Hypertension Treated With Antihypertensive DrugsPhase 2LODESTARNCT07645300
LOw DosE Spironolactone, chlorThAlidone oR Combination in CKD Trial
A Phase 2 study testing phase 2A Chlorthalidone, phase 2A Spironolactone and phase 2A Chlorthalidone + Spironolactone in people with Hypertension Treated With Antihypertensive Drugs and Chronic Kidney Disease, 3B and 4, run by VA Office of Research and Development at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 90 years
- Conditions the study is for
- Hypertension Treated With Antihypertensive Drugs, Chronic Kidney Disease, 3B and 4
- What is being tested?
- phase 2A Chlorthalidone, phase 2A Spironolactone and phase 2A Chlorthalidone + Spironolactone
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 160 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Oct 2026to 30 Jun 2032
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 90 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- Clinic AOBP of >=160/100 mmHg
- Use of:
- SPL
- eplerenone
- amiloride
- triamterene
Show all 14Show fewer
- 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
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site
Richard L. Roudebush VA Medical Center, Indianapolis, IN
Indianapolis, Indiana, 46202-2884
Rajiv Agarwal, MD MBBS, 317-988-2241, rajiv.agarwal@va.gov
Rajiv Agarwal, MD MBBS
About this study
Official title: 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.
Read the 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.
- Being tested
- phase 2A Chlorthalidone, phase 2A Spironolactone, phase 2A Chlorthalidone + Spironolactone, phase 2B Chlorthalidone LD + Spironolactone LD
- Keywords
- hypertension, chronic kidney disease
- Medical subject headings
- Renal Insufficiency, Chronic, Hypertension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
phase 2A ChlorthalidoneDrug
very low dose (VLD) x 6 weeks then low dose (LD) x 6 weeks
phase 2A SpironolactoneDrug
very low dose (VLD) x 6 weeks then low dose (LD) x 6 weeks
phase 2A Chlorthalidone + SpironolactoneDrug
very low dose (VLD) x 6 weeks then low dose (LD) x 6 weeks
phase 2B Chlorthalidone LD + Spironolactone LDDrug
compare combination LD with SPL LD at 12 weeks
| Study group | Role | What they receive |
|---|---|---|
| placebo | Placebo comparator | phase 2A Receives: Drug: phase 2A Chlorthalidone; Drug: phase 2A Spironolactone; Drug: phase 2A Chlorthalidone + Spironolactone |
| Chlorthalidone | Experimental | phase 2A Chlorthalidone(CTD) very low dose (VLD) x 6 weeks Receives: Drug: phase 2A Chlorthalidone |
| Spironolactone | Experimental | phase 2A Spironolactone(SPL) very low dose (VLD) x 6 weeks Receives: Drug: phase 2A Spironolactone |
| CTD + SPL | Experimental | phase 2A Chlorthalidone(CTD) VLD + Spironolactone(SPL) VLD x 6 weeks Receives: Drug: phase 2A Chlorthalidone + Spironolactone |
| 2B CTD | Active comparator | phase 2B Chlorthalidone(CTD) low dose (LD) x 12 weeks Receives: Drug: phase 2B Chlorthalidone LD + Spironolactone LD |
| 2B SPL | Active comparator | phase 2B Spironolactone(SPL) low dose (LD) x 12 weeks Receives: Drug: phase 2B Chlorthalidone LD + Spironolactone LD |
| 2B VLD CTD + VLD SPL | Experimental | phase 2B Chlorthalidone(CTD) VLD + Spironolactone(SPL) VLD x 12 weeks Receives: Drug: phase 2B Chlorthalidone LD + Spironolactone LD |
| 2B LD CTD + LD SPL | Experimental | phase 2B Chlorthalidone(CTD) LD + Spironolactone(SPL) LD x 12 weeks Receives: Drug: phase 2B Chlorthalidone LD + Spironolactone LD |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 12 weeks
Secondary outcomes (1)
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.
Measured: 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Jun 2026
- Study start1 Oct 2026 (estimated)
- Primary completion31 Mar 2032 (estimated)
- Study completion30 Jun 2032 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Hypertension Treated With Antihypertensive DrugsStudies of the same condition, open and under way.
- More trials run by VA Office of Research and DevelopmentThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- phase 2 A: Arm 1: placebo + placebo; Arm 2: placebo + spironolactone (SPL) very low dose (VLD); Arm 3: placebo + chlorthalidone (CTD) VLD; Arm 4: spironolactone VLD + chlorthalidone VLD. At 6 weeks, dose is doubled for further 6 weeks. phase 2 B: Arm 1: placebo + SPL LD; Arm 2: placebo + CTD LD; Arm 3: CTD VLD + SPL VLD; Arm 4: CTD LD + SPL LD all give 12 weeks
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 160 participants (estimated)
Sponsor and investigators
- Lead sponsor
- VA Office of Research and Development
- Sponsor type
- US federal agency
- Collaborators
- Michael E. DeBakey VA Medical Center, VA Salt Lake City Health Care System
- Responsible party
- Sponsor
- Investigators
- Rajiv Agarwal, MD MBBS, Principal investigator, Richard L. Roudebush VA Medical Center, Indianapolis, IN
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07645300
- Sponsor's protocol ID
- NEPH-011-25F
- Acronym
- LODESTAR
- Status last verified
- Jun 2026
- First submitted
- 8 Jun 2026
- Last updated
- 12 Jun 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 12 Jun 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- LOw DosE Spironolactone, chlorThAlidone oR Combination in CKD (LODESTAR) Trial
- ClinicalTrials.gov ID
- NCT07645300
- Acronym / sponsor ID
- LODESTAR / NEPH-011-25F
- Keywords
- hypertension, chronic kidney disease
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 160 participants (estimated)
- Lead sponsor
- VA Office of Research and DevelopmentUS federal agency
- Collaborators
- Michael E. DeBakey VA Medical Center, VA Salt Lake City Health Care System
- Study start
- 1 Oct 2026 (estimated)
- Primary completion
- 31 Mar 2032 (estimated)
- Study completion
- 30 Jun 2032 (estimated)
- First posted
- 12 Jun 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 8
- Model description
- phase 2 A: Arm 1: placebo + placebo; Arm 2: placebo + spironolactone (SPL) very low dose (VLD); Arm 3: placebo + chlorthalidone (CTD) VLD; Arm 4: spironolactone VLD + chlorthalidone VLD. At 6 weeks, dose is doubled for further 6 weeks. phase 2 B: Arm 1: placebo + SPL LD; Arm 2: placebo + CTD LD; Arm 3: CTD VLD + SPL VLD; Arm 4: CTD LD + SPL LD all give 12 weeks
| Arm | Type | Receives |
|---|---|---|
| placebo | Placebo comparator | Drug: phase 2A Chlorthalidone, Drug: phase 2A Spironolactone, Drug: phase 2A Chlorthalidone + Spironolactonephase 2A |
| Chlorthalidone | Experimental | Drug: phase 2A Chlorthalidonephase 2A Chlorthalidone(CTD) very low dose (VLD) x 6 weeks |
| Spironolactone | Experimental | Drug: phase 2A Spironolactonephase 2A Spironolactone(SPL) very low dose (VLD) x 6 weeks |
| CTD + SPL | Experimental | Drug: phase 2A Chlorthalidone + Spironolactonephase 2A Chlorthalidone(CTD) VLD + Spironolactone(SPL) VLD x 6 weeks |
| 2B CTD | Active comparator | Drug: phase 2B Chlorthalidone LD + Spironolactone LDphase 2B Chlorthalidone(CTD) low dose (LD) x 12 weeks |
| 2B SPL | Active comparator | Drug: phase 2B Chlorthalidone LD + Spironolactone LDphase 2B Spironolactone(SPL) low dose (LD) x 12 weeks |
| 2B VLD CTD + VLD SPL | Experimental | Drug: phase 2B Chlorthalidone LD + Spironolactone LDphase 2B Chlorthalidone(CTD) VLD + Spironolactone(SPL) VLD x 12 weeks |
| 2B LD CTD + LD SPL | Experimental | Drug: phase 2B Chlorthalidone LD + Spironolactone LDphase 2B Chlorthalidone(CTD) LD + Spironolactone(SPL) LD x 12 weeks |
Who may qualify
- Ages
- 18 to 90 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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
- Treatment with antihypertensive drugs
- Serum K 3.5 to 5.2 mEq/L at the time of randomization
Key exclusion criteria (14 listed)
- Clinic AOBP of >=160/100 mmHg
- Use of:
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| phase 2A Chlorthalidonevery low dose (VLD) x 6 weeks then low dose (LD) x 6 weeks | Drug | Chlorthalidone, placebo |
| phase 2A Spironolactonevery low dose (VLD) x 6 weeks then low dose (LD) x 6 weeks | Drug | Spironolactone, placebo |
| phase 2A Chlorthalidone + Spironolactonevery low dose (VLD) x 6 weeks then low dose (LD) x 6 weeks | Drug | CTD + SPL, placebo |
| phase 2B Chlorthalidone LD + Spironolactone LDcompare combination LD with SPL LD at 12 weeks | Drug | 2B CTD, 2B LD CTD + LD SPL, 2B SPL, 2B VLD CTD + VLD SPL |
Primary outcome
Unattended systolic automated office blood pressure in phase 2A
Time frame: 12 weeks
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.
Serum K phase 2A
Time frame: 12 weeks
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.
Unattended systolic automated office blood pressure in phase 2B
Time frame: 12 weeks
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.
1 secondary outcome
Mediation of BP lowering by volume markers
Time frame: 12 weeks
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Jun 2026.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Rajiv Agarwal, MD MBBS principal investigator
Richard L. Roudebush VA Medical Center, Indianapolis, IN
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing phase 2A Chlorthalidone, phase 2A Spironolactone and phase 2A Chlorthalidone + Spironolactone in people with Hypertension Treated With Antihypertensive Drugs and Chronic Kidney Disease, 3B and 4, run by VA Office of Research and Development at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 12 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Rajiv Agarwal, MD MBBS ((317) 988-2241, rajiv.agarwal@va.gov), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Unattended systolic automated office blood pressure in phase 2A (time frame: 12 weeks). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Jun 2026.