Chlorthalidone in Chronic Kidney Disease (CLICK)

• ClinicalTrials.gov Identifier: NCT02841280
• Recruitment Status: Recruiting
• First Posted: July 22, 2016
• Last Update Posted: January 24, 2019
• Sponsor: Indiana University
• Information provided by (Responsible Party): Rajiv Agarwal, Indiana University

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Renal Insufficiency, Chronic; Hypertension	Drug: Chlorthalidone; Drug: Placebo	Phase 2

Detailed Description:

This is a two-center, placebo-controlled, double-blind, randomized controlled trial of chlorthalidone (CTD) in patients with CKD and poorly controlled hypertension

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 160 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Study Start Date: July 2016
• Estimated Primary Completion Date: January 2021
• Estimated Study Completion Date: January 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Chlorthalidone; 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; This is a forced-titration study and the study drug or placebo will be increased if goal BP is not achieved (dosage of chlorthalidone not to exceed 50 mg)
Placebo Comparator: Placebo; 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; This is a forced-titration study and the study drug or placebo will be increased if goal BP is not achieved (dosage of chlorthalidone not to exceed 50 mg)

Outcome Measures

Primary Outcome Measures :

1. Change from baseline to 12 weeks in systolic ambulatory blood pressure in the chlorthalidone group compared to placebo. [ Time Frame: Baseline to 12 weeks ]

Secondary Outcome Measures :

1. Changes in albuminuria from baseline at each 4 week visit in the log transformed albumin/creatinine ratio in the chlorthalidone group compared to placebo, as measured by overnight urine collection. [ Time Frame: Baseline to 12 weeks ]
2. Change from baseline at each 4 week visit in log of aldosterone to renin ratio in the chlorthalidone group compared to placebo. No adjustments will be made for multiple comparisons. [ Time Frame: Baseline to 12 weeks ]
3. Change from baseline at each 4 week visit in log of B-type natriuretic peptide in the chlorthalidone group compared to placebo. No adjustments will be made for multiple comparisons. [ Time Frame: Baseline to 12 weeks ]
4. 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. [ Time Frame: Baseline to 12 weeks ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Age greater than 18 years.
2. 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.
3. Hypertension. This is defined as BP of either ≥130 systolic or ≥80 mmHg by 24-hour ambulatory BP monitoring.
4. 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.

Exclusion Criteria:

1. Use of thiazide or thiazide-like drugs in the previous 12 weeks.
2. Use of furosemide in a dose >200 mg/d.
3. BP of either ≥160 systolic or ≥100 mmHg by 24-hour ambulatory BP monitoring.
4. Expected to receive renal replacement therapy within the next 3 months.
5. Myocardial infarction, heart failure hospitalization, or stroke ≤3 months prior to randomization.
6. 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).
7. Known hypersensitivity to thiazide or sulfa drugs.
8. Organ transplant recipient or therapy with immunosuppressive agents.

Contacts and Locations

Contacts

Contact: Rajiv Agarwal, MD; 317-988-2241; ragarwal@iu.edu

Contact: William B Rogers, BS; 317-988-3024; rogersbe@iu.edu

Locations

United States, Indiana

Indiana University School of Medicine, Division of Nephrology; Recruiting

Indianapolis, Indiana, United States, 46202

Contact: Rajiv Agarwal, MD 317-988-2241 ragarwal@iu.edu

Contact: William Rogers, BS 317-988-3024 rogersbe@iu.edu

Principal Investigator: Rajiv Agarwal, MD

Sponsors and Collaborators

Indiana University

Investigators

• Principal Investigator: Rajiv Agarwal, MD; Indiana University

More Information

• Responsible Party: Rajiv Agarwal, Professor of Medicine, Indiana University
• ClinicalTrials.gov Identifier: NCT02841280
• Other Study ID Numbers: 1507540384
• First Posted: July 22, 2016
• Last Update Posted: January 24, 2019
• Last Verified: January 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Renal Insufficiency; Renal Insufficiency, Chronic; Kidney Diseases; Urologic Diseases; Chlorthalidone; Antihypertensive Agents; Diuretics; Natriuretic Agents; Physiological Effects of Drugs; Sodium Chloride Symporter Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action