Improving Fibrosis Outcomes With Metformin

Study Overview
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Brief Summary
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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
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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.

Official Title
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Improving Treatment and Liver Fibrosis Outcomes With Metformin in HCV-HIV Co-infected and HCV Mono-infected Patients With Insulin Resistance.

Conditions
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Hepatitis C, HIV Infection

Intervention / Treatment
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* Drug: Metformin
* Drug: No metformin treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, 18 to 79 years old inclusive Provision of informed consent Documented history of chronic HCV RNA infection Intending to start on any 8-12 week IFN-free HCV antiviral therapy If HIV-infected and not on HIV antiretroviral therapy, a CD4 count at least > 200 Insulin resistance as determined by a HOMA-IR of > 2.0 at screening Evidence of fibrosis on FibroScan® > 8.0 kPa, OR liver biopsy score > 2 (Batts-Ludwig System) [55] (within 2 years) Exclusion Criteria: Pregnant, suspected to be pregnant, planning to become pregnant or breastfeeding Chronic HBV infection HbA1c > 8.0 Use of immune suppressing medications Active malignancy Current or any previous treatment with Metformin, other oral diabetes medications,insulin Pre-existing diabetes (type 1, type 2 or gestational diabetes) Clinical evidence of decompensated cirrhosis (ascites, esophageal varices, hepatic encephalopathy, hepatocellular carcinoma) 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)) History of congestive heart failure requiring pharmacologic therapy Wilson's disease Alpha-1 antitrypsin Hemochromatosis Biliary Cirrhosis Alcohol consumption > 50 g / day on average (see Appendix B for conversion to volume) Participation in other clinical investigations during the study 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin + lifestyle modification<br>Metformin + lifestyle modification pre, during and post HCV antiviral therapy | Drug: Metformin<br>* metformin treatment + standard of care dietary and exercise advice<br>* Other names: lifestyle modification;|
| Placebo Comparator: No Metformin + Lifestyle modification<br>No metformin + lifestyle modification pre, during and post HCV antiviral therapy. | Drug: No metformin treatment<br>* no metformin treatment + standard of care dietary and exercise advice<br>* Other names: lifestyle modification;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in FibroScan® score (kPa) from baseline to week 12 (start of HCV treatment), compared between treatment groups. | liver elastography score (kPa) | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Virological response rates (SVR 12 weeks post HCV antiviral therapy) between treatment groups. | HCV RNA level (IU/mL) | 12 weeks | 
| Change in APRI measurements from baseline compared between treatment groups. | calculated APRI | 12, 24, 48weeks | 
| Change from baseline in glucose metabolism (HOMA-IR, fasting insulin, glucose levels) | fasting glucose and insulin | 4, 8, 12, 24, 36, 48 weeks | 
| Changes from baseline in lipid levels | fasting total cholesterol, LDL-c, HDL-c, triglycerides | 12, 36, 48 weeks | 
| Changes from baseline in anthropometric measures | waist circumference, body weight and BMI | 4, 8, 12, 24, 36, 48 weeks | 
| Changes from baseline in liver-related inflammatory markers | IL-6, IL-8, TNF-alpha, TGF-beta, C-reactive protein | 4, 8, 12, 24, 36 weeks | 
| Changes in AFP levels from baseline | AFP | 12, 24, 36, 48 weeks | 
| Participant acceptability to study medication dosing (in Arm 1 only) | Participant acceptability will be evaluated in Arm 1 only using the Treatment Satisfaction Questionnaire for Medication (TSQM), Version 1.4 | 8, 24, 48 weeks | 
| Changes from baseline in diet | Changes in diet from baseline will be captured using the International Physical Activity Questionnaire short-form (IPAQ-sf) | 24, 48 weeks | 
| Changes from baseline in physical exercise parameters | Changes in physical activity from baseline will be captured using the International Physical Activity Questionnaire short-form (IPAQ-sf) | 24, 48 weeks |