Low-Dose Pioglitazone in Patients With NASH (AIM 2)

NCT04501406 | Recruiting Phase 2 DMC FDA Drug

• 4 other identifiers: IRB202000690-N-AR01DK120331OCR34802PRO00025104
• Study Type: interventional
• Target: 166
• Locations: 1 country
• Sites: 1

Brief Summary

To determine the safety and efficacy of low-dose pioglitazone (15 mg per day) on liver histology in in patients with T2DM with biopsy-proven nonalcoholic steatohepatitis (NASH).

Conditions

Type 2 Diabetes Mellitus (T2DM); Nonalcoholic Steatohepatitis

Keywords

Nonalcoholic fatty liver disease; pioglitazone.

Outcome Measures

Primary Outcomes (1)

• The proportion of pioglitazone-treated patients relative to placebo achieving an improvement of ≥2 points in non-alcoholic fatty liver disease activity score (NAS) without an increase in fibrosis stage.

  The proportion of patients with liver histological improvement of ≥2 points in non-alcoholic fatty liver disease activity score (NAS) with a ≥1-point reduction in either ballooning or lobular inflammation and no increase in fibrosis stage by NASH CRN scoring criteria.

  72 weeks of treatment

Secondary Outcomes (12)

• Resolution of NASH without worsening of liver fibrosis.

  72 weeks

• Proportion of patients with improvement in the activity component of steatosis-activity-fibrosis (SAF) score.

  72 weeks.

• Proportion of patients with NAS improvement (0-8).

  72 weeks.

• Mean NAS change (0-8).

  72 weeks.

• Proportion of patients with a change of the individual components of the NAS score (steatosis, lobular inflammation and ballooning) by at least 1 point.

  72 weeks

Other Outcomes (10)

• Liver fibrosis by imaging.

  72 weeks.

• Intrahepatic triglyceride content

  72 weeks.

• CAP (controlled attenuation parameter) and vibration controlled transient elastography (VCTE)

  72 weeks.

Study Arms (2)

Pioglitazone

ACTIVE COMPARATOR

Two arm, randomized, double-blind, placebo-controlled, 72 week treatment study receiving pioglitazone 15mg/day.

Drug: Pioglitazone

Placebo

PLACEBO COMPARATOR

Two arm, randomized, double-blind, placebo-controlled, 72 week treatment study receiving placebo.

Other: Placebo

Interventions

Pioglitazone DRUG

An insulin-sensitizer FDA-approved to treat hyperglycemia caused by type 2 diabetes.

Also known as: Actos

Pioglitazone

Placebo OTHER

Placebo looks just like pioglitazone and is given in the same way but has no active drug in it.

Placebo

Eligibility Criteria

• Age: 21 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Able to communicate meaningfully with the investigator and legally competent to provide written informed consent.
• Aged 21 to 75 years.
• Patients with a diagnosis T2DM based on prior medical history, medication use, or results from a fasting plasma glucose or hemoglobin A1c, according to American Diabetes Association guidelines.
• Patients will be allowed to participate the glycosylated hemoglobin (HbA1c) is ≤ 9.5% on diet alone or on a stable dose (for at least 2 months) of the following diabetes medications: metformin, sulfonylurea, acarbose, DPP-IV inhibitors, SGLT2 inhibitors or insulin. The insulin total daily dose should be stable (defined as within 20% for the prior 2 months prior to study entry). A GLP-1 receptor agonist will be allowed if on a stable dose for 6 months prior to enrollment and body weight stable (defined as within 3%) in the prior 3 months. Diabetes medications will be continued at stable doses during the entire study (except if glycemic control deteriorates based on HbA1c; addition of metformin, sulfonylurea, acarbose, DPP-IV or insulin will be allowed if needed; pioglitazone, GLP-1RA or SGLT2 inhibitors will not).
• Hemoglobin level of at least 11.0 g/L (men) or at least 10.0 g/L (women), leukocyte count of at least 3.0 × 109 cells/L, neutrophil count of at least 1.5 × 109 cells/L, platelet count of at least 100 × 109 cells/L, albumin level of at least 2.5 g/L, serum creatinine level of 2.5 mg/dL or less, INR \> 1.4, bilirubin \> 1.3 mg/dL (unless if non-conjugated bilirubin elevated in the setting of Gilbert's syndrome), and AST and ALT levels no more than 8 times the ULN.

You may not qualify if:

• Past or current history of alcohol use (\>20 g/d of ethanol in females or \>30g/d in males). Alcohol abuse will be ruled out on the basis of physicians' judgment, self-reported alcohol use, and family members' report of the patient's alcohol use. In addition, the Alcohol Use Disorders Identification Test (AUDIT) score will be used to assess alcohol use.
• Receipt of long-term therapy with medications known to have adverse effects on glucose tolerance, unless the patient has been receiving a stable dose of such agents for 4 weeks before study entry.
• Use of medications that could induce steatosis, such as estrogen or other hormonal replacement therapy, amiodarone, methotrexate, tamoxifen, raloxifene, pharmacological doses of oral glucocorticoids (≥10 mg per day of prednisone or equivalent), or chloroquine.
• Use of vitamin E (doses ≥800 IU/dy) or pioglitazone or any FDA-approved drug for NASH to be approved during the study.
• Any cause of chronic liver disease other than NASH, including but not restricted to alcohol or drug abuse, medication, chronic hepatitis B or C virus infection, autoimmune liver disease, hemochromatosis, Wilson disease (if younger than age 50), α1-antitrypsin deficiency, history of exposure to hepatotoxic drugs or history of primary or metastatic liver cancer.
• Presence of other medical conditions known to cause fatty liver disease.
• Any clinical or laboratory evidence of cirrhosis or hepatic decompensation, such as history of ascites, esophageal bleeding varices, or spontaneous encephalopathy.
• Prior or scheduled surgical procedures, including gastroplasty or jejunoileal or jejunocolic bypass.
• Prior exposure to organic solvents, such as carbon tetrachloride.
• Total parenteral nutrition within the past 6 months.
• Patients with other forms of diabetes other than T2DM.
• History of clinically significant heart disease such as congestive heart failure (New York Heart Association Classification greater than grade II-IV), unstable cardiovascular disease such as unstable angina (i.e., new or worsening symptoms of coronary heart disease within the past 6 months), acute coronary syndrome or coronary artery intervention within the past 6 months, acute myocardial infarction in the past 6 months; history of (within prior 6 months) or current unstable cardiac dysrhythmias.
• Uncontrolled hypertension (systolic blood pressure \>160 mmHg and/or diastolic blood pressure \>100 mmHg); clinically evident peripheral vascular disease (history of claudication); stroke or transient ischemic attack within the prior 6 months; clinically significant pulmonary disease (dyspnea on exertion of ≤1 flight; abnormal breath sounds on auscultation), or kidney disease as defined above per plasma creatinine elevation or significant proteinuria (macroalbuminuria).
• Pregnancy or lactation in women. Must have a negative pregnancy test or at least be two-year post-menopausal. Women with childbearing potential (i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile) must be using a highly effective method of contraception (i.e. combined (estrogen and progesterone containing) hormonal/ progesterone-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner). The contraceptive method will have to be followed for at least one menstruation cycle after the end of the study.
• History of malignancy in the past 5 years and/or active neoplasm with the exception of resolved superficial nonmelanoma skin cancer.

Sponsors & Collaborators

• University of Florida: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

University of Florida

Gainesville, Florida, 32610, United States

RECRUITING

Related Publications (11)

• Bril F, Cusi K. Management of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes: A Call to Action. Diabetes Care. 2017 Mar;40(3):419-430. doi: 10.2337/dc16-1787.

  PMID: 28223446 BACKGROUND

• Gastaldelli A, Cusi K. From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment options. JHEP Rep. 2019 Jul 19;1(4):312-328. doi: 10.1016/j.jhepr.2019.07.002. eCollection 2019 Oct.

  PMID: 32039382 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 BACKGROUND

• Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, Spendlove I, Austin AS, Freeman JG, Morgan L, Webber J. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008 Oct;135(4):1176-84. doi: 10.1053/j.gastro.2008.06.047. Epub 2008 Jun 25.

  PMID: 18718471 BACKGROUND

• Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR; NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010 May 6;362(18):1675-85. doi: 10.1056/NEJMoa0907929. Epub 2010 Apr 28.

  PMID: 20427778 BACKGROUND

• Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, Tio F, Hardies J, Darland C, Musi N, Webb A, Portillo-Sanchez P. Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial. Ann Intern Med. 2016 Sep 6;165(5):305-15. doi: 10.7326/M15-1774. Epub 2016 Jun 21.

  PMID: 27322798 BACKGROUND

• Bril F, Biernacki DM, Kalavalapalli S, Lomonaco R, Subbarayan SK, Lai J, Tio F, Suman A, Orsak BK, Hecht J, Cusi K. Role of Vitamin E for Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes: A Randomized Controlled Trial. Diabetes Care. 2019 Aug;42(8):1481-1488. doi: 10.2337/dc19-0167. Epub 2019 May 21.

  PMID: 31332029 BACKGROUND

• Aronoff S, Rosenblatt S, Braithwaite S, Egan JW, Mathisen AL, Schneider RL. Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group. Diabetes Care. 2000 Nov;23(11):1605-11. doi: 10.2337/diacare.23.11.1605.

  PMID: 11092281 BACKGROUND

• Miyazaki Y, Matsuda M, DeFronzo RA. Dose-response effect of pioglitazone on insulin sensitivity and insulin secretion in type 2 diabetes. Diabetes Care. 2002 Mar;25(3):517-23. doi: 10.2337/diacare.25.3.517.

  PMID: 11874940 BACKGROUND

• Rosenstock J, Einhorn D, Hershon K, Glazer NB, Yu S; Pioglitazone 014 Study Group. Efficacy and safety of pioglitazone in type 2 diabetes: a randomised, placebo-controlled study in patients receiving stable insulin therapy. Int J Clin Pract. 2002 May;56(4):251-7.

  PMID: 12074206 BACKGROUND

• Rajagopalan S, Dutta P, Hota D, Bhansali A, Srinivasan A, Chakrabarti A. Effect of low dose pioglitazone on glycemic control and insulin resistance in Type 2 diabetes: A randomized, double blind, clinical trial. Diabetes Res Clin Pract. 2015 Sep;109(3):e32-5. doi: 10.1016/j.diabres.2015.05.030. Epub 2015 May 15.

  PMID: 26254513 BACKGROUND

Related Links

• Division of Endocrinology, Diabetes and Metabolism at the University of Florida

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Non-alcoholic Fatty Liver Disease

Interventions

Pioglitazone

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; 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 Florida

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kenneth Cusi, M.D.

CONTACT

3522738662; kcusi@ufl.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Randomized, placebo-controlled.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Parallel assignment.

Study Record Dates

• First Submitted: August 3, 2020
• First Posted: August 6, 2020
• Study Start: December 15, 2020
• Primary Completion (Estimated): August 31, 2027
• Study Completion (Estimated): August 31, 2027
• Last Updated: April 4, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)