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

Study Overview
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Brief Summary
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Open-label, inteRventional clinical Trial to assess EffIcacy and safety of the exteMporaneous combInation of Nebivolol and Ramipril in hypertenSIve pAtients.

Detailed Description
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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 NEB and RAM in reducing SBP and DBP in hypertensive patients uncontrolled by monotherapy. The trial will be conducted in approximately 20 investigational clinical sites in Bulgaria, Poland, and Hungary. Note: For the purpose of this study, uncontrolled BP is defined as sitting SBP/DBP ≥130/80 mmHg. Screening Visit 1 (Week -4): Hypertensive patients with SBP ranging from ≥140 to ≤179 mmHg and DBP ranging from ≥90 to ≤109 mmHg on treatment, for at least 30 days prior to screening, with NEB 5 mg or any other BB, or RAM 5 mg or any other ACE-i will be screened for eligibility (Visit 1). Patients that did not meet eligibility criteria will be considered as screening failures and will not be re-screened. 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 SBP/DBP <130/80 mmHg) will continue the same extemporaneous combination, while patients with uncontrolled BP levels 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: 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.

Official Title
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Open-label, Multicenter, multinAtionaL, inteRventional Clinical Trial to Assess Efficacy and Safety of the exteMporaneous combInation of Nebivolol and Ramipril in hypertenSIve pAtients - ARTEMISIA Study

Conditions
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Hypertension

Intervention / Treatment
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* Drug: Nebivolol 5 mg
* Drug: Ramipril 2.5/5/10 mg


Participation Criteria
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Eligibility Criteria
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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 to 65 years with hypertension with mean sitting SBP ≥140 mmHg and ≤179 mmHg and 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). 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 <60mmHg. 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 non-pharmacological treatment of hypertension. Any other contraindication to either NEB or RAM as per respective SmPC.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Nebivolol 5 mg<br>Single dose Phase (4 weeks): patients will be treated with Nebivolol 5 mg. Combination Phase (12 weeks): uncontrolled patients will be treated with the extemporaneous combination of Nebivolol 5 mg and Ramipril 2.5 mg for 4 weeks. Ramipril 2.5 mg will switched to Ramipril 5 mg in uncontrolled patients for further 4 weeks while controlled patients will continue with Nebivolol 5 mg/Ramipril 2.5 mg therapy. After 8 weeks Ramipril 5 mg will be switched to Ramipril 10 mg in the uncontrolled patients as well as Ramipril 2.5 mg will be switched to Ramipril 5 mg. Controlled patients will continue same therapy. | Drug: Nebivolol 5 mg<br>* 1 tablet of study medication to be administered orally according to instructions of Investigator.<br>Drug: Ramipril 2.5/5/10 mg<br>* 1 tablet of study medication to be administered orally according to instructions of Investigator.<br>|
| Active Comparator: Ramipril 2.5/5/10 mg<br>Single dose Phase (4 weeks): patients will be treated with Ramipril 2.5 mg. Combination Phase (12 weeks): uncontrolled patients will be treated with the extemporaneous combination of Nebivolol 5 mg and Ramipril 2.5 mg for 4 weeks. Ramipril 2.5 mg will switched to Ramipril 5 mg in uncontrolled patients for further 4 weeks while controlled patients will continue with Nebivolol 5 mg/Ramipril 2.5 mg therapy. After 8 weeks Ramipril 5 mg will be switched to Ramipril 10 mg in the uncontrolled patients as well as Ramipril 2.5 mg will be switched to Ramipril 5 mg. Controlled patients will continue same therapy. | Drug: Nebivolol 5 mg<br>* 1 tablet of study medication to be administered orally according to instructions of Investigator.<br>Drug: Ramipril 2.5/5/10 mg<br>* 1 tablet of study medication to be administered orally according to instructions of Investigator.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Outcome | Change in mean sitting DBP | From Visit 2 (Week 0) to Visit 5 (Week 12) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypertension, Combination Therapy, Nebivolol, Ramipril, Fixed Dose Combination