Low-Dose Pioglitazone in Patients With NASH (AIM 2)
- Conditions
- Type 2 Diabetes Mellitus (T2DM)Nonalcoholic Steatohepatitis
- Interventions
- Other: Placebo
- Registration Number
- NCT04501406
- Lead Sponsor
- University of Florida
- 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).
- Detailed Description
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).
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 166
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Two arm, randomized, double-blind, placebo-controlled, 72 week treatment study receiving placebo. Pioglitazone Pioglitazone Two arm, randomized, double-blind, placebo-controlled, 72 week treatment study receiving pioglitazone 15mg/day.
- Primary Outcome Measures
Name Time Method 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. 72 weeks of treatment 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.
- Secondary Outcome Measures
Name Time Method Mean NAS change (0-8). 72 weeks. Defined as the mean change in the NAS score by NASH CRN scoring criteria.
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 Defined as the proportion of patients with a change in steatosis, ballooning or inflammation by NASH CRN scoring criteria.
Mean change of the individual components of the NAS 72 weeks Defined as the mean change in steatosis, ballooning or inflammation by NASH CRN scoring criteria.
Fibrosis improvement. 72 weeks. Defined as the proportion of patients with ≥1-stage decrease in fibrosis with no worsening of lobular inflammation or hepatocellular ballooning by NASH CRN scoring criteria.
Improvement of fibrosis by at least 2 stages. 72 weeks. Defined as the proportion of patients with an improvement of fibrosis by 2 stages by NASH CRN scoring criteria.
Improvement of fibrosis AND resolution of NASH as a composite endpoint. 72 weeks. Defined as the proportion of patients with improvement in both endpoints being met in the same subject by NASH CRN scoring criteria.
No worsening of fibrosis AND no worsening of NASH 72 weeks. Defined as the proportion of patients with no worsening of fibrosis AND no worsening of ballooning or inflammation by NASH CRN scoring criteria.
Resolution of NASH without worsening of liver fibrosis. 72 weeks The proportion of pioglitazone-treated patients achieving NASH resolution, defined as hepatocellular ballooning score of 0 and lobular NASH CRN scoring criteria.
inflammation score of 0-1, with no increase in fibrosis stage.Proportion of patients with improvement in the activity component of steatosis-activity-fibrosis (SAF) score. 72 weeks. Proportion of patients with improvement in the activity component of steatosis-activity-fibrosis (SAF) score.
Proportion of patients with NAS improvement (0-8). 72 weeks. The proportion of pioglitazone-treated patients achieving NAS improvement compared to placebo by NASH CRN scoring criteria.
Progression of liver fibrosis. 72 weeks Defined by the proportion of patients with progression \>1 stage in liver fibrosis by NASH CRN scoring criteria.
Mean change in liver fibrosis 72 weeks. Defined as he mean change in liver fibrosis by NASH CRN scoring criteria.
Trial Locations
- Locations (1)
University of Florida
🇺🇸Gainesville, Florida, United States