ALiskiren or Losartan Effects on bioMARKers of Myocardial Remodeling

Study Overview
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Brief Summary
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The purpose of this study is to assess efficacy of aliskiren for reducing circulating levels of biomarkers of left ventricular (LV) remodeling associated with LV hypertrophy (LVH) in hypertensive patients.

Detailed Description
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Blood pressure was measured 10 weeks after starting treatment (visit 3). All patients who did not achieve the required blood pressure (<140/90 mmHg) after 8 weeks of treatment at the maximum doses of study medication were given 5 mg of amlodipine in addition to the study medication in order to reach the required BP (<140/90 mmHg). The patient's blood pressure was assessed at visit 4 (week 18) and if it was still not at the required level (<140/90 mmHg), the dose of amlodipine was increased to 10 mg. Blood pressure was again assessed at visit 5 (week 26) and if the required values had not been reached (<140/90 mmHg), a 12.5 mg dose of hydrochlorothiazide (HCTZ) was prescribed

Official Title
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The ALiskiren or Losartan Effects on bioMARKers of Myocardial Remodeling (ALLMARK) Study

Conditions
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Hypertension, Left Ventricle Hypertrophy

Intervention / Treatment
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* Drug: Aliskiren
* Drug: Losartan
* Drug: Amlodipine
* Drug: Hydrochlorothiazide (HCTZ)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with hypertension Confirmed concentric left ventricular hypertrophy: LVMI > 49.2 g/m2.7 for men and >46.7 g/m2.7 for women Relative wall thickness > 0.42 Exclusion Criteria: Sever or secondary HTN LV ejection fraction of <40% Patient with compelling indication to ACEIs or ARBs or BB History of myocardial infarction, coronary artery bypass surgery, PTC intervention, TIA or stroke within 6 months of study entry History of collagenopathies, osteopathy eGFR <30 ml/min/1,73 m2, serum potassium ≥5,2 mEq/L Morbid obesity (BMI ≥ 42 kg/m2 Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aliskiren<br>Aliskiren 150 mg od for 2 weeks and up-titration to aliskiren 300 mg od for 34 weeks. In addition to the study medication, amlodipine 5mg was given to patients who did not achieve the required blood pressure (<140/90 mmHg) after 8 weeks of treatment at the maximum doses of study medication. At week 18 the dose of amlodipine was increased to 10mg if the required level (<140/90 mmHg) was still not achieved. HCTZ 12.5mg was prescribed at week 26 if the required values (<140/90 mmHg) had not been reached. | Drug: Aliskiren<br>* Aliskiren 300 mg film coated tablets<br>* Other names: Rasilez;Drug: Amlodipine<br>* Amlodipine 5mg was given to patients who did not achieve the required blood pressure (<140/90 mmHg) after 8 weeks (visit 3)of treatment at the maximum doses of study medication in addition to the study medication in order to reach the required BP. at visit 4 (week 18) the dose of amlodipine was increased to 10mg if the required level (<140/90 mmHg) was still not achieved.<br>Drug: Hydrochlorothiazide (HCTZ)<br>* HCTZ 12.5mg was prescribed at visit 5 (week 26) if the required values (<140/90 mmHg) had not been reached.<br>|
| Active Comparator: Lostaran<br>Losartan 50 mg od for 2 weeks and up-titration to losartan 100 mg od for 34 weeks. In addition to the study medication, amlodipine 5mg was given to patients who did not achieve the required blood pressure (<140/90 mmHg) after 8 weeks of treatment at the maximum doses of study medication. At week 18 the dose of amlodipine was increased to 10mg if the required level (<140/90 mmHg) was still not achieved. HCTZ 12.5mg was prescribed at week 26 if the required values (<140/90 mmHg) had not been reached. | Drug: Losartan<br>* Losartan 100 mg tablets<br>Drug: Amlodipine<br>* Amlodipine 5mg was given to patients who did not achieve the required blood pressure (<140/90 mmHg) after 8 weeks (visit 3)of treatment at the maximum doses of study medication in addition to the study medication in order to reach the required BP. at visit 4 (week 18) the dose of amlodipine was increased to 10mg if the required level (<140/90 mmHg) was still not achieved.<br>Drug: Hydrochlorothiazide (HCTZ)<br>* HCTZ 12.5mg was prescribed at visit 5 (week 26) if the required values (<140/90 mmHg) had not been reached.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in C-terminal Propeptide of Procollagen Type I (PICP) | PICP is a measure of blood concentration of procollagen I carboxy-terminal propeptide (PICP), a peptide released from the myocardium when procollagen is converted to type I collagen. This biomarker exhibits good specificity and sensitivity for identifying myocardial fibrosis in hypertension. | Baseline, Week 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Biomarkers in Heart Disease | The plasma level of biomarkers parameters used to measure improvement in left ventricular (LV) function or reduction in left ventricular mass index (LVMI). The following biomarkers were analyzed: cardiotrophin-1 (CT-1), matrix metalloproteinase-1 (MMP-1); tissue inhibitor of MMPs (TIMP-1); annexin A5 (AnxA5); N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) | Baseline, Week 36 | 
| Change From Baseline in Biomarker Such as Aldosterone (Aldo) in Heart Disease | The plasma level of biomarker parameter (aldosterone (Aldo)) used to measure improvement in left ventricular (LV) function or reduction in left ventricular mass index (LVMI) | Baseline, Week 36 | 
| Change From Baseline in Left Ventricular (LV) Function, LV End-diastolic Volume by Simpson's Rule, and LV End-systolic Volume by Simpson's Rule | Reductions in the following measurements were analysed between the baseline visit and the final visit: LV end-diastolic volume by Simpson's rule, and LV end-systolic volume by Simpson's rule | Baseline, Week 36 | 
| Change From Baseline in Left Ventricular (LV) Function, LV Ejection Fraction (Teicholz), and LV Ejection Fraction (Simpson) | Reductions in the following measurements were analysed between the baseline visit and the final visit: LV ejection fraction (Teicholz), and LV ejection fraction (Simpson) | Baseline, Week 36 | 
| Change From Baseline in Left Ventricular (LV) Function, LA (Left Atrium) Diameter | Reductions in the following measurements were analysed between the baseline visit and the final visit: LA diameter | Baseline, Week 36 | 
| Change From Baseline in Left Ventricular (LV) Function, Left Atrial Volume (Biplane Simpson's Method) | Reductions in the following measurements were analysed between the baseline visit and the final visit: left atrial volume (biplane Simpson's method) | Baseline, Week 36 | 
| Change From Baseline in Reduction of Left Ventricular Mass Index (LVMI) | Echocardiogram was performed at week 1 and at week 36. Reduction in LVMI is defined as the difference between the LVMI at the final visit and the baseline LVMI | Baseline, Week 36 | 
| Change From Baseline in Combination of Aliskiren With Amlodipine in Biomarkers of Heart Disease. | The plasma level of biomarkers parameters used to measure improvement in left ventricular (LV) function or reduction in left ventricular mass index (LVMI). The following biomarkers were analyzed: cardiotrophin-1 (CT-1), matrix metalloproteinase-1 (MMP-1); tissue inhibitor of MMPs (TIMP-1); annexin A5 (AnxA5); N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) | Baseline, Week 36 | 
| Change From Baseline in Biomarker Such as Aldosterone (Aldo) in Heart Disease in Combination of Aliskiren With Amlodipine | The plasma level of biomarker parameter plasma aldosterone used to measure improvement in left ventricular (LV) function or reduction in left ventricular mass index (LVMI). | Baseline, Week 36 | 
| Change From Baseline in Left Ventricular (LV) Function, LV End-diastolic Volume by Simpson's Rule, and LV End-systolic Volume by Simpson's Rule in Combination of Aliskiren With Amlodipine | Reductions in the following measurements were analysed between the baseline visit and the final visit: LV end-diastolic volume by Simpson's rule, and LV end-systolic volume by Simpson's rule | Baseline, Week 36 | 
| Change From Baseline in Left Ventricular (LV) Function, LV Ejection Fraction (Teicholz), and LV Ejection Fraction (Simpson) in Combination of Aliskiren With Amlodipine | Reductions in the following measurements were analysed between the baseline visit and the final visit: LV ejection fraction (Teicholz), and LV ejection fraction (Simpson) | Baseline, Week 36 | 
| Change From Baseline in Left Ventricular (LV) Function, LA (Left Atrium) Diameter in Combination of Aliskiren With Amlodipine | Reductions in the following measurements were analysed between the baseline visit and the final visit: LA diameter | Baseline, Week 36 | 
| Change From Baseline in Left Ventricular (LV) Function, Left Atrial Volume (Biplane Simpson's Method) in Combination of Aliskiren With Amlodipine | Reductions in the following measurements were analysed between the baseline visit and the final visit: left atrial volume (biplane Simpson's method) | Baseline, Week 36 | 
| Change From Baseline of LVMI in Combination of Aliskiren With Amlodipine | Echocardiogram was performed at week 1 and at week 36. Reduction in LVMI is defined as the difference between the LVMI at the final visit and the baseline LVMI | Baseline, Week 36 | 
| Effectivness of Aliskiren in Controlling Blood Pressure Compare to Losartan in Terms of Reduction in Systolic Blood Pressure (SBP) | The mean systolic BP (SBP) and diastolic BP (DBP) readings for the aliskiren and losartan treatment groups, the difference in these values between the two groups and the comparison of post-baseline vs. baseline values | Baseline, Week 10,18,26,36 | 
| Effectivness of Aliskiren in Controlling Blood Pressure Compare to Losartan in Terms of Reduction in Diastolic Blood Pressure (DBP) | The mean systolic BP (SBP) and diastolic BP (DBP) readings for the aliskiren and losartan treatment groups, the difference in these values between the two groups and the comparison of post-baseline vs. baseline values | Baseline, Week 10,18,26,36 | 
| Effectivness of Aliskiren in Controlling Blood Pressure Compare to Losartan in Terms of Patients With Satisfactory Response Rate | Response rate was defined as the proportion of patients with a satisfactory systolic BP response (SBP < 140 mmHg or reduction of ≥ 10 mmHg compared to baseline) and a satisfactory diastolic BP response (DBP < 90 mmHg or reduction of ≥ 5 mmHg compared to baseline) | Baseline, Week10,18,26,36 | 
| Effectivness of Aliskiren in Controlling Blood Pressure Compare to Losartan in Terms of Patients With SBP < 140 mmHg and DBP < 90 mmHg Compared to Baseline | The control rate was defined as the proportion of patients with SBP < 140 mmHg and DBP < 90 mmHg compared to baseline | Week10,18,26,36 | 
| Effectivness of Aliskiren in Controlling Blood Pressure Compare to Losartan in Terms of Rate of Use of Added Antihypertensive Rescue Drugs | The rate of use of first and second antihypertensive rescue drugs added was also assessed at all visits after week 2. The rescue drug at week 10 and 18 for those patients not achieving the required BP was amlodipine, Patients who did not achieve the required BP at week 26 were treated with hydrochlorothiazide | Baseline, Week 10,18,26 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aliskiren, hypertension, concentric LVH, LV remodeling, LVMI, biomarkers, PICP, CT-1, MMP-1, TIMP-1, AnxA5, Aldosterone, Essential hypertension with concentric left ventricle hypertrophy