LOw DosE Spironolactone, chlorThAlidone oR Combination in CKD Trial (LODESTAR)

LOw DosE Spironolactone, chlorThAlidone oR Combination in CKD (LODESTAR) Trial

The purpose of this research is to gather information on the safety and effectiveness of spironolactone and chlorthalidone for treatment of high blood pressure in patients with moderate to advanced CKD. Both drugs have been approved by the Food and Drug Administration (FDA) for the treatment of high blood pressure since 1960.

Study Overview

• Status: Not yet recruiting
• Conditions: Hypertension Treated With Antihypertensive Drugs; Chronic Kidney Disease, 3B and 4
• Intervention / Treatment: Drug: phase 2A Chlorthalidone; Drug: phase 2A Spironolactone; Drug: phase 2A Chlorthalidone + Spironolactone; Drug: phase 2B Chlorthalidone LD + Spironolactone LD

Detailed Description

Highly prevalent among patients with chronic kidney disease (CKD) , poor blood pressure (BP) control is a modifiable risk factor for both kidney failure progression and cardiovascular (CV) disease. Although the mineralocorticoid receptor antagonist (MRA) spironolactone (SPL) is recommended to treat resistant hypertension in patients with CKD, 34% discontinue SPL within 12 weeks, mostly due to hyperkalemia. The potassium (K) binding agent patiromer reduced the discontinuation rate to 14%, but the added expense and potential drug interactions are of concern. SPL, a steroidal MRA, reduces albuminuria and rates of decline in eGFR. In type 2 diabetes and CKD, the non-steroidal MRA finerenone reduces kidney failure and CV outcomes but is not indicated for the treatment of hypertension. Due to concern of hyperkalemia, SPL is barely prescribed in these patients. In 2021, the investigators reported that chlorthalidone (CTD) in people with advanced CKD was effective in lowering BP and albuminuria by 50%. However, reversible changes in kidney function and hypokalemia were common. The investigators believe that a very low dose combination strategy of CTD + SPL will be effective in lowering BP, maintaining K, and providing target organ protection. However, the optimal dose to maintain K and lower BP remains unclear. To test this hypothesis, the investigators propose a pilot proof-of-concept study (phase 2A) followed by a larger phase 2B study. Proof of Concept, phase 2A: To test the hypothesis that low or very low dose CTD combined with SPL will improve BP, the investigators will perform a pilot, single-center, placebo-controlled, double-blind, randomized trial among patients with CKD and poorly controlled hypertension. After a two-week, patient-blind, placebo run-in, the investigators will randomize 50 hypertensive people to one of 4 groups in equal numbers: placebo; CTD very low dose; SPL very low dose QD; or a combination of CTD very low dose + SPL very low dose for 6 weeks. At 6 weeks, doses will be doubled for a further 6 weeks. The primary endpoint will be assessed by change from baseline to 6 weeks and 12 weeks in systolic AOBP and serum K for the combination group compared to placebo. If CTD + SPL is more effective than placebo, the investigators will perform the phase 2B trial. In this trial, the investigators will test the hypothesis that among patients with moderate to advanced CKD and poorly controlled hypertension, compared to add-on SPL or add-on CTD, treatment over 12 weeks with add-on combination of spironolactone (SPL) and chlorthalidone (CTD) will more effectively lower unattended systolic automated office blood pressure (uAOBP). Furthermore, combination therapy will reduce albuminuria more than either drug alone providing evidence for target organ protection. CTD will produce these effects by further reducing extracellular fluid volume in combination with SPL.

• Study Type: Interventional
• Enrollment (Estimated): 160
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Rajiv Agarwal, MD MBBS; Phone Number: (317) 988-2241; Email: rajiv.agarwal@va.gov

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202-2884
      • Richard L. Roudebush VA Medical Center, Indianapolis, IN
      • Principal Investigator: Rajiv Agarwal, MD MBBS
      • Contact: Rajiv Agarwal, MD MBBS; Phone Number: 317-988-2241; Email: rajiv.agarwal@va.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Study is limited to US Veterans
• GFR estimated by race-independent CKD-EPI formula < 45 ml/min/1.73m2 but 15 mL/min/1.73m2

• Hypertension

  • The investigators will use clinic AOBP of at least 135/85 to define hypertension

• Treatment with antihypertensive drugs

  • This would require the use of at least one antihypertensive drug
  • One of the drugs should be either an ACE inhibitor or ARB or a beta-blocker at the time of randomization
• Serum K 3.5 to 5.2 mEq/L at the time of randomization

Exclusion Criteria:

• Clinic AOBP of >=160/100 mmHg

• Use of:

  • SPL
  • eplerenone
  • amiloride
  • triamterene
  • finerenone
  • thiazide
  • thiazide-like drugs (CTD, HCTZ, metolazone, indapamide) or the use of K binders or fludrocortisone in the previous 4 weeks
  • K supplementation would be allowed
• Myocardial infarction, heart failure hospitalization, or stroke 8 weeks prior to randomization
• If the patient is only on an alpha blocker, as the sole antihypertensive drug, they will be excluded
• Pregnant or breastfeeding women or women who are planning to become pregnant or those not using a reliable form of contraception
• Known hypersensitivity or a prior documented adverse reaction to CTD or SPL

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo; phase 2A	Drug: phase 2A Chlorthalidone; very low dose (VLD) x 6 weeks then low dose (LD) x 6 weeks; Drug: phase 2A Spironolactone; very low dose (VLD) x 6 weeks then low dose (LD) x 6 weeks; Drug: phase 2A Chlorthalidone + Spironolactone; very low dose (VLD) x 6 weeks then low dose (LD) x 6 weeks
Experimental: Chlorthalidone; phase 2A Chlorthalidone(CTD) very low dose (VLD) x 6 weeks	Drug: phase 2A Chlorthalidone; very low dose (VLD) x 6 weeks then low dose (LD) x 6 weeks
Experimental: Spironolactone; phase 2A Spironolactone(SPL) very low dose (VLD) x 6 weeks	Drug: phase 2A Spironolactone; very low dose (VLD) x 6 weeks then low dose (LD) x 6 weeks
Experimental: CTD + SPL; phase 2A Chlorthalidone(CTD) VLD + Spironolactone(SPL) VLD x 6 weeks	Drug: phase 2A Chlorthalidone + Spironolactone; very low dose (VLD) x 6 weeks then low dose (LD) x 6 weeks
Active Comparator: 2B CTD; phase 2B Chlorthalidone(CTD) low dose (LD) x 12 weeks	Drug: phase 2B Chlorthalidone LD + Spironolactone LD; compare combination LD with SPL LD at 12 weeks
Active Comparator: 2B SPL; phase 2B Spironolactone(SPL) low dose (LD) x 12 weeks	Drug: phase 2B Chlorthalidone LD + Spironolactone LD; compare combination LD with SPL LD at 12 weeks
Experimental: 2B VLD CTD + VLD SPL; phase 2B Chlorthalidone(CTD) VLD + Spironolactone(SPL) VLD x 12 weeks	Drug: phase 2B Chlorthalidone LD + Spironolactone LD; compare combination LD with SPL LD at 12 weeks
Experimental: 2B LD CTD + LD SPL; phase 2B Chlorthalidone(CTD) LD + Spironolactone(SPL) LD x 12 weeks	Drug: phase 2B Chlorthalidone LD + Spironolactone LD; compare combination LD with SPL LD at 12 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Unattended systolic automated office blood pressure in phase 2A	phase 2A: the primary endpoint will be assessed by change from baseline to 6 weeks and 12 weeks in systolic AOBP for the combination group compared to placebo.	12 weeks
Serum K phase 2A	phase 2A: the primary endpoint will be assessed by change from baseline to 12 weeks in serum K for the combination group compared to placebo.	12 weeks
Unattended systolic automated office blood pressure in phase 2B	phase 2B: the primary endpoint will be assessed by change from baseline to 12 weeks in systolic AOBP for the combination LD group compared to SPL.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mediation of BP lowering by volume markers	The investigators will evaluate changes from baseline in the following markers: B-type natriuretic peptide (BNP), seated plasma renin activity and plasma aldosterone, and 24h urinary aldosterone. The investigators will use a mediation model to ascertain the mechanism of BP lowering whether it is via reduction of volume or blockade of the renin-angiotensin system. Each of the 4 mediation variables will be analyzed individually and then in aggregate as prespecified in the statistical analysis plan.	12 weeks

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Collaborators: Michael E. DeBakey VA Medical Center; VA Salt Lake City Health Care System
• Investigators: Principal Investigator: Rajiv Agarwal, MD MBBS, Richard L. Roudebush VA Medical Center, Indianapolis, IN

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): March 31, 2032
• Study Completion (Estimated): June 30, 2032

Study Registration Dates

• First Submitted: June 8, 2026
• First Submitted That Met QC Criteria: June 8, 2026
• First Posted (Actual): June 12, 2026

Study Record Updates

• Last Update Posted (Actual): June 12, 2026
• Last Update Submitted That Met QC Criteria: June 8, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: hypertension; chronic kidney disease
• Additional Relevant MeSH Terms: Urogenital Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Chronic Disease; Disease Attributes; Renal Insufficiency; Pathological Conditions, Signs and Symptoms; Hypertension; Renal Insufficiency, Chronic; Organic Chemicals; Polycyclic Compounds; Pregnanes; Steroids; Fused-Ring Compounds; Lactones; Pregnenes; Spironolactone
• Other Study ID Numbers: NEPH-011-25F

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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.: Yes