Management of Newly Diagnosed and Uncontrolled Hypertension With Fixed-Dose Combination of Perindopril/Amlodipine and Perindopril/Indapamide/Amlodipine

Hypertension Clinical Trial

— PRECIOUS  

Official title:

Fixed-Dose Combination of Perindopril/Amlodipine (Amlessa®) and Fixed-Dose Combination of Perindopril/Indapamide /Amlodipine (Co-Amlessa®) - Contribution to Management in Newly Diagnosed and Uncontrolled Hypertensive Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03738761
• Other study ID #: KCT 06/2017
• Secondary ID: 2017-001596-23
• Status: Completed
• Phase: Phase 4
• Start date: February 13, 2018
• Est. completion date: September 27, 2019

Study information

• Verified date: September 2019
• Source: KRKA
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

PRECIOUS Study aims to evaluate the efficacy and safety of therapy with fixed-dose combination (FDC) of perindopril/amlodipine (Amlessa®) and FDC of perindopril/indapamide/amlodipine (Co-Amlessa®) on blood pressure reduction in both previously untreated patients and patients with previous antihypertensive therapy.

Adult patients with AH who are treatment-naïve with systolic blood pressure (SBP) from 150 mmHg or higher AND/OR diastolic blood pressure (DBP) from 95 mmHg or higher (SBP ≥ 150 mm AND/OR DBP ≥ 90 mmHg for patients with type 2 diabetes mellitus ) and uncontrolled patients on mono, dual or triple antihypertensive therapy with systolic blood pressure (SBP) from 140 mmHg or higher AND/OR diastolic blood pressure (DBP) from 90 mmHg or higher (SBP ≥ 140 AND/OR DBP ≥ 85 mmHg for patients with type 2 diabetes mellitus) will be invited to participate in this study.

During 16-week trial, seven study visits are planned. At first study visit physical examination, medical history, BP measurement, electrocardiogram (ECG), laboratory analysis and of Ambulatory Blood Pressure Measurement (ABPM) will be performed. Based on their previous antihypertensive therapy, patients will receive to treatment with either Amlessa® or Co-Amlessa® for the duration of 16 weeks and blood pressure measurements, laboratory investigations and patient interviews will be performed at study follow-up visits to assess the treatment efficacy (proportion of patients reaching normal office blood pressure after 16 weeks of treatment) and safety.

Description:

PRECIOUS study is an interventional, open-label, prospective, international, multi-centre, Phase IV clinical trial (Phase III for countries without marketing authorisation for Co-Amlessa®).

The purpose of the study is to establish the efficacy and safety of fixed-dose combination (FDC) of perindopril/amlodipine (Amlessa®) and FDC of perindopril/indapamide/amlodipine (Co-Amlessa®) in wide populations of newly diagnosed and uncontrolled patients with arterial hypertension (AH) with special focus on effective continuous 24-hour blood pressure (BP) control. The purpose is also to establish the correlation between 24-hour central and peripheral BP.

Perindopril, indapamide and amlodipine are well known and extensively studied antihypertensive monotherapies. Clinical data and safety analyses provided are substantial body of evidence that perindopril, indapamide and amlodipine, which have been used for more than 15 years, are safe and well tolerated drugs. Perindopril, indapamide and amlodipine have complementary actions in reducing BP. Combining perindopril and amlodipine or perindopril, indapamide and amlodipine could improve adherence in uncontrolled hypertensive patients. Namely the combinations would reduce the number of tablets to be taken by patient and thus simplify the treatment regimen and are therefore expected to facilitate long-term adherence to antihypertensive therapy, which justifies their use. Both combinations could also improve safety profile which would be beneficial from the tolerability point of view. Namely, when calcium channel blockers (CCB) and angiotensin converting enzyme inhibitors (ACEI) are used in combination, there is a potential for lower incidence of peripheral oedema caused by CCB. Similarly, the incidence of ACEI-associated cough is attenuated by CCBs, including amlodipine.

This study aims evaluate the effect of therapy with Amlessa® and Co-Amlessa® on the blood pressure reduction in patients with essential arterial hypertension (AH) who are naïve with systolic blood pressure (SBP) from 150 mmHg or higher AND/OR diastolic blood pressure (DBP) from 95 mmHg or higher, (SBP ≥ 150 AND/OR DBP ≥ 90 mmHg for patients with type 2 diabetes mellitus) and in uncontrolled patients on mono, dual or triple antihypertensive with SBP from 140 mmHg or higher AND/OR DBP from 90 mmHg or higher (SBP ≥ 140 AND/OR DBP ≥ 85 mmHg for patients with type 2 diabetes mellitus). An objective of this trial is also to evaluate the safety of therapy with Amlessa® and Co-Amlessa® according to the frequency and severity of AR in patients with essential AH. Overall 510 patients are planned to conclude the assessment and to be analysed. In per-protocol analysis 450 patients are expected. In order to allow for the estimated drop-out rate, up to 570 patients are expected to be screened.

All patients start with an initial screening which is performed one day before visit 1 to verify eligibility. After inform consent signature and before therapy is allocated complete medical history, physical examination with measurements of heart rate (HR), body weight and height, lipid measurements and laboratory analysis including pregnancy test, BP, ambulatory blood pressure measurement (ABPM) and electrocardiogram (ECG) are performed. Patients take the last doses of previous AH therapy on the day of the screening visit. At Visit 1 (day 0) the data from ABPM device is collected (average BP, central BP, HR, pulse wave velocity [PWV] and Aortic augmentation index). BP and HR measurements are repeated. Based on data gathered from all previous examinations on visit -1 and visit 1 investigator verifies patient's eligibility. Patients will not be randomized to treatment. All eligible patients are assigned to start receiving any of the two study medication (Amlessa® and Co-Amlessa®) according to their previous antihypertensive therapy and as described in the protocol inclusion criteria. Patients on previous perindopril and amlodipine therapy will be automatically assigned to Co-Amlessa® group. Patient starts taking the study medication on day of the visit 1 (day 0).

The total active treatment duration is 16 weeks, with maximal allowed prolongation of 3 additional days per each of the four treatment periods due to possible unpredicted causes for delay in the follow-up visits. The whole trial treatment schedule was determined on the basis of published pharmacological data for all active substances in study medications. During the active treatment period each patient orally consumes one unit of assigned study medication once daily, at about the same time each day (± 3 hours), preferably in the morning and before a meal.

At visit 2, on day 28 of the treatment period, BP, HR measurements, safety assessing laboratory investigations (serum creatinine, serum potassium, ALT, AST, GammaGT) are repeated. Patient's compliance is assessed and safety assessment is carried out by the interview. After the control of patient status the decision is made to maintain the treatment if sufficient (normal office BP was reached) or to change the treatment in accordance with protocol treatment model. Normal office BP is defined as SBP < 140 mmHg and DBP < 90 mmHg; patients with type 2 diabetes mellitus: SBP < 140 mmHg and DBP < 85 mmHg.

At Visit 3 on day 56 of the active treatment period, BP, HR measurements measurements, lipid measurements and safety assessing laboratory investigations (serum creatinine, serum potassium, ALT, AST, GammaGT) are repeated. Patient's compliance is assessed and safety assessment is carried out by the interview. After the control of patient status the decision is made to maintain the treatment if sufficient (normal office BP was reached) or to change the treatment in accordance with protocol treatment model. Normal office BP is defined as SBP < 140 mmHg and DBP < 90 mmHg; patients with type 2 diabetes mellitus: SBP < 140 mmHg and DBP < 85 mmHg.

At Visit 4 on day 84 of the active treatment period, BP, HR measurements measurements are repeated. Patient's compliance is assessed and safety assessment is carried out by the interview. After the control of patient status the decision is made to maintain the treatment if sufficient (normal office BP was reached) or to change the treatment in accordance with protocol treatment model. Normal office BP is defined as SBP < 140 mmHg and DBP < 90 mmHg; patients with type 2 diabetes mellitus: SBP < 140 mmHg and DBP < 85 mmHg.

At Visit -5 on day 111, ABPM device is installed. Blood samples are taken, to provide the results of laboratory analysis the next day on visit 5 (final visit). At Visit 5 on day 112, the final efficacy and safety evaluation are carried out including patient's adherence. Physical examination with BP, PWV and HR measurements, lipid measurements, laboratory analysis and ABPM are performed. ABPM device is removed on the same day and the data from device is collected (average BP, central BP, HR, PWV and Aortic augmentation index). Completion of all the procedures at Visit 5 determines the end of the patient's involvement in this clinical trial. After this, patient's further antihypertensive regimen is left to the discretion of the investigator.

Once enrolled, patients can be excluded before the protocol defined end of therapy due to patients decision or loss-to-follow-up, patient non-compliance or safety issues as defined in the study protocol. Concomitant therapy with other drugs is avoided in this study, if possible.

The primary efficacy endpoint is the responder rate at final visit. Precisely, this is defined to be the proportion of patients reaching normal blood pressure at Visit 5 (after 16 weeks). Normal office BP is defined as SBP < 140 mmHg and DBP < 90 mmHg; patients with type 2 diabetes mellitus: SBP < 140 mmHg and DBP < 85 mmHg. It will be assessed with the two-sided ("equal-tails") Clopper-Pearson exact 95%-confidence interval for a population proportion.

This trial is going to be conducted in compliance with the approved protocol and in accordance with the principles of Good Clinical Practice (GCP) with its corresponding Directives and Declaration of Helsinki. Data management is carried out by the sponsor according to the data management plan, sponsor's standard operating procedures (SOPs) and GCP. Data to be collected according to the study protocol (and amendments, if any) will be recorded in electronic case report forms (eCRF).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 471
• Est. completion date: September 27, 2019
• Est. primary completion date: September 27, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

INCLUSION CRITERIA:

• Patients with essential arterial hypertension.*

• Men and women aged = 18 years

• Written informed consent

• Ability to adhere to study protocol

Additional inclusion criteria for Amlessa®*

Patients with essential arterial hypertension:

• Naïve patients with systolic blood pressure (SBP) from 150 mmHg or higher AND/OR diastolic blood pressure (DBP) from 95 mmHg or higher (SBP = 150 AND/OR DBP = 90 mmHg for patients with type 2 diabetes mellitus)

• Uncontrolled patients on antihypertensive monotherapy with SBP from 140 mmHg or higher AND/OR DBP from 90 mmHg or higher (SBP = 140 AND/OR DBP = 85 mmHg for patients with type 2 diabetes mellitus).

• Uncontrolled patients on dual antihypertensive therapy (either in monoforms or FDC) with SBP from 140 mmHg or higher AND/OR DBP from 90 mmHg or higher (SBP = 140 AND/OR DBP = 85 mmHg for patients with type 2 diabetes mellitus).

Additional inclusion criteria for Co-Amlessa®*

Patients with essential arterial hypertension (AH):

• Uncontrolled patients on dual antihypertensive therapy (either in monoforms or FDC, including perindopril+amlodipine combination) with SBP from 140 mmHg or higher AND/OR DBP from 90 mmHg or higher (SBP = 140 AND/OR DBP = 85 mmHg for patients with type 2 diabetes mellitus).

• Uncontrolled patients on triple antihypertensive therapy (either in monoforms or FDC) with SBP from 140 mmHg or higher AND/OR DBP from 90 mmHg or higher (SBP = 140 AND/OR DBP = 85 mmHg for patients with type 2 diabetes mellitus).

EXCLUSION CRITERIA:

• History of adverse reactions or hypersensitivity associated with the use of the active substances, or any other components of the Investigational medicinal products (IMPs) used in the trial.

• Hereditary/idiopathic angioedema.

• Known secondary AH (e.g. pheochromocytoma, primary aldosteronism, renal artery stenosis).

• Office measured Systolic blood pressure =200 mmHg.

• Unstable angina pectoris.

• Acute heart failure and heart failure New York Heart Association (NYHA) Class IV.

• 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.

• Severe liver impairment OR biliary cirrhosis OR cholestasis OR hepatic encephalopathy.

• Renal dysfunction - glomerular filtration rate (GFR) <60 ml/min, bilateral renal artery stenosis, renal artery stenosis in a solitary kidney, patients with only 1 kidney, or post-renal transplant patients, dialysis patients.

• Any of the following clinically relevant laboratory or ECG findings:

• significant anaemia with haemoglobin less than 100 g/l

• serum aspartate transaminase (AST) and/or alanine aminotransferase (ALT) and/or alkaline phosphatase (ALP) and/or gamma-glutamyltransferase (GGT) of more than 3 x upper limit of normal (ULN)

• hyperkalaemia (serum potassium of more than 5 mmol/l)

• A-V block grade 2 or 3

• ECG signs of acute ischemia

• Concurrent therapy with:

• aliskiren-containing products (in patients with diabetes mellitus or renal impairment)

• Other antihypertensive drugs or other medications that may cause hypotension:

exception are antihypertensive drugs used for other indication than AH (e.g. tachyarrhythmia, glaucoma) introduced more than 3 months before the study or in changed dosages more than 3 months before the study

• Drugs that may produce an increase in blood pressure: systemic corticosteroids, hormonal medications (chronically used oral contraceptives are allowed), adrenergic receptor agonists, cyclosporine, erythropoietin, migraine medications such as triptans and ergotamines

• Agents with important interactions with perindopril or to any other ACE inhibitor, to indapamide or to any other sulphonamides, to amlodipine or to dihydropyridine derivatives: lithium, estramustine

• Agents that may interfere with amlodipine hepatic metabolism (CYP3A4): protease inhibitors, rifampicin, macrolides like erythromycin or clarithromycin, azole antifungals like ketoconazole and itraconazole, Hypericum perforatum.

• Medications contraindicated in uncontrolled arterial hypertension:

anticoagulants, thrombolytics.

• Bradycardia with heart rate less than 50/min.

• Female patients who are pregnant, planning to become pregnant.

• Breastfeeding female patients.

• Any significant acute condition (severe infection, exacerbation or uncontrolled phase of a chronic disease, major trauma, major surgery) within 30 days prior to screening visit.

• Pathological clinical states (e.g. malignant diseases, excessive alcohol consumption, drug abuse or drug addiction, psychiatric conditions) or any life-threatening illness.

• Patients currently participating in another clinical trial.

• Patient's refusal to participate with the investigator.

• Normal average 24-hour SBP and DBP obtained by Ambulatory Blood Pressure Measurement (ABPM) device (<130/80 mmHg) at baseline.

• Severe orthostatic hypotension.

• Patients to whom ß-blocker therapy cannot be discontinued in one day.

• Previous or current therapy with perindopril and amlodipine and indapamide taken taken concomitantly all together as 3 separate tablets or as a fixed-dose combination.

• In Amlessa arm patients on previous or current therapy with perindopril and amlodipine taken concomitantly all together as 2 separate tablets or as a fixed-dose combination. (this exclusion criterion does not apply to Co-Amlessa arm).

Related Conditions & MeSH terms

• Hypertension

Intervention

Drug:
• Amlessa®
Fixed-dose combination (FDC) of perindopril/amlodipine, tablets. Strengths: 4mg/5 mg, 8mg/5 mg, 8mg/10 mg.
• Co-Amlessa®
Fixed-dose combination (FDC) of perindopril/indapamide/amlodipine, tablets. Strengths: 4mg/1.25 mg/5 mg, 8mg/2.5 mg/5 mg, 8mg/2.5 mg/10 mg.

Locations

Country	Name	City	State
Armenia	Unimed medical center	Abovyan
Armenia	Center of Preventive Cardiology	Yerevan
Croatia	Thalassotherapia Opatija, Specijalna bolnica za medicinsku rehabilitaciju, bolesti srca, pluca i reumatizma, Klinika za lijecenje, rehabilitaciju i prevenciju bolesti srca i krvnih žila	Opatija
Croatia	KBC Rijeka - Sušak, Klinika za internu medicinu, Zavod za nefrologiju, dijalizu i transplantaciju bubrega	RIjeka
Croatia	KB Merkur, Klinika za unutarnje bolesti, Zavod za kardiologiju	Zagreb
Croatia	KBC Sestre milosrdnice, Klinika za bolesti srca i krvnih žila, Zavod za bolesti krvnih žila	Zagreb
Croatia	KBC Zagreb, Klinika za bolesti srca i krvnih žila	Zagreb
Croatia	KBC Zagreb, Klinika za unutarnje bolesti, Zavod za nefrologiju, arterijsku hipertenziju, dijalizu i transplantaciju	Zagreb
Croatia	Poliklinika za prevenciju kardiovaskularnih bolesti i rehabilitaciju SRCANA	Zagreb
Hungary	Biatros Kft.	Biatorbágy
Hungary	General practitioner office	Budapest
Hungary	AD SANITATEM Bt.	Pilisvörösvár
Poland	Przychodnia Kardiologiczna w Zespole Przychodni Specjalistycznych DIAB-END-COR	Krakow
Poland	Niepubliczny Zaklad Opieki Zdrowotnej Neuromed M.i M. Nastaj Spólka Partnerska	Lublin
Poland	Poradnia Kardiologiczna, Nowodworskie Centrum Medyczne	Nowy Dwór Mazowiecki
Poland	Poradnia Kardiologiczna Samodzielnego Publicznego Zespolu Zakladów Opieki Zdrowotnej im. Marszalka Józefa Pilsudskiego w Plonsku	Plonsk
Poland	Poradnia Kardiologiczna w Niepublicznym Zakladzie Opieki Zdrowotnej Euro-Klinika Sp. z o.o. w Siemianowicach Slaskich	Siemianowice Slaskie
Poland	Poradnia internistyczno-kardiologiczna w Niepublicznym Zakladzie Opieki Zdrowotnej AURUM	Warsaw
Poland	Poradnia Kardiologiczna w Przychodni Rejonowej - Specjalistycznej (III) Samodzielnego Zespolu Publicznych Zakladów Lecznictwa Otwartego Warszawa - Ochota	Warsaw
Poland	Przychodnia ACTIV-MED.	Warsaw
Russian Federation	Federal State Budgetary Scientific Institution "Scientific Research Institute of Complex Problems of Cardiovascular Diseases"	Kemerovo
Russian Federation	Federal State budget organization National medical research center of cardiology of the Ministry of healthcare of the Russian Federation	Moscow
Russian Federation	State Budgetary Institution of Healthcare of Moscow "City Clinical Hospital ? 29 named after N.E. Bauman of Department of Healthcare of Moscow city" (SBIH "CCH ? 29 Bauman")	Moscow
Russian Federation	Federal State Budgetary Institution "V.A. Almazov National Medical Research Center" of the Ministry of Health of the Russian Federation (V.A. Almazov NMRC)	Saint Petersburg
Russian Federation	Federal State Budgetary Educational Institution Higher Education "Volgograd State Medical University" of the Ministry of Healthcare of the Russian Federation (FSBEI HE VolgSMU MOH Russia)	Volgograd
Serbia	KBC Dragiša Mišovic	Belgrad
Serbia	Klinicki centar Srbije	Belgrade
Serbia	Klinicki centar Niš	Niš
Serbia	Inštitut za kardiovaskularne bolesti Vojvodine	Sremska Kamenica
Slovenia	Univerzitetna klinika za pljucne bolezni in alergijo Golnik	Golnik
Slovenia	Splošna bolnišnica Jesenice	Jesenice
Slovenia	Ordinacija interne medicine Verboten Kopriva Renata	Litija
Slovenia	MC Medicor, d. d.	Ljubljana
Slovenia	Intermed, d. o. o.	Maribor

Sponsors (3)

Lead Sponsor	Collaborator
KRKA	Clinres Farmacija d.o.o., University Medical Centre Ljubljana

Countries where clinical trial is conducted

Armenia,  Croatia,  Hungary,  Poland,  Russian Federation,  Serbia,  Slovenia, 

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* Note: There are 52 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in serum total cholesterol from baseline to end of study (Week 16)	Mean absolute and relative change from baseline to week 16 in total serum cholesterol concentration (obtained by laboratory blood test) in patients with concomitant rosuvastatin therapy.	16 weeks
Other	Change in HDL-C from baseline to end of study (week 16)	Mean absolute and relative change from baseline to week 16 in high-density lipoprotein-cholesterol (HDL-C) serum concentration (obtained by laboratory blood test) in patients with concomitant rosuvastatin therapy.	16 weeks
Other	Change in LDL-C from baseline to end of study (week 16)	Mean absolute and relative change from baseline to week 16 in low-density lipoprotein-cholesterol (LDL-C) serum concentration (obtained by laboratory blood test) in patients with concomitant rosuvastatin therapy.	16 weeks
Other	Change in triglycerides from baseline to end of study (week 16)	Mean absolute and relative change from baseline to week 16 in triglycerides serum concentration (obtained by laboratory blood test) in patients with concomitant rosuvastatin therapy.	16 weeks
Other	Change in AST from baseline to end of study (week 16)	Mean absolute and relative changes above normal limit values from baseline to end of study value (week 16) in serum Aspartate transaminase (AST) concentration obtained by laboratory blood test.	16 weeks
Other	Change in ALT from baseline to end of study (week 16)	Mean absolute and relative changes above normal limit values from baseline to end of study value (week 16) in serum Alanine transaminase (ALT) concentration obtained by laboratory blood test.	16 weeks
Other	Change in GGT from baseline to end of study (week 16)	Mean absolute and relative changes above normal limit values from baseline to end of study value (week 16) in serum gamma-glutamyl transferase (GGT) concentration obtained by laboratory blood test.	16 weeks
Other	Change in Serum Creatinine from baseline to end of study (week 16)	Mean absolute and relative changes above normal limit values from baseline to end of study value (week 16) in Serum Creatinine concentration obtained by laboratory blood test.	16 weeks
Other	Change in Serum Potassium from baseline to end of study (week 16)	Mean absolute and relative changes above normal limit values from baseline to end of study value (week 16) in Serum Potassium concentration obtained by laboratory blood test.	16 weeks
Other	Incidence of adverse drug reactions from date of screening until study end (16 weeks)	Incidence of adverse drug reactions from date of screening until study end (16 weeks). A number/percentage of patients unable to finish active treatment periods due to clinically significant adverse reaction.	16 weeks
Primary	Systolic and diastolic blood pressure at Week 16	Responder rate at end of study (week 16): proportion of patients reaching office normal blood pressure defined as SBP < 140 mmHg and DBP < 90 mmHg (patients with type 2 diabetes mellitus: SBP < 140 mmHg and DBP < 85 mmHg). BP is measured using a validated automated BP-measuring device.	16 weeks
Secondary	Systolic and diastolic blood pressure at Week 4, Week 8 and Week 12	Responder rate at first, second and third study follow-up visits (week 4, week 8 and week 12): proportion of patients reaching office normal blood pressure defined as SBP < 140 mmHg and DBP < 90 mmHg (patients with type 2 diabetes mellitus: SBP < 140 mmHg and DBP < 85 mmHg). BP is measured using a validated automated BP-measuring device.	12 Weeks
Secondary	Mean absolute and relative change in Systolic and diastolic blood pressure from baseline to Week 4, Week 8, Week 12 and Week 16	Mean absolute and relative change from baseline in office SBP and DBP after 4, 8, 12 and 16 weeks (Visit 2, 3, 4, 5). BP is measured using a validated automated BP-measuring device.	16 weeks
Secondary	Average 24-hour blood pressure at Week 16	Proportion of patients reaching normal average 24h SBP and DBP (<130/80 mmHg) at study end (Week 16). Measurements are obtained with Ambulatory Blood Pressure Measuring (ABPM) device.	16 weeks
Secondary	Average awake time blood pressure at Week 16	Proportion of patients reaching normal average awake time SBP and DBP (<135/85 mmHg) at study end (Week 16). Measurements are obtained with Ambulatory Blood Pressure Measuring (ABPM) device.	16 weeks
Secondary	Average sleep time blood pressure at Week 16	Proportion of patients reaching normal average sleep time SBP and DBP (<120/70 mmHg) at study end (Week 16). Measurements are obtained with Ambulatory Blood Pressure Measuring (ABPM) device.	16 weeks
Secondary	Mean absolute and relative change in average 24-hour blood pressure from baseline to Week 16	Mean absolute and relative change from baseline to 16 weeks in average 24-hour SBP and DBP obtained with Ambulatory Blood Pressure Measuring (ABPM) device.	16 weeks
Secondary	Mean absolute and relative change in average awake time blood pressure from baseline to Week 16	Mean absolute and relative change from baseline to 16 weeks in average awake time SBP and DBP obtained with Ambulatory Blood Pressure Measuring (ABPM) device.	16 weeks
Secondary	Mean absolute and relative change in average sleep time blood pressure from baseline to Week 16	Mean absolute and relative change from baseline to 16 weeks in average sleep time SBP and DBP obtained with Ambulatory Blood Pressure Measuring (ABPM) device.	16 weeks
Secondary	Reduction of office SBP of at least 20 mmHg or DBP of at least 10 mmHg from baseline to 16 weeks	Proportion of patients reaching a reduction of office SBP by at least 20 mmHg or DBP by at least 10 mmHg from baseline after 16 weeks. BP is measured using a validated automated BP-measuring device.	16 weeks
Secondary	Central (systolic) blood pressure at Week 16	Proportion of patients with a reduction of central (systolic) blood pressure (obtained by 24-hour ABPM device measurement) below 120 mmHg at end of study (week 16).	16 weeks
Secondary	Change in Pulse wave velocity (PWV) from baseline to Week 16	Proportion of patients reaching a reduction of PWV (obtained by 24-hour ABPM device measurement) of at least 0,5 m/s from baseline to study end (week 16).	16 weeks
Secondary	Change in SBP and DBP variability from baseline to Week 16	Proportion of patients reaching a reduction of SBP and DBP variability expressed as reduction of day-night standard deviation (SDdn) of at least 0.5 and that of average real variability (ARV) of at least 0.5 at study end (week 16). Measurements are obtained with ABPM device.	16 weeks