| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with mild to moderate essential arterial hypertension AND primary hypercholesterolemia or mixed dyslipidaemia (LDL-c < 4.9 mmol/L or <189.5 mg/dl) with moderate, high or very high risk for cardiovascular event. |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with mild to moderate essential arterial hypertension AND primary hypercholesterolemia or mixed dyslipidaemia with moderate, high or very high risk for cardiovascular event. |
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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 | 10062060 |
| E.1.2 | Term | Hyperlipidaemia |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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| 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 | 10015488 |
| E.1.2 | Term | Essential 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 |
Main objective is to assess response rate defined as dual target achievement after 12 weeks of treatment with FDC of rosuvastatin/valsartan:
o in patients with mild to moderate essential AH AND primary hypercholesterolemia or mixed dyslipidaemia (type IIb) (LDL-c < 4.9 mmol/L or < 189.5 mg/dL) with moderate*, high* or very** high risk for CV event
with additional special focus on effects on arterial properties, 24-h BP variability and BP and LDL-c visit-to-visit variability.
* CV risk calculated according to ESC guidelines on CV disease prevention in clinical practice.
** Among very high risk only patients with diabetes mellitus without target organ damage can be included.
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Patients with mild to moderate essential AH* AND primary hypercholesterolemia or mixed dyslipidaemia (LDL-c < 4.9 mmol/L or <189.5 mg/dl) with moderate, high or very*** high risk for CV event.
• Female and male patients, aged 18-75 years
• Written informed consent
• Ability to adhere to trial protocol
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
Additional explanation of inclusion criteria:
o naïve patients with newly diagnosed AH* and newly diagnosed primary hypercholesterolemia or mixed dyslipidaemia** with moderate, high or very high*** risk for CV event
o Patients with newly diagnosed primary hypercholesterolemia or mixed dyslipidaemia** and controlled or uncontrolled* AH
o Patients with newly diagnosed mild to moderate essential AH* and controlled or uncontrolled** primary hypercholesterolemia or mixed dyslipidaemia
o Patients with uncontrolled AH* and uncontrolled primary hypercholesterolemia or mixed dyslipidaemia**
*SBP 140-179 mmHg and AND DBP 90-109 mmHg
** type IIb (LDL-c < 4.9 mmol/L or < 189.5 mg/dl)
*** Among very high risk patients only patients with diabetes mellitus without target organ damage can be included.
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| E.4 | Principal exclusion criteria |
• Patients unsuccessfully treated with 2 or more different active substances at once for lowering blood pressure whenever in the past.
• Secondary AH (e.g. pheochromocytoma, primary aldosteronism, renal artery stenosis).
• Suspected resistant hypertension or grade 3 of hypertension (SBP≥180 mmHg and/or DBP≥110mmHg).
• LDL-c level equal or higher than 4.9 mmol/L (189,5 mg/dL)
• Diabetes with target organ damage (e. g. proteinuria).
• Previous CV event (e.g. MI, transient ischemic attack, stroke…).
• History of adverse reactions or hypersensitivity associated with the use of active substances, any other angiotensin II receptor blocker, any other statin or any components of the investigational medicinal products used in the trial.
• Concomitant treatment with:
- antihypertensive drugs used for other indication than AH (e.g. tachyarrhythmia, glaucoma) less than 3 months before the study or in changed dosages less than 3 months before the study
- drugs that may produce an increase in BP: systemic corticosteroids, hormonal medications (chronically used oral contraceptives are allowed), adrenergic receptor agonists, cyclosporine, erythropoietin, migraine medications such as triptans.
- other lipid-lowering drugs (besides those allowed in protocol): statins, fibrates, nicotinic acid, bile acid exchangers, probucol, ezetimibe.
- drugs that may increase the incidence of myositis, myopathy and rhabdomyolyisis if used with HMG-CoA reductase inhibitors (as rosuvastatin) fibric acid derivates including gemfibrozil, cyclosporine, nicotinic acid, azole antifungals, protease inhibitors and macrolide antibiotic, systemic formulation of fusidic acid or within 7 days of stopping fusidic acid treatment.
-drugs which increase systemic exposure to rosuvastatin: various protease inhibitors (for ex. atazanavir, lopinavir, tipranavir) in combination with ritonavir.
-lithium
-acetylsalicylic acid in a dose more than 3 g per day
-heparin
• Patients to whom β-blocker therapy cannot be discountinued in one day.
• Renal dysfunction (creatinine clearance < 60 ml/min).Predisposition for development of renal failure (sepsis, hypotension, trauma, severe metabolic, endocrine and electrolyte disorders, uncontrolled seizures).
• Hepatic impairment (mild, moderate and severe), biliary cirrhosis and cholestasis, active liver disease including unexplained, persistent elevations of serum transaminases and any serum transaminase elevation exceeding 3 x the upper limit of normal (ULN).
• Pregnancy and lactation
• Personal or family history of hereditary muscular diseases and previous history of muscular toxicity with use of statins or fibrates, rabdomyolysis, myopathy.
• Elevated CK levels at baseline (>5xULN).
• Interstitial lung disease.
• History of angioedema (hereditary, idiopathic or related to previous treatment).
• Hypertensive encephalopathy.
• Normal average 24-hour SBP AND DBP obtained by 24h ABPM (<130/80 mmHg at baseline) (if patient’s 24h BP is over 130/80 mmHg, but patient’s office BP below 140/90 mmHg, patient is not included in the trial)*
• Less than 70 % valid measurements obtained by 24h ABPM device.
• A more than 3-hour discrepancy in 24h ABPM.
• Hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
• Pathological clinical states that could affect patient’s compliance or have any impact on patient’s survival rate (malignant diseases, alcohol abuse, medicine addiction, psychiatric diseases)
• Patients who under the opinion of the investigator will not be compliant with the trial protocol.
• Any other life-threatening illness.
*this doesn’t apply to patients with controlled hypertension
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| E.5 End points |
| E.5.1 | Primary end point(s) |
To assess response rate defined as dual target achievement* after 12 weeks of treatment with Ravalsyo®.
*proportion of patients achieving normal office BP and normal LDL-c levels at the same time
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After 12 weeks of treatment |
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| E.5.2 | Secondary end point(s) |
• To assess response rate defined as dual target achievement* after 4 and 8 weeks of treatment with Ravalsyo®.
• To assess mean change from baseline in SBP, DBP and LDL-c after 4, 8 and 12 weeks of treatment with Ravalsyo®.
• To assess proportions of patients treated with one or both RMs at the end of trial.
• To assess response rate defined as dual target achievement* among patients, treated with Ravalsyo® and with one or both RMs at the end of trial.
• To assess proportion of compliant patients at each control visit.
• To assess visit-to-visit variability of BP and LDL-c [Time Frame: baseline, week 4, week 8, week 12].
• To assess proportion of patients reaching a reduction of central (systolic) BP (in 24-hour measurement) below 120 mmHg [Time Frame: baseline, week 12].
• To assess proportion of patients reaching a reduction of PWV (in 24-hour measurement) for at least 0.5 m/s [Time Frame: baseline, week 12].
• To assess reduction of central pulse pressure [Time Frame: baseline, week 12].
• To assess reduction of total vascular resistance [Time Frame: baseline, week 12].
• To assess proportion of patients reaching a reduction of SBP and DBP variability expressed as reduction of day-night standard deviation (SDdn) by at least 0.5 and that of average real variability by at least 0.5.
• To assess response rate after 12 weeks in average 24-hour SBP and DBP, average awake time SBP and DBP, and average sleep time SBP and DBP, all obtained by 24h ABPM: proportion of patients reaching normal average 24h ABPM SBP and DBP (<130/80), normal average awake time SBP and DBP (<135/85) and normal average sleep time SBP and DBP (<120/70).
Subgroup 1: patients with baseline mild** HT
• To assess response rate defined as dual target achievement* after 4, 8 and 12 weeks of treatment with Ravalsyo®.
• To assess mean change from baseline in SBP, DBP and LDL-c after 4, 8 and 12 weeks of treatment with Ravalsyo®.
Subgroup 2: naïve patients
• To assess response rate defined as dual target achievement* after 4, 8 and 12 weeks of treatment with Ravalsyo®.
• To assess mean change from baseline in SBP, DBP and LDL-c after 4, 8 and 12 weeks of treatment with Ravalsyo®.
*proportion of patients achieving normal office BP and LDL-c levels at the same time
** SBP 140-159 mmHg and DBP 90-99 mmHg; for diabetic patients DBP 85-99mmHg
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After 4/ 8 / 12 weeks of treatment |
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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 | Yes |
| 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 | 1 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 |
| Hungary |
| Poland |
| Russian Federation |
| Serbia |
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
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