RAS Blockade at Bedtime Versus on Awakening for Aldosterone Breakthrough

Study Overview
=================
Brief Summary
-----------------
Objective: To show that the frequency of aldosterone breakthrough is lower when RAS blockers are given at bedtime compared to on awaking, and to analyze the determinants and consequences of aldosterone breakthrough. Duration of the study: Inclusion 2 years, follow-up one year, total 3 years Design: prospective, multicenter, randomized, controlled, open label, two parallel groups. Main selection criteria: Inclusion criteria Chronic kidney disease stage 3 to 4, ACEI (captopril, enalapril, or ramipril), and/or ARB (losartan, valsartan, or irbesartan) on awaking for at least three months, History of hypertension or proteinuria > 0,5 g/24h or g/g créatininurie. Exclusion criteria Office blood pressure ≥ 160/100 mmHg, Anti-aldosterone (spironolactone, eplerenone) or potassium sparing diuretics (modamide, amiloride), or direct renin inhibitor. Evaluation criteria: Primary: Serum aldosterone levels at one year. Secondary: Serum aldosterone/renin ratio, 24h urine aldosterone, Significant aldosterone breakthrough defined by a >10% increase of serum aldosterone levels over baseline values, Aldosterone breakthrough defined by an increase of serum aldosterone levels over baseline values, HbA1c, Urinary albumin/creatinine ratio (UACR) on spot morning urine samples, Systolic home blood pressure (SBP), Estimated glomerular filtration rate (eGFR) using the MDRD equation.

Detailed Description
-----------------
Rational: Serum aldosterone levels may increase despite blockade of the renin angiotensin system (RAS) with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). This aldosterone breakthrough might be associated with bad outcomes: left ventricular hypertrophy, proteinuria and progression of renal failure. Antihypertensive drugs are given either on awaking or at bedtime. RAS is stimulated during nighttime. RAS blockers and diuretics given on awaking may stimulate aldosterone synthesis, and favor aldosterone breakthrough. Objective: To show that the frequency of aldosterone breakthrough is lower when RAS blockers are given at bedtime compared to on awaking, and to analyze the determinants and consequences of aldosterone breakthrough. Duration of the study: Inclusion 2 years, follow-up one year, total 3 years Design: prospective, multicenter, randomized, controlled, open label, two parallel groups.

Official Title
-----------------
RAS Blockade at Bedtime Versus on Awakening for the Prevention of Aldosterone Breakthrough

Conditions
-----------------
Chronic Kidney Disease

Intervention / Treatment
-----------------
* Other: Randomization that determine the time of treatment


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Chronic kidney disease stage 3 to 4, ACEI (captopril, enalapril, or ramipril), and/or ARB (losartan, valsartan, or irbesartan) on awaking for at least three months, History of hypertension or proteinuria > 0,5 g/24h or g/g creatininuria, Adult with social security insurance, Informed consent signed. Exclusion Criteria: Office blood pressure ≥ 160/100 mmHg, Pathology with life expectancy < 1 year, Anti-aldosterone (spironolactone, eplerenone) or potassium sparing diuretics (modamide, amiloride), or direct renin inhibitor.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: MORNING<br>patients continue to take their treatments (RAS blockers and diuretics) on awaking | Other: Randomization that determine the time of treatment<br> <br> * Other names: Randomization determine if the treatment will be taken in the morning or in the evening without changing the treatment;|
| Experimental: EVENING<br>Patients take their treatments(RAS blockers and diurectics)at bedtime | Other: Randomization that determine the time of treatment<br> <br> * Other names: Randomization determine if the treatment will be taken in the morning or in the evening without changing the treatment;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum aldosterone levels at one year |  | Level change between baseline and one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum aldosterone/renin ratio |  | level change between baseline and 12 months | 
| Significant aldosterone breakthrough Significant aldosterone breakthrough | Significant aldosterone breakthrough defined by a >10% increase of serum aldosterone levels over baseline values, | changes between baseline and one year |