A Study of Peginterferon Alfa-2b Combined With TDF in Patients With Chronic Hepatitis B

Study Overview
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Brief Summary
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Current clinical practices has shown promising prospects of the therapy strategy of interferon combined with nucleos(t)ides in patients with chronic hepatitis B, but the safety and efficacy has not been fully studied. This study is aimed to exploit the safety and efficacy of the study drug, Peginterferon alfa-2b injection, with nucleos(t)ide (NAs), tenofovir disoproxil fumarate tablets (TDF), in the patients with hepatitis B, who has previously treated with nucleos(t)ides and who are treatment naïve.

Official Title
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A Multi-center, Randomized, Blinded Study to Evaluate the Efficacy and Safety of Peginterferon Alfa-2b Injection Combined With Tenofovir Disoproxil Fumarate Tablets in Patients With Chronic Hepatitis B

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: Peginterferon alfa-2b injection
* Drug: Peginterferon alfa-2b injection
* Drug: TDF
* Drug: Peginterferon alfa-2b injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Understand and sign the informed consent form voluntarily. Age between 18 and 65 years (including 18 and 65), no gender limit. HBsAg-positive for at least 6 months or other evidence supporting chronic infection with hepatitis B virus. HBsAg positive at screening. For NAs treated patients: Who should have continuously taken NAs for at least 9 months prior to screening, and are currently receiving the NAs. Simultaneously, the patients should have achieved the following criteria: HBsAg<1500IU/mL, HBV DNA<100IU/ml, HBeAg<10s/co at screening. For treatment naive patients: HBV DNA≥1×10^4IU/ml, and 2×ULN (upper limit of normal) ≤ALT≤10×ULN at screening. Pregnancy test of female of childbearing must be negative within 24 hours before the first medication, and the subjects (male and female) should take effective contraceptive measures during the whole study period. Exclusion Criteria: Women who are pregnant, breastfeeding or planning to pregnant during the study period. Subjects with neuropsychiatric diseases and/or neuropsychiatric family history, especially depression, anxiety, or mania schizophrenia. Co-infected with Hepatitis A, Hepatitis C, Hepatitis D, Hepatitis E, or HIV. Chronic hepatitis other than hepatitis B, e.g. alcoholic hepatitis, drugs-induced hepatitis, or autoimmune hepatitis, etc. Moderate to severe steatohepatitis. Evidence of acute severe hepatitis, e.g. ALT>10×ULN, significantly increasing in ALT accompanied by elevated bilirubin, etc. Evidence of liver decompensation, e.g. total bilirubin higher than 2×ULN, albumin lower than 35g/L, prothrombin time is 3 seconds longer than the upper limit of normal, prothrombin activity lower than 60%, or history of decompensated liver cirrhosis, etc. Evidence of hepatocellular carcinoma, or AFP>1×ULN. Significant kidney diseases, including acute nephritis, chronic nephritis, renal insufficiency, nephrotic syndrome, etc. or serum creatinine higher than upper limit of normal. Neutrophil count less than 1.5×10^9/L, or platelet count less than 90×10^9/L at screening. Serum phosphorus lower than 0.8mmol/L. Antinuclear antibody (ANA) exceeds 1:100. Autoimmune disease, including psoriasis, systemic lupus erythematosus, etc. Subjects with endocrine system disease, including thyroid, Diabetes mellitus, etc. Poorly controlled hypertension (blood pressure ≥140/90 mmHg). Subjects with severe heart disease, especially those with unstable angina or poorly controlled heart disease within 6 months prior to screening. Severe retinopathy or any other severe diseases in the eyes. Subject who had ever received organ transplants or are planning to receive organ transplant. For NAs-treated patients: who have received standard treatment of interferon products within 6 months prior to screening . For treatment naive patients: who have ever received standard treatment of interferon products, or who have ever received NAs within 6 months prior to screening. Subject who are allergic to interferon, tenofovir, or any excipients, or meet any of the contraindications described in the drug instructions. Subjects who participated in any other interventional trials within 3 months prior to screening, or with any other conditions which in the opinion of the investigator precluding enrollment from the study.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nucleot(s)ide-treated patients-Experimental Group 1<br> | Drug: Peginterferon alfa-2b injection<br>* Peginterferon alfa-2b injection (high dose) will be weekly subcutaneous injected for 8 weeks and then stop for 4 weeks, 12 week a cycle, up to 12 cycles (144 weeks) at most. TDF will be taken orally during the whole treatment period. And then followed for 24 weeks after treatment.<br>|
| Experimental: Nucleot(s)ide-treated patients-Experimental Group 2<br> | Drug: Peginterferon alfa-2b injection<br>* Peginterferon alfa-2b injection (low dose) will be weekly subcutaneous injected for 8 weeks and then stop for 4 weeks, 12 week a cycle, up to 12 cycles (144 weeks) at most. TDF will be taken orally during the whole treatment period. And then followed for 24 weeks after treatment.<br>|
| Active Comparator: Nucleot(s)ide-treated patients-Control Group<br> | Drug: TDF<br>* Patients will take TDF orally for the first 48 weeks, and then one can choose to continue the single-TDF treatment up to 144 weeks, or may choose to change to receive peginterferon alfa-2b combined TDF therapy for the later 96 weeks, peginterferon alfa-2b will be weekly subcutaneous injected for 8 weeks and then stop for 4 weeks, 12 weeks a cycle. And then followed for 24 weeks after treatment.<br>|
| Other: Treatment Naive Group<br> | Drug: Peginterferon alfa-2b injection<br>* Peginterferon alfa-2b injection will be weekly subcutaneous injected for 8 weeks and then stop for 4 weeks, 12 week a cycle, up to 12 cycles (144 weeks) at most. TDF will be taken orally during the whole treatment period. And then followed for 24 weeks after treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with HBsAg negative. |  | 24 weeks post treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes of HBsAg level from baseline. |  | up to 168 weeks. | 
| Proportion of patients with HBsAg seroconversion. |  | up to 168 weeks. | 
| Proportion of patients with HBeAg negative. |  | up to 168 weeks | 
| Proportion of patients with HBeAg seroconversion. |  | up to 168 weeks. | 
| Changes of HBeAg level from baseline. |  | up to 168 weeks. | 
| Proportion of patients with HBV DNA undetectable. |  | up to 168 weeks. | 
| Changes of HBV DNA level from baseline. |  | up to 168 weeks. | 
| Proportion of patients with ALT normalization. |  | up to 168 weeks. | 
| Proportion of patients with liver fibrosis. |  | up to 168 weeks. | 
| Proportion of patients with liver cirrhosis. |  | up to 168 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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peginterferon alfa-2b injection, interferon alfa, nucleos(t)ide, NUCs, NAs, chronic hepatitis B