Combination Therapy With Interferon Plus Interleukin 2 and Hepatitis B Vaccine in Chronic Hepatitis B Patients

Combination Therapy of Interferon Alfa-2b Plus Interleukin 2 and Hepatitis B Vaccine in Entecavir-experienced Chronic Hepatitis B Patients With HBeAg Seroclearance: a Prospective, Randomized Open-label Trial (Endeavor Study, a Pilot Study)

This study is a multi-center, randomized, prospective, open-label Phase IV Clinical trial to evaluate efficacy and safety of interferon alfa-2b therapy combinated with interleukin 2 and hepatitis B therapeutic vaccine versus interferon alfa-2b alone in chronic hepatitis B patients with entecavir achieving HBeAg seroclearance. Patients were randomized to one of 3 groups to receive different antiviral treatment.

Study Overview

• Status: Completed
• Conditions: Hepatitis B, Chronic
• Intervention / Treatment: Drug: Entecavir; Drug: Interferon alfa-2b; Drug: Interleukin 2; Drug: Hepatitis B Vaccine

Detailed Description

Patients who have been pretreated with entecavir for at least one year, with HBV (Hepatitis B Virus) DNA less than 1000 copies/ml and HBeAg seroclearance were randomized to one of 3 groups, to receive Entecavir 0.5 mg po daily for 72 weeks, or Interferon alfa-2b 600wIU qod iH for 48 weeks plus Entecavir 0.5mg qd po for 8 weeks, or Interferon alfa-2b 600wIU qod iH for 48 weeks plus Entecavir 0.5mg qd po for 8 weeks plus interleukin 2 25 wIU qod iH for 12 weeks plus Hepatitis B Vaccine 60ug qm im for 48 weeks.

• Study Type: Interventional
• Enrollment (Actual): 94
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Anhui
    • Hefei, Anhui, China
      • Anhui Provincial Hospital
  • Beijing
    • Beijing, Beijing, China
      • Beijing Youan Hospital, Capital Medical University
    • Beijing, Beijing, China
      • First Hospital, Beijing University
    • Beijing, Beijing, China
      • People'S Hospital Under Beijing University
  • Fujian
    • Fuzhou, Fujian, China
      • The First Affiliated Hospital of Fujian Medical University
  • Guangdong
    • Guangzhou, Guangdong, China
      • Department of infectious disease, Nanfang Hospital of Southern Medical University
  • Hubei
    • Wuhan, Hubei, China, 430030
      • Tongji Hospital
  • Hunan
    • Changsha, Hunan, China
      • Departmen of infectious disease, Xiangya Hospital, Central-south Universit
  • Liaoning
    • Shenyang, Liaoning, China
      • Shengjing Hospital Of China Medical University
  • Shanghai
    • Shanghai, Shanghai, China
      • Shanghai Ruijin Hospital, Jiao Tong University School of Medicine
  • Zhejiang
    • Hangzhou, Zhejiang, China
      • The First Affiliated Hospital of College of Medicine, Zhejiang University
    • Wenzhou, Zhejiang, China
      • The first affiliated hospital of Wenzhou medical universtiy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male and female patients from 18 to 65 years of age;
2. Undergoing treatment with entecavir for at least 1 year ;
3. HBsAg(+), HBeAg(+), HBV DNA≥ 100000 copies/ml，ALT≥2 ULN and ≤10 ULN before receiving entecavir treatment;
4. HBV DNA ≤1000 copies/mL;
5. HBeAg (-);
6. HBsAg (+);
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. Liver biopsy confirmed without cirrhosis (optional);
9. Agree to participate in the study and sign the patient informed consent.

Exclusion Criteria:

1. Patients who had NAs resistance;
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 6 conditions are met, the patient has to be excluded: a. Serum albumin < 3.5 g/L; b. Prothrombin time > 3 seconds prolonged; c. Serum bilirubin > 34 μ mol/L; d. History of encephalopathy; e. History of variceal bleeding; f. 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 herapeutic 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1, conventional control group; Entecavir 0.5 mg po daily for 72 weeks	Drug: Entecavir; In arm 1, Entecavir is used for 48 weeks and the follow up 24 weeks as conventional control, In arm 2 and 3, Entecavir is used for 8 weeks.; Other Names: ETV
Experimental: 2, combination and sequential group; Interferon alfa-2b 600wIU qod iH for 48 weeks plus Entecavir 0.5mg qd po for 8 weeks	Drug: Entecavir; In arm 1, Entecavir is used for 48 weeks and the follow up 24 weeks as conventional control, In arm 2 and 3, Entecavir is used for 8 weeks.; Other Names: ETV; Drug: Interferon alfa-2b; In arm 2 and 3, interferon alfa-2b is used for 48 weeks; Other Names: IFN a-2b
Experimental: 3, multitarget group; Interferon alfa-2b 600wIU qod iH for 48 weeks plus Entecavir 0.5mg qd po for 8 weeks plus interleukin 2 25 wIU qod iH for 12 weeks plus Hepatitis B Vaccine 60ug qm im for 48 weeks	Drug: Entecavir; In arm 1, Entecavir is used for 48 weeks and the follow up 24 weeks as conventional control, In arm 2 and 3, Entecavir is used for 8 weeks.; Other Names: ETV; Drug: Interferon alfa-2b; In arm 2 and 3, interferon alfa-2b is used for 48 weeks; Other Names: IFN a-2b; Drug: Interleukin 2; In arm 3, Interleukin 2 is used for 12 weeks; Other Names: IL-2; Drug: Hepatitis B Vaccine; In arm 3, Hepatitis B Vaccine is used for 48 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of HBsAg loss at week 48	Change from baseline in Percentage of HBsAg loss at week 48	week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
decline from baseline in HBsAg quantification at week 48	HBsAg quantification are measured.	week 48
Change from baseline in HBsAg seroconversion at week 48	HBsAg seroconversion from baseline is measured.	week 48

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of HBeAg seroconversion at week 48	Percentage of HBeAg seroconversion are measured at week 48	week 48
Percentage of HBV DNA normalization	Percentage of HBV DNA normalization is measured.	week 48
Percentage of sustained virology response at week 72	Sustained virology response is measure at follow up week 24	week 72
Percentage of ALT normalization at week 48	Percentage of ALT normalization at week 48 is measured.	week 48

Collaborators and Investigators

• Sponsor: Tongji Hospital
• Collaborators: Fujian Cosunter Pharmaceutical Co. Ltd; Beijing Kawin Technology Share-Holding Co., Ltd.
• Investigators: Principal Investigator: Qin Ning, Ph.D. M.D., Department of infectious Diseases, Tongji Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2013
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): April 1, 2017

Study Registration Dates

• First Submitted: February 2, 2015
• First Submitted That Met QC Criteria: February 5, 2015
• First Posted (Estimate): February 10, 2015

Study Record Updates

• Last Update Posted (Actual): May 9, 2018
• Last Update Submitted That Met QC Criteria: May 8, 2018
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Hepatitis, Chronic; Hepatitis B; Hepatitis; Hepatitis A; Hepatitis B, Chronic; Physiological Effects of Drugs; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antineoplastic Agents; Immunologic Factors; Interferons; Interferon-alpha; Interferon alpha-2; Entecavir; Interleukin-2
• Other Study ID Numbers: Endeavor study, a pilot study