NIH AIM 2 - Low Dose Pioglitazone in NASH

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).

Rationale: Several studies have shown that pioglitazone, at either 30 to 45 mg per day, is safe and effective in randomized, controlled trials (RCTs) of 6* to 24-month duration (Belfort et al, NEJM 2006; Aithal et al, Gastroenterology 2008; Sanyal et al, NEJM 2010; Cusi et al, Annals Int Med 2016; Bril et al, Diabetes Care 2019). However, pioglitazone has shown to also improve glucose and lipid metabolism at the lower dose of 15 mg per day in patients with type 2 diabetes (Aronoff et al, Diabetes Care 2000; Miyazaki et al, Diabetes Care 2002; Rosenstock et al, Int J Clin Pract. 2002; Rajagopalan et al, Diabetes Res Clin Pract 2015). However, the effect of pioglitazone at doses of 15 mg per day on liver histology in patients with steatohepatitis (NASH) has not been previously examined.

Study aim: To examine the safety and efficacy of "low-dose" (15 mg/day) pioglitazone compared to placebo (control) in patients with type 2 diabetes and NASH in a 72-week randomized controlled study design.

Description: This is a single center, phase 2A, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of pioglitazone in subjects that are 21 to 75 years of age, with nonalcoholic steatohepatitis (NASH) confirmed by liver biopsy and who have type 2 diabetes. Eligible subjects will be enrolled into two treatments arms: Pioglitazone 15 mg or placebo in a ratio 1:1. All subjects will be enrolled and followed at the our research center, the University of Florida NIH-sponsored Clinical Translational Science Institute. Upon study entry, patients will undergo a detailed medical history, physical exam, baseline routine laboratories, EKG, elastography (VCTE). Those who meet al inclusion/exclusion criteria will undergo further imaging by MRI and measurement of blood diagnostic panels hormones and biomarkers relevant to the disease state (steatohepatitis). A liver biopsy, if not done prior to study entry, will be performed. Patients that qualify (NASH with fibrosis F1-F3) will be randomized in a double-blind fashion to either pioglitazone or placebo. They will be followed during 10 scheduled visits after randomization for 72 weeks of treatment. Blood testing, imaging and a liver biopsy will be repeated as done at baseline. After completion of the study treatment period, subjects will be followed for an additional period of 4 weeks without study medication (week 76).

Inclusion criteria:

1. Able to communicate meaningfully with the investigator and legally competent to provide written informed consent.

2. Aged 21 to 75 years.

3. 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.

4. 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).

1. 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.

Exclusion criteria:

1. 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.

2. 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.

3. 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.

4. Use of vitamin E (doses ≥800 IU/dy) or pioglitazone or any FDA-approved drug for NASH to be approved during the study.

5. 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.

6. Presence of other medical conditions known to cause fatty liver disease.

7. Any clinical or laboratory evidence of cirrhosis or hepatic decompensation, such as history of ascites, esophageal bleeding varices, or spontaneous encephalopathy.

8. Prior or scheduled surgical procedures, including gastroplasty or jejunoileal or jejunocolic bypass.

9. Prior exposure to organic solvents, such as carbon tetrachloride.

10. Total parenteral nutrition within the past 6 months.

11. Patients with other forms of diabetes other than T2DM.

12. 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.

1. 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).

1. 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.

1. History of malignancy in the past 5 years and/or active neoplasm with the exception of

resolved superficial nonmelanoma skin cancer.

1. History of bladder disease and/or hematuria or has current hematuria unless due to a

recent urinary tract infection.

1. Hemostasis disorders or current treatment with anticoagulants.

2. Any other criteria that based on the assessment of the research team the patient is

deemed to be a poor research candidate.