Pentoxifylline Versus Pioglitazone In Non-Alcoholic Steatohepatiti (NASH)

Official Title: “A Study Of Metabolic Factors And Efficacy Of Pentoxifylline Versus Pioglitazone In Lean And Obese Nash (Non-Alcoholic Steatohepatitis) Patients.”

1. To assess the metabolic factors in lean and obese patients with NASH.

2. To compare the efficacy of pentoxifylline versus pioglitazone on the metabolic profile and liver histology of NASH patients.

A total of 40 patients with biopsy proven NASH will be enrolled.

Inclusion criteria - Abdominal USG showing diffusely echogenic liver suggestive of fatty infiltration of liver. - ALT > 1.2 times the upper limit of normal for > 6 months.(atleast three readings one month apart) - Liver Biopsy showing steatosis affecting >10% of hepatocytes with necroinflammatory activity, ballooning hepatocytes &/ or fibrosis.

Exclusion criteria - Alcohol intake of more than 20g/wk - Evidence of viral/ autoimmune hepatitis - PBC (Primary biliary cirrhosis) - Biliary obstrution - Wilson disease - Haemchromatosis - Decompensated cirrhosis - Drug ingestion of the follwing drugs for a period of more than 4 weeks during past 6 weeks - Amiodarone - Methotrexate - Perhexiline - Glucocorticoids - Estrogens - Tamoxifen - Nifedipine - Diltiazem - Tamoxifen - DM Type I

STUDY DESIGN

The study will be divided into two parts Part A and Part B.

Part A - A cross-sectional study of metabolic profile will be done at the enrollment with a detailed physical examination and laboratory investigations and certain specific tests for non-alcoholic steatohepatitis. - At enrollment following characteristics will be included- - Prior history of Diabetes, Hypertension, Dyslipidemia, Coronary artery disease. - Age, sex, weight, height, BMI(body mass index), waist & hip circumference. - USG abdomen - LFT - Fasting glucose, post-prandial blood sugar/oral GTT(glucose tolerance test) - Fasting insulin level - Fasting C- peptide - HOMA-IR (Homeostasis Model Assessment-insulin resistance) - Fasting lipid profile - Fasting TNF- α - Fasting Adiponectin - Fasting Leptin - Liver biopsy - Waist will be measured with soft tape on standing subjects midway between the lowest rib and iliac spine. - BMI of every patient will be calculated. - Lean patient will be defined as BMI of 18.5- 22.9 kg/m2 - Overweight as ≥ 23- 24.9 kg/m2 - Obese as ≥ 25 kg/m2 - Lean patient will be further categorized as

1. Normal waist circumference (< 90cm for men, < 80 cm for women)

2. Abnormal waist circumference (more than the above mentioned criteria) - Insulin resistance will be calculated by HOMA-IR - Fasting serum insulin (μIU/ ml) x Fasting serum glucose(mmol/l) ÷ 22.5 HOMA-IR >2 will be taken as insulin resistance. - TNF- α, adiponectin and leptin will be measured by ELISA method using standard kits. - Liver biopsy will be analyzed by pathologist at the time of enrollment into the study.

Histology reporting will be done by the method given by Brunt et al.23

Part B.

A Prospective Randomized Controlled Trial comparing efficacy of Pentoxyphylline versus Pioglitazone will be done.

A total of 40 NASH patients (lean and obese) will be enrolled. All will be advised dietary and exercise protocol. Twenty patients will be randomized to receive Pentoxifylline in a dose of 1200mg/day in 3 divided doses. Another twenty patients will receive Pioglitazone in a dose of 30 mg/day. The subjects will be randomly assigned to receive either pentoxifylline or pioglitazone (randomization will be computer-generated). Patients will be followed with liver biochemistry at monthly interval for initial 3 months and subsequently at 3 month interval. .Liver biopsy will be repeated at the end of 6 months of therapy. The pathologist will blinded to the drug administered to the NASH patients.

Adverse events associated with Pentoxifylline and pioglitazone will be inquired and recorded on follow-up visits. The known side-effects of Pentoxiphylline are nausea, headache, vomiting, dyspepsia, bloating, flushing, vertigo and gastroesophageal reflux and that of Pioglitazone are myalgia, weight gain and pedal edema.

END POINT OF THE STUDY

1. Repeat metabolic parameters and liver biopsy will be done at the end of 6 months.

2. Improvement by 50% or normalization of aminotransferase at the end of the study will be compared to the baseline.

3. Histology will be compared with the repeat liver biopsy.

Intervention(s) in this Clinical Trial

• Drug: Pioglitazone
  • Pentoxifylline 1200mg/day in 3 divided doses. Pioglitazone 30 mg/day in single dose
• Drug: Pioglitazone
  • 30 mg OD
• Drug: Pentoxifylline
  • 1200 mg/d

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: A
  • Pioglitazone
• Active Comparator: B
  • Pentoxifylline

Primary Measures

• Improvement in metabolic profile and histology
  • Time Frame: 6 months
    Safety Issue?: Yes

Secondary Measures

• Side effects
  • Time Frame: 6 months
    Safety Issue?: Yes

Inclusion Criteria:

• Patients with biopsy proven NASH will be enrolled. Abdominal USG showing diffusely echogenic liver suggestive of fatty infiltration of liver.
• ALT > 1.2 times the upper limit of normal for > 6 months.(atleast three readings one month apart)
• Liver Biopsy showing steatosis affecting >10% of hepatocytes with necroinflammatory activity, ballooning hepatocytes &/ or fibrosis.

Exclusion Criteria:

• Alcohol intake of more than 20g/wk
• Evidence of viral/ autoimmune hepatitis
• PBC (Primary biliary cirrhosis)
• Biliary obstrution
• Wilson disease
• Haemchromatosis
• Decompensated cirrhosis
• Drug ingestion of the follwing drugs for a period of more than 4 weeks during past 6 weeks - Amiodarone, Methotrexate, Perhexiline, Glucocorticoids, Estrogens, Tamoxifen, Nifedipine, Diltiazem, Tamoxifen.
• DM Type I

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 65 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Govind Ballabh Pant Hospital Other

Overall Clinical Trial Officials and Contacts

Barjesh Ch Sharma, MD, DM Principal Investigator G B Pant Hospital Hospital, New Delhi  

Overall Contact: Barjesh Ch Sharma, MD, DM 91-011-2323-4242 drbcsharma@hotmail.com

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00681733

Study ID Number: drakchaudhary

ClinicalTrials.gov Identifier: NCT00681733

Health Authority: India: Ministry of Health