Evaluation of the Effect of Acetazolamide, Mannitol and N-acetylcysteine on Cisplatin-Induced Nephrotoxicity

Cisplatin is a major anti-neoplastic drug used for the treatment of solid tumors. Its chief dose limiting side effect is nephrotoxicity. Twenty percent of patients receiving high-dose cisplatin undergo severe renal dysfunction. Acetazolamide and N-acetylcysteine (NAC) ameliorated Cisplatin-induced nephrotoxicity in rats. No study to date evaluated the protective effect of acetazolamide or NAC against cisplatin nephrotoxicity in humans.

Aim of the study was to evaluate the effect of acetazolamide or NAC against cisplatin nephrotoxicity in humans compared to mannitol and to each other.

Patients and methods. A total 52 patients receiving standard hydration measures for cisplatin were randomized to three groups: 20 patients receiving mannitol, 15 patients receiving acetazolamide and 17 patients receiving NAC. Patients' kidney function was monitored using serum creatinine, creatinine clearance and blood urea nitrogen; kidney injury was assessed using RIFLE criteria. Patients' liver function tests and hematological parameters were also monitored.

Study Overview

• Status: Completed
• Conditions: Cisplatin Nephrotoxicity
• Intervention / Treatment: Drug: Mannitol; Drug: saline; Drug: Cisplatin; Drug: Acetazolamide; Drug: Acetylcysteine

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Cancer patients to receive cisplatin based chemotherapy protocol.
2. Adult patients from 18 to 65 years.

Exclusion Criteria:

1. Existing renal impairment ( Creatinine clearance <30 ml/minute)
2. Severe hepatic impairment (Child Pugh score C).
3. Hypersensitivity to sulfonamides.
4. Patients with chronic non-congestive angle closure glaucoma.
5. Hypersensitivity to sulphur compounds, N-acetylcysteine or any component of the formulation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Mannitol group; patients received mannitol 20 % 100 ml half an hour before cisplatin and saline hydration.	Drug: Mannitol; patients received mannitol 20 % 100 ml half an hour before cisplatin and saline hydration.; Drug: saline; saline hydration 2500 ml before cisplatin therapy; Drug: Cisplatin; patients with tumours already prescribed cisplatin
Active Comparator: ACTZ group; patients received acetazolamide 250 mg half an hour before cisplatin with saline hydration.	Drug: saline; saline hydration 2500 ml before cisplatin therapy; Drug: Cisplatin; patients with tumours already prescribed cisplatin; Drug: Acetazolamide; patients received acetazolamide 250 mg half an hour before cisplatin with saline hydration.for prevention of cisplatin nephrotoxicity; Other Names: ACTZ
Active Comparator: NAC group; patients received acetylcysteine NAC (600 mg every 12 hours) for 4 doses beginning 24 hours before cisplatin with saline hydration.	Drug: saline; saline hydration 2500 ml before cisplatin therapy; Drug: Cisplatin; patients with tumours already prescribed cisplatin; Drug: Acetylcysteine; patients received NAC (600 mg every 12 hours) for 4 doses beginning 24 hours before cisplatin with saline hydration.for prevention of cisplatin nephrotoxicity; Other Names: NAC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Creatinine	Blood samples collected and measured in laboratory with the unit mg/dL	change from baseline after 3 cycles separated by 21 days
Creatinine clearance according to Cockroft-Gault equation	calculated using globalrph calculators , unit ml/min	change from baseline after 3 cycles separated by 21 days
Acute kidney injury	Acute kidney injury assessed by RIFLE criteria that was calculated for patients	change from baseline after 3 cycles separated by 21 days
Blood urea nitrogen (BUN)	Blood samples collected and measured in laboratory with the unit mg/dl	change from baseline after 3 cycles separated by 21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Aspartate Transaminase (AST)	Liver function tests were monitored by measuring AST for change from baseline after 3 cycles separated by 21 days	change from baseline after 3 cycles separated by 21 days
hemoglo bin	hemoglobin concentration g/dl was monitored for change from baseline after 3 cycles separated by 21 days	change from baseline after 3 cycles separated by 21 days
adverse events	Monitoring adverse events: to evaluate the difference between three groups regarding frequency of adverse events.	change from baseline after 3 cycles separated by 21 days
Alanine Transaminase (ALT)	Liver function tests were monitored by measuring ALT for change from baseline after 3 cycles separated by 21 days	change from baseline after 3 cycles separated by 21 days
platelets count	platelets count cells per ml was monitored for change from baseline after 3 cycles separated by 21 days	change from baseline after 3 cycles separated by 21 days
total leucocyte count	total leucocyte count cells per ml was monitored for change from baseline after 3 cycles separated by 21 days	change from baseline after 3 cycles separated by 21 days

Collaborators and Investigators

• Sponsor: Ain Shams University

Study record dates

Study Major Dates

• Study Start: November 1, 2013
• Primary Completion (Actual): October 1, 2015
• Study Completion (Actual): October 1, 2016

Study Registration Dates

• First Submitted: April 1, 2016
• First Submitted That Met QC Criteria: May 2, 2016
• First Posted (Estimate): May 4, 2016

Study Record Updates

• Last Update Posted (Estimate): January 24, 2017
• Last Update Submitted That Met QC Criteria: January 23, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antineoplastic Agents; Protective Agents; Carbonic Anhydrase Inhibitors; Natriuretic Agents; Diuretics, Osmotic; Diuretics; Anticonvulsants; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Cisplatin; Mannitol; Acetazolamide; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: MASTER