Comparison of Sevikar® and the Combination of Perindopril/Amlodipine on Central Blood Pressure

Efficacy of Sevikar® Compared to the Combination of Perindopril/ Amlodipine on Central Arterial Blood Pressure in Patients With Moderate to Severe Hypertension-

Comparison of the combination of amlodipine with an angiotensin receptor blocker or an angiotensin converting inhibitor, on central arterial blood pressure in patients with hypertension and additional risk factors. This is a randomised, double-blind, double-dummy, multicenter study. The duration of active treatment 24 weeks.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: Perindopril + amlodipine + if necessary, hydrochlorothiazide; Drug: olmesartan/amlodipine + hydrochlorothiazide, if necessary.

Detailed Description

The study, multi-center balanced, parallel group (two treatment arms), randomized, double-blind (double-dummy), non-inferiority study is designed to show non-inferiority of Sevikar® (olmesartan(OM)/amlodipine (AM)) 40/10 mg compared to the combination of Perindopril (PER) 8 mg plus Amlodipine 10 mg with regard to central systolic blood pressure lowering effect, using the change from baseline (Week 0) to final examination (Week 24).

Male and female Caucasians aged ≥ 40 years and <80 years with moderate to severe hypertension, defined by a systolic blood pressure (SBP) ≥ 160 and ≤ 200 or diastolic blood pressure (DBP) ≥ 100 and ≤ 115 mmHg for untreated patients, SBP ≥ 140 or DBP ≥ 90 mmHg for insufficiently pre-treated patients and SBP ≥ 130 mmHg or DBP ≥ 80 mmHg for insufficiently pretreated diabetics chronic kidney disease will be eligible for participation. In addition,three additional risk factors should be present.

During the course of the study three central blood pressure measurements (at randomization, at week 12 and at termination) will be performed with SphygmoCor ultrasound method. The conventional measurements with calibrated tensiometers (Omron) will be performed at each visit. Ambulatory blood pressure monitoring will be performed at randomisation.

The study starts with a 2-4 week run in phase. AM will be given as open-labelled 5 mg or 10 mg tablets, administered once daily. After randomization during the double-blind phase, study medication will comprise either OM/AM 40/10 mg or PER 8 mg (2x4 mg) plus AM 10 mg and will be administered once daily. Furthermore, open-label HCTZ 12.5 mg and 25.0 mg will be provided in tablets and administered once daily according to the treatment schedule.

The primary endpoint is the change in central SBP from baseline (Week 0, Visit 0) to final examination (Week 24, Visit 5) using Last Observation Carried Forward (LOCF) approach.

The study is conducted in approximately 15 centres in Spain. Depending on the previously administered drugs the run in phase is up to four weeks (Visits -2 and -1). Individual duration of active treatment (after randomization) will last 24 weeks (Visits 0-5). The total individual duration is 28 weeks.

A total of 518 patients (259 patients/arm) will be needed in the Per Protocol Set (PPS) for the confirmatory primary analysis using mean change from baseline (Week 0) to Final Examination assuming a drop out rate of 20% during Run-in Phase a total of 720 patients have to be screened in order to achieve 576 (288 patients/arm) randomised patients.

Assuming approximately 10% major protocol deviations, a total of 518 patients will remain in the PPS.

• Study Type: Interventional
• Enrollment (Actual): 486
• Phase: Phase 4

Contacts and Locations

Study Locations

• Spain
  • Albacete, Spain, 02200
    • Centro de Salud Casas Ibañez
  • Barcelona, Spain, 08003
    • Hospital del Mar
  • Cadiz, Spain, 11407
    • Hospital general de Jerez de la Frontera
  • Fuenlabrada (Madrid), Spain
    • Hospital Universitario de Fuenlabrada
  • Madrid, Spain, 28006
    • Hospital Universitario La Princesa
  • Madrid, Spain
    • Hospital Universitario Clinico San Carlos
  • Madrid, Spain
    • Hospital Universitario Ramón y Cajal
  • Madrid, Spain, 28041
    • Hospital Universitario 12 Octubre
  • Madrid, Spain
    • Hospital General Universitario La Paz
  • Madrid, Spain
    • Hospital Universitario de Mostoles
  • Malaga, Spain
    • Hospital General Carlos Haya
  • Murcia, Spain
    • Centro de Salud Murcia San Andrés
  • Puerto De Sagunto (Valencia), Spain
    • Hospital de Sagunto
  • Salamanca, Spain
    • Centro de Salud La Alamedilla
  • Sevilla, Spain, 41009
    • Hospital Virgen de la Macarena

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• moderate to severe hypertension
• 3 additional risk factors such as age > 55 (male), > 65 female, smoker, type 2 diabetes, obesity, cardiovascular disease, congestive heart failure, chronic kidney disease,
• ability to give informed consent

Exclusion Criteria:

• secondary or malignant hypertension
• contraindication to any of the study drugs
• Creatinine clearance level <40ml/min
• treatment with more than 3 antihypertensive drugs
• Myocardial infarction, percutaneous transluminal coronary angioplasty, cardiac bypass surgery < 6 month prior to start of the study,
• unstable angina pectoris,
• stroke, transient ischemic attack < 3 months prior to start,
• Congestive heart failure NYHA II-IV,
• clinically relevant concomitant diseases,
• alcohol or drug abuse,
• pregnancy or women of childbearing potential without contraceptive precaution,

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Perindopril+amlodipine	Drug: Perindopril + amlodipine + if necessary, hydrochlorothiazide; Two perindopril 4 mg tablets + 1 amlodipine 10 mg tablet + placebo tablet matching the olmesartan/amlodipine tablet. All tablets are taken once daily. The duration of administration of perindopril tablets and placebo is 24 weeks. The duration of administration of amlodipine tablets is 24-26 weeks. Hydrochlorthiazide tablets 12.5 mg or 25 mg, once daily, will be added, if necessary
Active Comparator: Olmesartan/amlodipine	Drug: olmesartan/amlodipine + hydrochlorothiazide, if necessary.; olmesartan/amlodipine tablets 40 mg/10 mg, + placebo tablets matching the perindopril tablet and amlodipine tablet. All tablets are taken once daily for 24 weeks. Hydrochlorthiazide tablets 12.5 mg or 25 mg, once daily, will be added, if necessary

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in central systolic blood pressure from baseline (Week 0, Visit 0) to Final Examination (Week 24, Visit 5) using last observation carried forward approach.	Baseline to week 24

Secondary Outcome Measures

Outcome Measure	Time Frame
Changes in systolic and diastolic ambulatory blood pressure (mean of 24h, daytime and night-time)	Baseline to week 24
Changes in conventional mean sitting systolic and diastolic blood pressure measurement	Baseline to 24 weeks
Incidence and profile of AEs separately by Run-in Phase and by double-blind Treatment Phase	Run in phase (2 weeks) to end of study (24 weeks)
Number of responders at Final Examination defined as normalized or a decrease of systolic blood pressure by at least 20 mmHg or diastolic blood pressure by at least 10 mmHg in conventional BP measurements.	Baseline to 24 weeks
Number of normalized at Final Examination (defined as blood pressure <140/90 mmHg or <130/80 mmHg in diabetics/chronic kidney disease, in conventional BP measurements.	Baseline to 24 weeks
Changes in mean sitting systolic and diastolic blood pressure (BP) measurements from week 12 to Final Exam in patients with stabilized BP (BP is < 140/90 mmHg or < 130/80 mmHg for diabetics/chronic kidney disease) from Week 12 and Week 18.	Week 12 to Week 18 or week 24
Changes in Central Systolic Blood Pressure from week 12 to Final Examination in patients with stabilised BP (i.e. patients whose BP is < 140/90 mmHg or < 130/80 mmHg for diabetics/chronic kidney disease) between Week 12 and Week 18.	Week 12 to week 18 or week 24

Collaborators and Investigators

• Sponsor: Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company

Publications and helpful links

General Publications

• Ruilope L, Schaefer A. The fixed-dose combination of olmesartan/amlodipine was superior in central aortic blood pressure reduction compared with perindopril/amlodipine: a randomized, double-blind trial in patients with hypertension. Adv Ther. 2013 Dec;30(12):1086-99. doi: 10.1007/s12325-013-0076-6. Epub 2013 Nov 30. Erratum In: Adv Ther. 2014 Apr;31(4):472. Adv Ther. 2014 Feb;31(2):243. Adv Ther. 2015 Feb;32(2):184-5.
• Ruilope LM, Schaefer A. Efficacy of Sevikar(R) compared to the combination of perindopril plus amlodipine on central arterial blood pressure in patients with moderate-to-severe hypertension: Rationale and design of the SEVITENSION study. Contemp Clin Trials. 2011 Sep;32(5):710-6. doi: 10.1016/j.cct.2011.04.011. Epub 2011 May 14.

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (Actual): November 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: April 7, 2010
• First Submitted That Met QC Criteria: April 7, 2010
• First Posted (Estimate): April 9, 2010

Study Record Updates

• Last Update Posted (Actual): December 24, 2018
• Last Update Submitted That Met QC Criteria: December 20, 2018
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Keywords: Sevikar®; Central Arterial Blood Pressure
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Enzyme Inhibitors; Protease Inhibitors; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Sodium Chloride Symporter Inhibitors; Amlodipine; Olmesartan; Hydrochlorothiazide; Perindopril
• Other Study ID Numbers: DSE- SEV-02-09; 2009-012966-30 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
• IPD Sharing Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• IPD Sharing Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code