Treating Nonalcoholic Steatohepatitis With Pioglitazone
Study Details
Study Description
Brief Summary
Nonalcoholic steatohepatitis (NASH) is a common liver disease that resembles alcoholic hepatitis but occurs in persons who drink little or no alcohol. The etiology of NASH is unclear, but it is commonly associated with diabetes, obesity, and insulin resistance. Several pilot studies, including a study of pioglitazone at the NIH Clinical Center (01-DK-0130), have shown that the insulin-sensitizing thiazolidinediones lead to decreases in serum alanine aminotransferase (ALT) levels and improved liver histology. Once therapy is stopped, however, ALT levels rapidly return to pre-treatment values. Inaddition we are currently enrolling patients with NASH in a pilot study of metformin therapy for 48-weeks, however our results in 3 patients thus far have not been very encouraging.
In the current study, patients who have completed the pilot study of pioglitazone and have been off therapy for 48 weeks will be offered re-treatment for 3 years. We also propose to treat patients who have not had a satisfactory response to metformin with pioglitazone for the same duration. After a repeat medical and metabolic evaluation and liver biopsy, patients with moderate-to-severe NASH (activity score greater than or equal to 4) will restart pioglitazone at a dose of 15 mg daily. If after 48 weeks, ALT levels are not normal or improved to the degree identified during the pilot study, the dose will be increased to 30 mg daily at the end of 3 years, all patients will undergo repeat medical and metabolic evaluation and liver biopsy. The primary end point will be improvement in liver histology. Secondary end points will be improvements in insulin sensitivity, reduction in visceral fat, liver volume, and liver biochemistry. The aim of this study is to evaluate whether long-term pioglitazone therapy can safely achieve and maintain biochemical and histological improvements in NASH.
...
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
Nonalcoholic steatohepatitis (NASH) is a common liver disease that resembles alcoholic hepatitis but occurs in persons who drink little or no alcohol. The etiology of NASH is unclear, but it is commonly associated with diabetes, obesity, and insulin resistance. Several pilot studies, including a study of pioglitazone at the NIH Clinical Center (01-DK-0130), have shown that the insulin-sensitizing thiazolidinediones lead to decreases in serum alanine aminotransferase (ALT) levels and improved liver histology. Once therapy is stopped, however, ALT levels rapidly return to pre-treatment values. Inaddition we are currently enrolling patients with NASH in a pilot study of metformin therapy for 48-weeks, however our results in 3 patients thus far have not been very encouraging.
In the current study, patients who have completed the pilot study of pioglitazone and have been off therapy for 48 weeks will be offered re-treatment for 3 years. We also propose to treat patients who have not had a satisfactory response to metformin with pioglitazone for the same duration. After a repeat medical and metabolic evaluation and liver biopsy, patients with moderate-to-severe NASH (activity score greater than or equal to 4) will restart pioglitazone at a dose of 15 mg daily. If after 48 weeks, ALT levels are not normal or improved to the degree identified during the pilot study, the dose will be increased to 30 mg daily at the end of 3 years, all patients will undergo repeat medical and metabolic evaluation and liver biopsy. The primary end point will be improvement in liver histology. Secondary end points will be improvements in insulin sensitivity, reduction in visceral fat, liver volume, and liver biochemistry. The aim of this study is to evaluate whether long-term pioglitazone therapy can safely achieve and maintain biochemical and histological improvements in NASH.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Pioglitazone
|
Drug: Actos (Pioglitazone)
Pts receive drug in a dose of 15 mg daily for at least 1 year; the dose is escalated to 30 mg daily if serum ALT levels do not fall to normal by the 1 year pt; if pts have a biochemical response, drug is continued for 3 years,
|
Outcome Measures
Primary Outcome Measures
- Number of Patients With Improvement in Liver Histology [48 weeks]
A histological response was defined as a reduction in the NASH activity index by 3 points or more with improvements of at least 1 point each in steatosis, parenchymal inflammation, and hepatocellular injury.
Secondary Outcome Measures
- Number of Patients With Impaired Glucose Tolerance After Treatment [48 weeks]
- Mean Increase of Insulin Sensitivity Index [48 weeks]
- Average Increase in Weight After Treatment [48 weeks]
- Mean BMI Change [48 weeks]
Eligibility Criteria
Criteria
- INCLUSION CRITERIA:
Completion of a 48-week course of pioglitazone in protocol 01-DK-0130 or completion of 48-weeks of metformin in protocol 03-DK-0233.
At least 48 weeks of follow up on no thiazolidinedione therapy after completion of protocol 01-DK-0130.
At least 24-weeks follow up on no metformin theray after completion of protocol 03-DK-0233.
Written informed consent.
Patients who participated in protocol 01-DK-0130 will also have to meet the following inclusion criteria:
Demonstrated improvements in liver histology and/or serum ALT levels during the 48-week course of pioglitazone therapy in protocol 01-DK-0130.
Elevations in serum ALT levels.
Liver biopsy showing NASH with a total NASH activity score of at least 4 (of a total possible score of 16) including a score of at least 1 each for parenchyma inflammation, cellular injury and steatosis on liver biopsy taken 48 weeks after stopping pioglitazone.
Willingness to receive pioglitazone for 3 years.
Patients who participated in protocol 03-DK-0233 will also have to me the following inclusion criteria:
Demonstrated no significant improvement in liver histology and/or serum ALT levels during the 48-week course of metformin treatment in protocol 03-DK-0233.
Elevations in serum ALT levels.
Liver biopsy showing NASH with a total activity score of at least 4 (of a total possible score of 16) including a score of at least 1 each for parenchymal inflammation, cellular injury and steatosis on liver biopsy taken at the end of the 48-week course of metofrmin.
EXCLUSION CRITERIA:
Evidence of another form of liver disease (these largely will have been excluded based upon enrollment in the previous study, 01-DK-0130 and 03-DK-0233).
Hepatitis B as defined as presence of hepatitis B surface antigen (HBsAg).
Hepatitis C as defined by presence of hepatitis C virus (HCV) RNA in serum.
Autoimmune hepatitis as defined by anti-nuclear antibody (ANA) of 1:160 or greater and liver histology consistent with autoimmune hepatitis or previous response to immunosuppressive therapy.
Autoimmune cholestatic liver disorders as defined by elevation of alkaline phosphatase and anti-mitochondrial antibody of greater than 1:80 or liver histology consistent with primary biliary cirrhosis or elevation of alkaline phosphatase and liver histology consistent with sclerosing cholangitis.
- Wilson disease as defined by ceruloplasmin below the limits of normal and liver histology consistent with Wilson disease.
Alpha-1-antitrypsin deficiency as defined by alpha-1-antitrypsin level less than normal and liver histology consistent with alpha-1-antitrypsin deficiency.
Hemochromatosis as defined by presence of 3+ or 4 iron on liver biopsy stain and homozygosity for C282Y or compound heterozygosity for C282Y/H63D.
Drug-induced liver disease as defined on the basis of typical exposure and history.
Bile duct obstruction as shown by imaging studies.
History of excess alcohol ingestion, averaging more than 30 gm/day (3 drinks per day) in the previous 10 years, or history of alcohol intake averaging greater than 10 gm/day (1 drink per day: 7 drinks per week) in the previous one year.
Contraindications to liver biopsy: platelet counts less than 75,000/mm(3) or prothrombin time greater than 16 seconds.
Decompensated liver disease, Child-Pugh score greater than or equal to 7 points.
History of gastrointestinal bypass surgery or ingestion of drugs known to produce hepatic steatosis including corticosteroids, high-dose estrogens, methotrexate, tetracycline or amiodarone in the previous 6 months.
Preexistent diabetes mellitus or the development of diabetes mellitus during the study requiring the use of another drug in addition to pioglitazone for glycaemic control. Diabetes being as defined by: fasting plasma glucose of greater than or equal to 126 mg/dl on two separate occasions, or diabetic symptoms with a random plasma glucose of greater than or equal to 200 mg/dl.
Use of anti-diabetic drugs, including insulin, biguanides, sulfonylureas, or thiazolidinediones at the time of enrollment or in the previous 48 weeks.
Significant systemic or major illnesses other than liver disease, including congestive heart failure, coronary artery disease, cerebrovascular disease, pulmonary disease, renal failure, organ transplantation, serious psychiatric disease, malignancy that, in the opinion of the investigator would preclude treatment with pioglitazone and adequate follow up.
Positive test for anti-HIV.
Active substance abuse, such as alcohol, inhaled or injection drugs within the previous one year.
Pregnancy or inability to practice adequate contraception in women of childbearing potential.
Evidence of hepatocellular carcinoma: alpha-fetoprotein levels greater than 200 ng/ml and/or liver mass on imaging study that is suggestive of liver cancer.
Any other conditions, which, in the opinion of the investigators would impede competence or compliance or possibility, hinder completion of the study.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland | United States | 20892 |
Sponsors and Collaborators
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
- Principal Investigator: Jay Hoofnagle, MD, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study Documents (Full-Text)
None provided.More Information
Publications
- Byron D, Minuk GY. Clinical hepatology: profile of an urban, hospital-based practice. Hepatology. 1996 Oct;24(4):813-5.
- Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology. 1999 Mar;29(3):664-9.
- Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980 Jul;55(7):434-8.
- 030212
- 03-DK-0212
Study Results
Participant Flow
| Recruitment Details | Between March 2001 and April 2002, 25 patients suspected of having NASH were evaluated, and 18 were enrolled in the study after screening. |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Pioglitazone |
|---|---|
| Arm/Group Description | Patients receive Pioglitazone in a dose of 15 mg daily for at least 1 year; the dose is escalated to 30 mg daily if serum Alanine transaminase levels do not fall to normal by the 1 year pt; if patients have a biochemical response, drug is continued for 3 years. |
| Period Title: Overall Study | |
| STARTED | 18 |
| COMPLETED | 18 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | Pioglitazone |
|---|---|
| Arm/Group Description | Patients receive Pioglitazone in a dose of 15 mg daily for at least 1 year; the dose is escalated to 30 mg daily if serum Alanine transaminase levels do not fall to normal by the 1 year pt; if patients have a biochemical response, drug is continued for 3 years. |
| Overall Participants | 18 |
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
46
(11)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
11
61.1%
|
| Male |
7
38.9%
|
| Race/Ethnicity, Customized (participants) [Number] | |
| Hispanic |
3
16.7%
|
| White |
13
72.2%
|
| Mixed |
2
11.1%
|
| Region of Enrollment (participants) [Number] | |
| United States |
18
100%
|
| Obesity Distribution (participants) [Number] | |
| BMI>30 |
11
61.1%
|
| BMI<=30 |
7
38.9%
|
| 2-hr glucose diabetes mellitus (participants) [Number] | |
| >200 mg/dL |
2
11.1%
|
| <=200 mg/dL |
16
88.9%
|
| 2-hr glucose (Impaired glucose tolerance) (participants) [Number] | |
| 140-199 mg/dL |
11
61.1%
|
| other |
7
38.9%
|
| Metabolic syndrome (participants) [Number] | |
| Yes |
7
38.9%
|
| No |
11
61.1%
|
| Fasting glucose (participant) [Number] | |
| 110-125 mg/dL |
2
|
| other |
16
|
Outcome Measures
| Title | Number of Patients With Improvement in Liver Histology |
|---|---|
| Description | A histological response was defined as a reduction in the NASH activity index by 3 points or more with improvements of at least 1 point each in steatosis, parenchymal inflammation, and hepatocellular injury. |
| Time Frame | 48 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Pioglitazone |
|---|---|
| Arm/Group Description | Patients receive Pioglitazone in a dose of 15 mg daily for at least 1 year; the dose is escalated to 30 mg daily if serum Alanine transaminase levels do not fall to normal by the 1 year pt; if patients have a biochemical response, drug is continued for 3 years. |
| Measure Participants | 18 |
| Number [participants] |
12
66.7%
|
| Title | Number of Patients With Impaired Glucose Tolerance After Treatment |
|---|---|
| Description | |
| Time Frame | 48 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Pioglitazone |
|---|---|
| Arm/Group Description | Patients receive Pioglitazone in a dose of 15 mg daily for at least 1 year; the dose is escalated to 30 mg daily if serum Alanine transaminase levels do not fall to normal by the 1 year pt; if patients have a biochemical response, drug is continued for 3 years. |
| Measure Participants | 18 |
| Number [participants] |
6
33.3%
|
| Title | Mean Increase of Insulin Sensitivity Index |
|---|---|
| Description | |
| Time Frame | 48 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Pioglitazone |
|---|---|
| Arm/Group Description | Patients receive Pioglitazone in a dose of 15 mg daily for at least 1 year; the dose is escalated to 30 mg daily if serum Alanine transaminase levels do not fall to normal by the 1 year pt; if patients have a biochemical response, drug is continued for 3 years. |
| Measure Participants | 18 |
| Mean (Standard Deviation) [percentage] |
126
(78)
|
| Title | Average Increase in Weight After Treatment |
|---|---|
| Description | |
| Time Frame | 48 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Pioglitazone |
|---|---|
| Arm/Group Description | Patients receive Pioglitazone in a dose of 15 mg daily for at least 1 year; the dose is escalated to 30 mg daily if serum Alanine transaminase levels do not fall to normal by the 1 year pt; if patients have a biochemical response, drug is continued for 3 years. |
| Measure Participants | 18 |
| Mean (Full Range) [kg] |
3.5
|
| Title | Mean BMI Change |
|---|---|
| Description | |
| Time Frame | 48 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Pioglitazone |
|---|---|
| Arm/Group Description | Patients receive Pioglitazone in a dose of 15 mg daily for at least 1 year; the dose is escalated to 30 mg daily if serum Alanine transaminase levels do not fall to normal by the 1 year pt; if patients have a biochemical response, drug is continued for 3 years. |
| Measure Participants | 18 |
| Mean (Standard Deviation) [kg/m2] |
1.3
(1.7)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Pioglitazone |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.004 |
| Comments | ||
| Method | paired t-test | |
| Comments | ||
Adverse Events
| Time Frame | ||
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Pioglitazone | |
| Arm/Group Description | Patients receive Pioglitazone in a dose of 15 mg daily for at least 1 year; the dose is escalated to 30 mg daily if serum Alanine transaminase levels do not fall to normal by the 1 year pt; if patients have a biochemical response, drug is continued for 3 years. | |
All Cause Mortality |
||
| Pioglitazone | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Pioglitazone | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/18 (0%) | |
| Gastrointestinal disorders | ||
| Worsened serum ALT levels | 0/18 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||
| Pioglitazone | ||
| Affected / at Risk (%) | # Events | |
| Total | 14/18 (77.8%) | |
| General disorders | ||
| dizziness | 1/18 (5.6%) | 1 |
| Weight gain | 13/18 (72.2%) | 13 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Jay H. Hoofnagle, MD |
|---|---|
| Organization | National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health |
| Phone | 3014961333 |
| hoofnaglej@extra.niddk.nih.gov |
- 030212
- 03-DK-0212