Spironolactone for Kidney Failure
(ACHIEVE Trial)
Recruiting in Palo Alto (17 mi)
+155 other locations
MW
Overseen byMichael Walsh, MD, PhD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Waitlist Available
Sponsor: Population Health Research Institute
Must not be taking: Mineralocorticoid antagonists
Disqualifiers: Hyperkalemia, Pregnancy, Transplant, others
Pivotal Trial (Near Approval)
Prior Safety Data
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?
This trial tests if spironolactone, a pill that blocks a harmful hormone, can reduce heart problems in dialysis patients. These patients are at high risk of heart failure and death, and the pill aims to lower blood pressure and protect their hearts. Spironolactone has been shown to effectively lower blood pressure in patients with resistant hypertension.
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.
What data supports the idea that the drug Spironolactone for Kidney Failure is an effective treatment?
The available research shows that Spironolactone can reduce oxidative stress in patients who have undergone kidney transplants. In a study, patients who received Spironolactone had less increase in markers of oxidative stress compared to those who received a placebo. This suggests that Spironolactone may help protect the kidneys from damage after a transplant. However, in patients with end-stage renal disease on dialysis, Spironolactone did not show significant improvements in heart-related health, although it was generally safe to use. This indicates that while Spironolactone may be beneficial in certain kidney-related situations, its effectiveness can vary depending on the specific condition.12345
What safety data is available for spironolactone in treating kidney failure?
Spironolactone has been studied for safety in various contexts, including heart failure and end-stage renal disease. In heart failure patients, it was generally well tolerated with low frequency of adverse effects related to renal function and potassium levels. In a study with dialysis-dependent patients, spironolactone was found to be safe with similar rates of hyperkalemia and hypotension compared to placebo, although hyperkalemia was more frequent at higher doses (50 mg). Gynecomastia was rare and not significantly different from placebo. Overall, spironolactone appears safe in carefully monitored patients, but hyperkalemia risk increases with higher doses.36789
Is the drug Spironolactone a promising treatment for kidney failure?
Research Team
MW
Michael Walsh, MD, PhD
Principal Investigator
McMaster University
PD
PJ Devereaux, MD, PhD
Principal Investigator
McMaster University
Eligibility Criteria
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.
See 2 more
Exclusion Criteria
My doctor says I must or must not take spironolactone.
I am currently on a medication like spironolactone or eplerenone and cannot stop.
Current or planned pregnancy or breastfeeding
See 5 more
Trial Timeline
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
Treatment Details
Interventions
- Placebo Oral Tablet (Placebo)
- Spironolactone (Mineralocorticoid Receptor Antagonist)
Trial OverviewThe 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.
Participant Groups
2Treatment groups
Active Control
Placebo Group
Group I: Spironolactone 25 MG TabletActive Control1 Intervention
25 mg of active spironolactone in tablet form
Group II: Placebo Oral TabletPlacebo Group1 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Royal Inland HospitalKamloops, Canada
Kelowna General HospitalKelowna, Canada
Penticton Regional HospitalPenticton, Canada
Cape Breton Regional HospitalSydney, Canada
More Trial Locations
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Who Is Running the Clinical Trial?
Population Health Research Institute
Lead Sponsor
Trials
165
Patients Recruited
717,000+
Canadian Institutes of Health Research (CIHR)
Collaborator
Trials
1417
Patients Recruited
26,550,000+
References
SC 23992: radioreceptor assays for therapeutic and side effects. [2019]1. A new spirolactone (SC 23992) has been assayed in vitro to determine its affinity for mineralocorticoid and androgen receptors. 2. Although two to eight times as potent as anti-aldosterone agent as Aldactone in vivo, SC 23992 has only approximately 10% the potency in vitro. 3. This discrepancy between potency in vivo and in vitro appears to be explained on radioreceptor assay of the principal metabolites of Aldactone SC 23992. 4. SC 23992 may represent an antimineralocorticoid with less antiandrogen side effects.
Spironolactone reduces oxidative stress in living donor kidney transplantation: a randomized controlled trial. [2020]Mineralocorticoid receptor antagonism prevents acute kidney injury induced by ischemia-reperfusion in rodent and pig preclinical models. In a pilot study, we showed that spironolactone (25 mg) reduced oxidative stress after 5 days of kidney transplant (KT). In the present study, we investigated the effects of higher doses (50 and 100 mg) of spironolactone on kidney function, tubular injury markers, and oxidative stress in living donor KT recipients. We included KT recipients aged 18 yr or older who received immunosuppression therapy with IL-2 receptor antagonist, mycophenolate mofetil, corticosteroids, and tacrolimus with negative cross-match, and compatible blood group. Patients were randomized to receive placebo (n = 27), spironolactone (50 mg, n = 25), or spironolactone (100 mg, n = 25). Treatment was given from 3 days before and up to 5 days after KT. Serum creatinine, K+, urine neutrophil gelatinase-associated lipocalin-2, heat shock protein 72, and 8-hydroxy-2-deoxyguanosine levels were assessed. As expected, kidney function was improved after KT. Serum K+ remained in the normal range along the study. There was no significant effect of spironolactone on urinary neutrophil gelatinase-associated lipocalin-2 levels, whereas the increase in urinary heat shock protein 72 levels tended to be less intense in the 100 mg spironolactone-treated group (P = 0.054). In the placebo-treated group, urinary 8-hydroxylated-guanosine levels increased on days 3 and 5 after transplantation. This effect was prevented in patients that received spironolactone. In conclusion, spironolactone reduces the acute increase in urinary oxidative stress in living donor KT recipients.
Safety and cardiovascular efficacy of spironolactone in dialysis-dependent ESRD (SPin-D): a randomized, placebo-controlled, multiple dosage trial. [2021]The safety and efficacy of spironolactone is uncertain in end-stage renal disease. We randomized 129 maintenance hemodialysis patients to placebo (n=51) or spironolactone 12.5 mg (n=27), 25 mg (n=26), or 50 mg (n=25) daily for 36 weeks in a double-blind, placebo-controlled, multiple dosage trial to assess safety, tolerability and feasibility and to explore cardiovascular efficacy. The primary safety endpoints were hyperkalemia (potassium > 6.5 mEq/L) and hypotension requiring emergency department visit or hospitalization. Diastolic function was assessed by Doppler echocardiography. 125 participants (97%) completed dose escalation, with no significant difference in permanent study drug discontinuation between the groups (27.5% in placebo versus 16.7% in the combined spironolactone groups and 28% in the 50 mg group). Hyperkalemia frequency was similar between spironolactone and placebo (0.49 versus 0.50 events per patient-year) but demonstrated a significant linear trend due primarily to an increased event rate at the 50 mg dose (0.89 events per patient-year). The primary hypotension outcome was infrequent and similar with spironolactone and placebo (0.11 versus 0 events per patient-year). Gynecomastia was rare and did not differ significantly between groups. Change in diastolic function was similar with spironolactone and placebo. Spironolactone appears safe in carefully monitored maintenance hemodialysis patients, but did not affect cardiovascular parameters in this small study. Hyperkalemia occurs more frequently as dosage increases to 50 mg daily.
The Effect of Spironolactone on the Incidence of Contrast-Induced Nephropathy in Patients Undergoing Cardiac Catheterization: Study Design and Rationale. [2020]Patients undergoing coronary catheterization are at high risk of developing contrast-induced nephropathy (CIN) acute kidney injury (AKI). Several approaches have been supposed to limit such an effect but with mixed results or non-practical methods. Spironolactone is supposed to be effective as a nephroprotective agent in animal studies. This study will try to measure the effect of spironolactone on the incidence of CIN-AKI in patients undergoing coronary catheterization (angiography angioplasty).
Antiandrogenic effect of spirolactones: mechanism of action. [2022]Spirolactones are aldosterone antagonists which inhibit the binding of aldosterone to the renal mineralocorticoid receptor. These molecules also possess an antiandrogenic effect which could be due, among other possibilities, to a peripheral antagonism of androgens. This hypothesis has been tested in the present study. From in vivo experiments, spironolactone K+ canrenoate appear to inhibit the binding of [3H]5alpha-dihydrotestosterone [3H]DHT to the cytosolic and nuclear receptor of the rat ventral prostate. The doses used are in the same range as those used for demonstrating the antimineralocorticoid effect of these molecules. In vitro incubations and in vitro displacement studies show that spironolactone and K+ canrenoate are respectively about 20 and 100 times less effective than DHT in displacing 50 percent of 5 times 10- minus 10 M [3H]DHT from its receptor. Spirolactones are also able to compete with [3H]DHT for the specific 8 S cytosolic receptor. Neither spironolactone nor K+ canrenoate decreases prostatic 5alpha-reductase activity, even at a concentration as high as 10- minus 5 M. It seems likely that spirolactones, besides their action on testosterone biosynthesis, exert their antiandrogenic activity via a peripheral androgen antagonism.
How prevalent is hyperkalemia and renal dysfunction during treatment with spironolactone in patients with congestive heart failure? [2019]Treatment with spironolactone (SPL) is beneficial in patients with severe congestive heart failure (CHF). In the Randomized Aldactone Evaluation Study SPL was well tolerated, particularly with regard to renal function and serum K(+) levels. Our aim was to investigate whether the reported low frequency of adverse effects during SPL treatment in a heart failure study population could be confirmed in an unselected heart failure outpatient cohort and to identify potential predictors of harmful effects.
Aldosterone antagonists. 3. Synthesis and activities of steroidal 7 alpha-(alkoxycarbonyl)-15,16-methylene spirolactones. [2019]Several A- and D-ring substituted steroidal 7 alpha-alkoxycarbonyl spirolactones were synthesized with the purpose of increasing the aldosterone antagonistic potency and reducing the endocrinological side effects relative to the standard drug spironolactone. It was found that the 15 beta,16 beta-methylene derivative 17 exhibited a 2-fold higher aldosterone antagonistic activity compared to either spironolactone or the 15,16-unsubstituted derivative 29 while showing remarkably reduced antiandrogenicity.
SC 25152: A potent mineralocorticoid antagonist with reduced affinity for the 5 alpha-dihydrotestosterone receptor of human and rat prostate. [2013]It has previously been shown that spironolactone possesses antiandrogenic activity in the rat and interacts with rat prostate 5 alpha-dihydrotestosterone cytoplasmic receptors to block the nuclear uptake of this hormone. Current evidence suggests that this androgen receptor interaction may be an important mechanism through which spironolactone causes endocrine side effects in rat and man. We have analyzed the interactions of several spirolactone analogs with the androgen receptor of human and rat prostate and the mineralocorticoid receptor of human and rat kidney. One analog, SC 25152, was found to have considerably reduced affinity for the prostate 5 alpha-dihydrotestosterone receptor [Ka = 24 +/- 1% and 19 +/- 6% (mean +/- SE) in the human and rat, respectively, of the Ka for spironolactone] while maintaining similar affinity for the mineralocorticoid receptors of human and rat kidney [Ka = 113 +/- 37% and 86 +/- 7% (mean +/- SE), respectively, of the Ka for spironolactone]. These findings would predict this analog to have reduced antiandrogenicity at equivalent therapeutic doses.
Long-Term Effects of Spironolactone on Kidney Function and Hyperkalemia-Associated Hospitalization in Patients with Chronic Kidney Disease. [2020]Spironolactone, a non-selective mineralocorticoid receptor antagonist, can protect against cardiac fibrosis and left ventricular dysfunction, and improve endothelial dysfunction and proteinuria. However, the safety and effects of spironolactone on patient-centered cardiovascular and renal endpoints remain unclear.
Spironolactone use in heart failure patients with end-stage renal disease on hemodialysis: is it safe? [2023]Spironolactone is used in the treatment of cardiovascular disease, but is contraindicated in renal dysfunction due to the risk of hyperkalemia. It is not known if patients with end-stage renal disease (ESRD) on hemodialysis are at the same risk for hyperkalemia. The objective of this study was to systematically review the evidence evaluating the incidence of hyperkalemia with spironolactone use in ESRD patients on hemodialysis.
Is spironolactone safe for dialysis patients? [2019]Spironolactone is useful in heart failure, but is not given to dialysis patients for fear of hyperkalaemia. This study evaluated the safety of spironolactone administration in haemodialysis patients.
The safety of spironolactone treatment in patients with heart failure. [2019]Spironolactone is increasingly being used in the treatment of heart failure. However, it has been associated with cases of hyperkalaemia. The common use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-2 receptor (AT2) antagonists in heart failure increases the risk of hyperkalaemia.