Clinical trial NCT03357822: A Real-World Study of Pegylated Interferon In Nucleoside-treated Patients With Chronic Hepatitis B
Official title: A Real-World Study of Sequential Combination Therapy With Pegylated Interferon In Nucleoside-treated Patients With Chronic Hepatitis B
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Chronic Hepatitis B
Keywords: Chronic hepatitis B
Nucleoside analog
Pegylated Interferon
Sequential combination therapy
HBsAg loss
Lead sponsor: Tongji Hospital
Sponsor class: OTHER
First posted: 2017-11-30
Enrollment: 2000
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The aim of the prospective real-world study is to evaluate whether sequential combination therapy with pegylated interferon plus entecavir/tenofovir could induce higher rates of HBsAg loss in nucleoside-treated patients with chronic hepatitis B compared to continuous nucleoside treatment.

Detailed description: Patents who were treated with NA at least one year and achieved hepatitis B virus (HBV) DNA suppression and HBsAg level\<3000 international unit (IU) /mL are enrolled in this study, they are assigned into two groups, in group I, patients will receive pegylated interferon plus entecavir/tenofovir for 48/72/96 weeks, in group II, patients will receive entecavir/tenofovir for 96 weeks. HBsAg loss rates at the end of treatment and sustained response at the end of follow up will be evaluated.

Eligibility criteria: Inclusion Criteria:

1. Male and female patients from 18 to 65 years of age;
2. HBsAg positive, entecavir and or adefovir dipivoxil are used at least 1 year including patients with nucleotides or nucleoside resistance history;
3. Before nucleotides or nucleosides treatment, ALT \> 2 upper limit of normal value (ULN), HBV DNA \>10000 copies/ml, HBsAg positive;
4. Serum HBV DNA ≤ 500 copies/ml;
5. HBsAg\<3000 IU/ml;
6. HBsAg positive;
7. Negative urine or serum pregnancy test (for women of childbearing potential) documented within the 24-hour period prior to the first dose of test drug;
8. Absence of cirrhosis confirmed by ultrasonic test;
9. Agree to participate in the study and sign the patient informed consent.

Exclusion Criteria:

1. HBV DNA \> 500 copies/ml;
2. Other antiviral, anti-neoplastic or immunomodulatory treatment (including supra physiologic doses of steroids and radiation) 6 months prior to the first dose of randomized treatment (except for 7 days of acyclovir for herpetic lesions more than 1 month prior to first administration of randomized treatment). Patients who are expected to need systemic antiviral therapy other than that provided by the study at any time during their participation are also excluded;
3. Women with ongoing pregnancy or breast-feeding;
4. Co-infection with active hepatitis A, hepatitis C, hepatitis D(Those hospitals which have the ability to do the test will do) and/or human immunodeficiency virus (HIV);
5. ALT \>10 ULN;
6. Evidence of decompensated liver disease (Child-Pugh score \> 5). Child-Pugh \> 5 means, if one of the following 5 conditions are met, the patient has to be excluded:
7. one of the following 5 conditions are met, the patient has to be excluded:
8. Serum albumin \< 3.5 g/L;
9. Prothrombin time \> 3 seconds prolonged;
10. Serum bilirubin \> 34 µ mol/L;
11. History of encephalopathy;
12. History of variceal bleeding;
13. Ascites;
14. 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);
15. Signs or symptoms of hepatocellular carcinoma, patients with a value of alpha-fetoprotein \> 100 ng/mL are excluded, unless stability (less than 10% increase) has been documented over at least the previous 3 months. Patients with values \< 20 ng/mL but \> 100 ng/mL may be enrolled, if hepatic neoplasia has been excluded by liver imaging;
16. Neutrophil count \< 1500 cells/mm3 or platelet count \<90,000 cells/mm3 at screening;
17. Hemoglobin \< 11.5 g/dL for females and \<12.5 g/dL for men;
18. Serum creatinine level \> 1.5 ULN in screening period.
19. Phosphorus \< 0.65 mmol/L;
20. antinuclear antibody (ANA) \> 1:100;
21. History of severe psychiatric disease, especially depression. Severe psychiatric disease is defined as treatment with an antidepressant medication or a major tranquilizer at therapeutic doses for major depression or psychosis, respectively, for at least 3 months at any previous time or any history of the following: a suicidal attempt hospitalization for psychiatric disease, or a period of disability due to a psychiatric disease;
22. History of a severe seizure disorder or current anticonvulsant use;
23. History of immunologically mediated disease, (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, scleroderma, rheumatoid arthritis etc.);
24. History of chronic pulmonary disease associated with functional limitation;
25. Diseases that interferon and nucleotides or nucleosides are not suitable.

Primary outcomes:
measure: HBsAg loss rate
timeFrame: at week 48
Secondary outcomes:
measure: HBsAg loss rate
timeFrame: at week 72
measure: HBsAg loss rate
timeFrame: at week 96
measure: HBsAg level
timeFrame: at week 48
measure: HBsAg level
timeFrame: at week 72
measure: HBsAg level
timeFrame: at week 96
measure: sustained HBsAg loss rate
timeFrame: at week 120
measure: decline in HBsAg level
timeFrame: at week 48
measure: decline in HBsAg level
timeFrame: at week 72
measure: decline in HBsAg level
timeFrame: at week 96
measure: HBsAb appearance rate
timeFrame: at week 48
measure: HBsAb appearance rate
timeFrame: at week 72
measure: HBsAb appearance rate
timeFrame: at week 96
measure: HBsAb seroconversion rate
timeFrame: at week 48
measure: HBsAb seroconversion rate
timeFrame: at week 72
measure: HBsAb seroconversion rate
timeFrame: at week 96
measure: HBeAg loss rate
timeFrame: at week 48
measure: HBeAg loss rate
timeFrame: at week 72
measure: HBeAg loss rate
timeFrame: at week 96
measure: HBeAg seroconversion rate
timeFrame: at week 48
measure: HBeAg seroconversion rate
timeFrame: at week 72
measure: HBeAg seroconversion rate
timeFrame: at week 96
measure: Rate of HBV DNA level <1000 copies/mL
timeFrame: at week 96
measure: Rate of alanine aminotransferase (ALT) normalization
timeFrame: at week 96
measure: The rate of progression to cirrhosis
timeFrame: at week 120
measure: The incidence rate of hepatocarcinoma
timeFrame: at week 120
Other outcomes:
Locations:
city: Beijing
country: China
facility: 302 Military Hospital of China
state: Beijing
city: Beijing
country: China
facility: BeiJing YouAn Hospital, Capital Medical University
state: Beijing
city: Chongqing
country: China
facility: The First Hospital Affiliated to AMU
state: Chongqing
city: Fuzhou
country: China
facility: The First Affiliated Hospital of Fujian Medical University
state: Fujian
city: Nanning
country: China
facility: The First Affiliated Hospital of Guangxi Medical University
state: Guangxi
city: Zhejiang
country: China
facility: The First Affiliated Hospital of College of Medicine, Zhejiang University
state: Hangzhou
city: Changsha
country: China
facility: Departmen of infectious disease, Xiangya Hospital, Central-south Universit
state: Hunan
city: Changsha
country: China
facility: The Second Xiangya Hospital of Central South University
state: Hunan
city: Nanjing
country: China
facility: The First Affiliated Hospital with Nanjing Medical University
state: Jiangsu
city: Nanjing
country: China
facility: The Second Hospital of Nanjing
state: Jiangsu
city: Shantou
country: China
facility: Traditional Chinese Medicine,Xiamen Hospital
state: Xiamen
city: Wenzhou
country: China
facility: The first affiliated hospital of Wenzhou medical universtiy
state: Zhejiang
Study officials:
affiliation: Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
name: Qin Ning
role: PRINCIPAL_INVESTIGATOR
References: