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

NCT01843309 | Terminated Phase 4

• 1 other identifier: AMPHYRO-628
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

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.

Conditions

Patients With Fungic Infections

Outcome Measures

Primary Outcomes (3)

• Incidence of hypokalemia ≤3.5mEq/L

  Researchers will collect daily plasma potassium

  Up to the 5th day

• Average potassium supplementation

  Researchers will collect the values of potassium supplements administered orally or parenterally.

  Within the first to 15 days

• Incidence of hyperkalemia

  Researchers will collect daily plasma potassium levels.

  Up to the 5 day

Secondary Outcomes (3)

• Acute kidney injury

  Within the first 15 days

• Incidence of renal tubular damage

  Up to the 7th day

• Incidence of hypomagnesemia

  Up to the 15 day

Study Arms (3)

Spironolactone 200mg

EXPERIMENTAL

Spironolactone 100 mg twice a day orally

Drug: Spironolactone 200mg

Placebo

PLACEBO COMPARATOR

Placebo twice a day orally

Drug: Placebo

Spironolactone 100mg

EXPERIMENTAL

Spironolactone 100mg once a day

Drug: Spironolactone 100mg

Interventions

Spironolactone 100mg DRUG

Spironolactone 100mg

Spironolactone 200mg DRUG

Spironolactone 200mg

Placebo DRUG

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with indications for AmB treatment

You may not qualify if:

• 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

Sponsors & Collaborators

• Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran: lead

Study Sites (1)

Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán

México, State of Mexico, 14000, Mexico

Location

MeSH Terms

Interventions

Canrenoic Acid; Spironolactone

Intervention Hierarchy (Ancestors)

Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Lactones; Organic Chemicals; Pregnenes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Fellow

Study Record Dates

• First Submitted: April 26, 2013
• First Posted: April 30, 2013
• Study Start: May 1, 2013
• Primary Completion: March 1, 2015
• Study Completion: March 1, 2015
• Last Updated: July 7, 2015

Record last verified: 2015-07

Locations

ME (1)