Effectiveness and Safety of Combination of Nebivolol and Amlodipine in Hypertensive Patients Versus Each Monotherapy

Open-laBel, Multicenter, multinatiOnal, inTerventional Clinical Trial to Assess effIcacy and Safety of the Extemporaneous Combination of nEbivoLol and amLodipine in Grade 1-2 Hypertensive patIents Versus Each Monotherapy

Study to assess the anti-hypertensive efficacy and safety of the extemporaneous combination of Nebivolol 5 mg in combination with Amlodipine 5 mg or AML 10 mg in lowering the sitting diastolic BP after 8 weeks of treatment inpatients with uncontrolled BP previously treated with Nebivolol (NEB) or Amlodipine (5 mg) monotherapies for at least 4 weeks.

Approximately 290 patients are planned to be screened to ensure at least 216 patients complete the run-in period and start with the assessment period.

Grade 1 - 2 hypertensive patients [BP ranging from ≥140 to ≤179 mmHg for Systolic Blood Pressure (SBP) and from ≥90 to ≤109 mmHg for Diastolic Blood Pressure (DBP)] on treatment with any Beta Blocker (BB) or Calcium Channel Blocker (CCB), including NEB (only 5 mg dosage allowed) or AML (only 5 mg dosage allowed) for at least one month prior to Visit 1 will be screened for eligibility.

Allowed CCBs at screening includes Felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nifedipine, and nisoldipine. Patients treated with Amlodipine or Nebivolol in dosages higher than 5 mg/daily will not be eligible.

On the same day of the Screening visit, the eligible patients will enter into a run-in period of 4 weeks after screening, during which:

• Patients receiving NEB 5 mg or AML 5 mg will continue the same therapy for 4 weeks.
• Patients on any other BBs or CCBs will be switched to NEB 5 mg or AML 5 mg. Patients entering this phase in therapy with NEB 5 mg or AML 5 mg should be in a 1:1 ratio.

After 4 weeks (±2 days) of run-in period of monotherapy, the BP will be further assessed (Visit 2). Patients with uncontrolled BP levels (sitting SBP/DBP ≥130/80 mmHg) at Visit 2, with the treatment adherence (ranging between 80% to 120%) and who did tolerate the treatment will enter into the assessment period and will be assigned to the extemporaneous combination of NEB 5 mg and AML 5 mg. Patients with controlled BP levels (sitting SBP/DBP <130/80 mmHg) and/or who do not tolerate the treatment or have an adherence range below 80% or above 120%, will be withdrawn from the study.

After 4 weeks ±2 days in the assessment period, patients BP will be further evaluated at Visit 3: patients with controlled BP levels (sitting SBP/DBP <130/80 mmHg) will continue the same extemporaneous combination, while patients with uncontrolled BP levels will be uptitrated from extemporaneous combination NEB/AML 5/5 mg to extemporaneous combination of NEB/AML 5/10 mg for further 4 weeks.

At the end of the assessment period (8 weeks ±4 days), the patients will attend an End of Treatment Visit 4.

To correctly evaluate the additional effect of the combination therapy, the number of patients with uncontrolled BP on NEB or AML monotherapy needs to be balanced at Visit 2. In order to maintain a 1:1 ratio during the assessment period, a cap of 110 patients for each treatment arm (ie. NEB and AML) will be included at Visit 2 in order to maintain a balanced number of uncontrolled patients entering the assessment period for each drug. The evaluation will be done every 50 patients. If the rate of entrance in the assessment period for one of the 2 tested drugs will deviate more than 5%, a corrective measure will be initiated.

Inclusion Criteria:

1. Male or female patients with Grade 1 - 2 hypertension with mean sitting SBP ≥140 mmHg and ≤179 mmHg and/or mean sitting DBP ≥90 mmHg and ≤109 mmHg at screening (in accordance with the 2018 European Society of Cardiology / European Society of Hypertension guidelines definition), ≥18 and <65 years of age, on monotherapy treatment either with BBs or CCBs for at least 4 weeks before Visit 1 (screening).

2. Patients are able to understand and have freely given written informed consent at Screening Visit.

3. Patients who are able to comply with all study procedures and who are available for the duration of the study.

4. Ability to take oral medication and willing to adhere to the drug regimen.

5. Female patients are eligible to participate if not pregnant, or not breastfeeding and if they refrain from donating or storing eggs. For females of reproductive potential: use of highly effective contraception (eg. method of birth control throughout the study period and for 4 weeks after study completion defined as a method which results in a failure rate of <1% per year) such as:

   • Combined hormonal contraception (estrogen- and progestogen-containing) associated with inhibition of ovulation (oral, intravaginal, and transdermal).
   • Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, and implantable).
   • Intrauterine device.
   • Intrauterine hormone-releasing system.
   • Bilateral tubal occlusion.
   • Vasectomized partner (procedure conducted at least 2 months before the screening), (provided the partner is the sole sexual partner of the trial participant and that the vasectomized partner has received medical assessment of the surgical success).

6. A male patient must agree to use contraception during the whole study period and for at least 1 week after the last dose of study treatment and refrain from donating sperms during this period.

Exclusion Criteria:

1. Patients with significant history of hypersensitivity to nebivolol, amlodipine, other BBs or other dihydropyridines, or any related products (including excipients of the formulations) as outlined in the relevant Investigators Brochures, summary of product characteristics12,13 or local package inserts for NEB and AML.
2. Patients with serious disorders (in the opinion of the Investigator) which may limit the ability to evaluate the efficacy or safety of the tested medications, including cerebrovascular, cardiovascular, renal, respiratory, hepatic, gastrointestinal, endocrine or metabolic, hematological, or oncological, neurological, and psychiatric diseases. The same applies for immunocompromised and/or neutropenic patients.
3. Patients having a history of the following conditions within the last 6 months: myocardial infarction, unstable angina pectoris, percutaneous coronary intervention, bypass surgery, heart failure, hypertensive encephalopathy, valve replacement (transcatheter aortic valve implantation, mitraclip), cerebrovascular accident (stroke), or transient ischemic attack.
4. Patients with condition of hypotension with SBP <90 mmHg and/or DBP <60 mmHg.
5. Acute heart failure, cardiogenic shock, or episodes of heart failure decompensation requiring intravenous inotropic therapy.
6. Patients with secondary hypertension of any etiology including renal diseases, pheochromocytoma, Cushing's syndrome, hyperaldosteronism, renovascular disease, and thyroid disorders.
7. Patients with a narrowing of the aortic or bicuspid valve, an obstruction of cardiac outflow (obstructive, hypertrophic cardiomyopathy), obstruction of the outflow tract of the left ventricle (eg. high grade aortic stenosis) or symptomatic coronary disease.
8. Patients with severe renal impairment or renal transplant.
9. Patients with clinically relevant hepatic impairment.
10. Patients with sick sinus syndrome, including sino-atrial block.
11. Patients with second- or third-degree heart block (without a pacemaker).
12. Patients with history of bronchospasm and bronchial asthma.
13. Patients with untreated pheochromocytoma.
14. Patients with bradycardia (heart rate <60 bpm; <50 bpm in patients already on BBs treatment).
15. Patient with metabolic acidosis.
16. Patients with severe peripheral circulatory disturbances.
17. Participation in another interventional study within the last 4 weeks before Screening Visit (Visit 1).
18. Patients with diseases that, in the opinion of the Investigator, prevent a careful adherence to the protocol.
19. Patients using and not suitable for withdrawing the prohibited medications prior to the administration of study treatment.