An Exploratory Study of RGT Strategy on Optimal NUC-experienced Patients

Chronic Hepatitis B Clinical Trial

Official title:

A Prospective, Randomized, Multicenter, Open-label, Exploratory Study of Utilizing of "Response-Guided-Therapy (RGT)" Strategy on Optimal Nucleoside Analogue (NUC)-Experienced Patients

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02560649
• Other study ID #: PYRAMID
• Status: Active, not recruiting
• Phase: Phase 4
• First received: September 22, 2015
• Last updated: September 23, 2015
• Start date: May 2015
• Est. completion date: February 2017

Study information

• Verified date: September 2015
• Source: Ruijin Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: China: Ethics Committee
• Study type: Interventional

Clinical Trial Summary

The aim of current study is to investigate whether the HBsAg clearance rate can be improved if applying RGT((Response-Guided Therapy) strategy in HBeAg positive CHB(chronic hepatitis B) patients treated by nucleoside analogue(NUC) achieved HBVDNA<1000copies/ml，and HBsAg<5000IU/ml; &HBeAg<100PEIU/ml (or470s/co), combined with PEG-IFN a-2a for 24 weeks.

Description:

The current study is a prospective, randomized, open, multi-center investigation. The aim of current study is to investigate whether the HBsAg clearance rate can be improved if applying RGT strategy in HBeAg positive CHB patients treated by NUC achieved HBVDNA<1000copies/ml，and HBsAg<5000IU/ml; &HBeAg<100PEIU/ml (or470s/co), combined with PEG-IFN a-2a for 24 weeks. Then the subjects will be divided into three groups according to qHBsAg levels of week 24 (RGT). For the subjects who qHBsAg<200IU/ml of week 24, they are defined in Group A; the subjects in Group A will continue to be treated by NUC combined with PEG-IFN a-2a 180μg for another 24 weeks(total will be 48 weeks). If the qHBsAg at week 24 did not achieve minor 200IU/ml, the subjects will be randomized to 2 groups: Group B: the subjects will continue to be treated by NUC combined with PEG-IFN a-2a 180μg for another 24 weeks (total will be 48 weeks); Group C: the subjects will be treated by NUC until 48 weeks.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 324
• Est. completion date: February 2017
• Est. primary completion date: August 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

1. Male and female patients with age =18 and =65 years;

2. There should be evidences that HBsAg and HBeAg have been positive for more than 6 months with HBsAb and HBeAb negative before treated with nucleoside analogue(NUC) (except of telbivudine);

3. Treated with NUC (except of telbivudine)for more than 24 weeks and achieve HBV DNA<1000copies/ml and HBsAg<5000IU/ml;&HBeAg<100PEIU/ml(470s/co);

4. Without contra-indications to Peginterferon alfa-2a therapy as detailed in the label;

5. Without co-infection with hepatitis C, hepatitis D and HIV;

6. Women without ongoing pregnancy or breast feeding and willing to take an effective contraceptive measure during the treatment

7. Agree to participate in the study and sign the patient informed consent form.

Exclusion criteria

1. Co-infection with active hepatitis A, hepatitis C, hepatitis D and/or human immunodeficiency virus (HIV)

2. AFP(alpha fetoprotein)>50ng/ml and/or evidence of hepatocellular carcinoma

3. Evidence of decompensated liver disease (Child-Pugh scores >5). Child-Pugh >5 means that, if one of the following 6 conditions is met, the patient has to be excluded:

• Serum albumin <35 g/L

• Prothrombin time prolonged= 4 seconds or PTA(prothrombin activity) < 60%

• Serum bilirubin > 34 µmol/L

• History of encephalopathy

• Ascites

4. 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)

5. Pregnant or breast-feeding Women

6. ANC(absolute neutrophil count)<1.5x 10^9/L or PLT(platelet count)<90x 10^9/L

7. Consuming alcohol in excess of 20g/day for women and 30g/day for men within 6 months prior to enrollment

8. History of severe psychiatric disease, especially depression. Severe psychiatric disease is defined as major depression or psychosis that treated with antidepressant medication or a major tranquilizer at therapeutic doses respectively at any time prior to 3 months or any history of the following: a suicidal attempt hospitalization for psychiatric disease, or a period of disability due to a psychiatric disease

9. History of immunologically mediated disease, (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, scleroderma, rheumatoid arthritis etc.)

10. History of esophageal varices bleeding or other evidence of esophageal varices bleeding or other symptoms consistent with decompensated liver disease

11. History of chronic pulmonary disease associated with functional limitation

12. History of severe cardiac disease (e.g., NYHA Functional Class III or IV, myocardial infarction within 6 months, ventricular tachyarrhythmias requiring ongoing treatment, unstable angina or other significant cardiovascular diseases)

13. Hemodialysis patients or patients with renal insufficiency

14. History of a severe seizure disorder or current anticonvulsant use

15. Major organ transplantation or other evidence of severe illness, malignancy, or any other conditions, which would make the patient, in the opinion of the investigator, unsuitable for the study

16. History of thyroid disease poorly controlled on prescribed medications

17. Evidence of severe retinopathy or clinically relevant ophthalmologic disorder

18. History of other severe disease or evidence of other severe disease or any other illness or conditions that the investigator believe that patients are not suitable to join in the study

19. Immunomodulatory treatment (including interferon) or LDT(telbivudine) within 1 year prior to the first dose of treatment

20. Patients included in another trial or having been given investigational drugs within 12 weeks prior to screening

Study Design

Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Hepatitis B
• Hepatitis B, Chronic
• Hepatitis, Chronic

Intervention

Drug:
• Peginterferon alfa-2a plus Entecavir
Peginterferon alfa-2a 180µg /wk plus Entecavir 0.5mg qd for 48 weeks(Arm A and B)
• Peginterferon alfa-2a plus Lamivudine
Peginterferon alfa-2a 180µg /wk plus Lamivudine 0.1g qd for 48 weeks(Arm A and B)
• Peginterferon alfa-2a plus Adefovir
Peginterferon alfa-2a 180µg /wk plus Adefovir 10mg qd for 48 weeks(Arm A and B)
• Peginterferon alfa-2a plus Tenofovir
Peginterferon alfa-2a 180µg /wk plus Tenofovir 300mg qd for 48 weeks(Arm A and B)
• Entecavir
Entecavir 0.5mg qd for 24 weeks(Arm C)
• Lamivudine
Lamivudine 0.1g qd for 24 weeks(Arm C)
• Adefovir
Adefovir 10mg qd for 24 weeks(ArmC)
• Tenofovir disoproxil
Tenofovir 300mg qd for 24 weeks(Arm C)

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Ruijin Hospital

References & Publications (3)

Brouwer WP, Xie Q, Sonneveld MJ, Zhang N, Zhang Q, Tabak F, Streinu-Cercel A, Wang JY, Idilman R, Reesink HW, Diculescu M, Simon K, Voiculescu M, Akdogan M, Mazur W, Reijnders JG, Verhey E, Hansen BE, Janssen HL; ARES Study Group. Adding pegylated interferon to entecavir for hepatitis B e antigen-positive chronic hepatitis B: A multicenter randomized trial (ARES study). Hepatology. 2015 May;61(5):1512-22. doi: 10.1002/hep.27586. Epub 2015 Feb 27. — View Citation

Ning Q, Han M, Sun Y, Jiang J, Tan D, Hou J, Tang H, Sheng J, Zhao M. Switching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: a randomised open-label trial (OSST trial). J Hepatol. 2014 Oct;61(4):777-84. doi: 10.1016/j.jhep.2014.05.044. Epub 2014 Jun 7. — View Citation

P. Hu et al. 2015 EASL abstract O116. PREDICTIVE VALUE OF BASELINE AND ON-TREATMENT qHBsAg LEVEL IN HBeAg POSITIVE CHB PATIENTS WHO SWITCHED FROM NUCS TO PEGYLATED INTERFERON A-2A: A FURTHER ANALYSIS FROM NEW SWITCH STUDY

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of participants who achieve HBsAg clearance	To investigate whether HBsAg clearance rate can be improved at week 48 following applying RGT strategy(week 24) in NUC-experience subjects will be measured by the number of participants who achieve HBsAg clearance	Week 48	Yes
Secondary	Number of participants who achieve HBsAg seroconversion	To investigate the HBsAg seroconversion rate at week 48 can be improved following applying RGT strategy in NUC-experience subjects will be measured by the number of participants who achieve HBsAg seroconversion	Week 48	No
Secondary	Number of participants who achieve HBeAg loss	To investigate the HBeAg loss rate at week 48 can be improved following applying RGT strategy in NUC-experience subjects will be measured by the number of participants who achieve HBeAg loss	Week 48	No
Secondary	Number of participants who achieve HBeAg seroconversion	To investigate the HBeAg seroconversion rate at week 48 will be improved following applying RGT strategy in NUC-experience subjects will be measured by the number of participants who achieve HBeAg seroconversion	Week 48	No
Secondary	Percentage of of participants who achieve HBsAg decline >2log from baseline(0 week)	To investigate HBsAg decline from baseline at week 48 following applying RGT strategy in NUC-experience subjects by measured the percentage of of participants who achieve HBsAg decline>2log from baseline(0 week)	Week 48	No
Secondary	Percentage of of participants who achieve HBsAg <10IU/mL	To investigate the percentage of of participants who achieve HBsAg <100IU/mLat week 48 following applying RGT strategy in NUC-experience subjects	Week 48	No
Secondary	Percentage of of participants who achieve combined response(defined as HBeAg seroconversion and HBVDNA<300copies/mL)	To investigate the percentage of of participants who achieve combined response at week 48 following applying RGT strategy in NUC-experience subjects will be measured by number of participants who achieve combined response	Week 48	No
Secondary	Percentage of of participants who achieve dural response I (defined as HBeAg seroconversion and HBsAg<100IU/mL)	To investigate the percentage of of participants who achieve dural response I at week 48 following applying RGT strategy in NUC-experience subjects will be measured by number of participants who achieve dural response	Week 48
Secondary	Percentage of of participants who achieve dural response II (defined as HBeAg seroconversion and HBsAg<10IU/mL)	To investigate the percentage of of participants who achieve dural response II at week 48 following applying RGT strategy in NUC-experience subjects will be measured by number of participants who achieve dural response	Week 48
Secondary	Number of participants who relapses (HBVDNA>1000copies/ml)	To investigate the number of participants who relapses following applying RGT strategy in NUC-experience subjects	Week 48	No
Secondary	Number of Participants with AE	Number of participants with adverse events as a measure of safety and tolerability	Week 48	Yes
Secondary	Number of Participants with SAE	Number of participants with SAEs as a measure of safety and tolerability	Week 48	Yes