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
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 266
- 试验地点
- 1
- 主要终点
- Primary Outcome: Change in Mean Sitting SBP
研究概览
简要总结
Open-label, inteRventional clinical Trial to assess EffIcacy and safety of the exteMporaneous combInation of Nebivolol and Ramipril in hypertenSIve pAtients.
详细描述
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):
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Nebivolol 5 mg
MONOTHERAPY PERIOD 1 (4 weeks): Eligible patients entered a 4 weeks run-in period (week -4 to week 0) on the same day of the screening visit.
Patients previously receiving Neb 5 mg continued the same treatment, while patients receiving any other BBs were switched to Neb 5 mg.
COMBINATION THERAPY PERIOD 2 (12 weeks): During the Assessment period of 12 weeks (week 0_Baseline to week 12) 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 be up-titrated 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 up-titrated to Ramipril 10 mg in the uncontrolled patients as well as Ramipril 2.5 mg will be up-titrated to Ramipril 5 mg. Controlled patients will continue same therapy.
干预措施: Nebivolol 5 mg (Drug)
Nebivolol 5 mg
MONOTHERAPY PERIOD 1 (4 weeks): Eligible patients entered a 4 weeks run-in period (week -4 to week 0) on the same day of the screening visit.
Patients previously receiving Neb 5 mg continued the same treatment, while patients receiving any other BBs were switched to Neb 5 mg.
COMBINATION THERAPY PERIOD 2 (12 weeks): During the Assessment period of 12 weeks (week 0_Baseline to week 12) 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 be up-titrated 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 up-titrated to Ramipril 10 mg in the uncontrolled patients as well as Ramipril 2.5 mg will be up-titrated to Ramipril 5 mg. Controlled patients will continue same therapy.
干预措施: Ramipril 2.5/5/10 mg (Drug)
Ramipril 2.5/5/10 mg
MONOTHERAPY PERIOD 1 (4 weeks): Eligible patients entered a 4 week run-in (week -4 to week 0) period on the same day of the screening visit.
Patients previously receiving RAM 5 mg continued the same treatment, while patients receiving any other ACE-i were switched to RAM 5 mg.
COMBINATION THERAPY PERIOD 2 (12 weeks): During the Assessment period of 12 weeks (week 0_Baseline to week 12) 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 be up-titrated 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 up-titrated to Ramipril 10 mg in the uncontrolled patients as well as Ramipril 2.5 mg will be up-titrated to Ramipril 5 mg. Controlled patients will continue same therapy.
干预措施: Nebivolol 5 mg (Drug)
Ramipril 2.5/5/10 mg
MONOTHERAPY PERIOD 1 (4 weeks): Eligible patients entered a 4 week run-in (week -4 to week 0) period on the same day of the screening visit.
Patients previously receiving RAM 5 mg continued the same treatment, while patients receiving any other ACE-i were switched to RAM 5 mg.
COMBINATION THERAPY PERIOD 2 (12 weeks): During the Assessment period of 12 weeks (week 0_Baseline to week 12) 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 be up-titrated 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 up-titrated to Ramipril 10 mg in the uncontrolled patients as well as Ramipril 2.5 mg will be up-titrated to Ramipril 5 mg. Controlled patients will continue same therapy.
干预措施: Ramipril 2.5/5/10 mg (Drug)
结局指标
主要结局
Primary Outcome: Change in Mean Sitting SBP
时间窗: 12 weeks of combination therapy treatment. From study Visit 2 (Week 0) to study Visit 5 (Week 12)
To assess the antihypertensive efficacy of the extemporaneous combination of Nebivolol 5 mg in combination with Ramipril 2.5 mg or 5 mg or 10 mg in lowering the sitting systolic BP between Visit 2(Week 0) and Visit 5 (Week 12) in patients with uncontrolled BP previously treated with Nebivolol 5 mg or Ramipril 5 mg monotherapies for at least 4 weeks during run-in period.
次要结局
未报告次要终点