Clinical trial NCT03738761: Management of Newly Diagnosed and Uncontrolled Hypertension With Fixed-Dose Combination of Perindopril/Amlodipine and Perindopril/Indapamide/Amlodipine
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hypertension
Keywords: Hypertension
Blood pressure control
Fixed-dose combination antihypertensives
Ambulatory blood pressure monitoring
Lead sponsor: KRKA
Sponsor class: INDUSTRY
Collaborators: name: Clinres Farmacija d.o.o.
name: University Medical Centre Ljubljana
First posted: 2018-11-13
Enrollment: 471
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Treatment is started at Visit 1 with Amlessa® 4mg/5mg (Amlessa® Arm) or Co-Amlessa® 4mg/1,25mg/5mg (Co-Amlessa® Arm) for 4 weeks.

At each of the three follow-up visits (at week 4, week 8 and week 12) patient BP is assessed and if normal office blood pressure was achieved, the treatment with the study medication prescribed for the previous treatment period is continued. If normal office blood pressure was not achieved at any of the follow-up visits (week 4, week 8 and week 12), Amlessa® or Co-Amlessa® strength is increased in accordance with the below sequence.

Amlessa® Arm Amlessa® 4mg/5mg (initial therapy) - Amlessa® 8mg/5mg - Amlessa® 8mg/10mg - Co-Amlessa® 8mg/2,5mg/10mg

Co-Amlessa® Arm Co-Amlessa® 4mg/1,25mg/5mg - Co-Amlessa® 8mg/2,5mg/5mg - Co-Amlessa® 8mg/2,5mg/10mg - end of study no further escalation of study medication dosage

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.
Primary purpose: TREATMENT

Brief 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.

Detailed 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).

Eligibility criteria: 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).

Primary outcomes:
measure: Systolic and diastolic blood pressure at Week 16
timeFrame: 16 weeks
Secondary outcomes:
measure: Systolic and diastolic blood pressure at Week 4, Week 8 and Week 12
timeFrame: 12 Weeks
measure: Mean absolute and relative change in Systolic and diastolic blood pressure from baseline to Week 4, Week 8, Week 12 and Week 16
timeFrame: 16 weeks
measure: Average 24-hour blood pressure at Week 16
timeFrame: 16 weeks
measure: Average awake time blood pressure at Week 16
timeFrame: 16 weeks
measure: Average sleep time blood pressure at Week 16
timeFrame: 16 weeks
measure: Mean absolute and relative change in average 24-hour blood pressure from baseline to Week 16
timeFrame: 16 weeks
measure: Mean absolute and relative change in average awake time blood pressure from baseline to Week 16
timeFrame: 16 weeks
measure: Mean absolute and relative change in average sleep time blood pressure from baseline to Week 16
timeFrame: 16 weeks
measure: Reduction of office SBP of at least 20 mmHg or DBP of at least 10 mmHg from baseline to 16 weeks
timeFrame: 16 weeks
measure: Central (systolic) blood pressure at Week 16
timeFrame: 16 weeks
measure: Change in Pulse wave velocity (PWV) from baseline to Week 16
timeFrame: 16 weeks
measure: Change in SBP and DBP variability from baseline to Week 16
timeFrame: 16 weeks
Other outcomes:
measure: Change in serum total cholesterol from baseline to end of study (Week 16)
timeFrame: 16 weeks
measure: Change in HDL-C from baseline to end of study (week 16)
timeFrame: 16 weeks
measure: Change in LDL-C from baseline to end of study (week 16)
timeFrame: 16 weeks
measure: Change in triglycerides from baseline to end of study (week 16)
timeFrame: 16 weeks
measure: Change in AST from baseline to end of study (week 16)
timeFrame: 16 weeks
measure: Change in ALT from baseline to end of study (week 16)
timeFrame: 16 weeks
measure: Change in GGT from baseline to end of study (week 16)
timeFrame: 16 weeks
measure: Change in Serum Creatinine from baseline to end of study (week 16)
timeFrame: 16 weeks
measure: Change in Serum Potassium from baseline to end of study (week 16)
timeFrame: 16 weeks
measure: Incidence of adverse drug reactions from date of screening until study end (16 weeks)
timeFrame: 16 weeks
Locations:
city: Abovyan
country: Armenia
facility: Unimed medical center
city: Yerevan
country: Armenia
facility: Center of Preventive Cardiology
city: Opatija
country: Croatia
facility: Thalassotherapia Opatija, Specijalna bolnica za medicinsku rehabilitaciju, bolesti srca, pluća i reumatizma, Klinika za liječenje, rehabilitaciju i prevenciju bolesti srca i krvnih žila
city: RIjeka
country: Croatia
facility: KBC Rijeka - Sušak, Klinika za internu medicinu, Zavod za nefrologiju, dijalizu i transplantaciju bubrega
city: Zagreb
country: Croatia
facility: KB Merkur, Klinika za unutarnje bolesti, Zavod za kardiologiju
city: Zagreb
country: Croatia
facility: KBC Sestre milosrdnice, Klinika za bolesti srca i krvnih žila, Zavod za bolesti krvnih žila
city: Zagreb
country: Croatia
facility: KBC Zagreb, Klinika za bolesti srca i krvnih žila
city: Zagreb
country: Croatia
facility: KBC Zagreb, Klinika za unutarnje bolesti, Zavod za nefrologiju, arterijsku hipertenziju, dijalizu i transplantaciju
city: Zagreb
country: Croatia
facility: Poliklinika za prevenciju kardiovaskularnih bolesti i rehabilitaciju SRČANA
city: Biatorbágy
country: Hungary
facility: Biatros Kft.
city: Budapest
country: Hungary
facility: General practitioner office
city: Pilisvörösvár
country: Hungary
facility: AD SANITATEM Bt.
city: Krakow
country: Poland
facility: Przychodnia Kardiologiczna w Zespole Przychodni Specjalistycznych DIAB-END-COR
city: Lublin
country: Poland
facility: Niepubliczny Zakład Opieki Zdrowotnej Neuromed M.i M. Nastaj Spółka Partnerska
city: Nowy Dwór Mazowiecki
country: Poland
facility: Poradnia Kardiologiczna, Nowodworskie Centrum Medyczne
city: Płońsk
country: Poland
facility: Poradnia Kardiologiczna Samodzielnego Publicznego Zespołu Zakładów Opieki Zdrowotnej im. Marszałka Józefa Piłsudskiego w Płońsku
city: Siemianowice Śląskie
country: Poland
facility: Poradnia Kardiologiczna w Niepublicznym Zakładzie Opieki Zdrowotnej Euro-Klinika Sp. z o.o. w Siemianowicach Śląskich
city: Warsaw
country: Poland
facility: Poradnia internistyczno-kardiologiczna w Niepublicznym Zakładzie Opieki Zdrowotnej AURUM
city: Warsaw
country: Poland
facility: Poradnia Kardiologiczna w Przychodni Rejonowej - Specjalistycznej (III) Samodzielnego Zespołu Publicznych Zakładów Lecznictwa Otwartego Warszawa - Ochota
city: Warsaw
country: Poland
facility: Przychodnia ACTIV-MED.
city: Kemerovo
country: Russian Federation
facility: Federal State Budgetary Scientific Institution "Scientific Research Institute of Complex Problems of Cardiovascular Diseases"
city: Moscow
country: Russian Federation
facility: Federal State budget organization National medical research center of cardiology of the Ministry of healthcare of the Russian Federation
city: Moscow
country: Russian Federation
facility: 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")
city: Saint Petersburg
country: Russian Federation
facility: Federal State Budgetary Institution "V.A. Almazov National Medical Research Center" of the Ministry of Health of the Russian Federation (V.A. Almazov NMRC)
city: Volgograd
country: Russian Federation
facility: 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)
city: Belgrade
country: Serbia
facility: Klinički centar Srbije
city: Belgrad
country: Serbia
facility: KBC Dragiša Mišović
city: Niš
country: Serbia
facility: Klinički centar Niš
city: Sremska Kamenica
country: Serbia
facility: Inštitut za kardiovaskularne bolesti Vojvodine
city: Golnik
country: Slovenia
facility: Univerzitetna klinika za pljučne bolezni in alergijo Golnik
city: Jesenice
country: Slovenia
facility: Splošna bolnišnica Jesenice
city: Litija
country: Slovenia
facility: Ordinacija interne medicine Verboten Kopriva Renata
city: Ljubljana
country: Slovenia
facility: MC Medicor, d. d.
city: Maribor
country: Slovenia
facility: Intermed, d. o. o.
Study officials:
affiliation: University Medical Centre Ljubljana Hospital dr. Peter Držaj
name: Jana Brguljan Hitij
role: PRINCIPAL_INVESTIGATOR
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