Evaluation of Effects of Silymarin on Cisplatin Induced Nephrotoxicity in Upper Gastrointestinal Adenocarcinoma

Phase 2-3 Study of Silymarin on Cisplatin Induced Nephrotoxicity

Cisplatin is a potent chemotherapeutic agent that has been widely used to treat many solid tumours. acute renal failure, despite conservative fluid and electrolyte management, frequently reported adverse event and limiting cisplatin use. Silymarin, a flavonolignan complex isolated from Silybum marianum, has a strong antioxidant, hepatoprotective, anticancer and in animal model nephroprotective properties. Neutrophil gelatinase-associated lipocalin (NGAL) protein is a promising biomarker to detect acute kidney injury due to cisplatin. Milk thistle extract inhibitory effects on epidermal growth factor receptor, vascular endothelial growth factor and insulin-like growth factor-I have shown in the previous in-vitro studies.The aim of present study,a randomized double-blind placebo- controlled clinical trial, to investigate the therapeutic effect of silymarin on cisplatin induced nephrotoxicity and it's impact on chemotherapy. Fifty-eight patients with diagnosed upper gastrointestinal tract carcinomas randomized to silymarin (420mg) or placebo plus chemotherapy [cisplatin 50-60 mg/m2, 5-fluorouracil mg/m2, docetaxel 60-80 mg/m2 every 21 days] for 63 day after inclusion. serum creatinin, blood urea nitrogen (BUN), serum and urine electrolyte will be measured daily during chemotherapy.

changes in urine NGAL, serum vascular endothelial growth factor (VEGF)and caspase activity assessed up to 64 days.

Study Overview

• Status: Completed
• Conditions: Cisplatin Adverse Reaction; Upper GI Cancer
• Intervention / Treatment: Drug: Placebo; Drug: chemotherapy; Drug: Silymarin

Detailed Description

This study will look for possible protective effects silymarin on kidney injury in patients receiving cisplatin.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Iran, Islamic Republic of
  • Tehran, Iran, Islamic Republic of
    • tehran university of medical science

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:

• age>18 years
• diagnosed
• measurable upper gastrointestinal adenocarcinoma
• swallow problem
• would like to participate in the study
• Glomerular filtration rate(GFR)>45ml/min/1.73m2

Exclusion Criteria:

• end stage renal disease
• requiring dialysis
• post transplantation
• receiving contrast media during last 72 hours
• chronic use of corticosteroids
• chronic use of angiotensin-converting enzyme inhibitor(ACEI )
• untreated hypo-and hyperthyroidism
• ejection fraction<60%
• active urinary tract infection
• iver disease ( five fold increase of liver enzyme in asymptomatic or 3 fold increase in symptomatic
• use of other nephrotoxic agents such as aminoglycoside, amphotericin
• karnofsky performance status <70

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Control arm; Placebo 420 mg daily in three divided doses for 65 days as control along with [cisplatin 50-60mg/m2 + fluorouracil 750 mg/m2 +docetaxel 60-80 mg/m2]	Drug: Placebo; placebo tablets: 420 mg in 3 divided dose; Other Names: Identical inert tablet to mimic silymarin (140 mg); Drug: chemotherapy; All patients will receive standard chemotherapy: cisplatin 50-60mg/m2 + fluorouracil 750 mg/m2 + docetaxel 60-80 mg/m2; Other Names: Cisplatin; Docetaxel; fluorouracil
ACTIVE_COMPARATOR: Exprimental: Silymarin and chemotherapy; silymarin 420 mg daily in three divided doses for 65 days along with standard chemotherapy [cisplatin 50-60mg/m2 + fluorouracil 750 mg/m2 +docetaxel 60-80 mg/m2 control	Drug: chemotherapy; All patients will receive standard chemotherapy: cisplatin 50-60mg/m2 + fluorouracil 750 mg/m2 + docetaxel 60-80 mg/m2; Other Names: Cisplatin; Docetaxel; fluorouracil; Drug: Silymarin; Silymarin 420 mg in 3 divided dose plus standard chemotherapy; Other Names: Milk thistle

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urine concentration of NGAL	All subject receive silymarin at dose of 420mg or placebo in three dose for 65 consecutive day, urine NGAL concentration will be measured.	up to 9 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in VEGF Serum concentration	To assess interaction between silymarin and cancer chemotherapy serum vascular endothelial growth factor will be measured.	up to 9 weeks
Tissue activity of caspase 3	To assess interaction between silymarin and cancer chemotherapy Tissue activity of caspase 3will be measured.	up to 9 weeks

Collaborators and Investigators

• Sponsor: Tehran University of Medical Sciences
• Investigators: Study Chair: Simin Dashti-Khavidaki, Dr, Tehran University Of Medical Sciences

Study record dates

Study Major Dates

• Study Start: August 1, 2013
• Primary Completion (ACTUAL): September 1, 2014
• Study Completion (ACTUAL): September 1, 2014

Study Registration Dates

• First Submitted: January 11, 2013
• First Submitted That Met QC Criteria: April 8, 2013
• First Posted (ESTIMATE): April 11, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): May 13, 2015
• Last Update Submitted That Met QC Criteria: May 11, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: cisplatin; nephrotoxicity; antioxidant; urine neutrophil gelatinase-associated lipocalin (NGAL)
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Protective Agents; Antioxidants; Docetaxel; Cisplatin; Fluorouracil; Silymarin
• Other Study ID Numbers: 91-03-33-18878