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Nonalcoholic SteatohepatitisPhase 4NCT00994682

University of Texas H.S.C. San Antonio Pioglitazone in Non-Alcoholic Steatohepatitis Trial (UTHSCSA NASH Trial)

A Phase 4 study testing Pioglitazone study drug and Pioglitazone Open Label in people with Nonalcoholic Steatohepatitis and Nonalcoholic Fatty Liver Disease, run by University of Florida at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

Obesity and Type 2 diabetes are creating a silent epidemic, Non-alcoholic fatty liver disease, which is a chronic liver disease associated with insulin resistance, impaired glucose intolerance, and hepatic fat accumulation. Read more about this study

Who is it for?
Ages 18 to 70 yearsHealthy volunteers can take part
What is being tested?
Pioglitazone study drug and Pioglitazone Open Label
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
176 participants
Where
1 siteUnited States
Study dates
Dec 2008to Dec 2014
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 70 years
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • Be able to communicate meaningfully with the investigators and be legally competent to provide written informed consent.
  • Age range between 18 to 70 years (inclusive).
  • Female patients must be non-lactating and must either be at least one year 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 (patches are acceptable as they deliver much lower estrogen systemically).
  • Participants must have the following laboratory values:
  • Hemoglobin ≥ 12 gm/dl in males, or ≥ 11 gm/dl in females,
  • WBC count ≥ 3,000/mm3
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  • Neutrophil count ≥ 1,500/mm3
  • Platelets ≥ 100,000/mm3
  • Albumin ≥3.0 g/dl
  • Serum creatinine ≤ 1.8 mg/dl
  • Creatinine phosphokinase ≤ 2 times upper limit of normal
  • AST and ALT ≤ 3.0 times upper limit of normal
  • Alkaline phosphatase ≤ 2.5 times upper limit of normal
  • A diagnosis of NASH by liver biopsy performed within the past 6 months,

Who cannot join

  • 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.
  • Current history of alcohol abuse (alcohol consumption greater than 20 grams of ethanol 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.
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  • 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), peripheral vascular disease (history of claudication), or diagnosed pulmonary disease (dyspnea on exertion of one flight or less; abnormal breath sounds on auscultation).
  • Patients with severe osteoporosis.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Bartter Research Unit, Audie L Murphy VA Hospital

    San Antonio, Texas, 78248

Other trials in United States

About this study

Official title: Long-term Role of Pioglitazone in Non-Alcoholic Fatty Liver Disease (NAFLD) in Type 2 Diabetes Mellitus (T2DM).

Obesity and Type 2 diabetes are creating a silent epidemic, Non-alcoholic fatty liver disease, which is a chronic liver disease associated with insulin resistance, impaired glucose intolerance, and hepatic fat accumulation. The thiazolidinedione pioglitazone improves glucose/lipid metabolism and histology in NASH by improving insulin resistance in the liver/peripheral/adipose tissues and reducing subclinical inflammation. The aim of this study is to assess the underlying mechanisms at the clinical and molecular level and the long-term efficacy and safety of pioglitazone in NASH in a multiethnic cohort of subjects (predominantly Hispanics, Caucasians and African-Americans - the most common ethnic groups locally) and examine the response including patients with normal glucose tolerance, impaired glucose tolerance or established type 2 diabetes mellitus (T2DM).

Read the detailed description

NASH is a disease characterized by elevated plasma aminotransferases and histopathological changes in liver characterized by hepatocellular steatosis, chronic inflammation and perisinusoidal fibrosis. NASH affects (~30-40%) of obese and type 2 diabetic subjects. While the pathogenesis of NASH is poorly understood, there is consensus that insulin resistance and its associated abnormalities in lipid metabolism play a key role in the development of liver fat accumulation. Insulin resistance in nonalcoholic steatohepatitis is frequently associated with chronic hyperinsulinemia, hyperglycemia, and an excessive supply of plasma free fatty acids to the liver. This in turn promotes hepatic lipogenesis. Pioglitazone, a thiazolidinedione (TZD), reverses these abnormalities by ameliorating insulin resistance in adipose tissue, liver and muscle. TZDs decrease excessive ectopic triglyceride accumulation in liver and muscle, reduce visceral fat, and redistribute fat to subcutaneous adipose stores. We have shown in a proof-of-concept 6-month study that pioglitazone is safe and effective for the treatment of T2DM. Patients with nonalcoholic steatohepatitis are also characterized by a low plasma adiponectin level. Thiazolidinediones increase plasma adiponectin levels, may activate AMP-activated protein kinase, stimulate hepatic/muscle fatty acid oxidation, and inhibit hepatic fatty acid synthesis in NASH nonalcoholic steatohepatitis. Thiazolidinediones also have antiinflammatory effects which are believed to be of value for therapy for NASH.

In order to evaluate this hypothesis, the investigators will treat for up to 36 months a group of patients with impaired (IGT) glucose tolerance and T2DM patients recruited from the University Hospital and medical school clinics and by newspaper add targeting the San Antonio and South Texas geographical area, with pioglitazone in a randomized, double-blinded, placebo-controlled trial. The primary endpoint will be liver histologic response assessed by liver biopsy performed at 18 and at 36 months of treatment.

Being tested
Pioglitazone study drug, Placebo, Pioglitazone Open Label
Keywords
Additional relevant MeSH terms:, Hypoglycemic Agents, Physiological Effects of Drugs, Pharmacologic Actions, Pioglitazone
Medical subject headings
Non-alcoholic Fatty Liver Disease, Diabetes Mellitus, Type 2

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Pioglitazone study drugDrug

    Also called Actos (brand name), manufactured by Takeda Pharmaceuticals.

    30 mg per day orally for 8 weeks, and if well tolerated, titrated to 45 mg per day until the end of 18 months

  • PlaceboDrug

    An oral tablet identical to pioglitazone will be given once daily but without active drug for 18 months.

  • Pioglitazone Open LabelDrug

    Also called Actos (brand name), manufactured by Takeda Pharmaceuticals.

    Patients in both arms were placed open label pioglitazone for an additional 18 months after successfully completing the double-blind, placebo-controlled portion of the study design.

Study groups in NCT00994682
Study groupRoleWhat they receive
PioglitazoneActive comparatorAfter all patients receive dietary counseling at the research unit (CTSA), patients with prediabetes or type 2 diabetes mellitus (T2DM) and NASH will be started on pioglitazone (or placebo) in a randomized, double-blind,placebo-controlled study design. Pioglitazone will be given at 30 mg/day for the first 2 months and titrated to 45 mg/day thereafter (if well tolerated).
Receives: Drug: Pioglitazone study drug; Drug: Pioglitazone Open Label
PlaceboPlacebo comparatorAfter dietary counseling to all patients at the research unit (CTSA), patients with prediabetes or type 2 diabetes mellitus (T2DM) and NASH will be started on pioglitazone (or placebo) in a randomized, double-blind,placebo-controlled study design. Pioglitazone will be given at 30 mg/day for the first 2 months and titrated to 45 mg/day thereafter (if well tolerated).
Receives: Drug: Placebo; Drug: Pioglitazone Open Label

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Liver Histology (Using Kleiner et al Criteria, Hepatology 2005)

    Number of patients with reduction of at least 2 points in the nonalcoholic fatty liver disease activity score (NAS) (with reduction in at least 2 different histological categories) without worsening of fibrosis. NAS is the sum of the separate scores for steatosis (0-3), hepatocellular ballooning (0-2) and lobular inflammation (0-3), and ranges from 0-8 .

    The scoring system is based on the following grading:

    Steatosis: 0 = <5%; 1 = 5-33%; 2 = >33-66%; 3 = >66%. Lobular Inflammation: 0 = No foci 1 = <2 foci/200x; 2 = 2-4 foci/200x, 3 = >4 foci/200x. Hepatocyte Ballooning: 0 = None; 1 = Few balloon cells; 2 = Many cells/prominent ballooning. Fibrosis: 0 = None; 1 = Perisinusoidal or periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis.

    Measured: At 18 months

Secondary outcomes (18)

  1. Number of Participants With Resolution of NASH

    Resolution of NASH was defined as absence of NASH after 18 months of therapy in patients with definite NASH (presence of zone 3 accentuation of macrovesicular steatosis of any grade, hepatocellular ballooning of any degree, and lobular inflammatory infiltrates of any amount) at baseline.

    Measured: Month 18

  2. Mean Individual Histological Scores

    Mean change in individual scores compared to baseline. Steatosis: 0 = <5%; 1 = 5-33%; 2 = >33-66%; 3 = >66%. Lobular Inflammation: 0 = No foci 1 = <2 foci/200x; 2 = 2-4 foci/200x, 3 = >4 foci/200x. Hepatocyte Ballooning: 0 = None; 1 = Few balloon cells; 2 = Many cells/prominent ballooning. Fibrosis: 0 = None; 1 = Perisinusoidal or periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis

    Measured: Baseline and Month 18

  3. Individual Histological Scores

    Number of patients with improvement of at least 1 grade in each of the histological parameters.

    Steatosis: 0 = <5%; 1 = 5-33%; 2 = >33-66%; 3 = >66%. Lobular Inflammation: 0 = No foci 1 = <2 foci/200x; 2 = 2-4 foci/200x, 3 = >4 foci/200x. Hepatocyte Ballooning: 0 = None; 1 = Few balloon cells; 2 = Many cells/prominent ballooning. Fibrosis: 0 = None; 1 = Perisinusoidal or periportal, 1A = Mild, zone 3, perisinusoidal "delicate" fibrosis; 1B = Moderate, zone 3, perisinusoidal "dense" fibrosis; 1C = Portal/periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis

    Measured: Month 18

  4. Mean Individual Histological Scores

    Steatosis: 0 = <5%; 1 = 5-33%; 2 = >33-66%; 3 = >66%. Lobular Inflammation: 0 = No foci 1 = <2 foci/200x; 2 = 2-4 foci/200x, 3 = >4 foci/200x. Hepatocyte Ballooning: 0 = None; 1 = Few balloon cells; 2 = Many cells/prominent ballooning. Fibrosis: 0 = None; 1 = Perisinusoidal or periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis

    Measured: Month 36

  5. Liver Transaminases (AST and ALT).

    Measured: 18 and 36 months

  6. Liver Fat by Magnetic Resonance and Spectroscopy (MRS).

    Liver fat content was calculated as the fat fraction: 100*(area under the curve [AUC] of fat peak / [AUC of fat peak + AUC of water peak]).

    Measured: 18 months

  7. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)

    Homeostatic model assessment of insulin resistance (HOMA-IR) is a method for assessing insulin resistance (IR) from basal fasting plasma glucose (FPG) and fasting plasma insulin (FPI). It is calculated as (FPG x FPI)/405.

    Measured: 18 and 36 months

  8. Hepatic Insulin Sensitivity

    Suppression of endogenous glucose production (Supp EGP) by low dose insulin (i.e., percentage of reduction of EGP with low dose insulin infusion compared to the baseline state). This was calculated as: 100*((EGP without insulin - EGP with insulin infusion)/EGP without insulin). All measurements are obtained at the same time point during an euglycemic insulin clamp.

    Measured: 18 months

  9. Adipose Tissue Insulin Sensitivity

    Suppression of free fatty acids by low dose insulin (i.e., percentage of reduction of plasma FFA with low dose insulin infusion compared to the baseline state). This was calculated as: 100*((plasma FFA without insulin - plasma FFA with insulin infusion)/plasma FFA without insulin). All measurements are obtained at the same time point during an euglycemic insulin clamp.

    Measured: 18 months

  10. Skeletal Muscle Insulin Sensitivity

    Rate of glucose disappearance (Rd) during high-dose insulin infusion. The rate of plasma glucose disappearance was calculated using Steele's non-steady-state equation.

    Measured: 18 months

  11. Body Mass Index (BMI)

    Measured: Months 18 and 36

  12. Total Body Fat

    Total body fat measured by dual-energy x-ray absorptiometry (DXA)

    Measured: Months 18

  13. Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (Adiponectin).

    Measured: 18 and 36 months

  14. Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (CK-18).

    Measured: 18 and 36 months

  15. Prevention of the Onset of T2DM and/or Reversal From IFG/IGT to NGT in Non-diabetics.

    Number of patients developing T2DM and number of patients regressing to NGT among patients with prediabetes (IFG/IGT).

    Measured: 18 months

  16. Osteoporotic Fractures

    Number of patients with osteoporotic fractures

    Measured: 18 and 36 months

  17. Molecular Pathways of Liver Glucose and Lipid Signaling; Inflammatory Pathways; Oxidative Stress; Other.

    Measured: At 18 (2nd liver biopsy) and 36 (3rd liver biopsy) months.

  18. Bone Mineral Density

    Bone mineral density measured at the levels of spine, femoral neck, hip, and wrist by DXA.

    Measured: 18 and 36 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Oct 2009 (estimated)
  2. Study startDec 2008
  3. Primary completionDec 2014
  4. Study completionDec 2014

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
176 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00994682
Sponsor's protocol ID
HSC20070654
Status last verified
Feb 2017
First submitted
12 Oct 2009
Last updated
5 Apr 2017
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Ipsen EO, Madsen KS, Chi Y, Pedersen-Bjergaard U, Richter B, Metzendorf MI, Hemmingsen B. Pioglitazone for prevention or delay of type 2 diabetes mellitus and its associated complications in people at risk for the development of type 2 diabetes mellitus. Cochrane Database Syst Rev. 2020 Nov 19;11(11):CD013516. doi: 10.1002/14651858.CD013516.pub2.

    PubMed 33210751

  • Bril F, Kalavalapalli S, Clark VC, Lomonaco R, Soldevila-Pico C, Liu IC, Orsak B, Tio F, Cusi K. Response to Pioglitazone in Patients With Nonalcoholic Steatohepatitis With vs Without Type 2 Diabetes. Clin Gastroenterol Hepatol. 2018 Apr;16(4):558-566.e2. doi: 10.1016/j.cgh.2017.12.001. Epub 2017 Dec 7.

    PubMed 29223443

  • 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.

    PubMed 27322798

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Pioglitazone study drug and Pioglitazone Open Label in people with Nonalcoholic Steatohepatitis and Nonalcoholic Fatty Liver Disease, run by University of Florida at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 5 Apr 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 5 Apr 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Liver Histology (Using Kleiner et al Criteria, Hepatology 2005) (time frame: At 18 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00994682, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Apr 2017.

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