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Use of Spironolactone for the Prevention of Electrolyte Abnormalities in Patients Treated With Amphotericin B

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ClinicalTrials.gov Identifier: NCT01843309
Recruitment Status : Terminated (Not possible to complete the sample within the estimated time by the use of new antifungals)
First Posted : April 30, 2013
Last Update Posted : July 7, 2015
Sponsor:
Information provided by (Responsible Party):
Bertha Manuela Córdova Sánchez, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Patients With Fungic Infections Drug: Spironolactone 100mg Drug: Spironolactone 200mg Drug: Placebo Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 36 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Use of Spironolactone for the Prevention of Electrolyte Abnormalities in Patients Treated With Amphotericin B
Study Start Date : May 2013
Actual Primary Completion Date : March 2015
Actual Study Completion Date : March 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Potassium

Arm Intervention/treatment
Experimental: Spironolactone 200mg
Spironolactone 100 mg twice a day orally
Drug: Spironolactone 200mg
Placebo Comparator: Placebo
Placebo twice a day orally
Drug: Placebo
Experimental: Spironolactone 100mg
Spironolactone 100mg once a day
Drug: Spironolactone 100mg



Primary Outcome Measures :
  1. Incidence of hypokalemia ≤3.5mEq/L [ Time Frame: Up to the 5th day ]
    Researchers will collect daily plasma potassium

  2. Average potassium supplementation [ Time Frame: Within the first to 15 days ]
    Researchers will collect the values of potassium supplements administered orally or parenterally.

  3. Incidence of hyperkalemia [ Time Frame: Up to the 5 day ]
    Researchers will collect daily plasma potassium levels.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. Incidence of hypomagnesemia [ Time Frame: Up to the 15 day ]
    Researchers will collect daily plasma magnesium



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01843309


Locations
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Mexico
Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
México, Mexico, 14000
Sponsors and Collaborators
Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

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Responsible Party: Bertha Manuela Córdova Sánchez, Fellow, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
ClinicalTrials.gov Identifier: NCT01843309     History of Changes
Other Study ID Numbers: AMPHYRO-628
First Posted: April 30, 2013    Key Record Dates
Last Update Posted: July 7, 2015
Last Verified: July 2015
Additional relevant MeSH terms:
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Congenital Abnormalities
Amphotericin B
Liposomal amphotericin B
Spironolactone
Mineralocorticoid Receptor Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Diuretics, Potassium Sparing
Diuretics
Natriuretic Agents
Amebicides
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Anti-Bacterial Agents
Antifungal Agents