Clinical trial NCT02060058: Boceprevir-based Therapy to Rescue HCV Genotype 1/HBV Infected Patients Refractory to Combination Therapy
Official title: Boceprevir-based Triple Therapy to Rescue HCV Genotype 1/HBV Dually Infected Patients Refractory to Peginterferon Plus Ribavirin Combination Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hepatitis C, Chronic
Keywords: hepatitis C virus
hepatitis B virus
boceprevir
null responder
partial responder
relapser
Lead sponsor: Kaohsiung Medical University Chung-Ho Memorial Hospital
Sponsor class: OTHER
Collaborators: name: National Taiwan University Hospital
First posted: 2014-02-11
Enrollment: 12
Sex: ALL
Minimum age (years): 20
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The aim of this study is to explore the efficacy and safety of boceprevir -based triple therapy to rescue HCV genotype 1 (HCV GT1)/HBV dually infected patients refractory to previous peginterferon (PEG-IFN) plus ribavirin (RBV) combination therapy.

Detailed description: Liver disease, especially viral hepatitis, is an important public health issue, which frequent leads to liver cirrhosis, hepatocellular carcinoma (HCC) and liver-related death. Around 340 to 400 million persons are infected with hepatitis B virus (HBV) and 130 to 210 million persons are infected with hepatitis C virus (HCV) worldwide, In Taiwan, the prevalence of HBV infection is 15-20%, and the prevalence of HCV infection is 2-5% in general population. Moreover, there are some HCV-hyperendemic areas in southern Taiwan with anti-HCV prevalence rate of as high as 30-40%.

HBV/HCV dual infections is not uncommon in HBV epidemic areas, such as Southeastern Asia, with a prevalence rate of 1.1% in southern Taiwan. Recent study showed that the risk of HCC incidence is even higher among HBV/HCV co-infected persons than those with HBV or HCV mono-infection, indicating the importance of disease control in this clinical setting.

The PEG-IFN/RBV has been effective in the treatment of HCV-dominant, treatment-naïve patients with HCV/HBV dual infections. For treatment-naive HCV genotype 1 (HCV GT1)/HBV co-infected patients, 48 weeks of peginterferon (PEG-IFN) plus ribavirin (RBV) could achieve an HCV sustained virological response (SVR) rate of 72%, which was comparable to 77% for patients with HCV GT1 monoinfection. For treatment-naive HCV GT2 or GT3 /HBV co-infected patients, 24 weeks of PEG-IFN plus RBV could achieve an HCV SVR rate of 83%, which was comparable to 84% for patients with HCV GT2/3 monoinfection . Furthermore, PEG-IFN plus RBV combination therapy could enhance seroclearance of hepatitis B surface antigen (HBsAg) with an HBsAg loss rate of upto 11%. Nevertheless, there is about 30% of HCV GT1/HBV and 20% of HCV GT2 or 3/HBV co-infected patients refractory to current PEG-IFN/RBV combination therapy, which remains at high risk of HCC and liver-related death.

Boceprevir is an oral antiviral drug, which is NS3/4A protease inhibitor. Boceprevir has been approved for treating HCV GT1 infection by Food and Drug Administration (FDA) on 11 May 2011. For HCV GT1 mono-infected patients who refractory to previous PEG-IFN plus RBV combination therapy, becoprevir combined with PEG-IFN/RBV triple therapy can improve the treatment efficacy. The SVR rate of becoprevir-based triple therapy is about 3 times when compared to patients who received PEG-IFN with RBV dual therapy \[14\].The investigators , therefore, hypothesize that boceprevir plus PEG-IFN/RBV is effective in treating HCV GT1/HBV dually infected patients who are refractory to previous PEG-IFN/RBV combination therapy.

Eligibility criteria: Inclusion Criteria:

* 1. Patient must be 20 years or older
* 2. Patient must have HCV GT1 infection combined with HBV infection.
* 3. Patients must be serum HCV RNA detectable, anti-HCV positive, HBsAg positive and HBeAg negative.
* 4. Patient has previously failed treatment with PEG-IFN-α 2a or 2b/RBV for minimum of 12 weeks of treatment.
* 5. Patient must have compensated liver disease consistent with CHC and/or CHB, and no other etiology. Note: patients with cirrhosis should have a liver imaging study (e.g. ultrasound, CT scan or MRI) within the preceding 6 months showing no evidence of hepatocellular carcinoma.
* 6. Patient meets all of the requirements and none of the contra-indications for treatment with PEG-IFN alpha-2b/RBV or boceprevir defined in the labels for the PEG-IFN/RBV to be used in combination with boceprevir.
* 7. Patient is able and willing to provide signed informed consent (prepared by and administered by the physician) as required by local country requirements.

Exclusion Criteria:

* 1. Mixed genotypes including HCV genotype other than genotype 1.
* 2. Patient has received boceprevir, narlaprevir, telaprevir, or any other HCV protease inhibitor treatment.
* 3. Patient has evidence of decompensated liver disease including but not limited to, a history or presence of clinical ascites, bleeding varices, or hepatic encephalopathy.
* 4. Patient meets any of the following exclusionary hematologic and biochemical criteria (documentation required) Hemoglobin \<12 gm/dL for females and \<13 gm/dL for males Neutrophils \<1500/mm3 Platelets \<100,000/mm3
* 5. Patient has an organ transplant other than cornea or hair.
* 6. Patient is co-infected with human immunodeficiency virus (HIV)
* 7. Patient requires or is anticipated to require any of the following prohibited medications: midazolam, pimozide, amiodarone, flecainide, propafenone, quinidine, and ergot derivatives
* 8. Patient with clinical diagnosis or evidence of substance abuse involving alcohol, intravenous drugs, inhalational psychotropics, narcotics, cocaine prescription or over-the-counter drugs.
* 9. Patient previously demonstrated clinically significant hypersensitivity or other contraindication to any component of the boceprevir formulation. This drug contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
* 10. Serious illness, including malignancy, active coronary artery disease or cardiac dysfunction within 24 weeks prior to study entry, that in the opinion of the site investigator may preclude completion of the treatment regimen.
* 11. Major hemoglobinopathy (e.g., thalassemia major), coagulopathy or any other cause of or tendency to hemolysis or bleeding

Primary outcomes:
measure: Number of Full Analysis Set Participants Who Received HCV Anti-viral Therapy With Sustained Virological Response (SVR)
timeFrame: week 24
Secondary outcomes:
measure: Key Secondary Endpoint of This Clinical Trial-SVR in mITT
timeFrame: week 24
Other outcomes:
measure: The Other Responses in the mITT Population/Safty- HBV Virologic Response
timeFrame: week 24
Locations:
city: Kaohsiung
country: Taiwan
facility: Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
Study officials:
affiliation: Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
name: Ming-Lung Yu, Professsor
role: STUDY_CHAIR
References:
citation: Chuang WL, Chang WY, Lu SN, Lin ZY, Chen SC, Hsieh MY, Wang LY, You SL, Chen CJ. The role of hepatitis C virus in chronic hepatitis B virus infection. Gastroenterol Jpn. 1993 May;28 Suppl 5:23-7. doi: 10.1007/BF02989199.
citation: Chen DS, Wang JT, Chen PJ, Wang TH, Sung JL. Hepatitis C virus infection in Taiwan. Gastroenterol Jpn. 1991 Jul;26 Suppl 3:164-6. doi: 10.1007/BF02779290.
citation: European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol. 2011 Aug;55(2):245-64. doi: 10.1016/j.jhep.2011.02.023. Epub 2011 Mar 1. No abstract available.
citation: Papatheodoridis GV, Manolakopoulos S, Liaw YF, Lok A. Follow-up and indications for liver biopsy in HBeAg-negative chronic hepatitis B virus infection with persistently normal ALT: a systematic review. J Hepatol. 2012 Jul;57(1):196-202. doi: 10.1016/j.jhep.2011.11.030. Epub 2012 Mar 23.
citation: Chen DS, Sung JL. Studies on the subtypes of hepatitis B surface antigen-demonstration of vertical and intrafamilial transmission of hepatitis B virus. Taiwan Yi Xue Hui Za Zhi. 1978 Mar;77(3):263-71. No abstract available.
citation: Stevens CE, Beasley RP, Tsui J, Lee WC. Vertical transmission of hepatitis B antigen in Taiwan. N Engl J Med. 1975 Apr 10;292(15):771-4. doi: 10.1056/NEJM197504102921503.
citation: Sheu JC, Wang JT, Wang TH, Wang CY, Yang PM, Huang GT, Shih LN, Lee HS, Chen DS. Prevalence of hepatitis C viral infection in a community in Taiwan. Detection by synthetic peptide-based assay and polymerase chain reaction. J Hepatol. 1993 Feb;17(2):192-8. doi: 10.1016/s0168-8278(05)80037-6.
citation: Yang JF, Lin CI, Huang JF, Dai CY, Lin WY, Ho CK, Hsieh MY, Lee LP, Ho NJ, Lin ZY, Chen SC, Hsieh MY, Wang LY, Yu ML, Chuang WL, Chang WY. Viral hepatitis infections in southern Taiwan: a multicenter community-based study. Kaohsiung J Med Sci. 2010 Sep;26(9):461-9. doi: 10.1016/S1607-551X(10)70073-5.
citation: Liu CJ, Chen PJ, Chen DS. Dual chronic hepatitis B virus and hepatitis C virus infection. Hepatol Int. 2009 Dec;3(4):517-25. doi: 10.1007/s12072-009-9147-9. Epub 2009 Aug 8.
citation: Huang YT, Jen CL, Yang HI, Lee MH, Su J, Lu SN, Iloeje UH, Chen CJ. Lifetime risk and sex difference of hepatocellular carcinoma among patients with chronic hepatitis B and C. J Clin Oncol. 2011 Sep 20;29(27):3643-50. doi: 10.1200/JCO.2011.36.2335. Epub 2011 Aug 22.
citation: Liu CJ, Chuang WL, Lee CM, Yu ML, Lu SN, Wu SS, Liao LY, Chen CL, Kuo HT, Chao YC, Tung SY, Yang SS, Kao JH, Liu CH, Su WW, Lin CL, Jeng YM, Chen PJ, Chen DS. Peginterferon alfa-2a plus ribavirin for the treatment of dual chronic infection with hepatitis B and C viruses. Gastroenterology. 2009 Feb;136(2):496-504.e3. doi: 10.1053/j.gastro.2008.10.049. Epub 2008 Oct 29.
citation: Potthoff A, Wedemeyer H, Boecher WO, Berg T, Zeuzem S, Arnold J, Spengler U, Gruengreiff K, Kaeser T, Schuchmann M, Bergk A, Forestier N, Deterding K, Manns MP, Trautwein C; Hep-Net B/C Co-infection Study Group. The HEP-NET B/C co-infection trial: A prospective multicenter study to investigate the efficacy of pegylated interferon-alpha2b and ribavirin in patients with HBV/HCV co-infection. J Hepatol. 2008 Nov;49(5):688-94. doi: 10.1016/j.jhep.2008.03.028. Epub 2008 Apr 29.
citation: Yu JW, Sun LJ, Zhao YH, Kang P, Gao J, Li SC. Analysis of the efficacy of treatment with peginterferon alpha-2a and ribavirin in patients coinfected with hepatitis B virus and hepatitis C virus. Liver Int. 2009 Nov;29(10):1485-93. doi: 10.1111/j.1478-3231.2009.02080.x. Epub 2009 Jul 7.
citation: Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, Poordad F, Goodman ZD, Sings HL, Boparai N, Burroughs M, Brass CA, Albrecht JK, Esteban R; HCV RESPOND-2 Investigators. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011 Mar 31;364(13):1207-17. doi: 10.1056/NEJMoa1009482.
citation: Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, Focaccia R, Younossi Z, Foster GR, Horban A, Ferenci P, Nevens F, Mullhaupt B, Pockros P, Terg R, Shouval D, van Hoek B, Weiland O, Van Heeswijk R, De Meyer S, Luo D, Boogaerts G, Polo R, Picchio G, Beumont M; REALIZE Study Team. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011 Jun 23;364(25):2417-28. doi: 10.1056/NEJMoa1013086.
citation: Yu ML, Lee CM, Chen CL, Chuang WL, Lu SN, Liu CH, Wu SS, Liao LY, Kuo HT, Chao YC, Tung SY, Yang SS, Kao JH, Su WW, Lin CL, Yang HC, Chen PJ, Chen DS, Liu CJ; Taiwan Liver-Net Consortium. Sustained hepatitis C virus clearance and increased hepatitis B surface antigen seroclearance in patients with dual chronic hepatitis C and B during posttreatment follow-up. Hepatology. 2013 Jun;57(6):2135-42. doi: 10.1002/hep.26266. Epub 2013 Apr 26.