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

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).