Evaluation of the Effect of Rosuvastatin on Cisplatin-induced Nephrotoxicity and Ototoxicity

Cisplatin is an effective anti-cancer drug for the treatment of many solid tumors in humans. Although the clinical response to cisplatin chemotherapy is encouraging, the nephrotoxicity and ototoxicity of the drug makes it difficult to continue its administration in many cases.

Cisplatin nephrotoxicity occurs through several mechanisms, mainly through the transport and accumulation of cisplatin into renal epithelial cells, injury to nuclear and mitochondrial DNA, activation of multiple cell death pathways and initiation of inflammatory response. Accordingly, several experimental strategies were developed to prevent this toxicity. For example, drugs that reduced renal cisplatin accumulation such as organic cation transporter 2 (OCT2) and copper transporter (Ctr1) inhibitors, antioxidants, antiapoptotic and anti-inflammatory agents were investigated. However, many of these drugs interfered with the cytotoxic effects of cisplatin.

Statins are agents used for reducing plasma cholesterol through the inhibition of the enzyme 3- hydroxy-3- methylglutaryl coenzyme A (HMG-CoA) reductase. In addition, statins are also proven to have pleiotropic, non-lipid dependent effects. These effects include anti-inflammatory actions and reduction of oxidative stress. Based on animal studies performed, statins have been shown to reduce the nephrotoxic effects of cisplatin in rats. In addition, ongoing clinical trials are aiming to investigate the role of statins in the protection against the ototoxicity of cisplatin as well. Our aim is to assess the protective effect of statins on cisplatin-induced nephrotoxicity and ototoxicity in humans.

Study Overview

• Status: Recruiting
• Conditions: Cisplatin Adverse Reaction
• Intervention / Treatment: Drug: Rosuvastatin 10mg

• Study Type: Interventional
• Enrollment (Anticipated): 65
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Aya T Moustafa, BSc; Phone Number: +201022666179; Email: ayatarek623@gmail.com

Study Locations

• Egypt
  • Cairo, Egypt
    • Recruiting
    • Kasr El-Aini Center of Radiation Oncology and Nuclear Medicine
    • Contact: Loay Kassem, PhD; Phone Number: +201003022907; Email: loay.kassem@cairocure.com
    • Principal Investigator: Loay Kassem, PhD
    • Principal Investigator: Aya T Moustafa, BSc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically proven lung and breast cancer patients indicated for cisplatin (4-6 cycles)
• Normal baseline serum creatinine levels
• Normal baseline audiometry
• Age between 18-70 years

Exclusion Criteria:

• Patients with more than one type of cancer
• Patients with prior chemotherapy treatment
• Treatment with statins within 12 months before assignment
• Treatment with fibrates within 4 weeks before assignment
• Pregnancy and Lactation
• Abnormal liver function tests or blood count

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Statin-Treated; This arm will be receiving: Cisplatin along with conventional nephroprotective interventions (IV hydration with 3 liters with electrolyte replacement administered on the same day of cisplatin); Rosuvastatin 10 mg/day	Drug: Rosuvastatin 10mg; The statin-treated arm will receive Rosuvastatin tablets 10 mg/day starting from the point of cisplatin initiation through the entire duration of therapy
No Intervention: Statin-Free; This arm will be receiving: -Cisplatin along with conventional nephroprotective interventions only (IV hydration with 3 liters with electrolyte replacement administered on the same day of cisplatin)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of cisplatin-induced nephrotoxicity	Increase in serum creatinine by ≥0.3 mg/dL or 1.5-2 fold increase from baseline	4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in biological research markers between both arms	Measurement of total antioxidant capacity and malondialdehyde levels	4 months
Difference in sensory-neural hearing impairment in both arms	Audiometry assessment	4 months
Incidence of electrolyte imbalance in both arms	Reduction in magnesium level ˂1.8 mg/dL and potassium level ˂3.5 mmol/L	4 months

Collaborators and Investigators

• Sponsor: Cairo University
• Collaborators: German University in Cairo
• Investigators: Study Chair: Mohamed H Solayman, PhD, German University in Cairo; Principal Investigator: Loay Kassem, PhD, Cairo University; Principal Investigator: Dalia S Elhelw, PhD, German University in Cairo; Principal Investigator: Aya T Moustafa, BSc, German University in Cairo

Publications and helpful links

General Publications

• An Y, Xin H, Yan W, Zhou X. Amelioration of cisplatin-induced nephrotoxicity by pravastatin in mice. Exp Toxicol Pathol. 2011 Mar;63(3):215-9. doi: 10.1016/j.etp.2009.12.002. Epub 2010 Jan 8.
• Fujieda M, Morita T, Naruse K, Hayashi Y, Ishihara M, Yokoyama T, Toma T, Ohta K, Wakiguchi H. Effect of pravastatin on cisplatin-induced nephrotoxicity in rats. Hum Exp Toxicol. 2011 Jul;30(7):603-15. doi: 10.1177/0960327110376551. Epub 2010 Jul 22.
• Seckl MJ, Ottensmeier CH, Cullen M, Schmid P, Ngai Y, Muthukumar D, Thompson J, Harden S, Middleton G, Fife KM, Crosse B, Taylor P, Nash S, Hackshaw A. Multicenter, Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Pravastatin Added to First-Line Standard Chemotherapy in Small-Cell Lung Cancer (LUNGSTAR). J Clin Oncol. 2017 May 10;35(14):1506-1514. doi: 10.1200/JCO.2016.69.7391. Epub 2017 Feb 27.
• Pabla N, Dong Z. Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int. 2008 May;73(9):994-1007. doi: 10.1038/sj.ki.5002786. Epub 2008 Feb 13.

Study record dates

Study Major Dates

• Study Start (Actual): November 17, 2020
• Primary Completion (Anticipated): August 1, 2021
• Study Completion (Anticipated): August 1, 2021

Study Registration Dates

• First Submitted: March 21, 2021
• First Submitted That Met QC Criteria: March 23, 2021
• First Posted (Actual): March 26, 2021

Study Record Updates

• Last Update Posted (Actual): July 28, 2021
• Last Update Submitted That Met QC Criteria: July 26, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: cisplatin; nephrotoxicity; rosuvastatin; ototoxicity
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Pathologic Processes; Wounds and Injuries; Otorhinolaryngologic Diseases; Ear Diseases; Drug-Related Side Effects and Adverse Reactions; Radiation Injuries; Ototoxicity; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Rosuvastatin Calcium
• Other Study ID Numbers: S-4-2020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes