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NCT Number: 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

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.

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Key information

Conditions

Chronic Kidney Disease(CKD) Chronic Disease Disease Attributes Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Kidney Diseases Male Urogenital Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms Renal Insufficiency Renal Insufficiency, Chronic Uncontrolled Hypertension Urogenital Diseases Urologic Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Department of Nephrology, University Hospital of Angers, Angers, France

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Antihypertensive algorithm

Drug

Antihypertensive algorithm based on diuretics agents

Standard of care

Drug

standard of care management for antihypertensive therapy intensification

Primary outcomes

  1. End stage kidney disease

    Time frame: Up to 36 months

    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

  2. eGFR decline of at least 40%

    Time frame: Up to 36 months

    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

  3. Cardiovascular events

    Time frame: Up to 36 months

    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

  4. All cause mortality

    Time frame: Up to 36 months

    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

Secondary outcomes

  1. Time to end-stage kidney disease

    Time frame: Up to 36 months

    All components of the composite endpoint will be assessed separately

  2. Time to eGFR decrease of at leat 40%

    Time frame: Up to 36 months

    All components of the composite endpoint will be assessed separately

  3. Time to the first cardiovascular event among myocardial infarction, heart failure, hospitalization and stroke

    Time frame: Up to 36 months

    All components of the composite endpoint will be assessed separately

  4. All-cause mortality

    Time frame: Up to 36 months

    All components of the composite endpoint will be assessed separately

  5. Change from baseline in blood pressure

    Time frame: From baseline and up to 36 months

    Systolic and diastolic blood pressure at months 3 and 6 then every 6 months (home blood pressure monitoring and office blood pressure measurement),

  6. Proportion of patients with controlled blood pressure

    Time frame: 24 months

    Proportion of patients with controlled blood pressure at 2 years (PA< 135/85mmHg with home blood pressure monitoring)

  7. Change from baseline in glomerular filtration rate

    Time frame: From baseline and up to 36 months

    Change from baseline in glomerular filtration rate estimated by CKD-EPI formula at months 3 and 6 then every 6 months

  8. Change from baseline in proteinuria (g/d) or proteinuria /creatinuria (g/g)

    Time frame: From baseline and up to 36 months

    Change from baseline in proteinuria (g/d) or proteinuria /creatinuria (g/g) at months 3 and 6 then every 6 months

  9. Proportion of patients who used at least one diuretic

    Time frame: Up to 36 months

  10. Change from baseline in quality of life

    Time frame: From baseline and up to 36 months

    Change from baseline in quality of life assessed by PROMIS-29 survey each year

Study contacts

Contact information is provided by the study sponsor or research team.

Bénédicte Sautenet, MD

CONTACT

[email protected]

02.34.37.96.86 ext. +33

Sponsors and collaborators

Lead sponsor

University Hospital, Tours

Other

Registry information

Official study 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

Acronym: THINK

Important dates

Study start
2023
Primary completion
2029
Study completion
2029
First posted
Feb 17, 2023
Registry last updated
Dec 1, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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