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

Overview

  • Study type

    Interventional
  • Study phase

    III
  • Study IDs

  • Describes the nature of a clinical study. Types include:

    • Observational study — observes people and measures outcomes without affecting results.
    • Interventional study (clinical trial) — studies new tests, treatments, drugs, surgical procedures or devices.
    • Medical records research — uses historical information collected from medical records of large groups of people to study how diseases progress and which treatments and surgeries work best.
  • During the early phases (phases 1 and 2), researchers assess safety, side effects, optimal dosages and risks/benefits. In the later phase (phase 3), researchers study whether the treatment works better than the current standard therapy. They also compare the safety of the new treatment with that of current treatments. Phase 3 trials include large numbers of people to make sure that the result is valid. There are also less common very early (phase 0) and later (phase 4) phases. Phase 0 trials are small trials that help researchers decide if a new agent should be tested in a phase 1 trial. Phase 4 trials look at long-term safety and effectiveness, after a new treatment has been approved and is on the market.

  • Site IRB
    • Jacksonville, Florida: 18-005342
    NCT ID: NCT03541174
    Sponsor Protocol Number: 080A301

About this study

The purpose of the study is to show the blood pressure lowering effect of aprocitentan, a new drug, when added to other anti-hypertensive drugs of patients with difficult to control (resistant) high blood pressure (hypertension), and to show that blood pressure reduction is kept for long period of time.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. If you need assistance understanding the eligibility criteria, please contact the study team.

See eligibility criteria

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 of 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). Beta-blockers are not counted as background antihypertensive medication.
  • Mean SiSBP ≥ 140 mmHg measured by AOBPM at screening visit.
  • Documentation in the subject’s medical records of diagnosis of RHT according to the site’s medical practice:
    • Exclusion of secondary causes of hypertension (e.g., serum aldosterone, plasma renin activity, duplex/doppler ultrasonography, computer tomography angiography assessments are performed to exclude the secondary causes of hypertension [Rimoldi 2013]);
    • Adherence to medication (e.g., how the adherence was checked and/or monitored) to eliminate apparent RHT.
  • A woman of childbearing potential is 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.
  • Mean trough SiSBP ≥ 140 mmHg measured by AOBPM at the switch from background antihypertensive medications (i.e., at least 3 medications from different pharmacological classes including a diuretic]) to the standardized background antihypertensive therapy.

RI 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 (end of RI)

  • Stable dose of the standardized background antihypertensive therapy since the start of the RI period.
  • Mean trough SiSBP ≥ 140 mmHg measured by AOBPM.
  • Subjects demonstrating ≥ 80% compliance (pill counting) to  study  treatment (i.e., placebo) as well as ≥ 80% compliance (pill counting) to the standardized background antihypertensive therapy during the RI period.

Exclusion Criteria:

Subjects must not fulfill any of the following exclusion criteria at the specified study visits. It is not permitted to waive any of the criteria for any subject:

Screening period criteria

Disease/condition

  • Pregnant or lactating subjects.
  • Apparent/pseudo RHT due to white coat effect, medical inertia, poor therapeutic adherence, or secondary causes of hypertension (not including obstructive sleep apnea).
  • Confirmed severe hypertension (grade 3) defined as mean SiSBP ≥ 180 mmHg and/or SiDBP ≥ 110 mmHg measured by AOBPM at two different time points.  The BP re-measurement can be during the screening visit (e.g., after at least 3 h), or at the next planned visit, or at an unscheduled visit. The time of re-measurement is at the investigator’s discretion, taking into consideration the subject’s medical history.
  • Known and documented transient ischemic attack, stroke, unstable angina or myocardial infarction (MI) within 6 months prior to Screening.
  • Clinically significant unstable cardiac disease in the opinion of the investigator; e.g., uncontrolled symptomatic arrhythmia, atrial fibrillation, NYHA stage III or IV congestive heart failure.
  • Severe renal insufficiency defined as an eGFR per the CKD Epidemiology (CKD-EPI) collaboration creatinine equation < 15 mL/min/1.73 m2.
  • Type 1 DM.
  • Subjects working night shifts.  A maximum of 2 night shifts per week is permitted except within 3 days prior to a study visit. Night shifts are not allowed during visits at which ABPM is recorded.
  • 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.
  • Known concomitant life-threatening disease with a life expectancy < 18 months of Screening.

Treatments

  • Treatment with any medication which may affect BP (e.g., treatment of psychiatric diseases).
  • Treatment with any other ERAs.
  • Contraindication and/or known hypersensitivity to any of the three components of the standardized background antihypertensive therapies (fixed combination of CCB [amlodipine], ARB [valsartan] and diuretic [HCTZ]) according to their labels or drugs of the same class, or to any of the excipients.
  • Known hypersensitivity to aprocitentan or drugs of the same class, or any of the excipients.
  • Planned treatment, or  treatment  with  another  investigational  treatment  within 3 months prior to Screening
  • Laboratory assessments based on central laboratory
    • ALT or AST > 3 times the upper limit of normal range, or severe hepatic impairment;
    • Hemoglobin < 100 g/L;
    • NT-proBNP ≥ 500 pg/mL;
    • If one of these criteria is not met based on central laboratory report, a re-test must be performed before Visit 2 (e.g., at the next screening visit, or at an unscheduled visit). If the value is confirmed, the subject must discontinue from screening.

RI period exclusion criteria

  • Confirmed severe hypertension (grade 3) defined as mean SiSBP ≥ 180 mmHg and/or SiDBP ≥ 110 mmHg measured by AOBPM at two different time points.
  • The BP re-measurement can be during the first RI Visit (e.g., after at least 3 h), or at the next planned visit, or at an unscheduled visit. The time of re-measurement is at the investigator’s discretion, taking into consideration the subject’s medical history.

Randomization exclusion criteria

  • Laboratory assessments based on local laboratory:
    • ALT or AST > 3 times the upper limit of normal range;
    • Hemoglobin < 100 g/L;
    • eGFR per the CKD-EPI creatinine equation < 15 mL/min/1.73 m2.
  • At any time between Screening and Randomization the investigator/delegate must verify that the subject does not fulfill the exclusion criteria checked at the screening visit (as applicable).

Criteria for women of childbearing potential

Definition of childbearing potential

A woman is considered to be of childbearing potential unless she meets at least one of the following criteria:

  • Previous bilateral salpingectomy, bilateral salpingo-oophorectomy or hysterectomy;
  • Postmenopausal (defined as 12 consecutive months with no menses without an alternative medical cause [ICH M3 definition]);
  • Premature ovarian failure (confirmed by a specialist), XY genotype, Turner syndrome, uterine agenesis.

Childbearing potential status will be assessed at each visit and recorded in the electronic case report form (eCRF).

Acceptable methods of contraception

  • The methods of birth control used (including non-pharmacological methods) must be recorded in the eCRF.
  • The use of one of the following options is regarded as a highly effective method of contraception:
    • Option 1 - One method from this list:
      • Standard intrauterine device (IUD)
      • (Copper T380A IUD)
      • Intrauterine system (LNg 20IUS:  progesterone IUS)
      • Progesterone implant
      • Tubal sterilization
    • Option 2 - One method from this list:
      • Estrogen and progesteren oral contraceptive ("the Pill")
      • Estrogen and progesteren transdermal patch
      • Progesterone injection
    • PLUS one method from this list:
      • Male condom
      • Diaphragm with spermicide
      • Cervical cap with spermicide
    • Option 3 - One method from this list:
      • Partner's vasectomy
    • PLUS one method from this list:
      • Male condom
      • Diaphragm with spermicide
      • Cervical cap with spermicide
      • Estrogen and progesteren oral contraceptive ("the Pill")
      • Estrogen and progesteren transdermal patch
      • Vaginal ring
      • Progesterone injection
    • If hormonal contraception is one of the methods used, then it must have been initiated at least 4 weeks prior to the screening visit (Visit 1).

      Option 3: vasectomized partner is a highly effective birth control method provided that the partner is the sole sexual partner of the woman of childbearing potential trial participant and that the vasectomized partner has received medical assessment of the surgical success.


       

 

 

 

 



 

 

 

If hormonal contraception is one of the methods used then it must have been initiated at least 4 weeks prior to the screening visit (Visit 1) [see Section 5.2.3].

Option 3: vasectomized partner is a highly effective birth control method provided that the partner is the sole sexual partner of the woman of childbearing potential trial participant and that the vasectomized partner has received medical assessment of the surgical success.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Screening period:

  • 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., before randomization);
    • 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 period (RI):

  • Switched to the standardized background antihypertensive therapy at least 4 weeks before the first RI visit;
  • Mean trough SiSBP ≥ 140 mmHg as measured by AOBPM.

Randomization period: 

  • Stable dose of the standardized background antihypertensive therapy since 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 timepoints;
  • 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) ≥ 200 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.

Participating Mayo Clinic locations

Study statuses change often. Please contact us for help.

Mayo Clinic Location Status Contact

Jacksonville, Fla.

Mayo Clinic principal investigator

Nabeel Aslam, M.D.

Contact us for the latest status

Contact information:

Samantha Eilerman

(904)953-3523

Eilerman.Samantha@mayo.edu

More information

Study Progress

This study has completed enrollment of targeted participants and currently is completing research activities including study intervention, specimen collection, testing and data analysis.

Publications

Publications are currently not available

Study Results Summary

Not yet available

Supplemental Study Information

Not yet available

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CLS-20440739

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