E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cardiovascular Disease Hypertensive patients |
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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 NEB 5 mg with RAM 2.5/5/10 mg in lowering sitting diastolic blood pressure (DBP) between Visit 2 (Week 0) and Visit 5 (Week 12) in patients with uncontrolled blood pressure (BP)* previously treated with NEB 5 mg or RAM 5 mg monotherapies for at least 30 days. .For the purpose of this study, uncontrolled BP is defined as sitting SBP/DBP ≥130/80 mmHg. |
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E.2.2 | Secondary objectives of the trial |
To assess the •antihypertensive efficacy of the extemporaneous combination of NEB5 mg with RAM 2.5/5/10 mg in lowering sitting DBP between Visit 2 (Week 0) and Visit 5 (Week 12) in patients with uncontrolled BP * previously treated with NEB5 mg or RAM5 mg monotherapies for at least 30 days. •antihypertensive efficacy of the extemporaneous combination of NEB5 mg with RAM 2.5/5/10 mg, in lowering sitting DBP and SBP between: - Visit 2(Week 0) and Visit 3(Week 4) - Visit 2(Week 0) and Visit 4(Week 8) •antihypertensive efficacy of the extemporaneous combination of NEB5 mg with RAM 2.5/5/10 mg by evaluating the patients who achieved the standard BP goal (sitting BP <140/90 mmHg) at Visit 5(Week 12). •antihypertensive efficacy of the extemporaneous combination of NEB 5 mg with RAM 2.5/5/10 mg by evaluating the patients who achieved the optimal BP goal (sitting BP <130/80 mmHg in patients <65years old/sitting BP<140/80 mmHg in patients ≥65 years old) at Visit 5 (Week 12).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patient will be considered eligible to be enrolled in the study only if he/she meets all the following inclusion criteria: 1. 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. 2. Male or female patients ≥18, 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). 3. Ability to take oral medication and willing to adhere to the drug regimen. 4. 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 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). 5. A male patient with female sexual partners 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. |
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E.4 | Principal exclusion criteria |
Any patient who meets any of the following criteria will not qualify for entry into the study: 1. Patients with documented history of hypersensitivity to NEB, RAM, other BBs or other ACE-is, or any related products (including excipients of the formulations) as outlined in the relevant Investigators Brochures, summary of product characteristics or local package inserts for Nebivolol and Ramipril. 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 <60 mmHg. 5. Acute heart failure (12 months before enrolment), cardiogenic shock, or episodes of heart failure decompensation requiring intravenous inotropic therapy. 6. Patients with secondary hypertension of any etiology including renal diseases, Cushing’s syndrome, hyperaldosteronism, renovascular disease and thyroid disorders. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the change in mean sitting SBP between Visit 2 (Week 0) and Visit 5 (Week 12). The statistical hypothesis will be defined as below: H0: There is no change or increase in the sitting SBP post combination therapy . H1: There is a difference in the sitting SBP post combination therapy. The above hypothesis will be tested as following: • Change from baseline in sitting DBP from prior and post combination therapy will be tested using paired t-test with one-sided significance level of 0.05%. The one-sided p-value obtained from the paired t-test will be presented. • Assumption of Normality will be investigated using Wilk-Shapiro test. If the data is found to be non-Normal, the paired t-test will be replaced by Wilcoxon signed rank test. • The primary endpoint will be summarized descriptively using n, mean, median, SD, Q1 (first quartile), Q3 (third quartile), minimum, and maximum. Sensitivity analysis The sensitivity analyses will be conducted using the PP population. The PP population will be used to assess the robustness of the results obtained using the mITT population. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint will be assessed before and after Assessment period at Week 12, by a paired t-test using the Modified Intent-to-Treat population and the Per-Protocol population. A sample size of 215 achieves 90% power to detect a Systolic BP difference of -2.4 mmHg between the null hypothesis mean of 3.0 mmHg and the alternative hypothesis of 5.4 mmHg with a known standard deviation of 12.0 mmHg and with a significance level (alpha) of 0.05 using a one sided one-sample t-test. Assuming an approximate 20% screen failure/drop-out rate, two-hundred and seventy (270) patients with uncontrolled hypertension are planned to be screened to obtain at least 215 completed patients at the end of the study (Visit 5) (patients who complete all visits including End of Study (EoS) Visit [Visit 5]). |
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E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints • Change in mean sitting DBP between Visit 2 (Week 0) and Visit 5 (Week 12). • Change in mean sitting DBP and SBP between: o Visit 2 (Week 0) and Visit 3 (Week 4) o Visit 2 (Week 0) and Visit 4 (Week 8) • Number and proportion of patients achieving the standard BP goal (sitting BP<140/90 mmHg) at Visit 5 (Week 12). • Number and proportion of patients achieving the optimal BP goal (sitting BP<130/80 mmHg in patients < 65 years old/sitting BP<140/80 mmHg in patients ≥ 65 years old) at Visit 5 (Week 12). • Adherence to treatment as (% of doses taken/doses to be taken) at Visit 2 (Week 0), at Visit 3 (Week 4), at Visit 4 (Week 8) and at Visit 5 (Week 12). • Safety and tolerability of the monotherapies (NEB 5 mg and RAM 5 mg) and of the extemporaneous combination (NEB/RAM 5/2.5 mg, NEB/RAM 5/5 mg, NEB/RAM 5/10 mg) measured by incidence, intensity (severity), seriousness of adverse events 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), laboratory parameters, and use of concomitant medications at Visit 2 (Week 0), Visit 3 (Week 4), Visit 4 (Week 8), and Visit 5 (Week 12). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
measured in • Change in mean sitting DBP between Visit 2 (Week 0) and Visit 5 (Week 12). • Change in mean sitting DBP and SBP between: o Visit 2 (Week 0) and Visit 3 (Week 4) o Visit 2 (Week 0) and Visit 4 (Week 8) • Achieved the standard BP goal (sitting BP<140/90mmHg) at Visit 5(Week 12) • Achieved optimal BP goal (sitting BP<130/80mmHg in patients <65 years old/sitting BP<140/80mmHg in patients ≥65 years old) at Visit 5(Week 12). •Adherence to treatment estimated as % of dose taken/doses to be taken at Visit 2 (Week 0), at Visit 3 (Week 4), at Visit 4 (Week 8), and at Visit 5 (Week 12). •Safety and tolerability evaluation - at Visit 2 (Week 0), Visit 3 (Week 4), Visit 4 (Week 8) and Visit 5 (Week 12). |
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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 | Yes |
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 | 13 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 26 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 7 |