E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Difficult to control high blood pressure despite treatment with at least 3 other anti-hypertensive medications |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020783 |
E.1.2 | Term | Hypertension not adequately controlled |
E.1.2 | System Organ Class | 100000004866 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
- To demonstrate the blood pressure (BP) lowering effect of aprocitentan when added to standard of care in true resistant hypertension (RHT) subjects. |
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E.2.2 | Secondary objectives of the trial |
- To demonstrate that the effect of aprocitentan on BP is durable when added to standard of care in true RHT subjects.
- To evaluate the long-term safety and tolerability of aprocitentan in true RHT subjects during 48 weeks of treatment. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Screening criteria: - Signed and dated ICF prior to any study-mandated procedure; - Male and female subjects; 18 years (or year of country specific majority) or older; - Historical documentation in the subject's medical records on uncontrolled BP despite at least 3 background antihypertensive medications within 1 year before screening visit; - Treated with at least 3 antihypertensive therapies of different pharmacological classes for at least 4 weeks before the screening visit (Visit 1); - Mean SiSBP ≥ 140 mmHg measured by AOBPM; - Women of childbearing potential are eligible only if the following applies; -- Negative pregnancy test at screening and at baseline (i.e., end of RI period); -- Agreement to undertake pregnancy tests during the study and up to 30 days after randomized study treatment discontinuation; -- Agreement to use methods of birth control from Screening up to atleast 30 days after randomized study treatment discontinuation.
Run-in entry criteria: - Switched to the standardized background antihypertensive therapy at least 4 weeks before the first RI visit; - Mean trough SiSBP ≥ 140 mmHg measured by AOBPM.
Randomization criteria: - Stable dose of the standardized background antihypertensive therapy for at least 1 week before Day -1 (end of the RI period); - Mean trough SiSBP ≥ 140 mmHg measured by AOBPM. |
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E.4 | Principal exclusion criteria |
- Apparent/pseudo RHT due to white coat effect, medical inertia, poor therapeutic adherence, or secondary causes of hypertension (except sleep apnea); - Confirmed severe hypertension (grade 3) defined as SiSBP ≥ 180 mmHg and/or SiDBP ≥ 110 mmHg as measured by AOBPM at two different time points.; - Pregnant or lactating subjects; - Clinically significant unstable cardiac disease at screening or in the past in the opinion of the investigator, e.g. uncontrolled symptomatic arrhythmia, atrial fibrillation, congestive heart failure NYHA stage II with relevant mitral valve insufficiency and/or aortic stenosis, congestive heart failure NYHA stage III or IV; - Severe renal insufficiency; - N-terminal pro-brain natriuretic peptide (NT-proBNP) ≥ 500 pg/mL; - Any known factor, disease or clinically relevant medical or surgical conditions that, in the opinion of the investigator, might put the subject at risk, interfere with treatment compliance, study conduct or interpretation of the results - Treatment with any medication which may affect blood pressure and/or treatment with high dose of loop diuretics (i.e., furosemide greater than 80 mg/day, or equivalent dosage of other loop diuretics). |
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E.5 End points |
E.5.1 | Primary end point(s) |
- Change from baseline to Week 4 of double-blind (DB) treatment in mean trough SiSBP measured by AOBPM. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline to Week 4 after treatment initiation. |
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E.5.2 | Secondary end point(s) |
- Change from Week 36 (i.e., start of double-blind withdrawal [DB-WD]) to Week 40 in mean trough SiSBP measured by AOBPM - Change from baseline to Week 4 of DB treatment in trough Sitting Diastolic BP (SiDBP) measured by AOBPM; - Changes from baseline to Week 4 of DB treatment in 24-h mean SBP and DBP measured by ABPM; - Change from Week 36 to Week 40 of DB-WD treatment in mean trough SiDBP measured by AOBPM; - Changes from Week 36 to Week 40 of DB-WD treatment in 24-h mean SBP and DBP measured by ABPM. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From baseline to week 4, or from week 36 to week 40. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | Yes |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
SB placebo run-in/randomized with 3 parts: (DB), (SB) and (DB-WD) |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 6 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 85 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Belgium |
Canada |
China |
Czech Republic |
Denmark |
Finland |
France |
Germany |
Greece |
Hungary |
Israel |
Italy |
Korea, Republic of |
Lithuania |
Netherlands |
Poland |
Russian Federation |
Spain |
Ukraine |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
End of the trial is defined as last subject last visit (LSLV) |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 25 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 45 |