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 lapel, cluster randomized controlled, phase 3 trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Regional Universitaire De Tours

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14], Diseases [C] - Male Urogenital Diseases [C12]

Trial duration

28 Mar 2023 → ongoing

Decision date (initial)

2023-01-23

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

Funding sources

DGOS

External identifiers

EU CT number

2022-501494-39-00

ClinicalTrials.gov

NCT05732727

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To assess the efficacy of an algorithm based on diuretic agents in patients with moderate to severe chronic kidney disease and uncontrolled hypertension in reducing the incidence of end-stage kidney disease, chronic kidney disease progression, cardiovascular events and mortality

Secondary objectives 11

1. To assess the efficacy of the strategy on end stage kidney disease (components of the primary objective)
2. To assess the efficacy of the strategy on chronic kidney disease progression (components of the primary objective)
3. To assess the efficacy of the strategy on cardiovascular events (components of the primary objective)
4. To assess the efficacy of the strategy on all cause mortality (components of the primary objective)
5. To assess the efficacy of the strategy on systolic and diastolic blood pressure
6. To assess the efficacy of the strategy on hypertension control
7. To assess the efficacy of the strategy on renal function changes
8. To assess the efficacy of the strategy on proteinuria
9. To assess the efficacy of the strategy on use of diuretics
10. To assess the efficacy of the strategy on quality of life
11. To assess the efficacy of the strategy on safety (clinical and biological)

Conditions and MedDRA coding

Uncontrolled Hypertension IN patients with moderate to severe chronic Kidney disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Male or female >=18 years with a clinical frailty score ≤5 for patient aged over 80
2. Participant covered by or entitled to social security
3. Written informed consent obtained from the participant
4. Advanced or moderate chronic kidney disease (eGFR 15.0 to 44.9 ml/mn/1.73m² using CKD-Epi formula)
5. 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.
6. 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.

Exclusion criteria 16

1. Patient following any measures of legal presentation
2. Two or more diuretic agents (loop diuretic, thiazides and thiazide-like diuretics)
3. Mineralocorticoid receptor antagonists
4. Autosomal dominant polycystic kidney disease treated with Tolvaptan
5. Contraindication to diuretics involved in the algorithm
6. Severe heart failure (NYHA III_IV)
7. Cirrhosis Child B-C
8. Pregnant or breastfeeding woman
9. Clinical signs of hypovolemia
10. Symptomatic orthostatic hypotension
11. Hyponatremia (<130 mmol/L)
12. Dyskalemia (<3,5 mmol/L or >5,5 mmol/L)
13. Major adverse cardiovascular event during the last three months: myocardial infarction, heart failure hospitalization, stroke
14. Current medical history of cancer requiring chemotherapy
15. Solid organ transplantation
16. 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)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Time to event outcome, considering the following composite endpoint: end stage kidney disease (need for kidney replacement therapy or renal transplantation), eGFR decline ≥40% (CKD-EPI formula), cardiovascular events (myocardial infarction, heart failure hospitalization, stroke), all cause mortality

Secondary endpoints 11

1. Time to end-stage kidney disease
2. Time to eGFR decrease ≥40%
3. Time to the first cardiovascular event (myocardial infarction, heart failure hospitalization, stroke)
4. All cause mortality
5. Change from baseline 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 at 2 years (PA< 135 and/or 85mmHg with home blood pressure monitoring)
7. 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 /creatininuria (g/g) at months 3 and 6 then every 6 months
9. Proportion of patients who used at least one diuretic
10. Change from baseline in quality of life assessed by PROMIS-29 survey each year
11. Safety: volume depletion, dyskalemia, hyponatremia, acute kidney injury, gout, orthostatic hypotension symptomatic/asymptomatic or complicated by falls

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Regional Universitaire De Tours

Sponsor organisation

Centre Hospitalier Regional Universitaire De Tours

Address

2 Boulevard Tonnelle

City

Tours Cedex 9

Postcode

37044

Country

France

Scientific contact point

Organisation

Centre Hospitalier Regional Universitaire De Tours

Contact name

Coordinating Investigator

Public contact point

Organisation

Centre Hospitalier Regional Universitaire De Tours

Contact name

Coordinating Investigator

Locations

1 EU/EEA country · 40 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 20 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications