HIVPhase 4NCT00742326
Pioglitazone to Treat Fatty Liver in Patients With HIV and Hepatitis C Infections
A Phase 4 study testing Pioglitazone in people with HIV and Hepatitis C, run by National Institute of Allergy and Infectious Diseases (NIAID) at 2 sites in United States.
Trial summary
This study will evaluate the effectiveness of pioglitazone in reducing liver fat content in patients with HIV and hepatitis C virus (HCV) infections. Fatty liver and accompanying insulin resistance in patients with HIV and HCV co-infections is associated with inflammatory changes, liver fibrosis and a poorer response… Read more about this study
- Who is it for?
- Ages 18 to 99 years
- Conditions the study is for
- HIV, Hepatitis C, Liver Disease
- What is being tested?
- Pioglitazone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 13 participants
- Where
- 2 sitesUnited States
- Study dates
- Aug 2008to Jan 2013
- 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 99 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Men and women, 18 years of age or greater
- Confirmed HIV infection by ELISA and Western blot
- No changes in antiretroviral regimen within the prior 3 months--Individuals not currently taking antiretroviral therapy will be eligible. Individuals requiring medically indicated adjustments of antiretroviral therapy during the course of the study will be eligible.
- Confirmed HCV infection, and no current or recent (within the past 3 months) HCV treatment and no plans to start HCV antiviral therapy in the foreseeable future.
- H-MRS liver fat content greater than 5 percent and confirmed steatosis on liver biopsy within 1 year
- Fasting glucose less than 126 mg/dL
Show all 12Show fewer
- Platelets greater than or equal to 75,000/uL; INR less than 1.6
- Willingness to avoid medications and herbal supplements which may increase the risk of bleeding for one week prior to and one week following liver biopsy (e.g. aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), Vitamin E, fish oil and gingko biloba).
- Willingness to restrict physical activity 72 hours after liver biopsy
- If premenopausal female, willingness to use 2 forms of effective birth control on this study to avoid pregnancy.
- Have a primary care physician
- Willingness to have specimens stored.
Who cannot join
- Current thiazolidinedione use or use in the last 6 months, known allergy or sensitivity to a thiazolidinedione
- Use of insulin or other oral hypoglycemics, or known diabetes
- Current pregnancy, breast feeding, or pregnancy within the past 6 months or desire to become pregnant within the next 2 years.
- Child-Pugh-Turcotte (CPT) score greater than class A
- ALT greater than 4 times the upper limit of normal
- Current or history of heart failure (New York Heart Association [NYHA] Class III or IV cardiac status)
Show all 18Show fewer
- Hemoglobin level less than 9g/dL
- Active or ongoing infection with Hepatitis A or B
- Known or suspected liver disease such as autoimmune hepatitis, Wilson's disease, alpha-1-antitrypsin deficiency, cystic fibrosis, hemochromatosis, glycogen storage disease, amyloidosis, primary biliary cirrhosis, sclerosing cholangitis, or any primary or secondary hepatic tumor
- Current alcohol/substance abuse
- Use of growth hormone, prednisone or other anabolic agents (except for physiologic testosterone replacement) currently or within the past 3 months. One day or less of corticosteroid within the prior 90 days of screening is allowed as is stable dose inhalation corticosteroids
- Concurrent use of ketoconazole
- Active opportunistic infection (except thrush) or neoplasm (except Kaposi's sarcoma, skin cancer, cancer of the cervix or anus)
- Any known contraindications to percutaneous liver biopsy including elevated PT/PTT
- Severe psychiatric illness that would interfere with adherence to protocol requirements
- Current treatment with interleukin-2, interferon-alpha, or other investigational agent(s) within the past 6 months (This does not pertain to ARVs obtained through expanded access)
- Any significant medical condition for which the investigator believes a liver biopsy or participation in the research protocol may be contraindicated
- Any contraindication to MRI scan, including excess body size
Trial locations and contacts
2 sites in 1 country.
United States2 sites
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
VA Medical Center
Washington D.C., District of Columbia, 20422
About this study
Official title: Pioglitazone for Hepatic Steatosis in HIV/HCV Co-infection
This study will evaluate the effectiveness of pioglitazone in reducing liver fat content in patients with HIV and hepatitis C virus (HCV) infections. Fatty liver and accompanying insulin resistance in patients with HIV and HCV co-infections is associated with inflammatory changes, liver fibrosis and a poorer response to HCV treatment. Pioglitazone is a drug that helps to reduce the body's resistance to insulin. It is approved by the Food and Drug Administration to treat diabetes.
Patients with HIV and HCV co-infections who have hepatic steatosis (fatty liver) may be eligible for this study. Candidates are screened with a medical history and physical examination, blood and urine tests, magnetic resonance imaging (MRI) of the liver to measure liver fat and, if needed, a liver biopsy to confirm the diagnosis of liver steatosis.
- Participants are randomly assigned to take either pioglitazone therapy or placebo for 48 weeks. This is followed by a second 48-week treatment period in which all participants take pioglitazone.
- There are approximately 12 visits during the 96 weeks of the study. Participants will receive a physical assessment, blood and urine tests at each visit. In addition, periodic assessments of dietary habits, body composition, oral glucose tolerance testing, and health related quality of life questionnaires will be completed.
- A repeat MRI of the liver is performed at 48 weeks and at the end of the study to evaluate any potential changes in liver fat and inflammation. In addition, there is a follow-up liver biopsy at 48 weeks and an optional liver biopsy at 96 weeks.
Read the detailed description
Following the introduction of effective antiretroviral therapy for HIV, the management of co-morbidities such as hepatitis C virus (HCV) has taken on increasing significance in the care and health maintenance of chronically infected patients. HCV co-infection is common in HIV, with an estimated prevalence of 30 percent among HIV-infected adults in the US. Further, the reported prevalence of hepatic steatosis in HIV/HCV co-infection is between 40-67 percent.
In recent years, the significance of hepatic steatosis and accompanying insulin resistance in HCV has gained increasing recognition. For example, steatosis is associated with increased rates of necro-inflammatory change and fibrosis in HIV/HCV co-infected patients. Furthermore, studies showed that, among non-HIV infected HCV patients, the presence of steatosis and/or insulin resistance was associated with poorer response to HCV therapy. These observations have led to research interest in treating hepatic steatosis in HCV, particularly in the context of pegylated interferon and ribavirin therapy.
Administration of the thiazolidinedione, pioglitazone, leads to significant reductions in hepatic steatosis, inflammation and in some cases fibrosis in patients with non-alcoholic steatohepatitis (NASH). Therefore, the potential benefits of pioglitazone therapy in the setting of HIV/HCV co-infection and hepatic steatosis will be determined. The proposed study is a 48-week, double-blind, randomized placebo-controlled trial of pioglitazone (45 mg/day) in 50 HIV/HCV-infected men and women. After the 48-week randomized portion of the trial, all participants will enter a 48-week open treatment extension arm irrespective of original randomization. It is anticipated that 100 subjects will be needed to be screened to identify a sufficient number of eligible participants to enroll in the study.
The primary outcome variable of interest in this trial will be the change in hepatic fat content measured by magnetic resonance (MR) spectroscopy. Important secondary outcomes will be histologic improvement on liver biopsy performed at baseline and 48 weeks, as well as improvements in transaminase levels and insulin resistance. The open treatment extension will allow all participants an opportunity to receive active study medication and it will allow the potential benefits of additional pioglitazone therapy to be assessed. In this way, important information about the efficacy of pioglitazone to treat hepatic steatosis and improve the metabolic profile in HIV/HCV co-infected patients will be obtained.
- Conditions
- HIV, Hepatitis C, Liver Disease, Fatty Liver, Steatosis
- Being tested
- Pioglitazone, Placebo
- Keywords
- HIV, Hepatitis C, Liver Disease, Fatty Liver, Steatosis
- Medical subject headings
- Hepatitis C, Liver Diseases, Fatty Liver
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PioglitazoneDrug
Also called Avandia
45 mg/daily
PlaceboDrug
one capsule daily
| Study group | Role | What they receive |
|---|---|---|
| Pioglitazone | Experimental | pioglitazone 45 mg daily for 48 weeks Receives: Drug: Pioglitazone |
| Placebo | Placebo comparator | one capsule daily for 48 weeks Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Hepatic Steatosis and Hepatic Inflammation/Fibrosis in HIV/HCV Co-infected Patients With Steatosis.
Change in hepatic steatosis and hepatic inflammation/fibrosis in HIV/HCV co-infected patients with steatosis. Change in Hepatic Fat Content measured by MR spectroscopy: 48 weeks compared to Baseline
Measured: 48 weeks
Secondary outcomes (1)
Change in Insulin Resistance in HIV- and HCV-infected Patients With Steatosis Compared to Placebo
Change in Glucose Area Under the Curve from standard oral glucose challenge ( baseline to 2 hours): Week 48 - Baseline values
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 posted27 Aug 2008 (estimated)
- Study startAug 2008
- Primary completionJan 2013
- Study completionJan 2013
Why it stopped: Enrollment stopped prior to complete enrollment due to slow accrual
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 (4)Papers the sponsor has linked to this study.
- Other trials for HIVStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)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 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 13 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Colleen M Hadigan, M.D., Principal investigator, National Institute of Allergy and Infectious Diseases (NIAID)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00742326
- Sponsor's protocol ID
- 080201
- Status last verified
- Oct 2016
- First submitted
- 26 Aug 2008
- Last updated
- 9 Dec 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No: Decision will be made at the time of request
Publications
Jain MK, Skiest DJ, Cloud JW, Jain CL, Burns D, Berggren RE. Changes in mortality related to human immunodeficiency virus infection: comparative analysis of inpatient deaths in 1995 and in 1999-2000. Clin Infect Dis. 2003 Apr 15;36(8):1030-8. doi: 10.1086/368186. Epub 2003 Apr 2.
PubMed 12684916Sulkowski MS, Mast EE, Seeff LB, Thomas DL. Hepatitis C virus infection as an opportunistic disease in persons infected with human immunodeficiency virus. Clin Infect Dis. 2000 Apr;30 Suppl 1:S77-84. doi: 10.1086/313842.
PubMed 10770916Sulkowski MS, Mehta SH, Torbenson M, Afdhal NH, Mirel L, Moore RD, Thomas DL. Hepatic steatosis and antiretroviral drug use among adults coinfected with HIV and hepatitis C virus. AIDS. 2005 Mar 24;19(6):585-92. doi: 10.1097/01.aids.0000163935.99401.25.
PubMed 15802977Matthews L, Kleiner DE, Chairez C, McManus M, Nettles MJ, Zemanick K, Morse CG, Benator D, Kovacs JA, Hadigan C. Pioglitazone for Hepatic Steatosis in HIV/Hepatitis C Virus Coinfection. AIDS Res Hum Retroviruses. 2015 Oct;31(10):961-6. doi: 10.1089/AID.2015.0093. Epub 2015 Aug 24.
PubMed 26214341
Study at a glance
From the registry record, last updated by the sponsor on 9 Dec 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pioglitazone for Hepatic Steatosis in HIV/HCV Co-infection
- ClinicalTrials.gov ID
- NCT00742326
- Acronym / sponsor ID
- 080201
- Conditions
- HIV, Hepatitis C, Liver Disease, Fatty Liver, Steatosis
- Keywords
- HIV, Hepatitis C, Liver Disease, Fatty Liver, Steatosis
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Enrollment stopped prior to complete enrollment due to slow accrual
- Enrolment
- 13 participants (actual)
- Lead sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)US National Institutes of Health
- Study start
- Aug 2008
- Primary completion
- Jan 2013 (actual)
- Study completion
- Jan 2013 (actual)
- First posted
- 27 Aug 2008 (estimated)
- Results
- Posted 16 Jun 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study will evaluate the effectiveness of pioglitazone in reducing liver fat content in patients with HIV and hepatitis C virus (HCV) infections. Fatty liver and accompanying insulin resistance in patients with HIV and HCV co-infections is associated with inflammatory changes, liver fibrosis and a poorer response to HCV treatment. Pioglitazone is a drug that helps to reduce the body's resistance to insulin. It is approved by the Food and Drug Administration to treat diabetes.
Patients with HIV and HCV co-infections who have hepatic steatosis (fatty liver) may be eligible for this study. Candidates are screened with a medical history and physical examination, blood and urine tests, magnetic resonance imaging (MRI) of the liver to measure liver fat and, if needed, a liver biopsy to confirm the diagnosis of liver steatosis.
- Participants are randomly assigned to take either pioglitazone therapy or placebo for 48 weeks. This is followed by a second 48-week treatment period in which all participants take pioglitazone.
- There are approximately 12 visits during the 96 weeks of the study. Participants will receive a physical assessment, blood and urine tests at each visit. In addition, periodic assessments of dietary habits, body composition, oral glucose tolerance testing, and health related quality of life questionnaires will be completed.
- A repeat MRI of the liver is performed at 48 weeks and at the end of the study to evaluate any potential changes in liver fat and inflammation. In addition, there is a follow-up liver biopsy at 48 weeks and an optional liver biopsy at 96 weeks.
Detailed description
Following the introduction of effective antiretroviral therapy for HIV, the management of co-morbidities such as hepatitis C virus (HCV) has taken on increasing significance in the care and health maintenance of chronically infected patients. HCV co-infection is common in HIV, with an estimated prevalence of 30 percent among HIV-infected adults in the US. Further, the reported prevalence of hepatic steatosis in HIV/HCV co-infection is between 40-67 percent.
In recent years, the significance of hepatic steatosis and accompanying insulin resistance in HCV has gained increasing recognition. For example, steatosis is associated with increased rates of necro-inflammatory change and fibrosis in HIV/HCV co-infected patients. Furthermore, studies showed that, among non-HIV infected HCV patients, the presence of steatosis and/or insulin resistance was associated with poorer response to HCV therapy. These observations have led to research interest in treating hepatic steatosis in HCV, particularly in the context of pegylated interferon and ribavirin therapy.
Administration of the thiazolidinedione, pioglitazone, leads to significant reductions in hepatic steatosis, inflammation and in some cases fibrosis in patients with non-alcoholic steatohepatitis (NASH). Therefore, the potential benefits of pioglitazone therapy in the setting of HIV/HCV co-infection and hepatic steatosis will be determined. The proposed study is a 48-week, double-blind, randomized placebo-controlled trial of pioglitazone (45 mg/day) in 50 HIV/HCV-infected men and women. After the 48-week randomized portion of the trial, all participants will enter a 48-week open treatment extension arm irrespective of original randomization. It is anticipated that 100 subjects will be needed to be screened to identify a sufficient number of eligible participants to enroll in the study.
The primary outcome variable of interest in this trial will be the change in hepatic fat content measured by magnetic resonance (MR) spectroscopy. Important secondary outcomes will be histologic improvement on liver biopsy performed at baseline and 48 weeks, as well as improvements in transaminase levels and insulin resistance. The open treatment extension will allow all participants an opportunity to receive active study medication and it will allow the potential benefits of additional pioglitazone therapy to be assessed. In this way, important information about the efficacy of pioglitazone to treat hepatic steatosis and improve the metabolic profile in HIV/HCV co-infected patients will be obtained.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Pioglitazone | Experimental | Drug: Pioglitazonepioglitazone 45 mg daily for 48 weeks |
| Placebo | Placebo comparator | Drug: Placeboone capsule daily for 48 weeks |
Who may qualify
- Ages
- 18 to 99 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- Men and women, 18 years of age or greater
- Confirmed HIV infection by ELISA and Western blot
- No changes in antiretroviral regimen within the prior 3 months--Individuals not currently taking antiretroviral therapy will be eligible. Individuals requiring medically indicated adjustments of antiretroviral therapy during the course of the study will be eligible.
- Confirmed HCV infection, and no current or recent (within the past 3 months) HCV treatment and no plans to start HCV antiviral therapy in the foreseeable future.
- H-MRS liver fat content greater than 5 percent and confirmed steatosis on liver biopsy within 1 year
Key exclusion criteria (18 listed)
- Current thiazolidinedione use or use in the last 6 months, known allergy or sensitivity to a thiazolidinedione
- Use of insulin or other oral hypoglycemics, or known diabetes
- Current pregnancy, breast feeding, or pregnancy within the past 6 months or desire to become pregnant within the next 2 years.
- Child-Pugh-Turcotte (CPT) score greater than class A
- ALT greater than 4 times the upper limit of normal
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 |
|---|---|---|
| PioglitazoneAlso: Avandia45 mg/daily | Drug | Pioglitazone |
| Placeboone capsule daily | Drug | Placebo |
Primary outcome
Change in Hepatic Steatosis and Hepatic Inflammation/Fibrosis in HIV/HCV Co-infected Patients With Steatosis.
Time frame: 48 weeks
Change in hepatic steatosis and hepatic inflammation/fibrosis in HIV/HCV co-infected patients with steatosis. Change in Hepatic Fat Content measured by MR spectroscopy: 48 weeks compared to Baseline
1 secondary outcome
Change in Insulin Resistance in HIV- and HCV-infected Patients With Steatosis Compared to Placebo
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 9 Dec 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 12684916Jain MK, Skiest DJ, Cloud JW, Jain CL, Burns D, Berggren RE. Changes in mortality related to human immunodeficiency virus infection: comparative analysis of inpatient deaths in 1995 and in 1999-2000. Clin Infect Dis. 2003 Apr 15;36(8):1030-8. doi: 10.1086/368186. Epub 2003 Apr 2.
- Background: PubMed 10770916Sulkowski MS, Mast EE, Seeff LB, Thomas DL. Hepatitis C virus infection as an opportunistic disease in persons infected with human immunodeficiency virus. Clin Infect Dis. 2000 Apr;30 Suppl 1:S77-84. doi: 10.1086/313842.
- Background: PubMed 15802977Sulkowski MS, Mehta SH, Torbenson M, Afdhal NH, Mirel L, Moore RD, Thomas DL. Hepatic steatosis and antiretroviral drug use among adults coinfected with HIV and hepatitis C virus. AIDS. 2005 Mar 24;19(6):585-92. doi: 10.1097/01.aids.0000163935.99401.25.
- Background: PubMed 26214341Matthews L, Kleiner DE, Chairez C, McManus M, Nettles MJ, Zemanick K, Morse CG, Benator D, Kovacs JA, Hadigan C. Pioglitazone for Hepatic Steatosis in HIV/Hepatitis C Virus Coinfection. AIDS Res Hum Retroviruses. 2015 Oct;31(10):961-6. doi: 10.1089/AID.2015.0093. Epub 2015 Aug 24.
- Individual participant dataSharing planned: No. Decision will be made at the time of request
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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.
Colleen M Hadigan, M.D. principal investigator
National Institute of Allergy and Infectious Diseases (NIAID)
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Pioglitazone in people with HIV and Hepatitis C, run by National Institute of Allergy and Infectious Diseases (NIAID) at 2 sites 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 12 inclusion and 18 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: stopped early, as of the sponsor's last update on 9 Dec 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites 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 16 Jun 2014). 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?
Change in Hepatic Steatosis and Hepatic Inflammation/Fibrosis in HIV/HCV Co-infected Patients With Steatosis. (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 NCT00742326, which also lists 4 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 9 Dec 2016.