Effectiveness and Safety of Combination of Nebivolol and Zofenopril in Hypertensive patIents Versus Each Monotherapy (Masaccio)

Open-label, Multicenter, Multinational, Interventional Clinical Trial to Assess Effectiveness and SAfety of the Extemporaneous Combination of Nebivolol and Zofenopril Calcium in Grade 1 to 2 Hypertensive patIents Versus Each mOnotherapy

Open-label, interventional clinical trial to assess effectiveness and safety of the extemporaneous combination of nebivolol and zofenopril calcium in grade 1 to 2 hypertensive patients versus each monotherapy

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: Zofenopril 30 mg; Drug: Zofenopril 30 mg + Nebivolol 5 mg; Drug: Nebivolol 5 mg

Detailed Description

This is a study with 2 periods (a run-in period of 4 weeks and an assessment period of 8 weeks). Grade 1-2 hypertensive patients (blood pressure [BP] ranging from ≥140/90 mmHg to ≤179/109 mmHg) on treatment with any angiotensin converting enzyme-inhibitors (ACEi) or beta blockers (BBs) including ZOF 30 mg or NEB 5 mg respectively will be screened for eligibility (Visit 1).

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

• Patients on ZOF 30 mg or NEB 5 mg will continue the same therapy for 4 weeks
• Patients on any other ACE-i will be assigned to monotherapy with ZOF 30 mg while patients on any other BB will be assigned to monotherapy with NEB 5 mg, respectively, for 4 weeks.

After the 4 weeks of monotherapy in the run-in period, if BP at Visit 2, remains uncontrolled (sitting Systolic Blood Pressure/Diastolic Blood Pressure >130/80 mmHg) despite an adherence to the treatments ranging from 80% to 120%, the patients will start treatment (Week 0, Visit 2) with the extemporaneous combination of NEB 5 mg/ZOF 30 mg (NEB/ZOF) and will be assessed for further 8 weeks (assessment period).

If the patients, at Visit 2 after the Run-In period, have controlled BP (sitting Systolic Blood Pressure/Diastolic Blood Pressure ≤130/80 mmHg), and/or do not tolerate the treatment, and/or do not maintain the adherence to the therapy (range from 80% to 120%), these patients will not be continued further in the study.

At the end of the assessment period (Visit 3) the anti-hypertensive effect of the extemporaneous combination of NEB 5 mg and ZOF 30 mg will be evaluated.

A total number of 290 patients will be screened considering 25% of drop-out rate, to obtain approximately 216 completed patients at the end of the study.

• Study Type: Interventional
• Enrollment (Actual): 283
• Phase: Phase 4

Contacts and Locations

Study Locations

• Italy
  • Milano, Italy, 20089
    • Istituto Clinico Humanitas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female Caucasian uncontrolled hypertensive patients (see definition in criterion 3) ≥18 and <65 years of age, in monotherapy either with ACE-i or BBs since at least 1 month, at Screening (Visit 1)
2. Patients are able to understand and have freely given written informed consent at Screening
3. Patients with mean sitting Systolic Blood Pressure ≥140 mmHg and ≤179 mmHg and/or mean sitting Diastolic Blood Pressure ≥ 90 mmHg and ≤109 mmHg at Screening (Visit 1)
4. Patient who are able to comply with all study procedures and who are available for the duration of the study
5. Ability to take oral medication and willing to adhere to the drug regimen
6. A 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 (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 less than 1% per year) and also must refrain from donating or storing eggs during this time. Highly effective contraception methods can be: a Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) b Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) c Intrauterine device (IUD) d Intrauterine hormone-releasing system (IUS) e Bilateral tubal occlusion f Vasectomized partner (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)
7. A male patient with female partner 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. Known contraindications, allergies, or hypersensitivities to any of the study medications or excipient as outlined in the investigators brochures (IBs), summary of product characteristics (SmPCs) or local package inserts for NEB and ZOF
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 within the last 6 months:

   myocardial infarction, unstable angina pectoris, percutaneous coronary intervention, bypass surgery, heart failure, hypertensive encephalopathy, cerebrovascular accident (stroke), or transient ischemic attack

4. Patients with secondary hypertension of any etiology such as renal diseases, pheochromocytoma, or Cushing's syndrome
5. 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) or symptomatic coronary disease
6. Patients with clinical evidence of renal disease as per the Investigator's judgement (including renovascular occlusive disease, nephrectomy and/or renal transplant, bilateral renal artery stenosis or unilateral renal artery stenosis in a solitary kidney, or severe renal impairment)
7. History of angioneurotic edema
8. Patients with clinically relevant hepatic impairment
9. Patients with sick sinus syndrome, including sino-atrial block
10. Patients with second- or third-degree heart block (without a pacemaker)
11. History of bronchospasm and bronchial asthma
12. Patients with bradycardia (heart rate <60 bpm)
13. Patient with metabolic acidosis
14. Patients with severe peripheral circulatory disturbances
15. Participation in another study within the last 4 weeks
16. Patients with diseases that, in the opinion of the Investigator, prevent a careful adherence to the protocol
17. Pregnant and breastfeeding women. A pregnancy test will be performed on all women of childbearing potential at each study visit

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Zofenopril arm; MONOTHERAPY PERIOD (one month): patients will be treated with Zofenopril 30 mg. COMBINATION THERAPY PERIOD (two months) patients will be treated with the extemporaneous combination of Zofenopril 30 mg and Nebivolol 5mg	Drug: Zofenopril 30 mg; Film-Coated tablets administered as one single dose to be taken in the morning (from 6 am to 10 am) with no restriction on food intake; Drug: Zofenopril 30 mg + Nebivolol 5 mg; Both Film coated tablets of Zofenopril 30 mg and Nebivolol 5 mg Tablets will be taken in the morning (from 6 am to 10 am) with no restriction on food intake
Active Comparator: Nebivolol arm; MONOTHERAPY PERIOD (one month): patients will be treated with Nebivolol 5 mg. COMBINATION THERAPY PERIOD (two months) patients will be treated with the extemporaneous combination of Zofenopril 30 mg and Nebivolol 5 mg	Drug: Zofenopril 30 mg + Nebivolol 5 mg; Both Film coated tablets of Zofenopril 30 mg and Nebivolol 5 mg Tablets will be taken in the morning (from 6 am to 10 am) with no restriction on food intake; Drug: Nebivolol 5 mg; Tablet administered as one single dose to be taken in the morning (from 6 am to 10 am) with no restriction on food intake

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Mean Sitting DBP Between Week 0 (Visit 2) and Week 8 (Visit 3)	To assess the antihypertensive efficacy of the extemporaneous combination of Nebivolol (NEB) 5 mg and Zofenopril (ZOF) 30 mg in lowering sitting diastolic blood pressure (DBP) from baseline (Visit 2) after 8 weeks of treatment (Visit 3), in patients with uncontrolled blood pressure (BP) who were previously treated with NEB or ZOF monotherapies for at least 4 weeks.	From Baseline (Week 0 - Visit 2) to week 8 (Visit 3)

Collaborators and Investigators

• Sponsor: Menarini International Operations Luxembourg SA
• Investigators: Principal Investigator: Massimo Volpe, Professor, University "Sapienza" Rome

Study record dates

Study Major Dates

• Study Start (Actual): May 26, 2021
• Primary Completion (Actual): December 22, 2021
• Study Completion (Actual): December 22, 2021

Study Registration Dates

• First Submitted: February 16, 2022
• First Submitted That Met QC Criteria: February 16, 2022
• First Posted (Actual): February 25, 2022

Study Record Updates

• Last Update Posted (Actual): September 20, 2024
• Last Update Submitted That Met QC Criteria: May 21, 2024
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Hypertension; Combination Therapy; Nebivolol; Fixed Dose Combination; Zofenopril
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Enzyme Inhibitors; Protease Inhibitors; Adrenergic Agonists; Angiotensin-Converting Enzyme Inhibitors; Adrenergic beta-Agonists; Adrenergic beta-1 Receptor Agonists; Nebivolol; Captopril; Zofenopril
• Other Study ID Numbers: MEIN/19/ZoNe-HYP/001; 2020-002340-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No