- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01843309
Use of Spironolactone for the Prevention of Electrolyte Abnormalities in Patients Treated With Amphotericin B
Purpose Invasive fungal infections cause significant morbidity and mortality in immunocompromised patients.
Amphotericin B deoxycholate (AmB) is a polyene antifungal agent. The broad spectrum of activity contributed to it being considered the gold standard of antifungal therapy despite being associated with high incidences of infusion related adverse events.
AmB exerts their antifungal effect binding to ergosterol; a sterol similar to cholesterol found in fungal cell membranes. However AmB also binds to cholesterol molecules in mammalian cell membranes forming intramembranous pores and vacuoles in the distal convoluted tubule of the kidney producing its nephrotoxic effects.
Nephrotoxicity is the major adverse effect of AmB, often limiting administrations of full dosage; it's manifested as acute kidney injury, impaired renal concentrating ability, augmented urinary potassium secretion through tubular Na+/K+ ATPase, type-1 renal tubular acidosis, which increases the elimination of potassium, and magnesium wasting. Furthermore potassium depletion potentiates the tubular toxicity of AmB.
The management of potassium wasting may be difficult, even high intravenous doses of potassium chloride may not be fully effective in correcting the hypokalemia. It has been probed the use of potassium-sparing diuretics to limit electrolyte wasting in patients treated with AmB.
In 1988 Smith et al, demonstrated that amiloride was well tolerated and provided effective control of plasma potassium in patients treated with AmB. This finding was confirmed in 2001 by Bearden et al. However in our country the only available commercial presentation of amiloride also contains hydrochlorothiazide, limiting its use in such patients.
Spironolactone acts on the distal renal tubule by competitive inhibition of aldosterone, thereby blocking the exchange between sodium and both potassium and hydrogen in the distal tubules and collecting ducts. These agents produce a sodium diuresis which results in potassium retention. There is only one clinical trial by Ural et al, using spironolactone to prevent hypokalemia in twenty-six neutropenic patients on AmB treatment; they demonstrated that those patients receiving concomitant AmB and spironolactone (100mg bid) had significantly higher plasma potassium levels than those receiving AmB alone (P=0.0027) and required significantly less potassium supplementation to maintain their plasma potassium within the normal range (P=0.022).
Renal vasoconstriction appears to play a major role in AmB induced reduction in GFR; recurrent ischemia may lead to structural and tubular damage and permanent nephrotoxic effects.
Aldosterone modulates the tone of the renal vasculature. Bobadilla et al have shown in animal models of cytotoxic damage using cyclosporine; that a mineralocorticoid receptor blockade with spironolactone reduces the structural renal damage, and also prevents renal dysfunction due to afferent and efferent vasoconstrictions. This group has also shown that prophylactic treatment with spironolactone completely prevents renal dysfunction and histological signs of tubular injury from ischemia-reperfusion injuries. And also has demonstrated the ability of spironolactone in animal models to protect the kidney after establishing an ischemic insult, when spironolactone was administrated immediately or 3h after the renal ischemic insult had occurred, reducing levels of sensitive biomarkers such as Kim-1 and Hsp70.
The investigators' hypothesis is that administration of spironolactone in patients treated with AmB will help to maintain significantly higher plasma potassium levels and will help to reduce potassium and magnesium supplementation. Moreover spironolactone will help to reduce the urinary excretion of potassium.
The investigators propose a randomized, double blind, placebo controlled trial approved by the local ethical committee, to compare the efficacy and security of spironolactone to reduce electrolytic derangements in three groups: AmB and placebo, AmB and spironolactone 100mg once a day, AmB and spironolactone 100mg twice a day. The investigators will include 12 patients per group. Researchers will collect daily plasma creatinine, sodium, potassium, BUN and urinary potassium, as well as the values of potassium and magnesium supplements administered orally or parenterally. The researchers will also collect by 7 days urinary levels of NGAL, KIM-1 and Hsp-70 as tubular injury markers.
Study Overview
Status
Conditions
Intervention / Treatment
Study Type
Enrollment (Actual)
Phase
- Phase 4
Contacts and Locations
Study Locations
-
-
-
México, Mexico, 14000
- Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Patients with indications for AmB treatment
Exclusion Criteria:
- Patients with acute kidney injury
- Hyperkalemia ≥5.2
- Hypersensibility to spironolactone
- HIV infection
- Pregnant women
- Solid organ transplant
- Hemodynamic instability
- CKDEPI ≤30ml/min/1.73m3
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Spironolactone 200mg
Spironolactone 100 mg twice a day orally
|
|
Placebo Comparator: Placebo
Placebo twice a day orally
|
|
Experimental: Spironolactone 100mg
Spironolactone 100mg once a day
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Incidence of hypokalemia ≤3.5mEq/L
Time Frame: Up to the 5th day
|
Researchers will collect daily plasma potassium
|
Up to the 5th day
|
Average potassium supplementation
Time Frame: Within the first to 15 days
|
Researchers will collect the values of potassium supplements administered orally or parenterally.
|
Within the first to 15 days
|
Incidence of hyperkalemia
Time Frame: Up to the 5 day
|
Researchers will collect daily plasma potassium levels.
|
Up to the 5 day
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Acute kidney injury
Time Frame: Within the first 15 days
|
Researchers will collect daily plasma creatinine and urinary output.
We will define acute kidney injury by creatinine elevation ≥0.3mg/dL above de baseline or reduction in urinary output according to AKIN criteria.
|
Within the first 15 days
|
Incidence of renal tubular damage
Time Frame: Up to the 7th day
|
Researchers will also collect by 7 days urinary levels of NGAL, KIM-1 and Hsp-70 as tubular injury markers.
|
Up to the 7th day
|
Incidence of hypomagnesemia
Time Frame: Up to the 15 day
|
Researchers will collect daily plasma magnesium
|
Up to the 15 day
|
Collaborators and Investigators
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- AMPHYRO-628
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Patients With Fungic Infections
-
Meir Medical CenterUnknownPatients With Normal ECG | Patients With Pathological ECGIsrael
-
IconOVir BioRecruitingPatients With Advanced Solid TumorsUnited States
-
Centre Hospitalier le MansCompletedPatients Living With HIVFrance
-
Sohag UniversityCompleted
-
Samsung Medical CenterNational Taiwan University Hospital; Chulalongkorn University; Asan Medical Center and other collaboratorsCompletedPatients Treated With AlemtuzumabKorea, Republic of, China, Indonesia, Thailand, Taiwan
-
Centre Hospitalier Universitaire DijonCompletedPatients Undergoing Cardiac Surgery | Patients With Coronary Artery Bypass Surgery With CECFrance
-
Université Catholique de LouvainNot yet recruitingUrinary Tract Infections | Patients With Suprabubic Catheter | Patients With Nephrostomy Catheter
-
Centre Francois BaclesseRecruitingPatients With CancerFrance
-
Yonsei UniversityRecruitingPatients With DefibrillatorKorea, Republic of
-
Philogen S.p.A.TerminatedPatients With CancerItaly, United Kingdom
Clinical Trials on Placebo
-
SamA Pharmaceutical Co., LtdUnknownAcute Bronchitis | Acute Upper Respiratory Tract InfectionKorea, Republic of
-
National Institute on Drug Abuse (NIDA)CompletedCannabis UseUnited States
-
AstraZenecaParexel; Spandauer Damm 130; 14050; Berlin, GermanyCompletedMale Subjects With Type II Diabetes (T2DM)Germany
-
Heptares Therapeutics LimitedCompletedPharmacokinetics | Safety IssuesUnited Kingdom
-
GlaxoSmithKlineCompletedPulmonary Disease, Chronic ObstructiveUnited Kingdom, Netherlands
-
Shijiazhuang Yiling Pharmaceutical Co. LtdXuanwu Hospital, BeijingCompleted
-
GlaxoSmithKlineCompletedInfections, BacterialUnited States
-
ItalfarmacoCompletedBecker Muscular DystrophyNetherlands, Italy
-
West Penn Allegheny Health SystemCompletedAsthma | Allergic RhinitisUnited States