SOFIA-LTT Study: A Study of Intermittent Long Term Treatment With PEGASYS (Peginterferon Alfa-2a (40KD)) in Patients With HBeAg Negative Chronic Hepatitis B (CHB).

Study Overview
=================
Brief Summary
-----------------
This 2 arm study will evaluate the efficacy and safety of intermittent treatment with PEGASYS in HBeAg negative patients with chronic hepatitis B who have demonstrated virological and biochemical response after treatment with interferon alfa. After 48 weeks therapy with interferon alfa, and 24 weeks treatment-free follow-up, eligible patients will be randomized into the PEGASYS or the observational group. Those in the PEGASYS group will receive 4 therapeutic cycles of long term intermittent treatment with PEGASYS (135 micrograms sc weekly for 12 weeks, followed by a treatment-free period of 12 weeks) and those in the observational arm will receive no specific antiviral treatment. The anticipated time on study treatment is 1-2 years, and the target sample size is 100 individuals.

Official Title
-----------------
Stop Progression of Fibrosis by Administration of Intermittent Continuous Treatment With Peginterferon Alfa-2a. Open-label, Randomized Efficacy and Safety Clinical Trial of Intermittent Continuous Treatment With Peginterferon Alfa-2a (PEGASYS) in Patients With HBeAg Negative Hepatitis B Responding to Prior Treatment With Interferon Alfa (SOFIA -LTT)

Conditions
-----------------
Hepatitis B, Chronic

Intervention / Treatment
-----------------
* Drug: PEGASYS [peginterferon alfa-2a]


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: adult patients, >=18 years of age; liver disease consistent with CHB; evidence of chronic HBeAg-negative CHB prior to initial course of interferon alfa; patients who have responded to previous 48 weeks treatment with interferon alfa. Exclusion Criteria: coinfection with HCV, HDV or HIV; decompensated liver disease, hepatocellular cancer, or evidence of a medical condition associated with chronic liver disease other than viral hepatitis; any other systemic antiviral, antineoplastic or immunomodulatory treatment <=6 months prior to first dose of randomized treatment.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PEGASYS<br>Participants received 4 treatment cycles of continuous intermittent treatment with PEGASYS® (Peginterferon alfa-2a) . Each cycle consisted of 12 weeks injection treatment with Peginterferon alfa-2a 135 micrograms in 0.5 ml solution in prefilled syringes, applied once weekly subcutaneously and followed by 12 weeks period without treatment. | Drug: PEGASYS [peginterferon alfa-2a]<br>* There were 4 treatment cycles of continuous intermittent treatment with Peginterferon alfa-2a. Each cycle consisted of 12 weeks injection treatment with Peginterferon alfa-2a 135 micrograms in 0.5 ml solution in prefilled syringes, applied once weekly subcutaneously and followed by 12 weeks period without treatment.<br>|
| No Intervention: No Intervention<br>Participants were on non- specific anti-viral treatment. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Stable Virological Response | Stable virological response is serum Hepatitis B virus deoxyribonucleic acid (HBV DNA) <20 000 copies/ml during the treatment (after each 12 weeks) and after the follow-up period (24 weeks after the last treatment period). | Up to Week 108 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Stable Virological and Biochemical Response | All participants who achieved virological response (serum HBV DNA < 20 000 copies/ml) and biochemical response (stable normalization of their alanine transaminase [ALT]) during the treatment cycle (after each 12 weeks) and after the follow-up period (24 weeks after the last treatment period). | Up to Week 108 | 
| Percentage of Participants With Loss of Hepatitis B Surface Antigen | Loss of Hepatitis B Surface Antigen (HBsAg) was defined as change of detectable HBsAg from positive to negative. | Up to Week 108 | 
| Percentage of Participants With HBsAg Seroconversion | The development of antibodies against HBsAg is known as HBsAg seroconversion. It signifies clearance of HBsAg and resolution of the chronic infection. НBsAg seroconversion is the final goal of anti-hepatitis B virus treatment and it is closest to the definition of cure but in practice it is very rare in HBeAg-negative chronic hepatitis B (CHB). | Up to Week 108 | 
| Percentage of Participants With HBV DNA Levels Under the Lower Limit (Serum HBV DNA Level < 300 Copies/ml) For a Significant Quantity | HBV DNA level, or viral load, is an indicator of viral replication. Higher HBV DNA levels are usually associated with an increased risk of liver disease and hepatocellular carcinoma. HBV DNA level typically falls in response to effective antiviral treatment. | Up to Week 108 | 
| Fibrosis-4 and Aspartate Aminotransferase to Platelet Ratio Index Scores For Change in Liver Fibrosis | Fibrosis-4 (FIB-4) and Aspartate Aminotransferase to Platelet Ratio Index (APRI) are non-invasive scoring systems, which are calculated on the basis of laboratory tests that indicates the level of liver fibrosis. The APRI scores are calculated based on Aspartate Aminotransferase (AST) levels and platelet counts whereas FIB-4 scores are calculated based on platelets, ALT, AST and age. For APRI, the scores are interpreted as ≤ 0.5 is 81% sensitive and 50% specific for a diagnosis of significant fibrosis in chronic hepatitis C (CHC), where as a cut-off > 1.5 is 35% sensitive and 91% specific for the diagnosis of significant fibrosis. The majority of biomarker panels will produce inconclusive results for a proportion of participants falling within the indeterminate range (between 0.5 and 1.5) for a specific fibrosis end-point. For FIB-4, the scores are interpreted as FIB-4 score of < 1.45: absence of cirrhosis, FIB-4 score of 1.45 to 3.25: inconclusive, FIB-4 score > 3.25: cirrhosis. | Up to Week 108 | 
| Mean Change From Baseline in HBsAg Levels | An early decrease in HBsAg from baseline to Weeks 12 or 24 has been identified as further on-treatment predictor for sustained HBsAg clearance and virological response in HBeAg negative participants. | Up to Week 108 | 
| Mean Change From Baseline in Hemoglobin | The hemoglobin values were planned to be calculated as arithmetic mean by treatment groups (PEGASYS and No Intervention). | Up to Week 108 | 
| Mean Change From Baseline in Hematology | The hematology parameters included erythrocytes, leucocytes, basophils, eosinophils, lymphocytes, monocytes, thrombocytes. All laboratory parameters were planned to be calculated as arithmetic mean by treatment groups (PEGASYS and No Intervention). | Up to Week 108 | 
| Mean Change From Baseline in Clinical Chemistry | The clinical chemistry parameters included alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP). All laboratory parameters were planned to be calculated as arithmetic mean by treatment groups (PEGASYS and No Intervention). | Up to Week 108 | 
| Mean Change From Baseline in Protein and Indirect Albumin | The clinical chemistry parameters included indirect protein and albumin. All laboratory parameters were planned to be calculated as arithmetic mean by treatment groups (PEGASYS and no intervention). | Up to Week 108 | 
| Mean Change From Baseline in Bilirubin Indirect and Bilirubin Direct | The laboratory parameters included bilirubin indirect and bilirubin direct. All laboratory parameters were planned to be calculated as arithmetic mean by treatment groups (PEGASYS and No Intervention). | Up to Week 108 | 
| Mean Change From Baseline in Blood Urea | The blood urea was planned to be calculated as arithmetic mean by treatment groups (PEGASYS and No Intervention). | Up to Week 108 | 
| Mean Change From Baseline in Creatinine and Uric Acid | The creatinine and uric acid values were planned to be calculated as arithmetic mean by treatment groups (PEGASYS and No Intervention). | Up to Week 108 | 
| Mean Change From Baseline in Blood Glucose | The blood glucose was measured for change from baseline. All blood glucose values were planned to be calculated as arithmetic mean by treatment groups (PEGASYS and No Intervention). | Up to Week 108 | 
| Mean Change From Baseline in Thyroid Stimulating Hormone (TSH) | The TSH was planned to be calculated as arithmetic mean by treatment groups (PEGASYS and No Intervention). | Up to Week 108 | 
| Mean Change From Baseline in Triiodothyronine and Thyroxine | The Triiodothyronine (T3) and thyroxine (T4) values were planned to be calculated as arithmetic mean by treatment groups (PEGASYS and No Intervention). | Up to Week 108 |