Chlorthalidone in Chronic Kidney Disease

NCT02841280 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 1507540384
• Study Type: interventional
• Target: 160
• Locations: 1 country
• Sites: 1

Brief Summary

It is estimated that in the United States there are approximately 8 million individuals who have moderate to severe chronic kidney disease (CKD). Among them hypertension is common and is often poorly controlled due to an expanded volume state; diuretics are frequently prescribed. Loop diuretics are potent and effective in lowering blood pressure (BP) but their use is associated with acute kidney injury. Thiazide diuretics, on the other hand, are less potent, their use may be associated with less acute kidney injury, but as yet there are no firm data to support that thiazide diuretic therapy can improve BP among subjects with advanced CKD. The investigators found 13 studies on the use of thiazide diuretics in advanced CKD either alone or in combination with loop diuretics and concluded that thiazides may be useful. Thiazides cause a negative Na balance, increase Na excretion by 10-15% and weight loss by 1-2 kg in observational studies. Observational data show that thiazides lead to an improvement in seated clinic BP of about 10-15 mmHg systolic and 5-10 mmHg diastolic whereas randomized trials show about a 15 mmHg reduction in mean BP. Randomized trials had only between 7 and 23 subjects each; accordingly, larger studies are needed to evaluate their safety and efficacy in moderate to advanced CKD.

Conditions

Renal Insufficiency, Chronic; Hypertension

Outcome Measures

Primary Outcomes (1)

• Change From Baseline to 12 Weeks in Systolic Ambulatory Blood Pressure in the Chlorthalidone Group Compared to Placebo.

  Baseline to 12 weeks

Secondary Outcomes (4)

• Changes in Albuminuria From Baseline at Each 4 Week Visit in the Log Transformed Albumin/Creatinine Ratio in the Chlorthalidone Group Compared to Placebo

  Baseline to 12 weeks

• Change From Baseline at Each 4 Week Visit in Log of Aldosterone and Log of Renin in the Chlorthalidone Group Compared to Placebo. No Adjustments Will be Made for Multiple Comparisons.

  Baseline to 12 weeks

• Change From Baseline at Each 4 Week Visit in Log of N-terminal Pro B-type Natriuretic Peptide (NTproBNP) in the Chlorthalidone Group Compared to Placebo. No Adjustments Will be Made for Multiple Comparisons.

  Baseline to 12 weeks

• Change From Baseline at Each 4 Week Visit in Body Volume in the Chlorthalidone Group Compared to Placebo. No Adjustments Will be Made for Multiple Comparisons.

  Baseline to 12 weeks

Study Arms (2)

Chlorthalidone

EXPERIMENTAL

Subjects with stage 4 chronic kidney disease (CKD) and poorly controlled hypertension confirmed by 24 hour ambulatory blood pressure monitoring will be randomized into two groups, one receiving placebo and one receiving a diuretic called chlorthalidone (12.5 mg at randomization). Doubling of the dose of the diuretic (up to 50 mg) or placebo will occur every 4 weeks if required by home blood pressure (BP) results.

Drug: Chlorthalidone

Placebo

PLACEBO COMPARATOR

Subjects with stage 4 CKD and poorly controlled hypertension confirmed by 24 hour ambulatory blood pressure monitoring will be randomized into two groups, one receiving placebo and one receiving a diuretic called chlorthalidone (12.5 mg at randomization). Doubling of the dose of the diuretic (up to 50 mg) or placebo will occur every 4 weeks if required by home BP results.

Drug: Placebo

Interventions

Chlorthalidone DRUG

This is a forced-titration study and the study drug will be increased if goal BP is not achieved (dosage of chlorthalidone not to exceed 50 mg)

Chlorthalidone

Placebo DRUG

This is a forced-titration study and placebo will be increased if goal BP is not achieved.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age greater than 18 years.
• Calculated glomerular filtration rate (GFR) by 4-component Modification of Diet in Renal Disease (MDRD) formula \< 30 ml/min/1.73m2 but ≥15 mL/min/1.73m2. The hospital laboratory uses isotope dilution mass spectrometry (IDMS) calibrated creatinine and the appropriate formula is used to estimate GFR.
• Hypertension. This is defined as BP of either ≥130 systolic or ≥80 mmHg by 24-hour ambulatory BP monitoring.
• Treatment with antihypertensive drugs: This would require the use of at least one antihypertensive drug. One of the drugs should be either an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). If these are contraindicated then use of a beta-blocker is required prior to randomization.

You may not qualify if:

• Use of thiazide or thiazide-like drugs in the previous 12 weeks.
• Use of furosemide in a dose \>200 mg/d.
• BP of either ≥160 systolic or ≥100 mmHg by 24-hour ambulatory BP monitoring.
• Expected to receive renal replacement therapy within the next 3 months.
• Myocardial infarction, heart failure hospitalization, or stroke ≤3 months prior to randomization.
• Pregnant or breastfeeding women or women who are planning to become pregnant or those not using a reliable form of contraception (oral contraceptives. condoms and diaphragms will be considered reliable).
• Known hypersensitivity to thiazide or sulfa drugs.
• Organ transplant recipient or therapy with immunosuppressive agents.

Sponsors & Collaborators

• Indiana University: lead

Study Sites (1)

Indiana University School of Medicine, Division of Nephrology

Indianapolis, Indiana, 46202, United States

Location

Related Publications (2)

• Agarwal R, Sinha AD, Cramer AE, Balmes-Fenwick M, Dickinson JH, Ouyang F, Tu W. Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease. N Engl J Med. 2021 Dec 30;385(27):2507-2519. doi: 10.1056/NEJMoa2110730. Epub 2021 Nov 5.

  PMID: 34739197 DERIVED

• Agarwal R, Cramer AE, Balmes-Fenwick M, Sinha AD, Ouyang F, Tu W. Design and Baseline Characteristics of the Chlorthalidone in Chronic Kidney Disease (CLICK) Trial. Am J Nephrol. 2020;51(7):542-552. doi: 10.1159/000508700. Epub 2020 Jul 14.

  PMID: 32663820 DERIVED

MeSH Terms

Conditions

Renal Insufficiency, Chronic; Hypertension

Interventions

Chlorthalidone

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Benzophenones; Phthalimides; Imides; Ketones; Sulfones; Sulfur Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

The trial was relatively small and had an underrepresentation of women (36 of 160 patients \[22%\] were women). In addition, very few patients were Asian or Hispanic.

Results Point of Contact

• Title: Dr. Rajiv Agarwal
• Organization: Indiana University

ragarwal@iu.edu

3179882241

Study Officials

• Rajiv Agarwal, MD

  Indiana University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: May 27, 2016
• First Posted: July 22, 2016
• Study Start: July 1, 2016
• Primary Completion: April 1, 2021
• Study Completion: April 1, 2021
• Last Updated: May 15, 2023
• Results First Posted: March 31, 2022

Record last verified: 2023-05

Locations

US (1)