Clinical trial NCT04817904: Evaluation of the Effect of Rosuvastatin on Cisplatin-induced Nephrotoxicity and Ototoxicity
Official title: Evaluation of the Effect of Rosuvastatin on Cisplatin-induced Nephrotoxicity and Ototoxicity
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Cisplatin Adverse Reaction
Keywords: cisplatin
rosuvastatin
nephrotoxicity
ototoxicity
Lead sponsor: Cairo University
Sponsor class: OTHER
Collaborators: name: German University in Cairo
First posted: 2021-03-26
Enrollment: 65
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Incidence of cisplatin-induced nephrotoxicity
timeFrame: 4 months
Secondary outcomes:
measure: Difference in biological research markers between both arms
timeFrame: 4 months
measure: Difference in sensory-neural hearing impairment in both arms
timeFrame: 4 months
measure: Incidence of electrolyte imbalance in both arms
timeFrame: 4 months
Other outcomes:
Locations:
city: Cairo
country: Egypt
facility: Kasr El-Aini Center of Radiation Oncology and Nuclear Medicine
Study officials:
affiliation: German University in Cairo
name: Mohamed H Solayman, PhD
role: STUDY_CHAIR
affiliation: Cairo University
name: Loay Kassem, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: German University in Cairo
name: Dalia S Elhelw, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: German University in Cairo
name: Aya T Moustafa, BSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.