Clinical trial NCT02327416: A Prospective Clinical Trial in Chronic Hepatitis B Patients NAs (Nucleotides or Nucleosides) Experienced (Anchor Study)
Official title: A Prospective Randomized Clinical Trial of Combination Sequential Treatment With Y Peginterferon Alfa-2b and ETV (Entecavir) in CHB (Chronic Hepatitis B) Patients NAs (Nucleotides or Nucleosides) Experienced (Anchor Study)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Hepatitis B, Chronic
Lead sponsor: Tongji Hospital
Sponsor class: OTHER
Collaborators: name: Xiamen Amoytop Biotech Co., Ltd.
First posted: 2014-12-30
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is a multi-center, randomized, prospective, open-label Phase III Clinical trial to assess the efficacy and safety of combination and sequential treatment with Y peginterferon Alfa-2b,entecavir and GMCSF in chronic hepatitis B patients nucleotides or nucleosides experienced. Patients were randomized to one of 3 groups to receive different antiviral treatment.

Detailed description: Patients who have been pretreated with and responded to one or two nucleotides or nucleosides for at least one year, with HBV (Hepatitis B Virus) DNA less than 1000 copies/ml and HBsAg less 3000 IU/ml were randomized to one of 3 groups, to receive Y peginterferon Alfa-2b 180mcg/week for 96 weeks, entecavir 0.5 mg po daily for 48 weeks plus GMCSF (Granulocyte-macrophage colony stimulating factor) for 48 weeks, or Y peginterferon Alfa-2b 180mcg/week for 96 weeks and entecavir 0.5 mg po daily for 48 weeks, or only ETV for 96 weeks.

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 if their HBV DNA obtained control;
3. Before nucleotides or nucleosides treatment, ALT \> 2 ULN, HBV DNA \>10000 copies/ml,HBsAg positive;
4. Serum HBV DNA \< 1000 copies/ml;
5. Serum 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. Patients who had NAs resistance and HBV DNA \> 1000 copies/ml, or treatment of drugs with IFN longer than 6 months;
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:

   one of the following 5 conditions are met, the patient has to be excluded:
   1. Serum albumin \< 3.5 g/L;
   2. Prothrombin time \> 3 seconds prolonged;
   3. Serum bilirubin \> 34 µ mol/L;
   4. History of encephalopathy;
   5. History of variceal bleeding;
   6. Ascites;
7. 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);
8. 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;
9. Neutrophil count \< 1500 cells/mm3 or platelet count \<90,000 cells/mm3 at screening;
10. Hemoglobin \< 11.5 g/dL for females and \<12.5 g/dL for men;
11. Serum creatinine level \> 1.5 ULN in screening period.
12. Phosphorus \< 0.65 mmol/L;
13. ANA \> 1:100;
14. 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;
15. History of a severe seizure disorder or current anticonvulsant use;
16. History of immunologically mediated disease, (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, scleroderma, rheumatoid arthritis etc.);
17. History of chronic pulmonary disease associated with functional limitation;
18. Diseases that IFN and Nucleotides or nucleosides are not suitable.

Primary outcomes:
measure: Percentage of HBsAg loss at week 96
timeFrame: week 96
Secondary outcomes:
measure: Change from baseline in HBsAg quantification and HBsAg decline at week 96
timeFrame: week 96
measure: Change from baseline in HBsAg seroconversion at week 96
timeFrame: week 96
Other outcomes:
measure: Percentage of HBeAg loss or HBeAg seroconversion at week 96 for HBeAg positive patients
timeFrame: week 96
measure: Percentage of HBV DNA normalization and ALT normalization at week 96
timeFrame: week 96
measure: Percentage of sustained virology response at week 120
timeFrame: week 120
Locations:
city: Beijing
country: China
facility: Beijing Youan Hospital
state: Beijing
city: Wuhan
country: China
facility: Tongji Hospital
state: Hubei
city: Changsha
country: China
facility: Xiangya Hospital, Central South University
state: Hunan
city: Wenzhou
country: China
facility: The First Affiliated Hospital of Wenzhou Medical University
state: Zhejiang
Study officials:
affiliation: Department of Infectious Diseases, Tongji Hospital
name: Qin Ning, Doctor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Huang D, Wu D, Wang P, Wang Y, Yuan W, Hu D, Hu J, Wang Y, Tao R, Xiao F, Zhang X, Wang X, Han M, Luo X, Yan W, Ning Q. End-of-treatment HBcrAg and HBsAb levels identify durable functional cure after Peg-IFN-based therapy in patients with CHB. J Hepatol. 2022 Jul;77(1):42-54. doi: 10.1016/j.jhep.2022.01.021. Epub 2022 Feb 8.