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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.
This is a placebo-controlled, double-blind, randomized controlled trial of chlorthalidone (CTD) in patients with CKD and poorly controlled hypertension
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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) |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline to 12 Weeks in Systolic Ambulatory Blood Pressure in the Chlorthalidone Group Compared to Placebo. | Baseline to 12 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Rajiv Agarwal, MD | Indiana University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Indiana University School of Medicine, Division of Nephrology | Indianapolis | Indiana | 46202 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38865199 | Derived | Agarwal R, Sinha AD, Tu W. Mechanisms of Antihypertensive Effect of Chlorthalidone in Advanced Chronic Kidney Disease: A Causal Mediation Analysis. Clin J Am Soc Nephrol. 2024 Aug 1;19(8):1025-1032. doi: 10.2215/CJN.0000000000000484. Epub 2024 Jun 12. | |
| 34739197 | Derived | 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. |
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Of the 403 consented patients, 160 met inclusion criteria and were randomized to treatment. Thus, 160 are considered enrolled for the purposes of this report.
Patients were recruited by screening for potential participants for eligibility at 3 medical centers between June 29, 2016 and January 7, 2021. The first participant consented on July 14, 2016, and the last participant was randomized on January 20, 2021.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. 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) |
| FG001 | 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. 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) |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. 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) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change From Baseline to 12 Weeks in Systolic Ambulatory Blood Pressure in the Chlorthalidone Group Compared to Placebo. | Posted | Mean | 95% Confidence Interval | mm Hg | Baseline to 12 weeks |
|
Adverse events were recorded during the period from the time of randomization to the discontinuation of the regimen (12 weeks).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. 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) |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Infection | Infections and infestations | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Infection | Infections and infestations | Systematic Assessment |
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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Rajiv Agarwal | Indiana University | 3179882241 | ragarwal@iu.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Dec 14, 2019 | Dec 9, 2021 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D051436 | Renal Insufficiency, Chronic |
| D006973 | Hypertension |
| ID | Term |
|---|---|
| D051437 | Renal Insufficiency |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
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| ID | Term |
|---|---|
| D002752 | Chlorthalidone |
| ID | Term |
|---|---|
| D000096926 | Benzenesulfonamides |
| D013449 | Sulfonamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
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| Placebo | Drug | This is a forced-titration study and placebo will be increased if goal BP is not achieved. |
|
| 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 |
| 32663820 | 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. |
| Lost to Follow-up |
|
| Withdrawal by Subject |
|
| Stop Point: BP above threshold |
|
| BG001 | 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. 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) |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Medical History of Diabetes Mellitus | Count of Participants | Participants |
|
| Cause of Chronic Kidney Disease | Count of Participants | Participants |
|
| Current Smoking | Count of Participants | Participants |
|
| Height | Mean | Standard Deviation | cm |
|
| Weight | Mean | Standard Deviation | kg |
|
| Body-Mass Index | Mean | Standard Deviation | kg/m^2 |
|
| Hip Circumference | Mean | Standard Deviation | cm |
|
| Waist Circumference | Mean | Standard Deviation | cm |
|
| Waist-to-Hip Ratio | Mean | Standard Deviation | ratio |
|
| Systolic Blood Pressure | Mean | Standard Deviation | mm Hg |
|
| Diastolic Blood Pressure | Mean | Standard Deviation | mm Hg |
|
| Pulse Rate | Mean | Standard Deviation | beats/min |
|
| Estimated Glomerular Filtration Rate | Mean | Standard Deviation | ml/min/1.73 m^2 |
|
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. 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) |
|
|
| Secondary | Changes in Albuminuria From Baseline at Each 4 Week Visit in the Log Transformed Albumin/Creatinine Ratio in the Chlorthalidone Group Compared to Placebo | Posted | Mean | 95% Confidence Interval | percentage of change in UACR | Baseline to 12 weeks |
|
|
|
| Secondary | 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. | Posted | Geometric Mean | 95% Confidence Interval | percentage of change | Baseline to 12 weeks |
|
|
|
| Secondary | 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. | Posted | Geometric Mean | 95% Confidence Interval | percentage of change in NTproBNP | Baseline to 12 weeks |
|
|
|
| Secondary | 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. | Posted | Mean | 95% Confidence Interval | Liters | Baseline to 12 weeks |
|
|
|
| 1 |
| 81 |
| 8 |
| 81 |
| 74 |
| 81 |
| EG001 | 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. 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) | 0 | 79 | 11 | 79 | 68 | 79 |
| Cardiovascular Event | Cardiac disorders | Systematic Assessment |
|
| Renal Event | Renal and urinary disorders | Systematic Assessment |
|
| Event of Interest | General disorders | Systematic Assessment | Event of Interest included orthostatic hypotension, acute kidney injury, hyperglycemia, and hypokalemia |
|
| Other | General disorders | Systematic Assessment |
|
| Cardiovascular Event | Cardiac disorders | Systematic Assessment |
|
| Other | General disorders | Systematic Assessment |
|
| Hypokalemia | Renal and urinary disorders | Systematic Assessment |
|
| Hypomagnesemia | Renal and urinary disorders | Systematic Assessment |
|
| Hyponatremia | Renal and urinary disorders | Systematic Assessment |
|
| Hypocalcemia | Renal and urinary disorders | Systematic Assessment |
|
| Hypercalcemia | Renal and urinary disorders | Systematic Assessment |
|
| Hyperglycemia | Renal and urinary disorders | Systematic Assessment |
|
| Hyperuricemia | Renal and urinary disorders | Systematic Assessment |
|
| Hyperkalemia | Renal and urinary disorders | Systematic Assessment |
|
| Hypernatremia | Renal and urinary disorders | Systematic Assessment |
|
| Acute Gout | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Syncope | Cardiac disorders | Systematic Assessment |
|
| Orthostatic Hypotension | Vascular disorders | Systematic Assessment | Orthostatic hypotension was defined as a decrease in the standing systolic blood pressure greater than 20 mm Hg, accompanied by a feeling of dizziness or light-headedness. |
|
| Dizziness | Cardiac disorders | Systematic Assessment | Dizziness was recorded when the patient felt dizzy when standing from a seated position but did not have a decrease in the systolic blood pressure greater than 20 mm Hg. |
|
| Asymptomatic Orthostatic Hypotension | Vascular disorders | Systematic Assessment | Asymptomatic orthostatic hypotension was defined as a decrease in the standing systolic blood pressure greater than 20 mm Hg that was not accompanied by a feeling of dizziness or light-headedness. |
|
| Acute Kidney Injury | Renal and urinary disorders | Systematic Assessment |
|
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| D005261 |
| Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D001555 |
| Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D001577 | Benzophenones |
| D010797 | Phthalimides |
| D007094 | Imides |
| D007659 | Ketones |
| D013450 | Sulfones |
| D013457 | Sulfur Compounds |
| D054833 | Isoindoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| Percent change in albuminuria 12 weeks from baseline in UACR |
|
| Percent change 12 weeks from baseline in aldosterone |
|
| Percent change 4 weeks from baseline in renin |
|
| Percent change 8 weeks from baseline in renin |
|
| Percent change 12 weeks from baseline in renin |
|
| Percent change from 12 weeks from baseline in NTproBNP |
|
| Change in body volume 12 weeks from baseline |
|