E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10020772 |
E.1.2 | Term | Hypertension |
E.1.2 | System Organ Class | 10047065 - Vascular disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the antihypertensive efficacy of the extemporaneous combination of nebivolol (NEB) 5 mg with amlodipine (AML) 5 mg or AML 10 mg in lowering the sitting diastolic blood pressure (DBP) between Visit 2 (Week 0) and Visit 4 (Week 8) in patients with uncontrolled BP, previously treated with NEB 5 mg or AML 5 mg monotherapies for at least 4 weeks. |
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E.2.2 | Secondary objectives of the trial |
1.To assess the antihypertensive efficacy of the extemporaneous combination of NEB 5mg with AML 5mg or AML 10mg in lowering SBP between Visit 2 and 4 in patients with uncontrolled BP previously treated with NEB 5mg or AML 5mg monotherapies for at least 4 weeks. 2.To assess the antihypertensive efficacy of the extemporaneous combination of NEB/AML 5/10mg versus extemporaneous combination NEB/AML 5/5mg, in lowering sitting DBP and SBP between Visit 3 and 4 in patients with uncontrolled BP previously treated with NEB 5mg or AML 5mg monotherapies for at least 4 weeks. 3.To assess the antihypertensive efficacy of the extemporaneous combination of NEB 5mg with AML 5mg or AML 10mg by evaluating the patients who achieve BP goal at Visit 2, 3, and 4. 4.To assess the compliance to the treatment at Visit 2, 3, and 4. 5.To evaluate the safety and tolerability of the monotherapies (NEB 5mg and AML 5mg) and of the extemporaneous combinations (NEB 5mg and AML 5/10mg) after 8 weeks of treatment. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 ESC/ESH 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 patient 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. |
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E.4 | Principal exclusion criteria |
1. 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 characteristics (SmPC) 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 <60mmHg. 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, 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 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in mean sitting DBP between Visit 2 (Week 0) and Visit 4 (Week 8). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Visit 2 (Week 0) and Visit 4 (Week 8) |
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E.5.2 | Secondary end point(s) |
1. Change in mean sitting SBP between Visit 2 (Week 0) and Visit 4 (Week 8). 2. Change in mean sitting DBP and SBP between Visit 3 (Week 4) and 4 (Week 8) in patients receiving extemporaneous combination of NEB/AML 5/5 mg versus patients uptitrated to the extemporaneous combination of NEB/AML 5/10 mg. 3. Number and proportion of patients achieving the BP goal (sitting SBP/DBP <130/80 mmHg) at Visit 2 (Week 0), Visit 3 (Week 4) and Visit 4 (Week 8). 4. Adherence to the treatments (% of doses taken/doses to be taken) at Visit 2 (Week 0), Visit 3 (Week 4), and Visit 4 (Week 8). 5. Safety and tolerability of the monotherapies (NEB 5 mg and AML 5 mg) and of the extemporaneous combinations (NEB 5 mg and AML 5mg or AML 10 mg) will be measured by incidence, intensity (severity), seriousness of Adverse Events (AEs) during the study period, (screening, run-in period and assessment period), relationship to the study treatments, clinically significant abnormal change in vital signs, electrocardiogram (ECG) (only at Visit 1 and Visit 4), laboratory parameters (if applicable) at Visit 2 (Week 0), Visit 3 (Week 4), and Visit 4 (Week 8). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Visit 2 (Week 0) and Visit 4 (Week 8) 2. Visit 3 (Week 4) and 4 (Week 8) 3. Visit 2 (Week 0), Visit 3 (Week 4) and Visit 4 (Week 8) 4. Visit 2 (Week 0), Visit 3 (Week 4), and Visit 4 (Week 8) 5. Visit 2 (Week 0), Visit 3 (Week 4), and Visit 4 (Week 8) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 30 |
E.8.9.2 | In all countries concerned by the trial months | 9 |