NCT02603809

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

Completed Phase 2 Results posted Last updated 23 November 2022

What this trial tests

Phase 2 trial testing Aprocitentan 5 mg in Essential Hypertension in 1,659 participants. Completed in 7 April 2017.

Timeline

14 December 2015

Primary endpoint
28 February 2017

7 April 2017

Quick facts

Lead sponsor	Idorsia Pharmaceuticals Ltd.
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	1,659
Start date	14 December 2015
Primary completion	28 February 2017
Estimated completion	7 April 2017
Sites	90 locations across Canada, United States, Israel, Puerto Rico

Drugs / interventions tested

• Aprocitentan 5 mg — full drug profile →
• Aprocitentan 10 mg — full drug profile →
• Aprocitentan 25 mg — full drug profile →
• Aprocitentan 50 mg — full drug profile →
• Lisinopril 20 mg — full drug profile →
• Placebo

Conditions studied

• Essential Hypertension — all drugs for Essential Hypertension →

Sponsor

Idorsia Pharmaceuticals Ltd. — full company profile →

Who can join

Adults 18 to 75, any sex, with Essential Hypertension. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough Primary · 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.

Baseline

Group	Value	95% CI
Placebo	97.5	± 5.4
Aprocitentan 5 mg	97.8	± 5.5
Aprocitentan 10 mg	97.7	± 4.3
Aprocitentan 25 mg	97.8	± 4.8
Aprocitentan 50 mg	98.2	± 5.3
Lisinopril 20 mg	96.8	± 4.6

Absolute Change from Baseline to Week 8

Group	Value	95% CI
Placebo	-4.9	± 11.1
Aprocitentan 5 mg	-6.3	± 8.9
Aprocitentan 10 mg	-9.9	± 8.7
Aprocitentan 25 mg	-12.0	± 8.2
Aprocitentan 50 mg	-10.0	± 7.9
Lisinopril 20 mg	-8.4	± 9.6

Change From Baseline to End of Double-blind Treatment in Sitting Systolic Blood Pressure at Trough Secondary · 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.

Baseline

Group	Value	95% CI
Placebo	149.2	± 13.1
Aprocitentan 5 mg	149.4	± 13.9
Aprocitentan 10 mg	149.8	± 12.7
Aprocitentan 25 mg	151.2	± 13.7
Aprocitentan 50 mg	148.6	± 12.8
Lisinopril 20 mg	149.8	± 14.2

Absolute Change from Baseline to Week 8

Group	Value	95% CI
Placebo	-7.7	± 18.8
Aprocitentan 5 mg	-10.3	± 15.3
Aprocitentan 10 mg	-15.0	± 14.5
Aprocitentan 25 mg	-18.5	± 15.0
Aprocitentan 50 mg	-15.1	± 11.8
Lisinopril 20 mg	-12.8	± 16.0

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

SiDBP less than 90 mmHg

Group	Value	95% CI
Placebo	22
Aprocitentan 5 mg	30
Aprocitentan 10 mg	37
Aprocitentan 25 mg	43
Aprocitentan 50 mg	39
Lisinopril 20 mg	38

SiDBP less than 85 mmHg (CHEP)

Group	Value	95% CI
Placebo	17
Aprocitentan 5 mg	15
Aprocitentan 10 mg	29
Aprocitentan 25 mg	29
Aprocitentan 50 mg	21
Lisinopril 20 mg	23

SiSBP less than 140 mmHg

Group	Value	95% CI
Placebo	34
Aprocitentan 5 mg	37
Aprocitentan 10 mg	43
Aprocitentan 25 mg	44
Aprocitentan 50 mg	47
Lisinopril 20 mg	39

SiSBP less than 135 mmHg (CHEP)

Group	Value	95% CI
Placebo	24
Aprocitentan 5 mg	27
Aprocitentan 10 mg	32
Aprocitentan 25 mg	38
Aprocitentan 50 mg	36
Lisinopril 20 mg	31

Response Rates at End of Double-blind Treatment Period Based on Trough Sitting Diastolic Blood Pressure Secondary · 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.

Group	Value	95% CI
Placebo	21
Aprocitentan 5 mg	21
Aprocitentan 10 mg	34
Aprocitentan 25 mg	40
Aprocitentan 50 mg	38
Lisinopril 20 mg	31

Response Rates at End of Double-blind Treatment Period Based on Trough Sitting Systolic Blood Pressure Secondary · 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.

Group	Value	95% CI
Placebo	16
Aprocitentan 5 mg	16
Aprocitentan 10 mg	22
Aprocitentan 25 mg	28
Aprocitentan 50 mg	22
Lisinopril 20 mg	20

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

Baseline 24-hour mean DBP

Group	Value	95% CI
Placebo	90.46	± 10.66
Aprocitentan 5 mg	90.60	± 10.19
Aprocitentan 10 mg	92.60	± 10.92
Aprocitentan 25 mg	89.28	± 9.53
Aprocitentan 50 mg	91.53	± 10.54
Lisinopril 20 mg	91.18	± 9.48

Absolute change in 24-hour mean DBP at Week 8

Group	Value	95% CI
Placebo	-2.49	± 5.52
Aprocitentan 5 mg	-3.76	± 6.36
Aprocitentan 10 mg	-6.55	± 7.04
Aprocitentan 25 mg	-8.86	± 7.35
Aprocitentan 50 mg	-5.98	± 6.63
Lisinopril 20 mg	-5.72	± 9.12

Baseline 24-hour mean SBP

Group	Value	95% CI
Placebo	140.28	± 14.2
Aprocitentan 5 mg	139.90	± 15.87
Aprocitentan 10 mg	144.30	± 15.68
Aprocitentan 25 mg	140.83	± 11.23
Aprocitentan 50 mg	141.28	± 14.73
Lisinopril 20 mg	143.35	± 17.53

Absolute change in 24-hour mean SBP at Week 8

Group	Value	95% CI
Placebo	-3.54	± 7.46
Aprocitentan 5 mg	-3.16	± 10.54
Aprocitentan 10 mg	-7.72	± 11.37
Aprocitentan 25 mg	-9.23	± 9.92
Aprocitentan 50 mg	-6.07	± 8.93
Lisinopril 20 mg	-7.23	± 14.33

Ratio of Group Mean at Trough to Group Mean at Peak for Diastolic Blood Pressure Based on Ambulatory Blood Pressure Monitoring (ABPM) Secondary · 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 tha

Group	Value	95% CI
Placebo	-48.03
Aprocitentan 5 mg	2.59
Aprocitentan 10 mg	0.90
Aprocitentan 25 mg	1.49
Aprocitentan 50 mg	1.25
Lisinopril 20 mg	0.65

Supportive Analysis of Primary Endpoint: Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough Secondary · 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.

Baseline

Group	Value	95% CI
Placebo	98.0	± 5.5
Aprocitentan 5 mg	97.5	± 5.3
Aprocitentan 10 mg	97.7	± 4.2
Aprocitentan 25 mg	98.2	± 5.0
Aprocitentan 50 mg	98.4	± 5.3
Lisinopril 20 mg	96.9	± 4.4

Absolute Change from Baseline to Week 8

Group	Value	95% CI
Placebo	-4.2	± 11.1
Aprocitentan 5 mg	-5.8	± 8.9
Aprocitentan 10 mg	-9.9	± 8.4
Aprocitentan 25 mg	-11.7	± 7.8
Aprocitentan 50 mg	-9.9	± 7.8
Lisinopril 20 mg	-8.2	± 9.7

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to 12 weeks after first intake of medication after randomization.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo

Serious: 0/82 (0%)

Deaths: 0/82

Aprocitentan 5 mg

Serious: 0/82 (0%)

Deaths: 0/82

Aprocitentan 10 mg

Serious: 0/82 (0%)

Deaths: 0/82

Aprocitentan 25 mg

Serious: 2/82 (2%)

Deaths: 0/82

Aprocitentan 50 mg

Serious: 0/81 (0%)

Deaths: 0/81

Lisinopril 20 mg

Serious: 1/81 (1%)

Deaths: 0/81

Serious adverse events (4 terms)

Reaction	System	Placebo	Aprocitentan 5 mg	Aprocitentan 10 mg	Aprocitentan 25 mg	Aprocitentan 50 mg	Lisinopril 20 mg
Bundle branch block left	Cardiac disorders	—	—	—	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—	—	—	—
Jaw fracture	Injury, poisoning and procedural complications	—	—	—	—	—	—
Neoplasm malignant	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—	—

Other adverse events (152 terms — click to expand)

Reaction	System	Placebo	Aprocitentan 5 mg	Aprocitentan 10 mg	Aprocitentan 25 mg	Aprocitentan 50 mg	Lisinopril 20 mg
Nasopharyngitis	Infections and infestations	—	—	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—	—
Hypertension	Vascular disorders	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—
Blood pressure increased	Investigations	—	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—
Oedema peripheral	General disorders	—	—	—	—	—	—
Blood glucose increased	Investigations	—	—	—	—	—	—
Haemoglobin decreased	Investigations	—	—	—	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Erectile dysfunction	Reproductive system and breast disorders	—	—	—	—	—	—
Nasal congestion	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Rhinorrhoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Orthostatic hypotension	Vascular disorders	—	—	—	—	—	—
Eosinophilia	Blood and lymphatic system disorders	—	—	—	—	—	—
Leukopenia	Blood and lymphatic system disorders	—	—	—	—	—	—
Lymphadenopathy	Blood and lymphatic system disorders	—	—	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—
Atrioventricular block first degree	Cardiac disorders	—	—	—	—	—	—
Palpitations	Cardiac disorders	—	—	—	—	—	—
Supraventricular tachycardia	Cardiac disorders	—	—	—	—	—	—
Tachycardia	Cardiac disorders	—	—	—	—	—	—
Deafness	Ear and labyrinth disorders	—	—	—	—	—	—
Deafness unilateral	Ear and labyrinth disorders	—	—	—	—	—	—
Ear pain	Ear and labyrinth disorders	—	—	—	—	—	—
Hypoacusis	Ear and labyrinth disorders	—	—	—	—	—	—
Motion sickness	Ear and labyrinth disorders	—	—	—	—	—	—
Tinnitus	Ear and labyrinth disorders	—	—	—	—	—	—
Vertigo	Ear and labyrinth disorders	—	—	—	—	—	—
Hyperthyroidism	Endocrine disorders	—	—	—	—	—	—
Eye haemorrhage	Eye disorders	—	—	—	—	—	—
Eye pain	Eye disorders	—	—	—	—	—	—
Lens disorder	Eye disorders	—	—	—	—	—	—
Vision blurred	Eye disorders	—	—	—	—	—	—
Vitreous degeneration	Eye disorders	—	—	—	—	—	—
Abdominal discomfort	Gastrointestinal disorders	—	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—

Most-reported serious reactions: Bundle branch block left, Fall, Jaw fracture, Neoplasm malignant.

Data from ClinicalTrials.gov NCT02603809 adverse events section.

Sponsor's own description

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.

Publications & conference data

7 peer-reviewed publications reference this trial (live from Europe PMC):

1. Randomized Dose-Response Study of the New Dual Endothelin Receptor Antagonist Aprocitentan in Hypertension.
   Verweij P, Danaietash P, Flamion B, Ménard J, et al · · 2020 · cited 60× · PMID 32063059 · DOI 10.1161/hypertensionaha.119.14504
2. Single- and multiple-dose tolerability, safety, pharmacokinetics, and pharmacodynamics of the dual endothelin receptor antagonist aprocitentan in healthy adult and elderly subjects.
   Sidharta PN, Melchior M, Kankam MK, Dingemanse J. · · 2019 · cited 33× · PMID 30962677 · DOI 10.2147/dddt.s199051
3. Effects of the Dual Endothelin Receptor Antagonist Aprocitentan on Body Weight and Fluid Homeostasis in Healthy Subjects on a High Sodium Diet.
   Gueneau de Mussy P, Sidharta PN, Wuerzner G, Maillard MP, et al · · 2021 · cited 19× · PMID 32897570 · DOI 10.1002/cpt.2043
4. Genomics of Blood Pressure and Hypertension: Extending the Mosaic Theory Toward Stratification.
   Lip S, Padmanabhan S. · · 2020 · cited 18× · PMID 32389342 · DOI 10.1016/j.cjca.2020.03.001
5. Systematic Review Article: New Drug Strategies for Treating Resistant Hypertension-the Importance of a Mechanistic, Personalized Approach.
   Nardoianni G, Pala B, Scoccia A, Volpe M, et al · · 2024 · cited 16× · PMID 38616212 · DOI 10.1007/s40292-024-00634-4
6. Aprocitentan in hypertension management: clinical efficacy, safety, and future prospects.
   Riaz R, Ahmed U, Naqi U, Afaq L, et al · · 2025 · cited 2× · PMID 40213178 · DOI 10.1097/ms9.0000000000003028
7. Current Knowledge About Aprocitentan in Hypertension.
   Bank-Mikkelsen EM, Grimm D, Wehland M. · · 2025 · PMID 41373585 · DOI 10.3390/ijms262311431