A Real-World Study of Pegylated Interferon In Nucleoside-treated Patients With Chronic Hepatitis B (COST)

A Real-World Study of Sequential Combination Therapy With Pegylated Interferon In Nucleoside-treated Patients With Chronic Hepatitis B

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.

Study Overview

• Status: Unknown
• Conditions: Chronic Hepatitis B
• Intervention / Treatment: Drug: Pegylated interferon; Drug: Entecavir; Drug: Tenofovir disoproxil fumarate

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.

• Study Type: Interventional
• Enrollment (Anticipated): 2000
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China
      • Not yet recruiting
      • Beijing Youan Hospital, Capital Medical University
      • Contact: Xinyue Chen, Doctor
    • Beijing, Beijing, China
      • Recruiting
      • 302 Military Hospital of China
      • Contact: Junliang Fu
  • Chongqing
    • Chongqing, Chongqing, China
      • Not yet recruiting
      • The First Hospital Affiliated To AMU
      • Contact: Xuqing Zhang
  • Fujian
    • Fuzhou, Fujian, China
      • Not yet recruiting
      • The First Affiliated Hospital of Fujian Medical University
      • Contact: Jiaji Jiang, Doctor
  • Guangxi
    • Nanning, Guangxi, China
      • Not yet recruiting
      • The First Affiliated Hospital of Guangxi Medical University
  • Hangzhou
    • Zhejiang, Hangzhou, China, Doctor
      • Not yet recruiting
      • The First Affiliated Hospital of College of Medicine, Zhejiang University
      • Contact: Qi Xia
  • Hunan
    • Changsha, Hunan, China
      • Not yet recruiting
      • The Second Xiangya Hospital of Central South University
      • Contact: Guozhong Gong
    • Changsha, Hunan, China
      • Not yet recruiting
      • Departmen of infectious disease, Xiangya Hospital, Central-south Universit
      • Contact: Deming Tan, Doctor
  • Jiangsu
    • Nanjing, Jiangsu, China
      • Not yet recruiting
      • The First Affiliated Hospital with Nanjing Medical University
      • Contact: Chuanlong zhu
    • Nanjing, Jiangsu, China
      • Not yet recruiting
      • The Second Hospital of Nanjing
      • Contact: Wei Zhao
  • Xiamen
    • Shantou, Xiamen, China
      • Not yet recruiting
      • Traditional Chinese Medicine,Xiamen Hospital
      • Contact: Qianguo Mao
  • Zhejiang
    • Wenzhou, Zhejiang, China
      • Not yet recruiting
      • The first affiliated hospital of Wenzhou medical universtiy
      • Contact: Yongping Chen, Doctor

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. 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sequential combination therapy group; Patients are treated with pegylated Interferon (180ug, subcutaneously, once a week) plus entecavir (0.5mg, orally, every day) or tenofovir disoproxil fumarate (300mg, orally, every day) for 48/72/96 weeks	Drug: Pegylated interferon; 180ug Pegylated interferon is injected subcutaneously once a week; Other Names: Pegylated interferon (PegIFN); Drug: Entecavir; 0.5mg entecavir is orally taken every day; Other Names: Entecavir (ETV); Drug: Tenofovir disoproxil fumarate; 300mg tenofovir is orally taken every day; Other Names: Tenofovir disoproxil fumarate (TDF)
Active Comparator: Nucleoside therapy group; Patients are treated with entecavir (0.5mg, orally, every day) or tenofovir disoproxil fumarate (300mg, orally, every day) for 96 weeks	Drug: Entecavir; 0.5mg entecavir is orally taken every day; Other Names: Entecavir (ETV); Drug: Tenofovir disoproxil fumarate; 300mg tenofovir is orally taken every day; Other Names: Tenofovir disoproxil fumarate (TDF)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HBsAg loss rate	Percentages of patients who achieve HBsAg loss at week 48	at week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HBsAg loss rate	Percentages of patients who achieve HBsAg loss at week 72	at week 72
HBsAg loss rate	Percentages of patients who achieve HBsAg loss at week 96	at week 96
HBsAg level	Dynamic change in HBsAg level from baseline to week 48	at week 48
HBsAg level	Dynamic change in HBsAg level from baseline to week 72	at week 72
HBsAg level	Dynamic change in HBsAg level from baseline to week 96	at week 96
sustained HBsAg loss rate	Percentages of patients who achieve HBsAg loss at week 120	at week 120
decline in HBsAg level	Decline in HBsAg level from baseline to week 48	at week 48
decline in HBsAg level	Decline in HBsAg level from baseline to week 72	at week 72
decline in HBsAg level	Decline in HBsAg level from baseline to week 96	at week 96
HBsAb appearance rate	Percentages of HBsAb appearance at week 48	at week 48
HBsAb appearance rate	Percentages of HBsAb appearance at week 72	at week 72
HBsAb appearance rate	Percentages of HBsAb appearance at week 96	at week 96
HBsAb seroconversion rate	Percentages of HBsAb seroconversion at week 48	at week 48
HBsAb seroconversion rate	Percentages of HBsAb seroconversion at week 72	at week 72
HBsAb seroconversion rate	Percentages of HBsAb seroconversion at week 96	at week 96
HBeAg loss rate	Percentages of HBeAg loss in the HBeAg-positive patients at week 48	at week 48
HBeAg loss rate	Percentages of HBeAg loss in the HBeAg-positive patients at week 72	at week 72
HBeAg loss rate	Percentages of HBeAg loss in the HBeAg-positive patients at week 96	at week 96
HBeAg seroconversion rate	Percentages of HBeAg seroconversion in the HBeAb-negative patients at week 48	at week 48
HBeAg seroconversion rate	Percentages of HBeAg seroconversion in the HBeAb-negative patients at week 72	at week 72
HBeAg seroconversion rate	Percentages of HBeAg seroconversion in the HBeAb-negative patients at week 96	at week 96
Rate of HBV DNA level <1000 copies/mL	Percentages of HBV DNA level <1000 copies/mL at week 96	at week 96
Rate of alanine aminotransferase (ALT) normalization	Percentages of ALT normalization at week 96	at week 96
The rate of progression to cirrhosis	The rate of progression to cirrhosis at week 120	at week 120
The incidence rate of hepatocarcinoma	The incidence rate of hepatocarcinoma at week 120	at week 120

Collaborators and Investigators

• Sponsor: Tongji Hospital
• Investigators: Principal Investigator: Qin Ning, Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

Study record dates

Study Major Dates

• Study Start (Actual): January 25, 2018
• Primary Completion (Anticipated): January 25, 2022
• Study Completion (Anticipated): July 25, 2022

Study Registration Dates

• First Submitted: November 20, 2017
• First Submitted That Met QC Criteria: November 24, 2017
• First Posted (Actual): November 30, 2017

Study Record Updates

• Last Update Posted (Actual): April 25, 2018
• Last Update Submitted That Met QC Criteria: April 23, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: Chronic hepatitis B; Pegylated Interferon; HBsAg loss; Nucleoside analog; Sequential combination therapy
• 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 B; Hepatitis; Hepatitis A; Hepatitis B, Chronic; Hepatitis, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antineoplastic Agents; Tenofovir; Interferons; Entecavir
• Other Study ID Numbers: COST study

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No