To Study the Effect of Adding on Pegylated Interferon (PEG-INF) Therapy for Patients Diagnosed With Chronic Hepatitis B

Study Overview
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Brief Summary
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To assess whether PEG-INF (Peglyated - interferon) Add-on therapy in patients of CHB who have achieved a maintained viral suppression (HBV DNA PCR( polymerase chain reaction) <200 for last 3-6 month) with NA's can result in increased rate of HBV infection eradication (HbsAg is undetectable by serological blood testing with or without seroconversion to HBs antibody).

Detailed Description
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Hepatitis B virus (HBV) infection remains a global health care problem with more than one third of world's population having serological evidence of been exposed to the virus and about 5% of global population ( 350-400 million) being chronically infected. About 15-40% of Patients with chronic hepatitis B (CHB) infection develop complications of liver cirrhosis, liver failure and hepatocellular carcinoma(HCC) in their life time , resulting in an estimated of 500,000 to 1.2 million deaths each year. In Saudi Arabia, chronic hepatitis B remains a serious medical problem, despite the implementation of mandatory HBV vaccination of children since 1989. According to a recent study conducted in Saudi hospital, HBV accounts for 49% of the hepatitis cases . Persistent viral replication is associated with disease progression to liver fibrosis, cirrhosis and development of HCC. Currently two classes of drugs are available for treatment of CHB namely immunomodulatory therapy (conventional & pegylated interferon (Pegasys) PEG-IFN) and nucleoside/nucleotide analogues(NA). Interferon(IFN)-α with its dual immunomodulatory and antiviral effects was the first drug (recombinant standard IFN- α) licensed for Chronic hepatitis B treatment in the 1990's followed by introduction of nucleos(t)ide analogues(NA) in 1998 that directly inhibit HBV polymerase and provide an effective on treatment maintained viral suppression . With the introduction of pegylated interferon- α (PEG-IFN) in 2005 that allows a convenient once a week dosing interval and of equal or superior treatment efficacy than conventional (IFN), the interferon based therapy has markedly improved its utility. Due to its predominant immunomodulatory effect peginterferon (PEG-IFN) offers the advantage of higher sustained off treatment response rate compared to NA thus allowing a finite duration of treatment. The NA act by directly inhibiting HBV polymerase resulting in effective on treatment maintained viral suppression (HBV DNA PCR <200 for last 3-6 month)). However, long term NA therapy has the problems of emergence of viral resistance, long -term safety, cost and patient compliance.

Official Title
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Randomized, Multicenter, Open -Label Clinical Trial to Study the Effect of Adding on Pegylated Interferon Therapy for Patients Diagnosed With Chronic Hepatitis B Showing Maintained Response While Receiving Ongoing Nucleotide Analogues

Conditions
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Hepatitis B

Intervention / Treatment
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* Drug: PEG-IFN & Nucleos(t)tide analogues
* Drug: Nucleos(t)tide analogues


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults ≥18 & < 70 years of both genders. CHB on NA's in maintained viral suppression (HBV DNA PCR <200 for last 3-6 month) Patients with measurable HBsAg quantitative levels Patients with any HBV genotypes. Patients with either CHB e Ag positive or eAg negative Patients who sign an informed consent for inclusion into the study. Patients with hepatitis Delta co-infection. only patients with a negative pregnancy test who are of child bearing potential and agree to utilize a strict birth control method will be enrolled Exclusion Criteria: Patients with following characteristics will not be considered for the trial: Decompensated liver Cirrhosis HCV (hepatitis C virus) or HIV co infection. Autoimmune disorders like SLE (Systemic lupus erythematosus), RA (Rheumatoid Arthritis ), AIH (Autoimmune Hemolytic Anemia), ITP (Immune thrombocytopenic purpura), psoriasis etc. Untreated psychiatric conditions like depression and alcohol or drug abuse. Comorbid conditions like chronic renal failure or post renal/liver transplantation on immunosuppressive therapy. Complicated diabetes mellitus and advanced heart failure. Pregnancy or not willing to practice contraception. Known allergy to Interferons. Concomitant treatment with Telbivudine Evidence of portal hypertension by Biochemical (Low Platelets less than 100), imaging or UGI (upper gastrointestinal)endoscopy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: PEG-IFN & NUCLEOTIDE ANALOGUES<br>Peginterferon alfa-2a 180 Mcg infusion per week with ongoing NUCLEOTIDE ANALOGUES for 48 weeks. | Drug: PEG-IFN & Nucleos(t)tide analogues<br>* Subjects who will be randomized to receive 180 Mcg/ week as an add-on Pegylated Interferon therapy α-2 A with their ongoing NUCLEOTIDE analogues for 48 weeks.<br>* Other names: Immunomodulatory therapy;Drug: Nucleos(t)tide analogues<br>* Subjects will continue on the same dose of Nucleoside/nucleotide analogues as they started the study.<br>* Other names: Nucleoside/nucleotide analogues;|
| Active Comparator: NUCLEOTIDE ANALOGUES<br>Nucleoside same dose as they started the study. | Drug: Nucleos(t)tide analogues<br>* Subjects will continue on the same dose of Nucleoside/nucleotide analogues as they started the study.<br>* Other names: Nucleoside/nucleotide analogues;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The loss of HbsAg between groups (NA) group and NA +Peg_INF group assessed by HbsAg test | The loss of HbsAg between groups (NA) group and NA +Peg_INF group assessed by HbsAg test | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The seroconversion to HBs antibody between groups (NA) group and NA +Peg_INF group assessed by Hbe Ab test | The seroconversion to HBs antibody between groups (NA) group and NA +Peg_INF group assessed by Hbe Ab test | 6 ,12 months & 48 weeks | 
| The HBeAg (Hepatitis B e-Antigen) loss in CHRONIC HBV eAg positive patient between groups (NA) group and NA +Peg_INF group assessed by HbeAg test | HBeAg loss in CHRONIC HBV eAg positive patient between groups (NA) group and NA +Peg_INF group assessed by HbeAg test | 6,12 months & 48 weeks | 
| The conversion of HBeAg to HBe-antibody in CHRONIC HBV eAg (eAntigen) positive patient between groups (NA) group and NA +Peg_INF group assessed by HBe-antibody test | The conversion of HBeAg to HBe-antibody in CHRONIC HBV eAg positive patient between groups (NA) group and NA +Peg_INF group assessed by HBe-antibody test | 6,12 months & 48 weeks | 
| The correlation between HBsAg ( Hepatitis B Surface Antigen) levels while on therapy at the a defined interval ie 8,12.24,36,48 weeks and rate of HBsAg loss at end of therapy assessed by measuring HBV s Ag during the period 8,12.24,36 and 48 weeks | The correlation between HBsAg levels while on therapy at the a defined interval ie 8,12.24,36,48 weeks and rate of HBsAg loss at end of therapy assessed by measuring HBV s Ag during that period 8,12.24,36 and 48 weeks | 8,12,24 and 48 weeks | 
| The relationship between HBV genotype and HBsAg loss at the end of the study assessed by measuring HBV genotype only at base line and see if any particular genotype have more HBV sAg loss at the end of the study | The relationship between HBV genotype and HBsAg loss at the end of the study assessed by measuring HBV genotype only at base line and see if any particular genotype have more HBV sAg loss at the end of the study | At base line & 48 weeks | 
| The relationship between IL28B (Interleukin 28B) genotypes ( polymorphism) and HBsAg loss with or without seroconversion to HBs antibody | The relationship between IL28B genotypes ( polymorphism) and HBsAg loss with or without seroconversion to HBs antibody assess by doing IL28B genotypes ( polymorphism) once during the study and see if any specific IL28B genotypes ( polymorphism) associated more with HBV sAg loss at the end of the study with or without seroconversion to HBs antibody). | At base line & 48 weeks | 
| The relationship between vitamin D deficiency and (HbsAg loss with or without seroconversion to HBs antibody) assess by measuring Vitamin D level at base line And correlate the baseline level of Vitamin with HBV sAg loss at the end of the study | The relationship between vitamin D deficiency and (HbsAg loss with or without seroconversion to HBs antibody) assess by measuring vitamin D level at base line And correlate the base line level of vitamin D with HBV sAg loss at the end of the study | At base line & 48 weeks |