Study to Evaluate the Possible Antifibrotic Effect of Zinc Sulphate in Chronic HCV Patient Receiving Direct Acting Anti-viral Therapy.

Study Overview
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Brief Summary
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This study aims to evaluate the possible antifibrotic effect of zinc sulphate in chronic HCV patient receiving direct acting anti-viral therapy

Detailed Description
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Chronic infection with hepatitis C virus (HCV) is a leading cause of liver-related morbidity and mortality worldwide and predisposes to liver fibrosis and end-stage liver complications. Liver fibrosis is the excessive accumulation of extracellular matrix proteins, including collagen, and is considered as a wound healing response to chronic liver injury. Removal or elimination of the causative agent such as control or cure of viral infection has shown that liver fibrosis is reversible. Thus, there is a huge unmet medical need for anti-fibrotic therapies to prevent liver disease progression and Hepatocellular Carcinoma (HCC) development. However, while many anti-fibrotic candidate agents have shown robust effects in experimental animal models, but uptill now, no approved therapy exists for liver fibrosis. The once-daily oral combination of Daclatasvir 60 mg and Sofosbuvir 400 mg once daily, for the treatment of non-cirrhotic naïve patients with chronic hepatitis C virus genotype 4 infection for 12 weeks, is effective and well tolerated in these patients. Zinc, an essential trace element, is involved in the enzymatic activities and structural maintenance of numerous enzymes and proteins, and it has various physiological roles in the body. Specifically, zinc works as a growth factor and exerts immunomodulatory , antioxidant, anti-apoptotic and anti-inflammatory effects. Zinc deficiency is prevalent in cirrhosis patients, whereas nitrogen metabolic disorders, particularly hypoalbuminemia, can be an indicator of zinc deficiency. Zinc supplementation therapy has a great benefit in the management of chronic liver disease and seems to improve liver pathology and reduce the incidence of liver fibrosis and HCC. It has been found that zinc supplementation inhibited liver inflammation and fibrosis in bile duct ligation (BDL) mice through selective suppression of M1 macrophages. Therefore, oral zinc supplementation is recommended as a means of suppressing HCC development in patients who have achieved sustained virological response (SVR) after direct acting antiviral therapies (DAAs) treatment . Zinc is a powerful supplement not only to increase SVR in non-responders but also to improve hepatic functions and fibrosis. Fibronectin (FN), which is produced by hepatic stellate cells (HSCs), is a multifunctional glycoprotein and extracellular matrix (ECM) component that is present in the cell membrane and cytoplasm and associated with cell cycle progression, participates in cell adhesion and proliferation, and has an important role in fibrotic progression, excessive FN deposition occurs prior to collagen deposition. Fibronectin expression was gradually increased in response to TGFβstimulation of HSCs, It is a good noninvasive marker for the assessment of liver fibrosis in patients with chronic HCV. Transforming growth factor (TGF)-β is a master profibrogenic cytokine and a promising target to treat fibrosis. Hyaluronic acid is a chief component of the extracellular matrix (ECM) of connective tissues and plays the main structural role in the formation of ECM. The most important organ involved in the synthesis of hyaluronic acid is the liver and the results of clinical studies have shown its high diagnostic sensitivity in the pathological processes of the liver.

Official Title
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Study to Evaluate the Possible Antifibrotic Effect of Zinc Sulphate in Chronic HCV Patient Receiving Direct Acting Anti-viral Therapy

Conditions
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Hepatitis C

Intervention / Treatment
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* Drug: Zinc Supplement


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • Patients with fibrosis stage (F1&F2) post chronic HCV infection. Age > 18 and < 65 years. Exclusion Criteria: Patients with prior history of liver transplantation. Patients with prior history of hepatocellular carcinoma. Patients coinfected with HIV or HBV. Patients with any malignancies. Pregnant and lactating women.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 65 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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 2<br>25 patients will receive 50mg Zinc Sulphate plus the standard direct acting anti-viral therapy for 3 months. | Drug: Zinc Supplement<br>* Zinc sulphate 50 mg<br>|
| No Intervention: Group 1<br>25 patients will receive their standard direct acting anti-viral therapy for 3 months | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Abdominal Ultrasonography | Assessment the change in the degree of liver fibrosis post treatment and compare their results before and post treatment | 3 months | 
| Serum fibronectin level | Fibronectin (FN), which is produced by hepatic stellate cells (HSCs), participates in cell adhesion and proliferation, and has an important role in fibrotic progression, excessive FN deposition occurs prior to collagen deposition | 3 months | 
| Serum transforming growth factor - beta 1 (TGF- β1) level | Transforming growth factor (TGF)-β is a good noninvasive marker for the assessment of liver fibrosis in patients with chronic HCV and also considered as a master profibrogenic cytokine and a promising target to treat fibrosis (15) | 3 months | 
| Fibrosis-4 (FIB-4) Score | The Fibrosis 4 score is a non-invasive scoring system based on several laboratory tests (AST/ALT/Platelets) that help to non-invasively estimate the amount of scarring in the liver. This score has been studied in liver disease due to Hepatitis C and Non-alcoholic steatohepatitis (NASH) FIB-4 = (Age (years)XAST Level (U/L))/(Platelet Count (〖10〗^9/L) X √(ALT (U/L))) FIB-4>3.25 confirms the presence of advanced fibrosis (F4) FIB-4<1.45 exclude the presence of advanced fibrosis (F3-F4) Values between 1.45 and 3.25 did not fully discriminate fibrosis and would need an additional method to predict liver fibrosis | 3 months | 
| AST to Platelet Ratio Index (APRI) score | The APRI model was developed as a simple, easily calculated method to predict significant, severe fibrosis (or cirrhosis) and has been tested in persons with HCV mono-infection and those with HCV and HIV Co-infection APRI = (AST Level /AST (Upper Limit of Normal))/(Platelet Count (〖10〗^9/L) )X100 If the score is less than or equal to 0.5, the liver is either completely free of fibrosis (F0), or has a tiny bit of scarring (F1 or F2 by METAVIR Score). If the score is 1.5 or greater, the liver has scarring and likely some cirrhosis (F3 or F4 by METAVIR Score) | 3 months | 
| Serum hyaluronic acid level | Hyaluronic acid is a chief component of the extracellular matrix (ECM) of connective tissues and The most important organ involved in the synthesis of hyaluronic acid is the liver | 3 months |