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

Sponsor

Tehran University of Medical Sciences (Other)

Overall Status

Completed

CT.gov ID

NCT01829178

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

2.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Upper GI Cancer Cisplatin Adverse Reaction	Drug: Silymarin Drug: Placebo Drug: chemotherapy	Phase 2/Phase 3

Detailed Description

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

Study Design

Study Type:

Interventional

Actual Enrollment :

30 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Care Provider)

Primary Purpose:

Treatment

Official Title:

Phase 2-3 Study of Silymarin on Cisplatin Induced Nephrotoxicity

Study Start Date :

Aug 1, 2013

Actual Primary Completion Date :

Sep 1, 2014

Actual Study Completion Date :

Sep 1, 2014

Arms and Interventions

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 fluorouracil Docetaxel
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: Silymarin Silymarin 420 mg in 3 divided dose plus standard chemotherapy Other Names: Milk thistle Drug: chemotherapy All patients will receive standard chemotherapy: cisplatin 50-60mg/m2 + fluorouracil 750 mg/m2 + docetaxel 60-80 mg/m2 Other Names: Cisplatin fluorouracil Docetaxel

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

fluorouracil

Docetaxel

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: Silymarin

Silymarin 420 mg in 3 divided dose plus standard chemotherapy

Other Names:

Milk thistle

Drug: chemotherapy

All patients will receive standard chemotherapy: cisplatin 50-60mg/m2 + fluorouracil 750 mg/m2 + docetaxel 60-80 mg/m2

Other Names:

Cisplatin

fluorouracil

Docetaxel

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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