HepatitisPhase 2NCT00062764
Treating Nonalcoholic Steatohepatitis With Pioglitazone
A Phase 2 study testing Actos (Pioglitazone) in people with Hepatitis, run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hepatitis
- What is being tested?
- Actos (Pioglitazone)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 18 participants
- Where
- 1 siteUnited States
- Study dates
- Jun 2003to Feb 2009
- Phase
- Phase 2
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: Long-Term Treatment of Nonalcoholic Steatohepatitis With Pioglitazone
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.
...
Read the 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.
- Conditions
- Hepatitis
- Being tested
- Actos (Pioglitazone)
- Keywords
- Insulin Resistance, Obesity, Fatty Liver, Cirrhosis, Diabetes, Pioglitazone, Thiazolidinediones, Peroxisome Proliferator-Advanced Receptor Gamma, PPAR Gama, Nonalcoholic Steatohepatitis, Hepatitis, Non-Alcoholic Steatohepatitis, NASH
- Medical subject headings
- Hepatitis, Insulin Resistance, Obesity, Fatty Liver, Fibrosis, Diabetes Mellitus, Non-alcoholic Fatty Liver Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Actos (Pioglitazone)Drug
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,
| Study group | Role | What they receive |
|---|---|---|
| Pioglitazone | Experimental | Not described Receives: Drug: Actos (Pioglitazone) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Patients With Improvement in Liver Histology
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.
Measured: 48 weeks
Secondary outcomes (4)
Number of Patients With Impaired Glucose Tolerance After Treatment
Measured: 48 weeks
Mean Increase of Insulin Sensitivity Index
Measured: 48 weeks
Average Increase in Weight After Treatment
Measured: 48 weeks
Mean BMI Change
Measured: 48 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Jun 2003 (estimated)
- Study startJun 2003
- Primary completionFeb 2009
- Study completionFeb 2009
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for HepatitisStudies of the same condition, open and under way.
- More trials run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 18 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Jay Hoofnagle, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Investigators
- Jay Hoofnagle, MD, Principal investigator, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00062764
- Sponsor's protocol ID
- 030212
- Other IDs
- 03-DK-0212
- Status last verified
- Dec 2012
- First submitted
- 12 Jun 2003
- Last updated
- 19 Dec 2012
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Byron D, Minuk GY. Clinical hepatology: profile of an urban, hospital-based practice. Hepatology. 1996 Oct;24(4):813-5. doi: 10.1002/hep.510240410.
PubMed 8855181Ludwig 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.
PubMed 7382552Caldwell 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. doi: 10.1002/hep.510290347.
PubMed 10051466
Study at a glance
From the registry record, last updated by the sponsor on 19 Dec 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Long-Term Treatment of Nonalcoholic Steatohepatitis With Pioglitazone
- ClinicalTrials.gov ID
- NCT00062764
- Acronym / sponsor ID
- 030212
- Conditions
- Hepatitis
- Keywords
- Insulin Resistance, Obesity, Fatty Liver, Cirrhosis, Diabetes, Pioglitazone, Thiazolidinediones, Peroxisome Proliferator-Advanced Receptor Gamma
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 18 participants (actual)
- Lead sponsor
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)US National Institutes of Health
- Study start
- Jun 2003
- Primary completion
- Feb 2009 (actual)
- Study completion
- Feb 2009 (actual)
- First posted
- 13 Jun 2003 (estimated)
- Results
- Posted 5 Apr 2011
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
...
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
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Pioglitazone | Experimental | Drug: Actos (Pioglitazone) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- 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:
Key exclusion criteria (22 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 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, | Drug | Pioglitazone |
Primary outcome
Number of Patients With Improvement in Liver Histology
Time frame: 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.
4 secondary outcomes
Number of Patients With Impaired Glucose Tolerance After Treatment
Time frame: 48 weeks
Mean Increase of Insulin Sensitivity Index
Time frame: 48 weeks
Average Increase in Weight After Treatment
Time frame: 48 weeks
Mean BMI Change
Time frame: 48 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Dec 2012.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 8855181Byron D, Minuk GY. Clinical hepatology: profile of an urban, hospital-based practice. Hepatology. 1996 Oct;24(4):813-5. doi: 10.1002/hep.510240410.
- Background: PubMed 7382552Ludwig 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.
- Background: PubMed 10051466Caldwell 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. doi: 10.1002/hep.510290347.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jay Hoofnagle, MD principal investigator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Actos (Pioglitazone) in people with Hepatitis, run by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 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 13 inclusion and 22 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 19 Dec 2012. 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. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
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 2011). 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?
Number of Patients With Improvement in Liver Histology (time frame: 48 weeks). 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 NCT00062764, 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 19 Dec 2012.