Pegylated Interferon(Peg-IFN) in Reducing Relapse Rate in Patients After Discontinuation of NUC Therapy

Chronic Hepatitis B Clinical Trial

Official title:

A Prospective, Randomized, Controlled Clinical Trial to Evaluate the Role of Peg-IFN Alfa-2a in Reducing RelapSe Rate in Patients With Hepatitis B e Antigen(HBeAg)-nEgative Chronic Hepatitis B After Discontinuation of NUC Therapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02594293
• Other study ID #: CEASE
• Status: Completed
• Phase: Phase 4
• Start date: October 2015
• Est. completion date: September 2022

Study information

• Verified date: October 2022
• Source: Huashan Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study evaluates whether Peg-IFN alfa-2a can reduce the recurrence rate of hepatitis B in 96 weeks after nucleoside analogue (NUC) withdrawal. The HBV HBeAg-Negative patients who received NUC anti-virus treatment for 2.5 years and reached stopping rule in 《Chinese chronic hepatitis B prevention and treatment guidelines》(2010) were randomly assigned into three groups: One group discontinue the NUC treatment and follow up for 96 weeks,One discontinue the NUC treatment ,receive Peg-IFN alfa-2a 180 μg by week for 24 weeks and follow up for 72 weeks,The other discontinue the NUC treatment ,receive Peg-IFN alfa-2a 180 μg by week for 48 weeks and follow up for 48 weeks.

Description:

NUC is a potent inhibitor of hepatitis B viral(HBV) replication, but long-term therapy may be required. Therefore, NUC resistance is an important clinical risk resulting from long-term therapy in chronic hepatitis B (CHB) management. Discontinuation of NUC is a feasible strategy to reduce resistance. However, the high rate of relapse after cessation of NUC treatment in CHB patients remains a big problem. NUC treatment of how to safely stop drug needs to be solved. Peg-IFN can clear HBV by direct anti-viral and immune regulation mechanisms including enhancing natural killer cell response, increased cluster of differentiation 8(CD8 +) T lymphocytes and other mechanisms to restore and enhance the immune response in patients with CHB. Response to PEG-IFN is frequently sustained after a finite treatment course due to its immune modulating capacity.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 180
• Est. completion date: September 2022
• Est. primary completion date: September 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

1. HBeAg-Negative Chronic Hepatitis B Patients:HBsAg-Positive,HBsAb-Negative,HBeAg-Negative,HBeAb-Positive during screening period and before NA treatment

2. NUC monotherapy (including adefovir and entecavir) for more than 2.5 years,and reached stopping rule in «Chinese chronic hepatitis B prevention and treatment guidelines»(2010):the patients who achieved undetectable HBV DNA (<300 copies/mL) with normal alanine aminotransferase (ALT) and the consolidation therapy reached 1.5 years ,total course of the treatment reached 2.5 years can stop NUC therapy

3. Willing to stop the drug, and signed a written informed consent

Exclusion Criteria:

1. HBsAb positive in screening period

2. Compensated or Decompensated liver cirrhosis:with history of cirrhosis before NUC treatment or Child-Pugh score = 5 or Complications of liver cirrhosis such as ascites, hepatic encephalopathy, esophageal gastric varices bleeding

3. Hypersensitivity to interferon(IFN) or its active substance, and ineligible to IFN

4. A history of immunoregulation drug therapy within one year before entry including IFN and so on.

5. Coinfection with HAV?HCV?HDV?HEV ?HIV or with Other chronic liver diseases such as Alcoholic Liver Disease,Inherited Metabolic Liver Disease,Drug induced Liver Disease and nonalcoholic fatty liver

6. Autoimmune disease including Autoimmune hepatitis and Psoriasis and so on.

7. Hepatocellular carcinoma(HCC) or alpha feto protein(AFP) levels more than 100 ng/ml and Hepatic malignant potential of Imaging examination or AFP levels more than 100 ng/ml for 3 months

8. A neutrophil count of less than 1500 per cubic millimeter or a platelet count of less than 90,000 per cubic millimeter

9. A serum creatinine level that was more than 1.5 times the upper limit of the normal range

10. With other malignant tumors(exclude the cured ones)

11. Severe organ dysfunction

12. With severe psychiatric condition or nervous disease such as epilepsy, depression, mania, epilepsy, schizophrenia and so on

13. Uncontrolled diabetes, hypertension or thyroid disease

14. Pregnant women and lactating women or patients with pregnancy plans and not willing to use contraception during the study period

15. Participate in other clinical studies at the same time

16. Patients unsuitable for the research

Related Conditions & MeSH terms

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

Intervention

Drug:
• PegIFN alfa-2a
180 µg/ 0.5 ml ,hypodermic injection once a week

Locations

Country	Name	City	State
China	Changzhou Third People's Hospital	Changzhou	Jiangsu
China	First Affiliated Hospital of Zhejiang University	Hangzhou	Jiangsu
China	Shandong Provincial Hospital	Jinan	Shandong
China	People's Hospital of Jiangsu Province	Nanjing	Jiangsu
China	Nantong Third People's Hospital	Nantong	Jiangsu
China	Changhai Hospital Affiliated to Second Military Medical University	Shanghai
China	Huashan Hospital Affiliated to Fudan University	Shanghai
China	Ruijin Hospital Affiliate to Shanghai Jiao Tong University School of Medicine	Shanghai
China	Shanghai Public Health Clinical Center	Shanghai
China	Shanghai Third People's Hospital	Shanghai
China	Shuguang Hospital Affiliate to Shanghai University of Traditional Chinese Medicine	Shanghai
China	The Infectious Disease Hospital of Shanghai Huangpu Distric	Shanghai
China	Suzhou Fifth People's Hospital	Suzhou	Jiangsu
China	The First Affiliated Hospital of Soochow University	Suzhou	Jiangsu
China	Taicang People's Hospital	Taicang	Jiangsu
China	The First Affiliated Hospital of Wenzhou Medical University	Wenzhou	Zhejiang
China	Wuhan Seventh People's Hospital	Wuhan	Hubei
China	Wuxi Infectious Disease Hospital	Wuxi	Jiangsu
China	Affiliated Hospital of Xuzhou Medical College	Xuzhou	Jiangsu

Sponsors (1)

Lead Sponsor	Collaborator
Huashan Hospital

Country where clinical trial is conducted

China, 

References & Publications (17)

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Chen J, Wang Y, Wu XJ, Li J, Hou FQ, Wang GQ. Pegylated interferon a-2b up-regulates specific CD8+ T cells in patients with chronic hepatitis B. World J Gastroenterol. 2010 Dec 28;16(48):6145-50. — View Citation

European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol. 2012 Jul;57(1):167-85. doi: 10.1016/j.jhep.2012.02.010. Epub 2012 Mar 20. Erratum in: J Hepatol. 2013 Jan;58( — View Citation

Ganem D, Prince AM. Hepatitis B virus infection--natural history and clinical consequences. N Engl J Med. 2004 Mar 11;350(11):1118-29. Review. Erratum in: N Engl J Med. 2004 Sep 16;351(12):351. — View Citation

Jeng WJ, Sheen IS, Chen YC, Hsu CW, Chien RN, Chu CM, Liaw YF. Off-therapy durability of response to entecavir therapy in hepatitis B e antigen-negative chronic hepatitis B patients. Hepatology. 2013 Dec;58(6):1888-96. doi: 10.1002/hep.26549. Epub 2013 Oc — View Citation

Kim YJ, Kim K, Hwang SH, Kim SS, Lee D, Cheong JY, Cho SW. Durability after discontinuation of nucleos(t)ide therapy in chronic HBeAg negative hepatitis patients. Clin Mol Hepatol. 2013 Sep;19(3):300-4. doi: 10.3350/cmh.2013.19.3.300. Epub 2013 Sep 30. — View Citation

Liang X, Bi S, Yang W, Wang L, Cui G, Cui F, Zhang Y, Liu J, Gong X, Chen Y, Wang F, Zheng H, Wang F, Guo J, Jia Z, Ma J, Wang H, Luo H, Li L, Jin S, Hadler SC, Wang Y. Epidemiological serosurvey of hepatitis B in China--declining HBV prevalence due to he — View Citation

Liang X, Bi S, Yang W, Wang L, Cui G, Cui F, Zhang Y, Liu J, Gong X, Chen Y, Wang F, Zheng H, Wang F, Guo J, Jia Z, Ma J, Wang H, Luo H, Li L, Jin S, Hadler SC, Wang Y. Evaluation of the impact of hepatitis B vaccination among children born during 1992-20 — View Citation

Liaw YF, Leung N, Kao JH, Piratvisuth T, Gane E, Han KH, Guan R, Lau GK, Locarnini S; Chronic Hepatitis B Guideline Working Party of the Asian-Pacific Association for the Study of the Liver. Asian-Pacific consensus statement on the management of chronic h — View Citation

Liu F, Wang L, Li XY, Liu YD, Wang JB, Zhang ZH, Wang YZ. Poor durability of lamivudine effectiveness despite stringent cessation criteria: a prospective clinical study in hepatitis B e antigen-negative chronic hepatitis B patients. J Gastroenterol Hepato — View Citation

Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009 Sep;50(3):661-2. doi: 10.1002/hep.23190. — View Citation

Lu FM, Zhuang H. Management of hepatitis B in China. Chin Med J (Engl). 2009 Jan 5;122(1):3-4. — View Citation

Marcellin P, Bonino F, Yurdaydin C, Hadziyannis S, Moucari R, Kapprell HP, Rothe V, Popescu M, Brunetto MR. Hepatitis B surface antigen levels: association with 5-year response to peginterferon alfa-2a in hepatitis B e-antigen-negative patients. Hepatol I — View Citation

Micco L, Peppa D, Loggi E, Schurich A, Jefferson L, Cursaro C, Panno AM, Bernardi M, Brander C, Bihl F, Andreone P, Maini MK. Differential boosting of innate and adaptive antiviral responses during pegylated-interferon-alpha therapy of chronic hepatitis B — 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: 10.101 — View Citation

Ouzan D, Pénaranda G, Joly H, Khiri H, Pironti A, Halfon P. Add-on peg-interferon leads to loss of HBsAg in patients with HBeAg-negative chronic hepatitis and HBV DNA fully suppressed by long-term nucleotide analogs. J Clin Virol. 2013 Dec;58(4):713-7. do — View Citation

Seto WK, Hui AJ, Wong VW, Wong GL, Liu KS, Lai CL, Yuen MF, Chan HL. Treatment cessation of entecavir in Asian patients with hepatitis B e antigen negative chronic hepatitis B: a multicentre prospective study. Gut. 2015 Apr;64(4):667-72. doi: 10.1136/gutj — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of participants who relapse	The total number of relapse (HBV DNA>2000 IU/ml on 2 separate occasions 1 months apart) during the research period.	96 weeks
Secondary	Number of participants who relapse	The total number of relapse (HBV DNA>2000 IU/ml on 2 separate occasions 1 months apart) during the research period.	48 weeks
Secondary	Number of participants who achieve HBsAg seroconversion	To investigate whether Peg-IFN alfa-2a can improve the HBsAg seroconversion in CHB patients at the point of discontinuation of PegIFN therapy compared to the control group ,which will be measured by the number of participants who achieve HBsAg seroconversion. Pegasys 24 weeks Group:24 weeks and Pegasys 48 weeks Group:48 weeks	At the point of discontinuation of PegIFN therapy
Secondary	Number of participants who achieve HBsAg seroconversion	To investigate whether Peg-IFN alfa-2a can improve the HBsAg seroconversion in CHB patients at 24,48 or 72 weeks post-discontinuation of PegIFN therapy compared to the control group ,which will be measured by the number of participants who achieve HBsAg seroconversion. Pegasys 24 weeks Group:48,72,96 weeks and Pegasys 48 weeks Group:72,96 weeks	24,48,72 weeks post-discontinuation of PegIFN therapy
Secondary	HBsAg changes from Baseline	Pegasys 24 weeks Group:12,24 weeks and Pegasys 48 weeks Group:12,24,48 weeks	12,24 and 48 weeks
Secondary	Predictive value of other markers for recurrence after NUC withdrawal	To investigate whether the other markers including HBcAb quantification and so on can predict the recurrence of hepatitis B.	48 weeks and 96 weeks