Spironolactone for Kidney Failure

(ACHIEVE Trial)

No longer recruiting at 166 trial locations

Overseen By Colin Hardy, B.A.

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Population Health Research Institute

Must not be taking: Mineralocorticoid antagonists

Disqualifiers: Hyperkalemia, Pregnancy, Transplant, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether spironolactone, a pill that helps prevent heart problems, can also benefit people on dialysis. Dialysis patients often face a higher risk of heart failure, and the study aims to determine if spironolactone can reduce that risk and be safely tolerated. Participants will receive either spironolactone or a placebo (a pill with no active medication) to compare outcomes. Suitable candidates for this trial include those who have been on dialysis for at least 90 days, have frequent dialysis sessions, and are not currently experiencing high potassium levels (a condition that can affect the heart). As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Do I have to stop taking my current medications for the trial?

The trial requires you to stop taking any mineralocorticoid receptor antagonists like spironolactone or eplerenone if you are currently on them and unable to withdraw. Other medications are not specified, so check with the trial coordinators.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that spironolactone is generally well tolerated by patients with early-stage chronic kidney disease (CKD), but it requires careful monitoring, especially at the start of treatment. While spironolactone can improve heart health for some, it may increase the risk of high potassium levels (hyperkalemia) and worsen kidney function. Overall, spironolactone is linked to a higher risk of serious high potassium levels in CKD patients. Prospective trial participants should be aware of these possible side effects and discuss them with their doctor. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about spironolactone for kidney failure because it offers a unique approach compared to traditional treatments, like ACE inhibitors or angiotensin receptor blockers. Unlike these standard options that primarily focus on controlling blood pressure and reducing proteinuria, spironolactone is a mineralocorticoid receptor antagonist. This means it targets the hormone aldosterone, which can contribute to kidney damage. By blocking aldosterone, spironolactone may help protect the kidneys from further harm and slow disease progression, offering a promising new avenue for patients with kidney failure.

What evidence suggests that spironolactone might be an effective treatment for heart failure in dialysis patients?

This trial will compare spironolactone with a placebo to evaluate its effects on kidney failure. Research has shown that spironolactone can reduce heart failure and related deaths in patients not on dialysis. It blocks a hormone called aldosterone, which can raise blood pressure and damage the heart. However, for patients on dialysis, studies have not shown clear benefits. Specifically, one major study found that spironolactone did not help these patients. While it is effective for some heart conditions, its benefits for dialysis patients remain uncertain. ^{1 2 3 6 7}

Who Is on the Research Team?

PJ Devereaux, MD, PhD

Principal Investigator

McMaster University

Michael Walsh, MD, PhD

Principal Investigator

McMaster University

Are You a Good Fit for This Trial?

This trial is for adults on dialysis due to kidney failure, who've been receiving treatment for at least 90 days. It's open to those aged 45 and above or adults over 18 with diabetes. Participants must not be pregnant, breastfeeding, have high potassium levels, known allergies to spironolactone, or be in another similar drug trial.

Inclusion Criteria

I am at least 45 years old or I am 18 or older with diabetes.

Provides informed consent

I am on dialysis, either hemodialysis twice a week or peritoneal dialysis daily.

Exclusion Criteria

My doctor says I must or must not take spironolactone.

Current or planned pregnancy or breastfeeding

The doctor thinks you have less than 6 months to live.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either spironolactone or placebo to evaluate its effect on reducing cardiac mortality and hospitalizations for heart failure in dialysis patients

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Placebo Oral Tablet
• Spironolactone

Trial Overview The study tests if Spironolactone can reduce heart failure and related deaths in patients on dialysis. Half of the participants will receive Spironolactone while the other half will get a placebo (a pill with no active drug), to compare outcomes between the two groups.

How Is the Trial Designed?

Group I: Spironolactone 25 MG Tablet Active Control 1 Intervention

25 mg of active spironolactone in tablet form

Group II: Placebo Oral Tablet Placebo Group 1 Intervention

A tablet with no active medication that will be an exact match of the active spironolactone in taste and appearance

Spironolactone is already approved in United States, European Union for the following indications:

Approved in United States as Aldactone for:

• High blood pressure
• Heart failure
• Liver scarring
• Kidney disease
• Low blood potassium
• Early puberty in boys
• Acne
• Excessive hair growth in women

Approved in European Union as Aldactone for:

• Fluid retention due to heart failure
• Liver scarring
• Kidney disease
• High blood pressure
• Low blood potassium

Who Is Running the Clinical Trial?

Population Health Research Institute

Lead Sponsor

Trials

165

Recruited

717,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Published Research Related to This Trial

In a study of 129 maintenance hemodialysis patients over 36 weeks, spironolactone was found to be safe with no significant increase in hyperkalemia or hypotension compared to placebo, although higher doses (50 mg) did show a greater risk of hyperkalemia.

Despite its safety, spironolactone did not demonstrate any significant improvement in cardiovascular function or diastolic parameters compared to placebo, suggesting limited efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and cardiovascular efficacy of spironolactone in dialysis-dependent ESRD (SPin-D): a randomized, placebo-controlled, multiple dosage trial. Charytan, DM., Himmelfarb, J., Ikizler, TA., et al.[2021]

This study aims to evaluate the effectiveness of a single dose of spironolactone (200 mg) in preventing contrast-induced nephropathy (CIN) in over 400 patients undergoing coronary catheterization, which is a procedure known to pose a high risk for acute kidney injury.

The primary outcome will measure the incidence of CIN by assessing changes in serum creatinine levels within 2-3 days post-procedure, providing valuable insights into the nephroprotective potential of spironolactone in this high-risk population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effect of Spironolactone on the Incidence of Contrast-Induced Nephropathy in Patients Undergoing Cardiac Catheterization: Study Design and Rationale. Mujtaba, A., Taher, MA., Hazza, MA., et al.[2020]

Spirolactones, such as spironolactone and K+ canrenoate, inhibit the binding of the androgen 5alpha-dihydrotestosterone (DHT) to its receptors in the prostate, suggesting a mechanism for their antiandrogenic effects.

The study indicates that spirolactones exert their antiandrogenic activity primarily through peripheral antagonism of androgens rather than affecting the production of testosterone or inhibiting prostatic 5alpha-reductase activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antiandrogenic effect of spirolactones: mechanism of action. Corvol, P., Michaud, A., Menard, J., et al.[2022]

Spironolactone has been shown to block the action of androgens by interacting with androgen receptors, which may lead to endocrine side effects in both rats and humans.

The spirolactone analog SC 25152 exhibits significantly lower affinity for the androgen receptor compared to spironolactone, suggesting it may have reduced antiandrogenic effects while still effectively targeting mineralocorticoid receptors in the kidneys.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SC 25152: A potent mineralocorticoid antagonist with reduced affinity for the 5 alpha-dihydrotestosterone receptor of human and rat prostate. Cutler, GB., Pita, JC., Rifka, SM., et al.[2013]

A new steroidal compound, the 15 beta,16 beta-methylene derivative 17, was developed and showed twice the aldosterone antagonistic potency compared to the standard drug spironolactone.

This new compound also demonstrated significantly reduced antiandrogenic side effects, suggesting it could be a safer alternative for patients needing aldosterone antagonism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aldosterone antagonists. 3. Synthesis and activities of steroidal 7 alpha-(alkoxycarbonyl)-15,16-methylene spirolactones. Nickisch, K., Bittler, D., Laurent, H., et al.[2019]

In a study of 2079 patients with stage 3-4 chronic kidney disease (CKD), spironolactone users had a significantly lower incidence of end-stage renal disease (ESRD) compared to non-users, with an adjusted hazard ratio of 0.66, indicating it may help slow CKD progression.

However, spironolactone users experienced a higher incidence of hyperkalemia-associated hospitalizations (HKAH), with an adjusted hazard ratio of 3.17, suggesting that while it is effective for CKD, careful monitoring for hyperkalemia is essential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Effects of Spironolactone on Kidney Function and Hyperkalemia-Associated Hospitalization in Patients with Chronic Kidney Disease. Yang, CT., Kor, CT., Hsieh, YP.[2020]

SC 23992 is a new spirolactone that shows two to eight times greater potency as an anti-aldosterone agent in vivo compared to Aldactone, although it has only about 10% potency in vitro.

This new compound may offer a safer alternative for patients, as it appears to have fewer antiandrogen side effects compared to traditional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SC 23992: radioreceptor assays for therapeutic and side effects. Funder, JW., Mercer, J., Hood, J.[2019]

In a study of 15 haemodialysis patients treated with spironolactone for 28 days, the mean potassium levels did not significantly increase, suggesting that spironolactone can be safely administered without causing hyperkalaemia in selected patients.

Despite some patients experiencing mild side effects, spironolactone showed no significant changes in aldosterone or renin levels, indicating its potential as a treatment option for chronic haemodialysis patients with heart disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is spironolactone safe for dialysis patients? Hussain, S., Dreyfus, DE., Marcus, RJ., et al.[2019]

In a retrospective analysis, patients taking spironolactone alongside ACE inhibitors or AT2 antagonists had a higher rate of stopping spironolactone and developed hyperkalaemia more frequently than expected, indicating a significant risk associated with this combination.

Patients with diabetes or lower haematocrit levels were particularly at risk for developing hyperkalaemia, highlighting the need for careful monitoring in these populations when prescribing spironolactone with other heart failure medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety of spironolactone treatment in patients with heart failure. Anton, C., Cox, AR., Watson, RD., et al.[2019]

In a study of 125 elderly patients with severe congestive heart failure (CHF) treated with spironolactone (SPL), adverse effects such as hyperkalemia and impaired renal function were found to be more common than previously reported, with 36% experiencing elevated potassium levels and 55% showing significant increases in serum creatinine.

The study highlights the need for careful monitoring and management of SPL treatment, especially in patients with an LVEF <20%, and suggests discontinuing potassium supplements and adjusting diuretic doses to mitigate risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How prevalent is hyperkalemia and renal dysfunction during treatment with spironolactone in patients with congestive heart failure? Svensson, M., Gustafsson, F., Galatius, S., et al.[2019]

A systematic review of six prospective trials found that spironolactone use in patients with end-stage renal disease (ESRD) on hemodialysis did not lead to a higher incidence of hyperkalemia compared to control groups.

These preliminary results suggest that spironolactone may be safe for use in ESRD patients on hemodialysis, but larger studies are necessary to confirm these findings before it can be routinely recommended.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spironolactone use in heart failure patients with end-stage renal disease on hemodialysis: is it safe? Chua, D., Lo, A., Lo, C.[2023]

In a study involving kidney transplant recipients, spironolactone at doses of 50 mg and 100 mg was found to significantly reduce acute urinary oxidative stress, as indicated by lower levels of 8-hydroxy-2-deoxyguanosine compared to placebo.

While spironolactone did not significantly affect urinary markers of tubular injury, the 100 mg dose showed a trend towards less intense increases in urinary heat shock protein 72, suggesting potential protective effects on kidney function post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spironolactone reduces oxidative stress in living donor kidney transplantation: a randomized controlled trial. Morales-Buenrostro, LE., Ortega-Trejo, JA., Pérez-Villalva, R., et al.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3370349/

The safety and tolerability of spironolactone in patients ... Spironolactone did reduce proteinuria but this effect was modest and was associated, perhaps causatively, with blood pressure reduction. However, these data are ...

2. academic.oup.com academic.oup.com/ckj/article/18/9/sfaf247/8223405

Effect of spironolactone on cardiovascular and renal outcomes ... In patients with CKD, spironolactone use was associated with a decreased risk of stroke but increased risks of severe hyperkalemia and all-cause ...

3. nature.com nature.com/articles/s41591-024-03263-5

Low-dose spironolactone and cardiovascular outcomes in ... Our results suggest that spironolactone should not be used in people with CKD without another specific indication, such as heart failure. The ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0140673625011948

Spironolactone in patients on chronic haemodialysis at ... The results of ALCHEMIST and the accompanying meta-analysis indicate that spironolactone does not provide clinical benefit to patients with ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT00291720

Study Details | NCT00291720 | Is Spironolactone Safe and ... Patients with kidney failure have a poor survival rate that is due to a much higher than average rate of heart and vascular disease. The reason that kidney ...

6. acc.org acc.org/latest-in-cardiology/journal-scans/2019/01/11/13/45/efficacy-and-safety-of-spironolactone-in-patients-with

Efficacy and Safety of Spironolactone in HFpEF and CKD In this analysis, the primary safety outcome was drug discontinuation due to an AE of persistent hyperkalemia (>5.5 mmol/L), worsening kidney ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S221317791830787X

Efficacy and Safety of Spironolactone in Patients With ... Spironolactone may increase risk for hyperkalemia and worsening renal function, particularly in patients with chronic kidney disease.