The Efficacy and Safety of Pioglitazone in Patients With Nonalcoholic Steatohepatitis

• ClinicalTrials.gov Identifier: NCT01068444
• Recruitment Status: Completed
• First Posted: February 15, 2010
• Last Update Posted: July 23, 2020
• Sponsor: Kaohsiung Medical University Chung-Ho Memorial Hospital
• Information provided by (Responsible Party): Wan-Long Chuang, Kaohsiung Medical University Chung-Ho Memorial Hospital

Tracking Information

• First Submitted Date: February 11, 2010
• First Posted Date: February 15, 2010
• Last Update Posted Date: July 23, 2020
• Study Start Date: April 2009
• Actual Primary Completion Date: July 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 12, 2010)

• Comparison between Pioglitazone and placebo groups in terms of steatosis and liver function tests [ Time Frame: 9 months ]
• Evaluation of clinical safety of Pioglitazone [ Time Frame: 9 months ]

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures (submitted: February 12, 2010): Comparison between Pioglitazone and placebo groups in terms of liver necroinflammation and fibrosis. [ Time Frame: 9 months ]
• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: The Efficacy and Safety of Pioglitazone in Patients With Nonalcoholic Steatohepatitis
• Official Title: A Double-Blind, Randomized, Placebo-Controlled, Phase II Study to Assess the Efficacy and Safety of Pioglitazone in Patients With Nonalcoholic Steatohepatitis

Brief Summary

Recent studies have demonstrated that PPARγ as well as diet control could improve glycemic control, decrease serum ALT level, decrease hepatic fat distribution, and increase intrahepatic insulin sensitivity. The purposes of this study are:

1. Primary aims:

1. Comparison between Pioglitazone and placebo groups in terms of steatosis and liver function tests.
2. Evaluation of clinical safety of Pioglitazone

2. Secondary aims:

1. Comparison between Pioglitazone and placebo groups in terms of liver necroinflammation and fibrosis.
2. The impact of Pioglitazone on the related metabolic index, including insulin resistance(HOMA-IR), newly-onset diabetes, metabolic syndrome, lipid profiles (T-Chol, HDL-C, LDL-C, TG).
3. Comparison between Pioglitazone and placebo groups in terms of high-sensitive C-reactive protein changes.

3. Interventional aim: Assessment the association between magnetic resonance imaging study and intrahepatic fat distribution before and after Pioglitazone treatment.

Detailed Description

Pioglitazone belongs to thiazolidinediones and anti-diabetes drug which decreases the insulin resistance. It increases the use of glucose of peripheral tissues and decrease the production of glucose from liver and dose not influence the production of insulin. It is agonist of peroxisome proliferator-activated receptor-gamma (PPARγ) and by binding to the receptors of PPARγ in various tissues it has effects on transcription of the insulin-dependent gene. In animal model, pioglitazone has shown to influence the metabolism by the insulin-dependent mechanism.

Recent studies have demonstrated that PPARγ as well as diet control could improve glycemic control, decrease serum ALT level, decrease hepatic fat distribution, and increase intrahepatic insulin sensitivity. Meanwhile, PPARγ could also prevent the development of alcohol-induced steatohepatitis, improve hepatic necroinflammatory activity, and decrease lipid deposition. It is not yet clearly known how the effect of P-PARγ agonist among Asian peoples.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Hepatitis

Intervention

• Drug: Pioglitazone
  1. Name: GLITOS（Pioglitazone）
  2. Dosage form: Tablets
  3. Dose(s): 30mg
  4. Dosing schedule: QD
  5. Duration: 6 months
  Other Name: GLITOS
• Drug: placebo
  placebo 30 mg/d for 6 months

Study Arms

• Experimental: Pioglitazone
  Pioglitazone 30 mg/day for 6 months and 3 months of follow-up period after treatment
  Intervention: Drug: Pioglitazone
• Placebo Comparator: Placebo
  Placebo 30 mg/day for 6 months and 3 months of follow-up period after treatment
  Intervention: Drug: placebo

Publications *

• Huang JF, Dai CY, Huang CF, Tsai PC, Yeh ML, Hsu PY, Huang SF, Bair MJ, Hou NJ, Huang CI, Liang PC, Lin YH, Wang CW, Hsieh MY, Chen SC, Lin ZY, Yu ML, Chuang WL. First-in-Asian double-blind randomized trial to assess the efficacy and safety of insulin sensitizer in nonalcoholic steatohepatitis patients. Hepatol Int. 2021 Oct;15(5):1136-1147. doi: 10.1007/s12072-021-10242-2. Epub 2021 Aug 12.
• Huang JF, Yeh ML, Huang CF, Huang CI, Tsai PC, Tai CM, Yang HL, Dai CY, Hsieh MH, Chen SC, Yu ML, Chuang WL. Cytokeratin-18 and uric acid predicts disease severity in Taiwanese nonalcoholic steatohepatitis patients. PLoS One. 2017 May 4;12(5):e0174394. doi: 10.1371/journal.pone.0174394. eCollection 2017.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 12, 2010): 90
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: July 2020
• Actual Primary Completion Date: July 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Main inclusion criteria:

1. Male and female patients with 18-70 years of age
2. Liver biopsy findings consistent with the diagnosis of NASH with or without compensated cirrhosis within one year before baseline
3. Compensated liver disease
4. Negative urine or blood pregnancy test (for women of childbearing potential) documented within the 24-hour period prior to the first dose of study drug
5. All fertile males and females must be using two forms of effective contraception during treatment during the 3 months after treatment.
6. ALT level between 1.3-5 x ULN for 2 occasions during 6 months before screening.
7. HbA1C ≦ 8.0 during screening

Main exclusion criteria:

1. Therapy with any systemic anti-neoplastic or immunomodulatory treatment (including supraphysiologic doses of steroids and radiation) *6 months before baseline.
2. History or other evidence of a medical condition associated with chronic liver disease other than NASH (e.g., hemochromatosis, autoimmune hepatitis, alcoholic liver disease, > 20 g/day for female or > 40 g/day for male, toxin exposures)
3. hepatocellular carcinoma
4. History or other evidence of bleeding from esophageal varices or other conditions consistent with decompensated liver disease
5. Serum creatinine level >1.5 times the upper limit of normal at screening and calculated creatinine clearance as calculated by Cockcroft and Gault < 60mL/min during screening
6. History of ischemic heart disease during screening
7. New York Heart Association (NYHA) Functional Class 1-4 cardiac status during screening
8. Albumin <3.2g/dL during screening
9. Total bilirubin >1.2 x ULN during screening. Patients with history of asymptomatic indirect hyperbilirubinemia whose total bilirubin < 2 x ULN and direct bilirubin < 20% of total bilirubin could be included.
10. History of prothrombin time > 15 seconds or International normalized ratio (INR) > 1.3
11. Organ, stem cell, or bone marrow transplant
12. History of serious concurrent medical illness that in the investigator's opinion might interfere with therapy this includes significant systemic illnesses (other than liver disease) such as chronic pancreatitis
13. Active systemic autoimmune disorder
14. Pregnancy (or lactation) or, in subjects capable of bearing children, inability / unwillingness to practice adequate contraception
15. Females of child-bearing potential (post-puberty) unwilling or unable to have pregnancy testing at any study visit
16. Therapy with a systemic antiviral agent (with the exception of prophylaxis or treatment of influenza or chronic HSV) within the past 30 days prior to screening.
17. Concurrent participation in another clinical trial in which the subject is or will be exposed to another investigational or a non-investigational drug or device within 6 weeks of the screening visit
18. Current therapy with insulin within 1 week prior to screening.
19. Experienced use with PPARg agonist (e.g., rosiglitazone, pioglitazone) within 6 months prior to screening.
20. Known hypersensitivity to any component of PPARg agonists
21. A history of hepatotoxicity to TZDs and/or a history of severe edema or a medically serious fluid-related event associated with the use of TZDs
22. History of metformin use within 3 months prior to screening.
23. Type Ⅰ diabetes
24. Seropositive of HBsAg, anti-HCV or anti-HIV during screening or 3 month prior to screening.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Taiwan

Administrative Information

• NCT Number: NCT01068444
• Other Study ID Numbers: KMUH-HB9608
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Wan-Long Chuang, Kaohsiung Medical University Chung-Ho Memorial Hospital
• Original Responsible Party: Kaohsiung Medical University Hospital
• Current Study Sponsor: Kaohsiung Medical University Chung-Ho Memorial Hospital
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Wan-Long Chuang, MD, PhD; Kaohsiung Medical University

• PRS Account: Kaohsiung Medical University Chung-Ho Memorial Hospital
• Verification Date: July 2020