Combined Therapy With Peginterferon Alfa-2a With NA in NA-treated HBeAg Positive Patients

Study Overview
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Brief Summary
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This is a prospective, randomized, multicenter, open-label study. After more than 24 weeks NA treatment, HBeAg positive CHB patients who achieved HBV DNA<1000copies/ml but HBeAb negative, will be randomized (1:1) into 2 study arms as follows: Arm A: Peginterferon alfa-2a 180μg /wk plus NA 1 piece qd for 48 weeks Arm B: Entecavir 0.5mg qd for 48 weeks

Detailed Description
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This is a prospective, randomized, multicenter, open-label study. After more than 24 weeks NA treatment, HBeAg positive CHB patients who achieved HBV DNA<1000copies/ml but HBeAb negative, will be randomized (1:1) into 2 study arms as follows: Arm A: Peginterferon alfa-2a 180μg /wk plus NA 1piece qd for 48 weeks Arm B:NA 1 piece qd for 48 weeks The primary endpoint: HBeAg seroconversion at week 48

Official Title
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A Prospective, Randomized, Multicenter, Open-label Study Evaluating HBeAg Seroconversion in HBeAg Positive CHB Patients on Treatment With NA Switched to Combined Therapy With Peginterferon Alfa-2a and NA for 48 Weeks

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: Peginterferon alfa-2a
* Drug: nucleos(t)ide analgoue


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male and female patients with age ≥18 and ≤65 years; There should be evidences that HBsAg and HBeAg have been positive for more than 6 months with HBsAb and HBeAb negative before treated with Entecavir; Treated with NA for more than 24 weeks and achieve HBV DNA<1000copies/ml with HBeAb negative; Women without ongoing pregnancy or breast feeding and willing to take an effective contraceptive measure during the treatment Agree to participate in the study and sign the patient informed consent. Exclusion Criteria: Co-infection with active hepatitisA, hepatitisC, hepatitisD and/or human immunodeficiency virus (HIV) AFP>50ng/ml and/or evidence of hepatocellular carcinoma Evidence of decompensated liver disease (Child-Pugh scores >5). Child-Pugh >5 means that, if one of the following 6 conditions is met, the patient has to be excluded: Serum albumin <35 g/L; Prothrombine time prolonged≥ 4 seconds or PTA < 60%; Serum bilirubin > 34 µmol/L; History of encephalopathy; Ascites History or other evidence of a medical condition associated with chronic liver disease other than viral hepatitis (e.g., hemochromatosis, autoimmune hepatitis, metabolic liver disease, alcoholic liver disease, toxin exposures, thalassemia) Pregnant or breast-feeding Women ANC<1.5x 10^9/L or PLT<90x 10^9/L Consuming alcohol in excess of 20g/day for women and 30g/day for men within 6 months prior to enrollment History of severe psychiatric disease, especially depression. Severe psychiatric disease is defined as major depression or psychosis that treated with antidepressant medication or a major tranquilizer at therapeutic doses respectively at any time prior to 3 months or any history of the following: a suicidal attempt hospitalization for psychiatric disease, or a period of disability due to a psychiatric disease History of immunologically mediated disease, (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, scleroderma, rheumatoid arthritis etc.) History of esophageal varices bleeding or other evidence of esophageal varices bleeding or other symptoms consistent with decompensated liver disease History of chronic pulmonary disease associated with functional limitation History of severe cardiac disease (e.g., NYHA Functional Class III or IV, myocardial infarction within 6 months, ventricular tachyarrhythmias requiring ongoing treatment, unstable angina or other significant cardiovascular diseases) Hemodialysis patients or patients with renal insufficiency History of a severe seizure disorder or current anticonvulsant use Major organ transplantation or other evidence of severe illness, malignancy, or any other conditions, which would make the patient, in the opinion of the investigator, unsuitable for the study History of thyroid disease poorly controlled on prescribed medications Evidence of severe retinopathy or clinically relevant ophthalmologic disorder History of other severe disease or evidence of other severe disease or any other illness or conditions that the investigator believe that patients are not suitable to join in the study Immunomodulatory treatment (including interferon) or LDT within 1 year prior to the first dose of treatment Patients included in another trial or having been given investigational drugs within 12 weeks prior to screening

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PegINF plus nucleos(i)de analgoue<br>Peginterferon alfa-2a 180μg /wk plus nucleos(t)ide analgoue (NA) 1 piece qd for 48 weeks | Drug: Peginterferon alfa-2a<br>* Peginterferon alfa-2a 180ug/wk s.c for 48 weeks<br>* Other names: Pegasys;Drug: nucleos(t)ide analgoue<br>* nucleos(t)ide analgoue (NA) 1 piece p.o for 48 weeks<br>|
| Active Comparator: nucleos(t)ide analgoue<br>nucleos(t)ide analgoue (NA) 1 piece qd for 48 weeks | Drug: nucleos(t)ide analgoue<br>* nucleos(t)ide analgoue (NA) 1 piece p.o for 48 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants who achieve HBeAg seroconversion | To investigate whether the combined therapy with Peginterferon alfa-2a with Entecavir can improve the HBeAg seroconversion in HBeAg positive CHB patients on treatment with Entecavir and with HBV DNA <1000copies/ml which will be measured by the number of participants who achieve HBeAg seroconversion | at week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants who achieve HBeAg loss | To investigate whether the combined therapy with Peginterferon alfa-2a with Entecavir can improve HBeAg seroconversion which will be measured by number of participants who achieve HBeAg loss | at week 48 | 
| Number of participants who achieve HBsAg loss | To investigate whether the combined therapy with Peginterferon alfa-2a with Entecavir can improve HBsAg loss which will be measured by number of participants who achieve HBsAg loss | at week 48 | 
| Number of participants who achieve HBsAg seroconversion | To investigate whether the combined therapy with Peginterferon alfa-2a with Entecavir can improve HBsAg seroconversion which will be measured by number of participants who achieve HBsAg seroconversion | at week 48 | 
| HBsAg decline from baseline | To investigate whether the combined therapy with Peginterferon alfa-2a with Entecavir can improve HBsAg decline from baseline | at week 48 | 
| Percentage of participants who achieve HBsAg <1000IU/mL | To investigate whether the combined therapy with Peginterferon alfa-2a with Entecavir can improve the percentage of participants who achieve HBsAg<1000IU/mL | at week 48 | 
| Percentage of of participants who achieve HBsAg <100IU/mL | To investigate whether the combined therapy with Peginterferon alfa-2a with Entecavir can improve the percentage of of participants who achieve HBsAg<100IU/mL | at week 48 | 
| Number of participants who achieve combined response I (defined as HBeAg seroconversion and HBV DNA<100000copies/mL) | To investigate whether the combined therapy with Peginterferon alfa-2a with Entecavir can improve the combined response I which will be measured by number of participants who achieve combined response I | at week 48 | 
| Number of participants who achieve combined response II (defined as HBeAg seroconversion and HBV DNA<1000copies/mL) | To investigate whether the combined therapy with Peginterferon alfa-2a with Entecavir can improve the combined response II which will be measured by number of participants who achieve combined response II | at week 48 | 
| Number of participants who achieve dural response I (defined as HBeAg seroconversion and HBsAg<1000IU/mL) | To investigate whether the combined therapy with Peginterferon alfa-2a with Entecavir can improve the dural response I which will be measured by number of participants who achieve dural response I | at week 48 | 
| Number of participants who achieve dural response II (defined as HBeAg seroconversion and HBsAg<100IU/mL) | To investigate whether the combined therapy with Peginterferon alfa-2a with Entecavir can improve the dural response II which will be measured by number of participants who achieve dural response II | at week 48 | 
| Number of Participants with AE | Number of participants with adverse events as a measure of safety and tolerability | at week 48 | 
| Number of Participants with SAE | Number of participants with SAEs as a measure of safety and tolerability | at week 48 |