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

Uncontrolled Hypertension Clinical Trial

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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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05732727
• Other study ID #: DR210320
• Secondary ID: 2022-501494-39-0
• Status: Recruiting
• Phase: Phase 3
• Start date: March 28, 2023
• Est. completion date: March 2027

Study information

• Verified date: October 2023
• Source: University Hospital, Tours
• Contact: Bénédicte Sautenet, MD
• Phone: 02.34.37.96.86
• Email: benedicte.sautenet[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 720
• Est. completion date: March 2027
• Est. primary completion date: March 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Chronic Kidney Disease(CKD)
• Hypertension
• Kidney Diseases
• Renal Insufficiency, Chronic
• Uncontrolled Hypertension

Intervention

Drug:
• Antihypertensive algorithm
Antihypertensive algorithm based on diuretics agents
• Standard of care
standard of care management for antihypertensive therapy intensification

Locations

Country	Name	City	State
France	Department of Nephrology, University Hospital of Angers	Angers
France	Department of Nephrology, University Hospital of Bordeaux	Bordeaux
France	AUB Santé foundation, Brest	Brest
France	Department of Nephrology, University Hospital of Brest	Brest
France	Department of Nephrology, Hospital of Chalon-sur-Saône	Chalon-sur-Saône
France	Department of Nephrology, Hospital of Chartres	Chartres
France	Department of Nephrology, University Hospital of Clermont-Ferrand	Clermont-Ferrand
France	Department of Nephrology, Hospital of Colmar	Colmar
France	Department of Nephrology, University Hospital of Grenoble	Grenoble
France	Department of Nephrology, Hospital of Haguenau	Haguenau
France	Department of Nephrology, Departemental Hospital of Vendée	La Roche-sur-Yon
France	ECHO Santé Association, Le Mans	Le Mans
France	Department of Nephrology, Hospital of Le Puy en Velay	Le Puy-en-Velay
France	Department of Nephrology, University Hospital of Limoges	Limoges
France	Department of Nephrology, University Hospital of Lyon	Lyon
France	Department of Nephrology, University Hospital of Marseille	Marseille
France	Department of Nephrology, Regional Hospital of Metz	Metz
France	Department of Nephrology, Régional Hospital of Mulhouse	Mulhouse
France	Department of Nephrology, University Hospital of Nantes	Nantes
France	ECHO Santé Association, Nantes	Nantes
France	Department of Nephrology, University Hospital of Nîmes	Nîmes
France	Department of Nephrology, Bichat Hospital, AP-HP	Paris
France	Department of Nephrology, European Hospital Georges Pompidou, AP-HP	Paris
France	Department of Nephrology, Necker Hospital, AP-HP	Paris
France	Department of Nephrology, Tenon Hospital, AP-HP	Paris
France	Department of Nephrology, Hospital of Perpignan	Perpignan
France	Department of Nephrology, University Hospital of Reims	Reims
France	Department of Nephrology, University Hospital of Rennes	Rennes
France	Department of Nephrology, Hospital of Roubaix	Roubaix
France	Department of Nephrology, University Hospital of Rouen	Rouen
France	Department of Nephrology, University Hospital of Saint Etienne	Saint-Étienne
France	ECHO Santé Association, Saint Herblain	Saint-Herblain
France	Department of Nephrology, Hospital of Saint Malo	Saint-Malo
France	Department of Nephrology, University Hospital of Tours	Tours
France	Department of Nephrology, Hospital of Valenciennes	Valenciennes
France	Department of Nephrology, University Hospital of Nancy	vandoeuvre les Nancy

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Tours

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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	Time to end-stage kidney disease	All components of the composite endpoint will be assessed separately	Up to 36 months
Secondary	Time to eGFR decrease of at leat 40%	All components of the composite endpoint will be assessed separately	Up to 36 months
Secondary	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
Secondary	All-cause mortality	All components of the composite endpoint will be assessed separately	Up to 36 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Proportion of patients who used at least one diuretic		Up to 36 months
Secondary	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