Clinical trial NCT02306070: Improving Fibrosis Outcomes With Metformin
Official title: Improving Treatment and Liver Fibrosis Outcomes With Metformin in HCV-HIV Co-infected and HCV Mono-infected Patients With Insulin Resistance.
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: HIV Infection
Hepatitis C
Lead sponsor: Ottawa Hospital Research Institute
Sponsor class: OTHER
Collaborators: name: CIHR Canadian HIV Trials Network
First posted: 2014-12-03
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will evaluate the role of Metformin on liver fibrosis in HCV-HIV co-infected and HCV mono-infected patients with insulin resistance receiving DAA HCV treatment.

Detailed description: HCV antiviral therapy has evolved rapidly in recent years and access to these medications has improved. While SVR is associated with improved liver outcomes, the rate of liver fibrosis regression with SVR is variable and predictors of regression are not well established. In addition, achieving SVR in patients with cirrhosis does not necessarily prevent decompensation or eliminate the risk of HCC. A better understanding of the role insulin resistance and impaired glucose metabolism have on these outcomes in HCV patients who achieve SVR are needed.

Identifying and targeting potentially modifiable risk factors such as IR may be of significant importance in preventing progression of and promoting regression of liver fibrosis, reducing mortality and improving outcomes for HCV-HIV co-infected and HCV-mono-infected patients.

This proposed pilot study will be the first to evaluate the role of Metformin on liver fibrosis in HCV-HIV co-infected and HCV mono-infected patients with IR receiving DAA HCV treatment.

If Metformin is effective in reducing liver fibrosis in this patient population, this will represent a well-tolerated, easy to administer, inexpensive therapy that will protect against negative HCV outcomes. This study will also be an opportunity to evaluate the impact of insulin resistance and hyperglycemia have on viral clearance HCV-infected patients treated with interferon-free regimens. In addition, the study will further explore the relationship between HCV, insulin resistance and AFP levels.

Eligibility criteria: Inclusion Criteria:

1. Male or female, 18 to 79 years old inclusive
2. Provision of informed consent
3. Documented history of chronic HCV RNA infection
4. Intending to start on any 8-12 week IFN-free HCV antiviral therapy
5. If HIV-infected and not on HIV antiretroviral therapy, a CD4 count at least \> 200
6. Insulin resistance as determined by a HOMA-IR of \> 2.0 at screening
7. Evidence of fibrosis on FibroScan® \> 8.0 kPa, OR liver biopsy score \> 2 (Batts-Ludwig System) \[55\] (within 2 years)

Exclusion Criteria:

1. Pregnant, suspected to be pregnant, planning to become pregnant or breastfeeding
2. Chronic HBV infection
3. HbA1c \> 8.0
4. Use of immune suppressing medications
5. Active malignancy
6. Current or any previous treatment with Metformin, other oral diabetes medications,insulin
7. Pre-existing diabetes (type 1, type 2 or gestational diabetes)
8. Clinical evidence of decompensated cirrhosis (ascites, esophageal varices, hepatic encephalopathy, hepatocellular carcinoma)
9. Presence of renal impairment or when renal function is not known, and also in patients with serum creatinine levels above upper limit of normal range. Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels \>= 136 umol/L (males), \>= 124 umol/L (females) or abnormal creatinine clearance (60 mL/min))
10. History of congestive heart failure requiring pharmacologic therapy
11. Wilson's disease
12. Alpha-1 antitrypsin
13. Hemochromatosis
14. Biliary Cirrhosis
15. Alcohol consumption \> 50 g / day on average (see Appendix B for conversion to volume)
16. Participation in other clinical investigations during the study
17. History of lactic acidosis, irrespective of precipitating factors

Active illicit drug use and stable health illness will not be exclusionary assuming it is unlikely to compromise study adherence to protocol and study drug. In HIV-infected participants, HIV antiretroviral use and suppressed HIV viral load will not be required for participation.

HCV antiviral therapy will not be withheld for any participant that is eligible and desires to start treatment. If HCV treatment is anticipated to be started during the 48-week period of assessment, then participants will not be enrolled.

Primary outcomes:
measure: Change in FibroScan® score (kPa) from baseline to week 12 (start of HCV treatment), compared between treatment groups.
timeFrame: 12 weeks
Secondary outcomes:
measure: Virological response rates (SVR 12 weeks post HCV antiviral therapy) between treatment groups.
timeFrame: 12 weeks
measure: Change in APRI measurements from baseline compared between treatment groups.
timeFrame: 12, 24, 48weeks
measure: Change from baseline in glucose metabolism (HOMA-IR, fasting insulin, glucose levels)
timeFrame: 4, 8, 12, 24, 36, 48 weeks
measure: Changes from baseline in lipid levels
timeFrame: 12, 36, 48 weeks
measure: Changes from baseline in anthropometric measures
timeFrame: 4, 8, 12, 24, 36, 48 weeks
measure: Changes from baseline in liver-related inflammatory markers
timeFrame: 4, 8, 12, 24, 36 weeks
measure: Changes in AFP levels from baseline
timeFrame: 12, 24, 36, 48 weeks
measure: Participant acceptability to study medication dosing (in Arm 1 only)
timeFrame: 8, 24, 48 weeks
measure: Changes from baseline in diet
timeFrame: 24, 48 weeks
measure: Changes from baseline in physical exercise parameters
timeFrame: 24, 48 weeks
Other outcomes:
Locations:
city: Ottawa
country: Canada
facility: The Ottawa Hospital, General Campus
state: Ontario
Study officials:
affiliation: The Ottawa Hospital Division of Infectious Diseases
name: Curtis Cooper, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Doyle MA, Singer J, Lee T, Muir M, Cooper C. Improving treatment and liver fibrosis outcomes with metformin in HCV-HIV co-infected and HCV mono-infected patients with insulin resistance: study protocol for a randomized controlled trial. Trials. 2016 Jul 20;17(1):331. doi: 10.1186/s13063-016-1454-6.