Clinical trial NCT05732727: Intensification of Blood Pressure Lowering Therapeutics Based on Diuretics Versus Usual Management for Uncontrolled Hypertension IN Patients With Moderate to Severe Chronic Kidney Disease
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Chronic Kidney Disease(CKD)
Uncontrolled Hypertension
Lead sponsor: University Hospital, Tours
Sponsor class: OTHER
First posted: 2023-02-17
Enrollment: 720
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Cluster randomized controlled
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: End stage kidney disease
timeFrame: Up to 36 months
measure: eGFR decline of at least 40%
timeFrame: Up to 36 months
measure: Cardiovascular events
timeFrame: Up to 36 months
measure: All cause mortality
timeFrame: Up to 36 months
Secondary outcomes:
measure: Time to end-stage kidney disease
timeFrame: Up to 36 months
measure: Time to eGFR decrease of at leat 40%
timeFrame: Up to 36 months
measure: Time to the first cardiovascular event among myocardial infarction, heart failure, hospitalization and stroke
timeFrame: Up to 36 months
measure: All-cause mortality
timeFrame: Up to 36 months
measure: Change from baseline in blood pressure
timeFrame: From baseline and up to 36 months
measure: Proportion of patients with controlled blood pressure
timeFrame: 24 months
measure: Change from baseline in glomerular filtration rate
timeFrame: From baseline and up to 36 months
measure: Change from baseline in proteinuria (g/d) or proteinuria /creatinuria (g/g)
timeFrame: From baseline and up to 36 months
measure: Proportion of patients who used at least one diuretic
timeFrame: Up to 36 months
measure: Change from baseline in quality of life
timeFrame: From baseline and up to 36 months
Other outcomes:
Locations:
city: Angers
country: France
facility: Department of Nephrology, University Hospital of Angers
city: Bordeaux
country: France
facility: Department of Nephrology, University Hospital of Bordeaux
city: Brest
country: France
facility: AUB Santé foundation, Brest
city: Brest
country: France
facility: Department of Nephrology, University Hospital of Brest
city: Chalon-sur-Saône
country: France
facility: Department of Nephrology, Hospital of Chalon-sur-Saône
city: Chartres
country: France
facility: Department of Nephrology, Hospital of Chartres
city: Clermont-Ferrand
country: France
facility: Department of Nephrology, University Hospital of Clermont-Ferrand
city: Colmar
country: France
facility: Department of Nephrology, Hospital of Colmar
city: Grenoble
country: France
facility: Department of Nephrology, University Hospital of Grenoble
city: Haguenau
country: France
facility: Department of Nephrology, Hospital of Haguenau
city: La Roche-sur-Yon
country: France
facility: Department of Nephrology, Departemental Hospital of Vendée
city: Le Mans
country: France
facility: ECHO Santé Association, Le Mans
city: Le Puy-en-Velay
country: France
facility: Department of Nephrology, Hospital of Le Puy en Velay
city: Limoges
country: France
facility: Department of Nephrology, University Hospital of Limoges
city: Lyon
country: France
facility: Department of Nephrology, University Hospital of Lyon
city: Marseille
country: France
facility: Department of Nephrology, University Hospital of Marseille
city: Metz
country: France
facility: Department of Nephrology, Regional Hospital of Metz
city: Mulhouse
country: France
facility: Department of Nephrology, Régional Hospital of Mulhouse
city: Nantes
country: France
facility: Department of Nephrology, University Hospital of Nantes
city: Nantes
country: France
facility: ECHO Santé Association, Nantes
city: Nîmes
country: France
facility: Department of Nephrology, University Hospital of Nîmes
city: Paris
country: France
facility: Department of Nephrology, European Hospital Georges Pompidou, AP-HP
city: Paris
country: France
facility: Department of Nephrology, Necker Hospital, AP-HP
city: Paris
country: France
facility: Department of Nephrology, Bichat Hospital, AP-HP
city: Paris
country: France
facility: Department of Nephrology, Tenon Hospital, AP-HP
city: Perpignan
country: France
facility: Department of Nephrology, Hospital of Perpignan
city: Reims
country: France
facility: Department of Nephrology, University Hospital of Reims
city: Rennes
country: France
facility: Department of Nephrology, University Hospital of Rennes
city: Roubaix
country: France
facility: Department of Nephrology, Hospital of Roubaix
city: Rouen
country: France
facility: Department of Nephrology, University Hospital of Rouen
city: Saint-Herblain
country: France
facility: ECHO Santé Association, Saint Herblain
city: Saint-Malo
country: France
facility: Department of Nephrology, Hospital of Saint Malo
city: Saint-Étienne
country: France
facility: Department of Nephrology, University Hospital of Saint Etienne
city: Tours
country: France
facility: Department of Nephrology, University Hospital of Tours
city: Valenciennes
country: France
facility: Department of Nephrology, Hospital of Valenciennes
city: vandoeuvre les Nancy
country: France
facility: Department of Nephrology, University Hospital of Nancy
Study officials:
affiliation: University Hospital, Tours
name: Bénédicte Sautenet, MD
role: PRINCIPAL_INVESTIGATOR
References: