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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Uncontrolled Hypertension; Chronic Kidney Disease(CKD)
• Intervention / Treatment: Drug: Antihypertensive algorithm; Drug: Standard of care

• Study Type: Interventional
• Enrollment (Estimated): 720
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Bénédicte Sautenet, MD; Phone Number: +33 02.34.37.96.86; Email: benedicte.sautenet@gmail.com

Study Locations

• France
  • Angers, France, 49933
    • Recruiting
    • Department of Nephrology, University Hospital of Angers
    • Contact: Martin PLANCHAIS, MD
    • Principal Investigator: Martin PLANCHAIS, MD
  • Bordeaux, France, 33000
    • Recruiting
    • Department of Nephrology, University Hospital of Bordeaux
    • Contact: Pierre PFIRMANN, MD-PhD
    • Principal Investigator: Pierre PFIRMANN, MD-PhD
  • Brest, France, 29200
    • Recruiting
    • Department of Nephrology, University Hospital of Brest
    • Contact: Yannick LE MEUR, MD-PhD
    • Principal Investigator: Yannick LE MEUR, MD-PhD
  • Brest, France, 29200
    • Recruiting
    • AUB Santé foundation, Brest
    • Contact: Morgane GOSSELIN, MD
    • Principal Investigator: Morgane GOSSELIN, MD
  • Chalon-sur-Saône, France
    • Recruiting
    • Department of Nephrology, Hospital of Chalon-sur-Saône
    • Contact: Magali LOUIS, MD
    • Principal Investigator: Magali LOUIS, MD
  • Chartres, France, 28630
    • Recruiting
    • Department of Nephrology, Hospital of Chartres
    • Contact: Nestor NANKEU, MD
    • Principal Investigator: Nestor NANKEU, MD
  • Clermont-Ferrand, France, 63001
    • Recruiting
    • Department of Nephrology, University Hospital of Clermont-Ferrand
    • Contact: Julien ANIORT, MD
    • Principal Investigator: Julien ANIORT, MD
  • Colmar, France, 68024
    • Recruiting
    • Department of Nephrology, Hospital of Colmar
    • Contact: Alexandre KLEIN, MD
    • Principal Investigator: Alexandre KLEIN, MD
  • Grenoble, France, 38043
    • Recruiting
    • Department of Nephrology, University Hospital of Grenoble
    • Contact: Pierre Louis CARRON, MD
    • Principal Investigator: Pierre Louis CARRON, MD
  • Haguenau, France, 67500
    • Recruiting
    • Department of Nephrology, Hospital of Haguenau
    • Contact: Julien OTT, MD
    • Principal Investigator: Julien OTT, MD
  • La Roche-sur-Yon, France, 85925
    • Recruiting
    • Department of Nephrology, Departemental Hospital of Vendée
    • Contact: Anne Hélène QUERARD, MD
    • Principal Investigator: Anne Hélène QUERARD, MD
  • Le Mans, France, 72100
    • Recruiting
    • ECHO Santé Association, Le Mans
    • Contact: Louis Marie VERNIER, MD
    • Principal Investigator: Louis Marie VERNIER, MD
  • Le Puy-en-Velay, France, 43012
    • Recruiting
    • Department of Nephrology, Hospital of Le Puy en Velay
    • Principal Investigator: Marc BOUILLER, MD
    • Contact: Marc BOUILLER, MD
  • Lille, France, 59000
    • Recruiting
    • Department of Nephrology, University Hospital of Lille
    • Contact: Marie FRIMAT, Md-PhD
    • Principal Investigator: Marie FRIMAT, Md-PhD
  • Limoges, France, 87042
    • Recruiting
    • Department of Nephrology, University Hospital of Limoges
    • Contact: Fatouma TOURE, MD-PhD
    • Principal Investigator: Fatima TOURE, MD-PhD
  • Lorient, France, 56100
    • Recruiting
    • AUB Santé foundation, Lorient
    • Contact: Gabrielle DUNEAU, MD
    • Principal Investigator: Gabrielle DUNEAU, MD
  • Lyon, France, 69003
    • Recruiting
    • Department of Nephrology, University Hospital of Lyon
    • Contact: Jean Pierre FAUVEL, MD-PhD
    • Principal Investigator: Jean Pierre FAUVEL, MD-PhD
  • Marseille, France, 13005
    • Recruiting
    • Department of Nephrology, University Hospital of Marseille
    • Contact: Stéphane BURTEY, MD-PhD
    • Principal Investigator: Stéphane BURTEY, MD-PhD
  • Metz, France, 57085
    • Recruiting
    • Department of Nephrology, Regional Hospital of Metz
    • Contact: Thomas QUINAUX, MD
    • Principal Investigator: Thomas QUINAUX, MD
  • Mulhouse, France, 68100
    • Recruiting
    • Department of Nephrology, Régional Hospital of Mulhouse
    • Contact: François CHANTREL, MD
    • Principal Investigator: François CHANTREL, MD
  • Nantes, France, 44093
    • Recruiting
    • Department of Nephrology, University Hospital of Nantes
    • Contact: Caroline GOURRAUD VERCEL, MD
    • Principal Investigator: Caroline GOURRAUD VERCEL, MD
  • Nantes, France, 44402
    • Recruiting
    • ECHO Santé Association, Nantes
    • Contact: Lila GHOUTI TERKI, MD
    • Principal Investigator: Lila GHOUTI TERKI, MD
  • Nîmes, France, 30029
    • Recruiting
    • Department of Nephrology, University Hospital of Nîmes
    • Contact: Olivier MORANNE, MD-PhD
    • Principal Investigator: Olivier MORANNE, MD-PhD
  • Orléans, France, 45067
    • Recruiting
    • Department of Nephrology, Hospital of Orléans
    • Contact: Marion DEKEYSER, MD
    • Principal Investigator: Marion DEKEYSER, MD
  • Paris, France, 75015
    • Active, not recruiting
    • Department of Nephrology, European Hospital Georges Pompidou, AP-HP
  • Paris, France, 75020
    • Active, not recruiting
    • Department of Nephrology, Tenon Hospital, AP-HP
  • Paris, France, 75015
    • Recruiting
    • Department of Nephrology, Necker Hospital, AP-HP
    • Contact: Dominique JOLY, MD-PhD
    • Principal Investigator: Dominique JOLY, MD-PhD
  • Paris, France, 75018
    • Recruiting
    • Department of Nephrology, Bichat Hospital, AP-HP
    • Contact: François VRTOVSNIK, MD-PhD
    • Principal Investigator: François VRTOVSNIK, MD-PhD
  • Perpignan, France, 66046
    • Recruiting
    • Department of Nephrology, Hospital of Perpignan
    • Contact: Sébastien CANET, MD
    • Principal Investigator: Sébastien CANET, MD
  • Reims, France, 51092
    • Recruiting
    • Department of Nephrology, University Hospital of Reims
    • Contact: Pierre Guillaume DELIEGE, MD
    • Principal Investigator: Pierre Guillaume DELIEGE, MD
  • Rennes, France, 35033
    • Recruiting
    • Department of Nephrology, University Hospital of Rennes
    • Contact: Thierry FROUGET, MD
    • Principal Investigator: Thierry FROUGET, MD
  • Roubaix, France, 59100
    • Recruiting
    • Department of Nephrology, Hospital of Roubaix
    • Contact: Thomas GUINCESTRE, MD
    • Principal Investigator: Thomas GUINCESTRE, MD
  • Rouen, France, 76230
    • Recruiting
    • Department of Nephrology, University Hospital of Rouen
    • Contact: Dominique GUERROT, MD-PHD
    • Principal Investigator: Dominique GUERROT, MD-PhD
  • Saint-Etienne, France, 42270
    • Recruiting
    • Department of Nephrology, University Hospital of Saint Etienne
    • Contact: Christophe MARIAT, MD-PhD
    • Principal Investigator: Christophe MARIAT, MD-PhD
  • Saint-Herblain, France, 44819
    • Active, not recruiting
    • ECHO Santé Association, Saint Herblain
  • St-Malo, France, 35400
    • Recruiting
    • Department of Nephrology, Hospital of Saint Malo
    • Contact: Eric RENAUDINEAU, MD
    • Principal Investigator: Eric RENAUDINEAU, MD
  • Strasbourg, France, 67000
    • Recruiting
    • Department of Nephrology, Hospital of Strasbourg
    • Contact: Nans FLORENS, MD-PhD
    • Principal Investigator: Nans FLORENS, MD-PhD
  • Tours, France, 37044
    • Recruiting
    • Department of Nephrology, University Hospital of Tours
    • Contact: Bénédicte SAUTENET, MD
    • Principal Investigator: Bénédicte SAUTENET, MD
  • Valenciennes, France, 59322
    • Recruiting
    • Department of Nephrology, Hospital of Valenciennes
    • Contact: Marc ULRICH, MD
    • Principal Investigator: Marc ULRICH, MD
  • Vandœuvre-lès-Nancy, France, 54511
    • Recruiting
    • Department of Nephrology, University Hospital of Nancy
    • Contact: Adrien FLAHAULT, MD-PhD
    • Principal Investigator: Adrien v, MD-PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female >=18 years with a clinical frailty score ≤5 for patient aged over 80
• 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 in combination with or in the event of intolerance to ACE inhibitors or ARBs.
• Uncontrolled office BP
• Uncontrolled office BP (>140 and/or 90 mmHg) confirmed by home blood pressure monitoring (>135 and/or 85 mmHg) or Day-time Ambulatory Blood Pressure Monitoring
• 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
• Symptomatic 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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental group; 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; Antihypertensive algorithm based on diuretics agents
Active Comparator: Control group; 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; standard of care management for antihypertensive therapy intensification

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
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
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

Collaborators and Investigators

• Sponsor: University Hospital, Tours
• Investigators: Principal Investigator: Bénédicte Sautenet, MD, University Hospital, Tours

Study record dates

Study Major Dates

• Study Start (Actual): March 28, 2023
• Primary Completion (Estimated): March 1, 2029
• Study Completion (Estimated): March 1, 2029

Study Registration Dates

• First Submitted: February 8, 2023
• First Submitted That Met QC Criteria: February 8, 2023
• First Posted (Actual): February 17, 2023

Study Record Updates

• Last Update Posted (Actual): December 1, 2025
• Last Update Submitted That Met QC Criteria: November 27, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Chronic Disease; Disease Attributes; Renal Insufficiency; Pathological Conditions, Signs and Symptoms; Renal Insufficiency, Chronic; Health Services Administration; Health Care Quality, Access, and Evaluation; Quality of Health Care; Quality Indicators, Health Care; Standard of Care
• Other Study ID Numbers: DR210320; 2022-501494-39-00 (Other Identifier: EU CT)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No