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

Study Overview
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Brief Summary
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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.

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

Conditions
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Cisplatin Adverse Reaction

Intervention / Treatment
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* Drug: Rosuvastatin 10mg


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Statin-Treated<br>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<br>* The statin-treated arm will receive Rosuvastatin tablets 10 mg/day starting from the point of cisplatin initiation through the entire duration of therapy<br>|
| No Intervention: Statin-Free<br>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?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cisplatin, rosuvastatin, nephrotoxicity, ototoxicity