The primary objective of the study is to demonstrate the BP lowering effect ofaprocitentan when added to standard-of-care in true resistant hypertension subjects.The secondary objectives of the study are• to demonstrate that the effect of…
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Source
Brief title
Condition
- Cardiac arrhythmias
- Vascular hypertensive disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint is the change from baseline to Week 4 of DB
treatment in mean trough sitting SBP measured by AOBPM.
Baseline is defined as the last available measurement before the start of DB
treatment.
Secondary outcome
The key secondary efficacy endpoint is the change from Week 36 to Week 40 of
double blind withdrawal treatment in mean trough sitting SBP measured by AOBPM.
Background summary
Hypertension is a *silent* killer that rarely causes symptoms. Hypertension is
defined in adults by (office) systolic/diastolic blood pressure >= 140/90 mmHg.
This condition represents a significant global public health concern, as it
contributes to vascular and renal morbidity, cardiovascular mortality, and
economic burden.
Despite current knowledge on the management of hypertension and the
availability of numerous effective antihypertensive drugs, hypertension remains
inadequately controlled in many patients. A number of these uncontrolled
patients are considered to have so called *resistant hypertension* or
*difficult-to-control hypertension*, which is defined as uncontrolled blood
pressure in patients adhering to lifestyle modifications and to an appropriate
regimen of three or more antihypertensive drugs from different pharmacological
classes, including a diuretic, in the absence of secondary cause of
hypertension.
The estimated prevalence of resistant hypertension varies from 2 to 30% of the
hypertensive population. This broad range of the estimate is mainly due to the
different sources of information (e.g., insurance healthcare systems,
registries, well-controlled therapeutic clinical trials). It is not always
clear from these reports whether the prevalence is for *apparent* or *true*
resistant hypertension.
A critical characteristic of most *true* resistant hypertension patients is
their complex medical condition.
Compared to the hypertensive population, resistant hypertension patients are
more likely to be older (> 75 years), to be of black race, to have a higher
body mass index, albuminuria, reduced renal function, self-reported
co-morbidities of diabetes mellitus, coronary heart disease, and sleep apnea.
Chronic kidney disease and diabetes mellitus, in particular, amplify the
resistant hypertension patients* vulnerability and increase the complexity of
resistant hypertension treatment. In addition, in resistant hypertension
patients, the risk of cardiovascular events is much higher than in the rest of
the hypertensive population. This has been consistently shown in different
settings (i.e., clinical trials, observational studies, and international
registries) comparing resistant hypertension vs non- resistant hypertension
patients. Consequently, it is important to control BP in the resistant
hypertension population.
Study objective
The primary objective of the study is to demonstrate the BP lowering effect of
aprocitentan when added to standard-of-care in true resistant hypertension
subjects.
The secondary objectives of the study are
• to demonstrate that the effect of aprocitentan on BP is durable when added to
standard-of-care in true resistant hypertension subjects
• to evaluate the long-term safety and tolerability of aprocitentan in true
resistant hypertension subjects during 48 weeks of treatment.
Other objectives:
• Evaluate steady-state trough plasma concentrations of aprocitentan after 4
weeks of treatment.
• Evaluate the endothelin system activity and the effect of aprocitentan on
micro- and macrovascular complications based on specific biomarkers.
Study design
This is a prospective, multicenter, randomized, parallel-group, blinded Phase 3
study with aprocitentan in subjects with true resistant hypertension.
Approximately 4000 subjects are expected to be screened, in order to enroll
about 1500 subjects with diagnosis of resistant hypertension into the SB
placebo Randomized I period. At least 600 subjects will be randomized and at
least 300 subjects are expected to complete the study (i.e., the 30 day safety
follow-up period). The study will be conducted in approximately 100 sites in
approximately 20 countries.
The study comprises the following consecutive periods: screening period,
placebo run-in period, randomized treatment period and safety follow-up.
Subject participation in the study will be up to 68 weeks.
Intervention
During the screening period, subjects will be switched to the standardized
background antihypertensive therapy.
In the run-in period all subjects will receive placebo in a single blinded
fashion.
At Visit 4 the subjects are randomized to aprocitentan 12.5 mg, aprocitentan 25
mg or placebo in a 1:1:1 ratio.
At the end of the double blind part (Week 4) all subjects will be assigned to
25 mg aprocitentan.
Study burden and risks
Based on the mechanism of action of aprocitentan, current nonclinical data, and
clinical data from the Phase 1 studies and Phase 2 study in adult subjects with
essential hypertension on mono-therapy, it is anticipated that aprocitentan
will reduce the blood pressure of subjects participating in this study in a
durable and safe manner.
During the study subjects will be carefully followed at regular visits for up
to 68 weeks in hypertension specialized hospital departments. All visit
assessments (e.g., blood pressure measurement, blood sampling,
electrocardiogram [ECG]) are part of the routine standard-of-care for subjects
with resistant hypertension, although their frequency may be higher in the
study. The most invasive procedure repeated at each visit will be blood
sampling.
An Independent Data Monitoring Committee (IDMC) has overall responsibility for
safeguarding the interests of subjects by monitoring the relationship between
benefits and risks and by giving the appropriate recommendations on the basis
of all reported data. This ensures that the IDMC ensures that the research is
carried out in compliance with the highest scientific and ethical standards.
The IDMC will be fully operational before the first subject is included in the
study. The composition and operation of the IDMC are described in the IDMC
charter.
An independent Clinical Adjudication Committee assesses and confirms in a
blinded way, all reported cases of Major Adverse Cardiac Events.
Hegenheimermattweg 91
Allschwil 4123
CH
Hegenheimermattweg 91
Allschwil 4123
CH
Listed location countries
Age
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 including a diuretic 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 at least
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 since
the start of the RI period;
Mean trough SiSBP >= 140 mmHg measured by AOBPM.
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 in the opinion of the
investigator;
- 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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-004393-33-NL |
| CCMO | NL65338.018.18 |