S3
76	Canadian Phase Onwards Inc	Toronto	Ontario	Canada	M3J 2C5
77	Manna Research - Toronto	Toronto	Ontario	Canada	M9W 4L6
78	Manna Research - Levis	Levis	Quebec	Canada	G6W 0M6
79	Diex Recherche Montreal Inc	Montreal	Quebec	Canada	H2Y 1S1
80	Diex Recherche Montreal Inc	Montréal	Quebec	Canada	H2Y 1S1
81	Manna Research - Pointe Claire	Pointe-Claire	Quebec	Canada	H9R 4S3
82	Diex Reserach Sherbrooke Inc	Sherbrooke	Quebec	Canada	J1H 1Z1
83	Cardiology Department Barzilai	Ashkelon		Israel	78278
84	Soroka University Hospital - Hypertension Unit	Beer Sheva		Israel	84101
85	The Hyper Unit, Edith Wolfson Medical Center	Holon		Israel	58100
86	Hypertension Treatment Center, Internal Dep, Hadassah	Jerusalem		Israel	91240
87	Hypertension And Nephrology Department, Meir Medical Center	Kefar Sava		Israel	44261
88	Clinical Research Unit Kaplan Medical Center	Rehovot		Israel	76100
89	Internal Med Department A, Ziv Medical Center	Safed		Israel	13100
90	Advanced Medical Concepts, PSC	Cidra		Puerto Rico	00739
91	Research & Cardiovascular Corp.	Ponce		Puerto Rico	00717

Sponsors and Collaborators

• Idorsia Pharmaceuticals Ltd.

Investigators

• Study Director: ClinicalTrials, Idorsia Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - May 30, 2016
• Statistical Analysis Plan - May 15, 2017

More Information

Publications

None provided.

• Responsible Party: Idorsia Pharmaceuticals Ltd.
• ClinicalTrials.gov Identifier: NCT02603809
• Other Study ID Numbers: AC-080A201
• First Posted: Nov 13, 2015
• Last Update Posted: Apr 27, 2020
• Last Verified: Apr 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Hypertension; Essential Hypertension; Lisinopril

Study Results

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 Detail	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.

Arm/Group Title	Placebo	Aprocitentan 5 mg	Aprocitentan 10 mg	Aprocitentan 25 mg	Aprocitentan 50 mg	Lisinopril 20 mg
Arm/Group Description	After a 4 to 6-week single-blind placebo run-in period, participants received placebo orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.	After a 4 to 6-week single-blind placebo run-in period, participants received 5 mg aprocitentan orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.	After a 4 to 6-week single-blind placebo run-in period, participants received aprocitentan 10 mg orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.	After a 4 to 6-week single-blind placebo run-in period, participants received aprocitentan 25 mg orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.	After a 4 to 6-week single-blind placebo run-in period, participants received aprocitentan 50 mg orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.	After a 4 to 6-week single-blind placebo run-in period, participants received lisinopril 20 mg orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.
Period Title: Overall Study
STARTED	82	82	82	82	81	81
Per-protocol Set	67	68	71	67	68	69
Modified Per-Protocol Set	66	68	71	67	68	69
Completed Study	75	79	79	76	78	75
COMPLETED	70	74	75	70	70	71
NOT COMPLETED	12	8	7	12	11	10

Baseline Characteristics

Arm/Group Title	Placebo	Aprocitentan 5 mg	Aprocitentan 10 mg	Aprocitentan 25 mg	Aprocitentan 50 mg	Lisinopril 20 mg	Total
Arm/Group Description	Participants randomized to placebo treatment for 8 weeks.	Participants randomized to 5 mg aprocitentan treatment for 8 weeks.	Participants randomized to 10 mg aprocitentan treatment for 8 weeks.	Participants randomized to 25 mg aprocitentan treatment for 8 weeks.	Participants randomized to 50 mg aprocitentan treatment for 8 weeks.	Participants randomized to 20 mg lisinopril treatment for 8 weeks.	Total of all reporting groups
Overall Participants	82	82	82	82	81	81	490
Age (years) [Mean (Standard Deviation) ]
Full Analysis Set	53.5 (9.1)	54.1 (8.5)	55.3 (9.8)	55.1 (10.0)	54.2 (9.3)	56.0 (9.0)	54.7 (9.3)
Per Protocol Set	53.9 (9.1)	55.0 (8.5)	55.8 (9.5)	55.7 (9.8)	54.0 (9.4)	56.1 (9.4)	55.1 (9.3)
modified Per Protocol Set	54.0 (9.1)	55.0 (8.5)	55.8 (9.5)	55.7 (9.8)	54.0 (9.4)	56.1 (9.4)	55.1 (9.3)
Sex: Female, Male (Count of Participants)
Female	27 32.9%	34 41.5%	31 37.8%	37 45.1%	28 34.6%	36 44.4%	193 39.4%
Male	55 67.1%	48 58.5%	51 62.2%	45 54.9%	53 65.4%	45 55.6%	297 60.6%
Female	22 26.8%	27 32.9%	26 31.7%	30 36.6%	24 29.6%	31 38.3%	160 32.7%
Male	45 54.9%	41 50%	45 54.9%	37 45.1%	44 54.3%	38 46.9%	250 51%
Female	22 26.8%	27 32.9%	26 31.7%	30 36.6%	24 29.6%	31 38.3%	160 32.7%
Male	44 53.7%	41 50%	45 54.9%	37 45.1%	44 54.3%	38 46.9%	249 50.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	23 28%	26 31.7%	31 37.8%	27 32.9%	28 34.6%	26 32.1%	161 32.9%
Not Hispanic or Latino	59 72%	56 68.3%	51 62.2%	55 67.1%	53 65.4%	55 67.9%	329 67.1%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Hispanic or Latino	19 23.2%	22 26.8%	28 34.1%	24 29.3%	25 30.9%	23 28.4%	141 28.8%
Not Hispanic or Latino	48 58.5%	46 56.1%	43 52.4%	43 52.4%	43 53.1%	46 56.8%	269 54.9%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.2%	0 0%	2 2.4%	1 1.2%	0 0%	0 0%	4 0.8%
Asian	2 2.4%	0 0%	1 1.2%	0 0%	0 0%	2 2.5%	5 1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	1 1.2%	1 0.2%
Black or African American	31 37.8%	28 34.1%	26 31.7%	35 42.7%	26 32.1%	32 39.5%	178 36.3%
White	48 58.5%	54 65.9%	53 64.6%	46 56.1%	55 67.9%	46 56.8%	302 61.6%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
American Indian or Alaska Native	0 0%	0 0%	2 2.4%	1 1.2%	0 0%	0 0%	3 0.6%
Asian	1 1.2%	0 0%	1 1.2%	0 0%	0 0%	1 1.2%	3 0.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	1 1.2%	1 0.2%
Black or African American	26 31.7%	22 26.8%	19 23.2%	26 31.7%	21 25.9%	26 32.1%	140 28.6%
White	40 48.8%	46 56.1%	49 59.8%	40 48.8%	47 58%	41 50.6%	263 53.7%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Canada	3 3.7%	1 1.2%	6 7.3%	4 4.9%	2 2.5%	5 6.2%	21 4.3%
United States	75 91.5%	75 91.5%	74 90.2%	73 89%	75 92.6%	71 87.7%	443 90.4%
Israel	4 4.9%	6 7.3%	2 2.4%	5 6.1%	4 4.9%	5 6.2%	26 5.3%
Weight (kilograms) [Mean (Standard Deviation) ]
Full Analysis Set	92.0 (18.9)	88.6 (16.9)	90.1 (18.3)	91.1 (16.9)	87.6 (15.8)	87.0 (17.2)	89.4 (17.37)
Per Protocol Set	91.0 (19.2)	88.3 (17.6)	89.3 (19.0)	91.7 (18.1)	87.1 (15.8)	86.5 (16.0)	89.0 (17.7)
modified Per Protocol Set	90.6 (19.0)	88.3 (17.6)	89.3 (19.0)	91.7 (18.1)	87.1 (15.8)	86.5 (16.0)	89.0 (17.7)
Body Mass Index (kilograms per square meter) [Mean (Standard Deviation) ]
Full Analysis Set	30.6 (5.07)	30.1 (4.56)	30.8 (4.52)	31.0 (4.16)	30.2 (4.55)	30.4 (4.59)	30.5 (4.57)
Per Protocol Set	30.1 (5.1)	29.8 (4.5)	30.4 (4.6)	31.0 (4.3)	30.3 (4.7)	30.4 (4.6)	30.3 (4.6)
modified Per Protocol Set	30.1 (5.1)	29.8 (4.5)	30.4 (4.6)	31.0 (4.3)	30.3 (4.7)	30.4 (4.6)	30.3 (4.6)
Duration of essential hypertension at screening (years) [Mean (Standard Deviation) ]
Full Analysis Set	9.13 (8.72)	8.12 (8.25)	10.48 (10.18)	9.56 (8.97)	10.60 (9.95)	11.79 (10.47)	9.94 (9.48)
Per Protocol Set	9.24 (8.93)	8.38 (8.62)	10.6 (10.51)	9.19 (8.61)	10.35 (10.07)	12.53 (10.88)	10.06 (9.7)
Antihypertensive treatment at screening (participants) [Number]
Full Analysis Set	57 69.5%	56 68.3%	45 54.9%	49 59.8%	54 66.7%	56 69.1%	317 64.7%
Per Protocol Set	46 56.1%	48 58.5%	38 46.3%	39 47.6%	45 55.6%	48 59.3%	264 53.9%
modified Per Protocol Set	45 54.9%	48 58.5%	38 46.3%	39 47.6%	45 55.6%	48 59.3%	263 53.7%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Aprocitentan 5 mg	Aprocitentan 10 mg	Aprocitentan 25 mg	Aprocitentan 50 mg	Lisinopril 20 mg
Arm/Group Description	One capsule each of placebo matching aprocitentan and placebo matching lisinopril orally, once daily in the morning for 8 weeks.	One capsule of 5 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.	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.	One capsule of 50 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.	One capsule of 20 mg lisinopril, orally, once daily in the morning for 8 weeks, along with placebo capsule matching aprocitentan.
Measure Participants	66	68	71	67	68	69
Baseline	97.5 (5.4)	97.8 (5.5)	97.7 (4.3)	97.8 (4.8)	98.2 (5.3)	96.8 (4.6)
Absolute Change from Baseline to Week 8	-4.9 (11.1)	-6.3 (8.9)	-9.9 (8.7)	-12.0 (8.2)	-10.0 (7.9)	-8.4 (9.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Aprocitentan 5 mg, Aprocitentan 10 mg, Aprocitentan 25 mg, Aprocitentan 50 mg
	Comments	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.)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Multiple Comparison Procedure-Modeling
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Aprocitentan 5 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8117
	Comments
	Method	ANCOVA
	Comments	with Dunnett correction.
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-1.31
	Confidence Interval	(2-Sided) 95%; -5.10 to 2.49
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.548
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Aprocitentan 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0053
	Comments
	Method	ANCOVA
	Comments	with Dunnett correction.
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-4.93
	Confidence Interval	(2-Sided) 95%; -8.68 to -1.17
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.532
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Aprocitentan 25 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANCOVA
	Comments	with Dunnett correction.
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-6.99
	Confidence Interval	(2-Sided) 95%; -10.80 to -3.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.554
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Aprocitentan 50 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0057
	Comments
	Method	ANCOVA
	Comments	with Dunnett correction.
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-4.95
	Confidence Interval	(2-Sided) 95%; -8.75 to -1.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.549
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline to End of Double-blind Treatment in Sitting Systolic Blood Pressure at Trough
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Aprocitentan 5 mg	Aprocitentan 10 mg	Aprocitentan 25 mg	Aprocitentan 50 mg	Lisinopril 20 mg
Arm/Group Description	One capsule each of placebo matching aprocitentan and placebo matching lisinopril orally, once daily in the morning for 8 weeks	One capsule of 5 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.	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.	One capsule of 50 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.	One capsule of 20 mg lisinopril, orally, once daily in the morning for 8 weeks, along with placebo capsule matching aprocitentan.
Measure Participants	66	68	71	67	68	69
Baseline	149.2 (13.1)	149.4 (13.9)	149.8 (12.7)	151.2 (13.7)	148.6 (12.8)	149.8 (14.2)
Absolute Change from Baseline to Week 8	-7.7 (18.8)	-10.3 (15.3)	-15.0 (14.5)	-18.5 (15.0)	-15.1 (11.8)	-12.8 (16.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Aprocitentan 5 mg, Aprocitentan 10 mg, Aprocitentan 25 mg, Aprocitentan 50 mg
	Comments	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.)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Multiple Comparison Procedure-Modeling
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Aprocitentan 5 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7071
	Comments
	Method	ANCOVA
	Comments	with Dunnett correction.
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-2.45
	Confidence Interval	(2-Sided) 95%; -8.44 to 3.54
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.445
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Aprocitentan 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0138
	Comments
	Method	ANCOVA
	Comments	with Dunnett correction.
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-7.05
	Confidence Interval	(2-Sided) 95%; -12.98 to -1.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.420
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Aprocitentan 25 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	ANCOVA
	Comments	with Dunnett correction.
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-9.90
	Confidence Interval	(2-Sided) 95%; -15.92 to -3.88
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.457
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Aprocitentan 50 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0077
	Comments
	Method	ANCOVA
	Comments	with Dunnett correction.
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-7.58
	Confidence Interval	(2-Sided) 95%; -13.58 to -1.59
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0077
	Estimation Comments

3. Secondary Outcome

Title	Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Aprocitentan 5 mg	Aprocitentan 10 mg	Aprocitentan 25 mg	Aprocitentan 50 mg	Lisinopril 20 mg
Arm/Group Description	One capsule each of placebo matching aprocitentan and placebo matching lisinopril orally, once daily in the morning for 8 weeks.	One capsule of 5 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.	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.	One capsule of 50 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.	One capsule of 20 mg lisinopril, orally, once daily in the morning for 8 weeks, along with placebo capsule matching aprocitentan.
Measure Participants	66	68	71	67	68	69
SiDBP less than 90 mmHg	22 26.8%	30 36.6%	37 45.1%	43 52.4%	39 48.1%	38 46.9%
SiDBP less than 85 mmHg (CHEP)	17 20.7%	15 18.3%	29 35.4%	29 35.4%	21 25.9%	23 28.4%
SiSBP less than 140 mmHg	34 41.5%	37 45.1%	43 52.4%	44 53.7%	47 58%	39 48.1%
SiSBP less than 135 mmHg (CHEP)	24 29.3%	27 32.9%	32 39%	38 46.3%	36 44.4%	31 38.3%

4. Secondary Outcome

Title	Response Rates at End of Double-blind Treatment Period Based on Trough Sitting Diastolic Blood Pressure
Description	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)

Outcome Measure Data

Analysis Population Description

Modified Per Protocol Set (mPPS).

Arm/Group Title	Placebo	Aprocitentan 5 mg	Aprocitentan 10 mg	Aprocitentan 25 mg	Aprocitentan 50 mg	Lisinopril 20 mg
Arm/Group Description	One capsule each of placebo matching aprocitentan and placebo matching lisinopril orally, once daily in the morning for 8 weeks.	One capsule of 5 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.	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.	One capsule of 50 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.	20 mg Lisinopril: 20 mg capsules orally o.d. for 8 weeks
Measure Participants	66	68	71	67	68	69
Count of Participants [Participants]	21 25.6%	21 25.6%	34 41.5%	40 48.8%	38 46.9%	31 38.3%

5. Secondary Outcome

Title	Response Rates at End of Double-blind Treatment Period Based on Trough Sitting Systolic Blood Pressure
Description	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)

Outcome Measure Data

Analysis Population Description

Modified Per Protocol Set (mPPS).

Arm/Group Title	Placebo	Aprocitentan 5 mg	Aprocitentan 10 mg	Aprocitentan 25 mg	Aprocitentan 50 mg	Lisinopril 20 mg
Arm/Group Description	One capsule each of placebo matching aprocitentan and placebo matching lisinopril orally, once daily in the morning for 8 weeks.	One capsule of 5 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.	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.	One capsule of 50 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.	One capsule of 20 mg lisinopril, orally, once daily in the morning for 8 weeks, along with placebo capsule matching aprocitentan.
Measure Participants	66	68	71	67	68	69
Count of Participants [Participants]	16 19.5%	16 19.5%	22 26.8%	28 34.1%	22 27.2%	20 24.7%

6. Secondary Outcome

Title	Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM)
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Aprocitentan 5 mg	Aprocitentan 10 mg	Aprocitentan 25 mg	Aprocitentan 50 mg	Lisinopril 20 mg
Arm/Group Description	One capsule each of placebo matching aprocitentan and placebo matching lisinopril orally, once daily in the morning for 8 weeks.	One capsule of 5 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.	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.	One capsule of 50 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.	One capsule of 20 mg lisinopril, orally, once daily in the morning for 8 weeks, along with placebo capsule matching aprocitentan.
Measure Participants	27	36	36	30	33	30
Baseline 24-hour mean DBP	90.46 (10.66)	90.60 (10.19)	92.60 (10.92)	89.28 (9.53)	91.53 (10.54)	91.18 (9.48)
Absolute change in 24-hour mean DBP at Week 8	-2.49 (5.52)	-3.76 (6.36)	-6.55 (7.04)	-8.86 (7.35)	-5.98 (6.63)	-5.72 (9.12)
Baseline 24-hour mean SBP	140.28 (14.2)	139.90 (15.87)	144.30 (15.68)	140.83 (11.23)	141.28 (14.73)	143.35 (17.53)
Absolute change in 24-hour mean SBP at Week 8	-3.54 (7.46)	-3.16 (10.54)	-7.72 (11.37)	-9.23 (9.92)	-6.07 (8.93)	-7.23 (14.33)

7. Secondary Outcome

Title	Ratio of Group Mean at Trough to Group Mean at Peak for Diastolic Blood Pressure Based on Ambulatory Blood Pressure Monitoring (ABPM)
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Aprocitentan 5 mg	Aprocitentan 10 mg	Aprocitentan 25 mg	Aprocitentan 50 mg	Lisinopril 20 mg
Arm/Group Description	One capsule each of placebo matching aprocitentan and placebo matching lisinopril orally, once daily in the morning for 8 weeks.	One capsule of 5 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.	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.	One capsule of 50 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.	One capsule of 20 mg lisinopril, orally, once daily in the morning for 8 weeks, along with placebo capsule matching aprocitentan.
Measure Participants	27	37	36	30	33	30
Number [Ratio of mean at trough to mean at peak]	-48.03	2.59	0.90	1.49	1.25	0.65

8. Other Pre-specified Outcome

Title	Supportive Analysis of Primary Endpoint: Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Aprocitentan 5 mg	Aprocitentan 10 mg	Aprocitentan 25 mg	Aprocitentan 50 mg	Lisinopril 20 mg
Arm/Group Description	One capsule each of placebo matching aprocitentan and placebo matching lisinopril orally, once daily in the morning for 8 weeks	One capsule of 5 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.	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.	One capsule of 50 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.	One capsule of 20 mg lisinopril, orally, once daily in the morning for 8 weeks, along with placebo capsule matching aprocitentan.
Measure Participants	81	79	80	77	77	79
Baseline	98.0 (5.5)	97.5 (5.3)	97.7 (4.2)	98.2 (5.0)	98.4 (5.3)	96.9 (4.4)
Absolute Change from Baseline to Week 8	-4.2 (11.1)	-5.8 (8.9)	-9.9 (8.4)	-11.7 (7.8)	-9.9 (7.8)	-8.2 (9.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Aprocitentan 5 mg, Aprocitentan 10 mg, Aprocitentan 25 mg, Aprocitentan 50 mg
	Comments	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.)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Multiple Comparison Procedure-Modeling
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Aprocitentan 5 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5356
	Comments
	Method	ANCOVA
	Comments	with Dunnett correction.
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-1.75
	Confidence Interval	(2-Sided) 95%; -5.19 to 1.69
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.401
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Aprocitentan 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	ANCOVA
	Comments	with Dunnett correction.
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-5.82
	Confidence Interval	(2-Sided) 95%; -9.25 to -2.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.396
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Aprocitentan 25 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	ANCOVA
	Comments	with Dunnett correction.
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-7.50
	Confidence Interval	(2-Sided) 95%; -10.96 to -4.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.410
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Aprocitentan 50 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	ANCOVA
	Comments	with Dunnett correction.
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-5.65
	Confidence Interval	(2-Sided) 95%; -9.11 to -2.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.410
	Estimation Comments

Adverse Events

Time Frame	Up to 12 weeks after first intake of medication after randomization.
Adverse Event Reporting Description	The treatment-emergent adverse events were defined as those adverse events with onset on or after the first day of double-blind study treatment intake up to the last day of double-blind study treatment intake plus 30 days.
Arm/Group Title	Placebo		Aprocitentan 5 mg		Aprocitentan 10 mg		Aprocitentan 25 mg		Aprocitentan 50 mg		Lisinopril 20 mg
Arm/Group Description	Participants received placebo orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.		Participants received aprocitentan 5 mg orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.		Participants received aprocitentan 10 mg orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.		Participants received aprocitentan 25 mg orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.		Participants received aprocitentan 50 mg orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.		Participants received lisinopril 20 mg orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.
All Cause Mortality
	Placebo		Aprocitentan 5 mg		Aprocitentan 10 mg		Aprocitentan 25 mg		Aprocitentan 50 mg		Lisinopril 20 mg
	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	0/82 (0%)		0/82 (0%)		0/82 (0%)		0/82 (0%)		0/81 (0%)		0/81 (0%)
Serious Adverse Events
	Placebo		Aprocitentan 5 mg		Aprocitentan 10 mg		Aprocitentan 25 mg		Aprocitentan 50 mg		Lisinopril 20 mg
	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	0/82 (0%)		0/82 (0%)		0/82 (0%)		2/82 (2.4%)		0/81 (0%)		1/81 (1.2%)
Cardiac disorders
Bundle branch block left	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/81 (0%)	0
Injury, poisoning and procedural complications
Fall	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/81 (1.2%)	1
Jaw fracture	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/81 (1.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm malignant	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/81 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Aprocitentan 5 mg		Aprocitentan 10 mg		Aprocitentan 25 mg		Aprocitentan 50 mg		Lisinopril 20 mg
	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	30/82 (36.6%)		18/82 (22%)		24/82 (29.3%)		32/82 (39%)		22/81 (27.2%)		25/81 (30.9%)
Blood and lymphatic system disorders
Anaemia	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	2/82 (2.4%)	2	1/81 (1.2%)	1	0/81 (0%)	0
Eosinophilia	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/81 (0%)	0
Leukopenia	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Lymphadenopathy	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/81 (1.2%)	1
Neutropenia	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/81 (0%)	0
Cardiac disorders
Atrioventricular block first degree	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Palpitations	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	1/81 (1.2%)	1
Supraventricular tachycardia	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Tachycardia	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/81 (1.2%)	1
Ear and labyrinth disorders
Deafness	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Deafness unilateral	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Ear pain	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Hypoacusis	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Motion sickness	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Tinnitus	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Vertigo	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/81 (0%)	0
Endocrine disorders
Hyperthyroidism	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Eye disorders
Eye haemorrhage	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/81 (0%)	0
Eye pain	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/81 (0%)	0
Lens disorder	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/81 (0%)	0
Vision blurred	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	1/81 (1.2%)	1
Vitreous degeneration	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/81 (0%)	0
Gastrointestinal disorders
Abdominal discomfort	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Abdominal pain	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Constipation	0/82 (0%)	0	0/82 (0%)	0	3/82 (3.7%)	3	0/82 (0%)	0	1/81 (1.2%)	1	0/81 (0%)	0
Diarrhoea	1/82 (1.2%)	1	0/82 (0%)	0	1/82 (1.2%)	1	1/82 (1.2%)	1	0/81 (0%)	0	1/81 (1.2%)	1
Dry mouth	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	1/81 (1.2%)	1	0/81 (0%)	0
Dyspepsia	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/81 (0%)	0
Gastritis	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Nausea	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	1/81 (1.2%)	1	1/81 (1.2%)	1
Oral pain	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/81 (1.2%)	1
Toothache	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	1/81 (1.2%)	1	0/81 (0%)	0
Vomiting	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
General disorders
Asthenia	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Face oedema	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/81 (0%)	0
Inflammation	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/81 (0%)	0
Non-cardiac chest pain	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/81 (0%)	0
Oedema peripheral	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	2/82 (2.4%)	2	2/81 (2.5%)	2	0/81 (0%)	0
Tenderness	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Hepatobiliary disorders
Hepatic function abnormal	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Hepatic steatosis	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/81 (0%)	0
Immune system disorders
Hypersensitivity	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Infections and infestations
Abscess	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/81 (1.2%)	1
Bronchitis	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Gastroenteritis	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	1/82 (1.2%)	1	1/81 (1.2%)	1	0/81 (0%)	0
Influenza	1/82 (1.2%)	1	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Laryngitis	0/82 (0%)	0	1/82 (1.2%)	1	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Localised infection	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Nasopharyngitis	1/82 (1.2%)	1	1/82 (1.2%)	1	2/82 (2.4%)	2	2/82 (2.4%)	2	0/81 (0%)	0	4/81 (4.9%)	4
Parotitis	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Pneumonia viral	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/81 (0%)	0
Rhinitis	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Sinusitis	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	2	0/81 (0%)	0	0/81 (0%)	0
Tooth abscess	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/81 (1.2%)	1
Tooth infection	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/81 (0%)	0
Upper respiratory tract infection	1/82 (1.2%)	1	0/82 (0%)	0	4/82 (4.9%)	4	1/82 (1.2%)	1	2/81 (2.5%)	2	1/81 (1.2%)	1
Urinary tract infection	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	1/82 (1.2%)	1	1/81 (1.2%)	1	1/81 (1.2%)	1
Viral infection	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Viral upper respiratory tract infection	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/81 (0%)	0
Injury, poisoning and procedural complications
Arthropod bite	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Hand fracture	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/81 (0%)	0
Laceration	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Ligament sprain	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Meniscus injury	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	1/82 (1.2%)	1	0/81 (0%)	0	0/81 (0%)	0
Muscle strain	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/81 (1.2%)	1
Periorbital haemorrhage	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Rib fracture	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Skin abrasion	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Sunburn	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Wound	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/81 (0%)	0
Investigations
Alanine aminotransferase increased	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/81 (0%)	0
Aspartate aminotransferase increased	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/81 (0%)	0
Blood creatinine increased	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Blood glucose abnormal	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Blood glucose decreased	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Blood glucose increased	2/82 (2.4%)	2	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Blood pressure increased	3/82 (3.7%)	3	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Creatinine renal clearance decreased	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Creatinine renal clearance increased	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Electrocardiogram abnormal	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Eosinophil count increased	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/81 (1.2%)	1
Haematocrit decreased	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Haematocrit increased	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/81 (1.2%)	1
Haemoglobin decreased	0/82 (0%)	0	0/82 (0%)	0	2/82 (2.4%)	2	1/82 (1.2%)	1	0/81 (0%)	0	1/81 (1.2%)	1
Haemoglobin increased	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/81 (1.2%)	1
Hepatic enzyme increased	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Lymphocyte count decreased	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Lymphocyte count increased	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/81 (1.2%)	1
Neutrophil count increased	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/81 (1.2%)	1
Norovirus test positive	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Transaminases increased	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Tri-iodothyronine free increased	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Weight decreased	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Weight increased	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/81 (0%)	0
White blood cell count decreased	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
White blood cell count increased	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/81 (1.2%)	1
Metabolism and nutrition disorders
Fluid retention	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/81 (0%)	0
Hyperglycaemia	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Type 2 diabetes mellitus	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	2/82 (2.4%)	2	0/82 (0%)	0	1/82 (1.2%)	1	1/82 (1.2%)	1	3/81 (3.7%)	3	0/81 (0%)	0
Back pain	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/81 (1.2%)	1
Metatarsalgia	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/81 (0%)	0
Muscle spasms	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/81 (0%)	0
Musculoskeletal chest pain	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/81 (0%)	0
Musculoskeletal pain	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/81 (0%)	0
Musculoskeletal stiffness	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/81 (0%)	0
Myalgia	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Neck pain	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/81 (0%)	0
Osteoarthritis	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/81 (0%)	0
Pain in extremity	1/82 (1.2%)	1	1/82 (1.2%)	1	0/82 (0%)	0	1/82 (1.2%)	1	2/81 (2.5%)	2	0/81 (0%)	0
Spinal osteoarthritis	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/81 (0%)	0
Temporomandibular joint syndrome	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/81 (1.2%)	1
Tendonitis	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Nervous system disorders
Dizziness	1/82 (1.2%)	1	1/82 (1.2%)	1	1/82 (1.2%)	1	1/82 (1.2%)	1	0/81 (0%)	0	1/81 (1.2%)	1
Headache	1/82 (1.2%)	1	1/82 (1.2%)	1	2/82 (2.4%)	2	2/82 (2.4%)	2	2/81 (2.5%)	2	4/81 (4.9%)	4
Migraine	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Sciatica	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/81 (0%)	0
Somnolence	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Psychiatric disorders
Anxiety	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Bruxism	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/81 (1.2%)	1
Confusional state	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Insomnia	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/81 (0%)	0
Persistent depressive disorder	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/81 (0%)	0
Suicidal ideation	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Renal and urinary disorders
Micturition frequency decreased	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/81 (1.2%)	1
Renal failure	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/81 (1.2%)	1
Urethral stenosis	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Reproductive system and breast disorders
Erectile dysfunction	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	2/81 (2.5%)	2
Fibrocystic breast disease	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Ovarian cyst	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/81 (0%)	0
Dysphonia	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Dyspnoea	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/81 (1.2%)	1
Epistaxis	0/82 (0%)	0	1/82 (1.2%)	2	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Nasal congestion	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	2/82 (2.4%)	2	0/81 (0%)	0	0/81 (0%)	0
Oropharyngeal pain	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/81 (1.2%)	1
Respiratory tract congestion	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Rhinorrhoea	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	2/82 (2.4%)	2	0/81 (0%)	0	0/81 (0%)	0
Throat irritation	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Wheezing	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Skin and subcutaneous tissue disorders
Dermatitis	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/81 (0%)	0
Ecchymosis	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Eczema	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Rash	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	1/81 (1.2%)	1	0/81 (0%)	0
Rash generalised	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	0/81 (0%)	0
Skin irritation	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	1/81 (1.2%)	1
Surgical and medical procedures
Abdominal hernia repair	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/81 (0%)	0
Mole excision	0/82 (0%)	0	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Umbilical hernia repair	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	1/81 (1.2%)	1	0/81 (0%)	0
Vascular disorders
Hot flush	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	0/82 (0%)	0	0/81 (0%)	0	0/81 (0%)	0
Hypertension	4/82 (4.9%)	4	1/82 (1.2%)	1	0/82 (0%)	0	2/82 (2.4%)	2	3/81 (3.7%)	3	3/81 (3.7%)	3
Orthostatic hypotension	1/82 (1.2%)	1	0/82 (0%)	0	0/82 (0%)	0	1/82 (1.2%)	1	0/81 (0%)	0	2/81 (2.5%)	2

Limitations/Caveats

[Not Specified]

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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.