Management of Newly Diagnosed and Uncontrolled Hypertension With Fixed-Dose Combination of Perindopril/Amlodipine and Perindopril/Indapamide/Amlodipine
- Conditions
- Hypertension
- Interventions
- Drug: Co-Amlessa®Drug: Amlessa®
- Registration Number
- NCT03738761
- Lead Sponsor
- KRKA
- 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).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 471
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Co-Amlessa® Arm Co-Amlessa® Patients allocated to treatment with Co-Amlessa® (starting FDC perindopril 4mg/indapamide 2,5mg/amlodipine 5mg) 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® arm. Amlessa® Arm Co-Amlessa® Patients allocated to treatment with Amlessa® (starting FDC of perindopril 4mg/amlodipine 5mg) according to their previous antihypertensive therapy and as described in the protocol inclusion criteria. Amlessa® Arm Amlessa® Patients allocated to treatment with Amlessa® (starting FDC of perindopril 4mg/amlodipine 5mg) according to their previous antihypertensive therapy and as described in the protocol inclusion criteria.
- Primary Outcome Measures
Name Time Method Systolic and diastolic blood pressure at Week 16 16 weeks 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.
- Secondary Outcome Measures
Name Time Method Mean absolute and relative change in Systolic and diastolic blood pressure from baseline to Week 4, Week 8, Week 12 and Week 16 16 weeks 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.
Change in Pulse wave velocity (PWV) from baseline to Week 16 16 weeks 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).
Mean absolute and relative change in average 24-hour blood pressure from baseline to Week 16 16 weeks 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.
Reduction of office SBP of at least 20 mmHg or DBP of at least 10 mmHg from baseline to 16 weeks 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.
Systolic and diastolic blood pressure at Week 4, Week 8 and Week 12 12 Weeks 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.
Average awake time blood pressure at Week 16 16 weeks 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.
Average sleep time blood pressure at Week 16 16 weeks 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.
Central (systolic) blood pressure at Week 16 16 weeks 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).
Average 24-hour blood pressure at Week 16 16 weeks 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.
Mean absolute and relative change in average awake time blood pressure from baseline to Week 16 16 weeks 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.
Mean absolute and relative change in average sleep time blood pressure from baseline to Week 16 16 weeks 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.
Change in SBP and DBP variability from baseline to Week 16 16 weeks 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.
Trial Locations
- Locations (34)
Unimed medical center
🇦🇲Abovyan, Armenia
KBC Zagreb, Klinika za bolesti srca i krvnih žila
🇭🇷Zagreb, Croatia
Biatros Kft.
🇭🇺Biatorbágy, Hungary
Przychodnia Kardiologiczna w Zespole Przychodni Specjalistycznych DIAB-END-COR
🇵🇱Krakow, Poland
Poradnia internistyczno-kardiologiczna w Niepublicznym Zakładzie Opieki Zdrowotnej AURUM
🇵🇱Warsaw, Poland
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
KBC Dragiša Mišović
🇷🇸Belgrad, Serbia
Univerzitetna klinika za pljučne bolezni in alergijo Golnik
🇸🇮Golnik, Slovenia
Splošna bolnišnica Jesenice
🇸🇮Jesenice, Slovenia
MC Medicor, d. d.
🇸🇮Ljubljana, Slovenia
Intermed, d. o. o.
🇸🇮Maribor, Slovenia
KB Merkur, Klinika za unutarnje bolesti, Zavod za kardiologiju
🇭🇷Zagreb, Croatia
AD SANITATEM Bt.
🇭🇺Pilisvörösvár, Hungary
KBC Rijeka - Sušak, Klinika za internu medicinu, Zavod za nefrologiju, dijalizu i transplantaciju bubrega
🇭🇷RIjeka, Croatia
Niepubliczny Zakład Opieki Zdrowotnej Neuromed M.i M. Nastaj Spółka Partnerska
🇵🇱Lublin, Poland
Center of Preventive Cardiology
🇦🇲Yerevan, Armenia
Thalassotherapia Opatija, Specijalna bolnica za medicinsku rehabilitaciju, bolesti srca, pluća i reumatizma, Klinika za liječenje, rehabilitaciju i prevenciju bolesti srca i krvnih žila
🇭🇷Opatija, Croatia
Poliklinika za prevenciju kardiovaskularnih bolesti i rehabilitaciju SRČANA
🇭🇷Zagreb, Croatia
Inštitut za kardiovaskularne bolesti Vojvodine
🇷🇸Sremska Kamenica, Serbia
Ordinacija interne medicine Verboten Kopriva Renata
🇸🇮Litija, Slovenia
KBC Sestre milosrdnice, Klinika za bolesti srca i krvnih žila, Zavod za bolesti krvnih žila
🇭🇷Zagreb, Croatia
KBC Zagreb, Klinika za unutarnje bolesti, Zavod za nefrologiju, arterijsku hipertenziju, dijalizu i transplantaciju
🇭🇷Zagreb, Croatia
Poradnia Kardiologiczna w Przychodni Rejonowej - Specjalistycznej (III) Samodzielnego Zespołu Publicznych Zakładów Lecznictwa Otwartego Warszawa - Ochota
🇵🇱Warsaw, Poland
Klinički centar Srbije
🇷🇸Belgrade, Serbia
General practitioner office
🇭🇺Budapest, Hungary
Poradnia Kardiologiczna w Niepublicznym Zakładzie Opieki Zdrowotnej Euro-Klinika Sp. z o.o. w Siemianowicach Śląskich
🇵🇱Siemianowice Śląskie, Poland
Przychodnia ACTIV-MED.
🇵🇱Warsaw, Poland
Federal State Budgetary Scientific Institution "Scientific Research Institute of Complex Problems of Cardiovascular Diseases"
🇷🇺Kemerovo, Russian Federation
Poradnia Kardiologiczna, Nowodworskie Centrum Medyczne
🇵🇱Nowy Dwór Mazowiecki, Poland
Poradnia Kardiologiczna Samodzielnego Publicznego Zespołu Zakładów Opieki Zdrowotnej im. Marszałka Józefa Piłsudskiego w Płońsku
🇵🇱Płońsk, Poland
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, Russian Federation
Klinički centar Niš
🇷🇸Niš, Serbia