Role of Pioglitazone in the Treatment of Non-alcoholic Steatohepatitis (NASH)

NCT00227110 | Completed Phase 4

• 1 other identifier: UTHSCSA IRB# 001-5014-331
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 1

Brief Summary

To determine the role of pioglitazone in the treatment of nonalcoholic steatohepatitis (NASH) in patients with glucose intolerance or type 2 diabetes mellitus (T2DM).

Conditions

Nonalcoholic Steatohepatitis

Keywords

NASH, IGT, T2DM

Outcome Measures

Primary Outcomes (1)

• Liver histology (Kleiner criteria, Hepatology 2005)

  6 months.

Secondary Outcomes (2)

• Liver fat content by MRS.

  6 months.

• Double-tracer OGTT (EGP, glucose clearance).

  6 months.

Study Arms (2)

Pioglitazone

ACTIVE COMPARATOR

Pioglitazone 30 mg/d will be given for 8 weeks and titrated to 45 mg/d until the end of the 6-month study in a randomized, double-blind, study design.

Drug: Pioglitazone

Placebo

PLACEBO COMPARATOR

Placebo once daily is given following a randomized, double-blind, placebo-controlled study design.

Drug: Placebo

Interventions

Pioglitazone DRUG

30 mg/d for 8 weeks and titrated to 45 mg/d until completing 6 months of treatment.

Also known as: Actos (Takeda Pharmaceuticals).

Pioglitazone

Placebo DRUG

Placebo is given to match pioglitazone.

Placebo

Eligibility Criteria

• Age: 21 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Be able to communicate meaningfully with the Investigator and be legally competent to provide written informed consent.
• Patients must have an age range between 21 to 70 years (inclusive).
• NASH confirmed by liver biopsy.
• Subjects must meet the criteria for impaired glucose tolerance (FPG concentration \<126 mg/dl and a two hour plasma glucose value during the oral glucose tolerance test \[OGTT\] ≥140 but \<200 mg/dl) or type 2 diabetes mellitus (FPG concentration ≥ 126 mg/dl or a two hour plasma glucose value during the OGTT ≥200 mg/dl) (62). Subjects with a FPG greater than 260 mg/dl will be excluded from the study.
• Diabetic patients will be allowed to be on sulfonylureas or repaglinide but not on metformin, a thiazolidinedione or insulin. Patients must have been on a stable dose of allowed chronic medications for four weeks prior to entering the double-blind treatment period.
• Female patients must be non-lactating and must either be at least two years post-menopausal, or be using adequate mechanical contraceptive precautions (i.e. intrauterine device, diaphragm with spermicide, condom with spermicide), or be surgically sterilized (i.e. bilateral tubal ligation, bilateral oophorectomy). Female patients who have undergone a hysterectomy are eligible for participation in the study. Female patients (except for those patients who have undergone a hysterectomy or a bilateral oophorectomy) are eligible only if they have a negative pregnancy test throughout the study period. Patients on oral contraceptives or an hormonal implant will be excluded.
• All participants must have the following laboratory values:
• Hemoglobin ≥ 13 gm/dl in males, or
• ≥ 12 gm/dl in females WBC count ≥ 3,000/mm3 Neutrophil count ≥ 1,500/mm3 Platelets ≥ 100,000/mm3 Prothrombin time within 3 seconds of control Albumin ≥3.0 g/dl Serum creatinine ≤ 1.6 mg/dl Creatinine phosphokinase ≤ 2 times upper limit of normal AST (SGOT) ≤ 2.5 times upper limit of normal ALT (SGPT) ≤ 2.5 times upper limit of normal Alkaline phosphatase ≤ 2.5 times upper limit of normal

You may not qualify if:

• Any cause of chronic liver disease other than NASH (such as -but not restricted to- alcohol or drug abuse, medication, chronic hepatitis B or C, autoimmune, hemochromatosis, Wilson's disease, alpha1-antitrypsin deficiency).
• Any clinical evidence or history of ascitis, bleeding varices, or spontaneous encephalopathy.
• No past (for at least for 1 year) or current history of alcohol abuse (alcohol consumption greater than one drink per day).
• Prior surgical procedures to include gastroplasty, jejuno-ileal or jejunocolic bypass.
• Prior exposure to organic solvents such as carbon tetrachloride.
• Total parenteral nutrition (TPN) within the past 6 months.
• Diabetics with a FPG greater than 260 mg/dl on initial visit.
• Diabetics who are taking metformin, a thiazolidinedione or insulin.
• Subjects with type 1 diabetes mellitus.
• Patients on chronic medications with known adverse effects on glucose tolerance levels unless the patient has been on a stable dose of such agents for 4 weeks before entry into the study. Patients on estrogens or other hormonal replacement therapy, tamoxifen, raloxifene, oral glucocorticoids or chloroquine will be excluded.
• Patients with a history of clinically significant heart disease (New York Heart Classification greater than grade II; more than non-specific ST-T wave changes on EKG), peripheral vascular disease (history of claudication), or pulmonary disease (dyspnea on exertion of one flight or less; abnormal breath sounds on auscultation), will not be studied.

Sponsors & Collaborators

• The University of Texas Health Science Center at San Antonio: lead
• National Institutes of Health (NIH): collaborator
• Takeda Pharmaceuticals North America, Inc.: collaborator

Study Sites (1)

Audie L Murphy VA Hospital

San Antonio, Texas, 78229, United States

Location

Related Publications (6)

• Cusi K. Thiazolidinediones in NASH. An odd couple meant to be? J Clin Gastroenterol. 2009 Jul;43(6):503-5. doi: 10.1097/MCG.0b013e3181a15e51. No abstract available.

  PMID: 19384246 BACKGROUND

• Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, Balas B, Gastaldelli A, Tio F, Pulcini J, Berria R, Ma JZ, Dwivedi S, Havranek R, Fincke C, DeFronzo R, Bannayan GA, Schenker S, Cusi K. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006 Nov 30;355(22):2297-307. doi: 10.1056/NEJMoa060326.

  PMID: 17135584 RESULT

• Balas B, Belfort R, Harrison SA, Darland C, Finch J, Schenker S, Gastaldelli A, Cusi K. Pioglitazone treatment increases whole body fat but not total body water in patients with non-alcoholic steatohepatitis. J Hepatol. 2007 Oct;47(4):565-70. doi: 10.1016/j.jhep.2007.04.013. Epub 2007 May 24.

  PMID: 17560678 RESULT

• Gastaldelli A, Harrison SA, Belfort-Aguilar R, Hardies LJ, Balas B, Schenker S, Cusi K. Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis. Hepatology. 2009 Oct;50(4):1087-93. doi: 10.1002/hep.23116.

  PMID: 19670459 RESULT

• Ali R, Cusi K. New diagnostic and treatment approaches in non-alcoholic fatty liver disease (NAFLD). Ann Med. 2009;41(4):265-78. doi: 10.1080/07853890802552437.

  PMID: 19353360 RESULT

• Cusi K. Nonalcoholic fatty liver disease in type 2 diabetes mellitus. Curr Opin Endocrinol Diabetes Obes. 2009 Apr;16(2):141-9. doi: 10.1097/MED.0b013e3283293015.

  PMID: 19262374 RESULT

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease

Interventions

Pioglitazone

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Thiazolidinediones; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Kenneth Cusi, MD

  University of Texas

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: September 23, 2005
• First Posted: September 27, 2005
• Study Start: October 1, 2002
• Primary Completion: November 1, 2005
• Study Completion: January 1, 2006
• Last Updated: October 14, 2009

Record last verified: 2009-10

Locations

US (1)