Open-label inteRventional Clinical Trial to Assess Efficacy and Safety of the exteMporaneous combInation of Nebivolol and Ramipril in hypertenSIve pAtients

This is a Phase IV, interventional, multicenter, open-label, multinational study with 2 study periods (a Run-in period of 4 weeks and an Assessment period of 12 weeks) to assess the efficacy and safety of the extemporaneous combination of Nebivolol (NEB) and Ramipril (RAM) in reducing Systolic blood pressure (SBP) and Diastolic blood pressure (DBP) in hypertensive patients uncontrolled by monotherapy.

The trial was conducted in 16 investigational clinical sites in Bulgaria, Poland, and Hungary.

Note: For the purpose of this study, uncontrolled blood pressure (BP) is defined as sitting SBP/DBP:

• ≥ 130/80 mmHg in patients < 65 years old
• ≥ 140/80 mmHg in patients ≥ 65 years old

Screening Visit 1 (Week -4):

Hypertensive patients with SBP ranging from ≥ 140 to ≤ 179 mmHg and/or DBP ranging from ≥ 90 to ≤ 109 mmHg on treatment, for at least 30 days prior to screening, with NEB 5 mg or any other Beta Blockers (BBs), or RAM 5 mg or any other Angiotensin-converting enzyme inhibitors (ACE-i) will be screened for eligibility (Visit1). Patients that did not meet eligibility criteria will be considered as screening failures and will not be re-screened.

Run-in period from Visit 1 (Week -4) to Visit 2 (Week 0):

On the same day of the Screening Visit, eligible patients will enter a Run-in period, during which:

• Patients receiving NEB 5 mg or RAM 5 mg will continue the same therapy for 4 weeks.
• Patients on any other BB will be assigned to monotherapy with NEB 5 mg while patients on any other ACE-i will be assigned to monotherapy with RAM 5 mg for 4 weeks. The study is designed in order to ensure that 1:1 ratio between patients in the NEB and RAM arms will be achieved.

Assessment period from Visit 2 (Week 0) to Visit 5 (Week 12):

After 4 weeks (± 2 days) of the Run-in period of monotherapy (Week 0), BP will be further assessed at Visit 2. Patients with uncontrolled BP levels (sitting BP ≥ 130/80 mmHg in patients < 65 years old/sitting BP ≥ 140/80 mmHg in patients ≥ 65 years old) at Visit 2, with adequate 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/RAM 5/2.5 mg. Patients with controlled BP levels (sitting BP < 130/80 mmHg in patients < 65 years old/sitting BP < 140/80 mmHg in patients ≥ 65 years old) and/or who do not tolerate the treatment or have an adherence range below 80% or above 120%, will be withdrawn from the study (drop-out patients).

After 4 weeks ± 2 days in the Assessment period (Week 4), patients BP will be further evaluated at Visit 3: patients with controlled BP levels (sitting BP < 130/80 mmHg in patients < 65 years old/sitting BP < 140/80 mmHg in patients ≥ 65 years old) will continue the same extemporaneous combination, while patients with uncontrolled BP levels (sitting BP ≥ 130/80 mmHg in patients < 65 years old/sitting BP ≥ 140/80 mmHg in patients ≥ 65 years old) will be up-titrated from NEB/RAM 5/2.5 mg to NEB/RAM 5/5 mg for further 4 weeks ± 2 days.

After further 4 weeks ± 2 days (Week 8) the BP will be assessed again (Visit 4): controlled patients will continue the same extemporaneous combination, while uncontrolled patients:

• if on NEB/RAM 5/2.5 mg, will be up-titrated to NEB/RAM 5/5 mg for further 4 weeks

± 2 days (Visit 5, Week 12);

• if on NEB/RAM 5/5 mg, will be up-titrated to NEB/RAM 5/10 mg for further 4 weeks ± 2 days (Visit 5, Week 12).

At the end of the Assessment period (12 weeks ± 2 days), at Visit 5, the antihypertensive effect of the extemporaneous combination (NEB/RAM 5/2.5 mg, NEB/RAM 5/5 mg or NEB/RAM 5/10 mg) will be evaluated.

To correctly evaluate the additional effect of the combination therapy, the number of patients with uncontrolled BP on NEB or RAM monotherapy needs to be balanced at Visit 2. To maintain a 1:1 ratio during the Assessment period a cap of 110 patients for each treatment arm (i.e., NEB and RAM) will be included at Visit 2 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 entrance in the Assessment period for 1 of the 2 tested drugs will deviate more than 5%, a corrective measure will be initiated: according to the enrollment site statistics, 1 or more sites will be informed to enroll a greater number of patients being treated with the least represented drug in the Assessment period.

Inclusion criteria

Patient will be considered eligible to be enrolled in the study only if he/she meets all the following inclusion criteria:

• Willing to comply with all study activities and procedures for the duration of the study and provided signed, written informed consent prior to any study procedures at Screening Visit.
• Male or female patients aged ≥ 18 years with hypertension with mean sitting SBP ≥ 140 mmHg and ≤ 179 mmHg and/or mean sitting DBP ≥ 90 mmHg and

≤ 109 mmHg at Visit 1 (screening), while on monotherapy treatment either with BBs (NEB 5 mg or any dose if other BB) or ACE-is (RAM 5 mg or any dose if other ACE-i) for at least 30 days before Visit 1 (screening) and, as per Investigator's judgement, is deemed appropriate for a combination treatment with BB and ACE-i.

• Ability to take oral medication and willing to adhere to the drug regimen.
• Female patient of childbearing potential is eligible to participate if she is not pregnant, or not breastfeeding. A woman is considered fertile following menarche and until becoming postmenopausal unless permanently sterile. Women of childbearing potential must agree to use of highly effective contraception (e.g., 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 less than 1% per year) and also must refrain from donating or storing eggs during this time. Highly effective contraception methods can be:

• 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 that partner is the sole sexual partner of the trial participant and that the vasectomized partner has received medical assessment of the surgical success).
• 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 sperm during this period.

Exclusion criteria

Any patient who meets any of the following criteria will not qualify for entry into the study:

• Patients with documented history of hypersensitivity to NEB, RAM, other BBs or other ACE-is, or any related products, excipients of the formulations, as outlined in the relevant Investigator's Brochure (IB), summary of product characteristics (SmPC) or local package inserts for Nebivolol and Ramipril.
• 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.
• 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.

• Patients with condition of hypotension with SBP < 90 mmHg and/or DBP < 60 mmHg.
• Acute heart failure (12 months before enrolment), cardiogenic shock, or episodes of heart failure decompensation requiring intravenous inotropic therapy.
• Patients with secondary hypertension of any etiology including renal diseases, Cushing's syndrome, hyperaldosteronism, renovascular disease and thyroid disorders.
• Patients with severe heart failure (New York Heart Association classification III-IV) 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 (e.g., high grade aortic stenosis) or symptomatic coronary disease.
• Patients with clinical evidence of renal disease (including significant bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney), severe renal impairment or renal transplant.
• Patients with clinically relevant hepatic impairment.
• Patients with a history of angioneurotic edema.
• Patients with sick sinus syndrome, including sino-atrial block.
• Patient with second- and third-degree heart block (without a pacemaker).
• History of bronchospasm and bronchial asthma.
• Untreated phaeochromocytoma.
• Patients with bradycardia (heart rate < 60 bpm; < 50 bpm in patients already on BBs treatment).
• Patient with history of metabolic acidosis.
• Patients with severe peripheral circulatory disturbances.
• Participation in another interventional study within the last 30 days before Screening Visit (Visit 1).
• Patients with diseases that, in the opinion of the Investigator, prevent a careful adherence to the protocol.
• Patients using and not suitable for withdrawing the prohibited medications prior to the administration of study treatment.
• Pregnant and breastfeeding women. NOTE: a pregnancy test will be performed on all women of childbearing potential at each study visit.
• Patients with medical history of cirrhosis (Child Pugh class B or higher).
• History of unexplained syncope within the prior 2 years, or a known syncopal disorder.
• Patients who received renal denervation in the last 3 years or other device-based nonpharmacological treatment of hypertension.
• Any other contraindication to either NEB or RAM as per respective SmPC.