Improving Fibrosis Outcomes With Metformin

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

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.

Study Overview

• Status: Withdrawn
• Conditions: HIV Infection; Hepatitis C
• Intervention / Treatment: Drug: Metformin; Drug: No metformin 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.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada
      • The Ottawa Hospital, General Campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Ottawa Hospital Research Institute
• Collaborators: CIHR Canadian HIV Trials Network
• Investigators: Principal Investigator: Curtis Cooper, MD, The Ottawa Hospital Division of Infectious Diseases

Publications and helpful links

General Publications

• 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.

Helpful Links

• CIHR Canadian HIV Trials Network

Study record dates

Study Major Dates

• Study Start: January 1, 2016
• Primary Completion (Actual): September 30, 2017
• Study Completion (Anticipated): April 3, 2018

Study Registration Dates

• First Submitted: November 2, 2014
• First Submitted That Met QC Criteria: November 28, 2014
• First Posted (Estimate): December 3, 2014

Study Record Updates

• Last Update Posted (Actual): April 17, 2018
• Last Update Submitted That Met QC Criteria: April 13, 2018
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Hepatitis; Hepatitis C; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: CTNPT 019