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