Intensification of Blood Pressure Lowering Therapeutics Based on Diuretics Versus Usual Management for Uncontrolled Hypertension IN Patients With Moderate to Severe Chronic Kidney Disease

Study Overview
=================
Brief Summary
-----------------
Chronic kidney disease (CKD) is a major public health issue worldwide. Hypertension is the first risk factor in patients with CKD for mortality, cardiovascular disease and end-stage renal disease. It's now well established that lowering blood pressure (BP) reduces renal and cardiovascular complications in this high-risk population. In the general population, in addition to lifestyle interventions, the strategy to initiate and escalate a BP-lowering drug treatment is well described. The drug therapies recommended to achieve optimal BP control in the general population are the following: blockers of the renin-angiotensin system (angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB)), diuretics (thiazides and thiazide-like diuretics), and calcium channel blockers. For patients with CKD, the guidelines advise to start the BP-lowering agent with ACEi or ARB, but then, there is no strong evidence to support the preferential use of any particular agent in controlling BP and the results of clinical trials are discordant. In the NephroTest cohort, a French cohort of patients with CKD stage 1 to 5, among 2015 patients, 1782 had hypertension, only 54% had a diuretic and 44% had uncontrolled hypertension. In this cohort, extracellular fluid (ECF) overload was an independent determinant of hypertension, uncontrolled hypertension and apparent treatment resistant hypertension. In the same cohort, ECF overload was independently associated with end-stage kidney disease and death. Our hypothesis is that patients with CKD and uncontrolled hypertension are fluid overloaded and that the second line of treatment after an ACEi or an ARB should be a diuretic. We hypothesize that a specific algorithm to lower BP in patients with moderate to severe CKD based on diuretics will be more effective in term of cardiovascular event, mortality and evolution to end-stage kidney disease as compared to standard of care.

Official Title
-----------------
Intensification of Blood Pressure Lowering Therapeutics Based on Diuretics Versus Usual Management for Uncontrolled Hypertension IN Patients With Moderate to Severe Chronic Kidney Disease: an Open Label, a Cluster Randomized Controlled, Phase 3 Trial

Conditions
-----------------
Chronic Kidney Disease(CKD), Uncontrolled Hypertension

Intervention / Treatment
-----------------
* Drug: Antihypertensive algorithm
* Drug: Standard of care


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female >=18 years and <80 years of age Advanced or moderate chronic kidney disease (eGFR 15 to 44.9 mL/min/1.73m² using CKD-EPI formula) Arterial hypertension treated with at least one blood pressure lowering drug therapy among blockers of the renin-angiotensin system (ACEi or ARB), at the maximal posology tolerated by the patients stable since at least one month. Other blood pressure lowering drug therapies are tolerated. Uncontrolled office BP (>140 and/or 90 mmHg) confirmed by home blood pressure monitoring (>135/85 mmHg) Participant covered by or entitled to social security Written informed consent obtained from the participant Exclusion Criteria: Patient following any measures of legal presentation Pregnant or breastfeeding woman woman of childbearing without a highly effective contraceptive measure (combined or progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device or intrauterine hormone-releasing system) Clinical signs of hypovolemia Orthostatic hypotension Hyponatremia (<130 mmol/L) Dyskalemia (<3,5 mmol/L or >5,5 mmol/L) Major adverse cardiovascular event during the last three months: myocardial infarction, heart failure hospitalization, stroke Current medical history of cancer requiring chemotherapy Solid organ transplantation Two or more diuretic agents (loop diuretic, thiazides and thiazide-like diuretics) Mineralocorticoid receptor antagonists Autosomal dominant polycystic kidney disease treated with Tolvaptan Contraindication to diuretics involved in the algorithm Severe heart failure (NYHA III_IV) Cirrhosis Child B-C

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Cluster randomized controlled
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental group<br>Antihypertensive algorithm based on diuretics agents : the clinicians will adjust the drug therapy according to the antihypertensive algorithm based on diuretics agents. | Drug: Antihypertensive algorithm<br>* Antihypertensive algorithm based on diuretics agents<br>|
| Active Comparator: Control group<br>Standard of care : the clinicians will adapt the antihypertensive strategy according to his own standard of care which can be pharmacological or non-pharmacological therapies. | Drug: Standard of care<br>* standard of care management for antihypertensive therapy intensification<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| End stage kidney disease | The primary endpoint is a time to event outcome, considering the following composite endpoint: End stage kidney disease eGFR decline of at least 40% Cardiovascular events among myocardial infarction, heart failure, hospitalization and stroke All cause mortality | Up to 36 months | 
| eGFR decline of at least 40% | The primary endpoint is a time to event outcome, considering the following composite endpoint: End stage kidney disease eGFR decline of at least 40% Cardiovascular events among myocardial infarction, heart failure, hospitalization and stroke All cause mortality | Up to 36 months | 
| Cardiovascular events | The primary endpoint is a time to event outcome, considering the following composite endpoint: End stage kidney disease eGFR decline of at least 40% Cardiovascular events among myocardial infarction, heart failure, hospitalization and stroke All cause mortality | Up to 36 months | 
| All cause mortality | The primary endpoint is a time to event outcome, considering the following composite endpoint: End stage kidney disease eGFR decline of at least 40% Cardiovascular events among myocardial infarction, heart failure, hospitalization and stroke All cause mortality | Up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to end-stage kidney disease | All components of the composite endpoint will be assessed separately | Up to 36 months | 
| Time to eGFR decrease of at leat 40% | All components of the composite endpoint will be assessed separately | Up to 36 months | 
| Time to the first cardiovascular event among myocardial infarction, heart failure, hospitalization and stroke | All components of the composite endpoint will be assessed separately | Up to 36 months | 
| All-cause mortality | All components of the composite endpoint will be assessed separately | Up to 36 months | 
| Change from baseline in blood pressure | Systolic and diastolic blood pressure at months 3 and 6 then every 6 months (home blood pressure monitoring and office blood pressure measurement), | From baseline and up to 36 months | 
| Proportion of patients with controlled blood pressure | Proportion of patients with controlled blood pressure at 2 years (PA< 135/85mmHg with home blood pressure monitoring) | 24 months | 
| Change from baseline in glomerular filtration rate | Change from baseline in glomerular filtration rate estimated by CKD-EPI formula at months 3 and 6 then every 6 months | From baseline and up to 36 months | 
| Change from baseline in proteinuria (g/d) or proteinuria /creatinuria (g/g) | Change from baseline in proteinuria (g/d) or proteinuria /creatinuria (g/g) at months 3 and 6 then every 6 months | From baseline and up to 36 months | 
| Proportion of patients who used at least one diuretic |  | Up to 36 months | 
| Change from baseline in quality of life | Change from baseline in quality of life assessed by PROMIS-29 survey each year | From baseline and up to 36 months |