Clinical trial NCT00532701: Peginterferon Alfa-2a and Ribavirin for Genotype 2 Chronic Hepatitis C: Duration and Ribavirin Dose Stratified by RVR
Official title: Peginterferon Alfa-2a Plus Ribavirin in Patients With Genotype 2 Chronic Hepatitis C: A Randomized Study of Treatment Duration and Ribavirin Dose Stratified by Rapid Virologic Response
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Chronic Hepatitis C
Keywords: Chronic hepatitis C
Genotype
Interferon
Ribavirin
Genotype 2
Peginterferon
Lead sponsor: National Taiwan University Hospital
Sponsor class: OTHER
Collaborators: name: National Science and Technology Council, Taiwan
name: Department of Health, Executive Yuan, R.O.C. (Taiwan)
First posted: 2007-09-20
Enrollment: 880
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Treatment with peginterferon plus daily low dose (800 mg) or weight-based ribavirin (800-1400 mg) for 24 to 48 weeks has achieved 70-93% sustained virologic response (SVR) rates in patients with genotype 2 or 3 chronic hepatitis C (CHC). Recently, a large randomized study has shown that patients with genotype 2 or 3 CHC have comparable SVR rates for those who received peginterferon for 24 or 48 weeks, and who received daily low dose (800 mg) or standard dose (1000-1200 mg) ribavirin. Therefore, the currently recommended treatment for these patients is 24 weeks of peginterferon plus low dose ribavirin. Because of the high response rates, several studies have shown that when these patients had rapid virologic response (RVR), defined as undetectable hepatitis C virus (HCV) ribonucleic acid (RNA) levels, at week 4 of peginterferon plus weight-based ribavirin, 12-16 weeks of treatment could have 82-94% SVR rates. However, treatment with peginterferon plus low dose ribavirin for 24 weeks showed significantly higher SVR rates than that for 16 weeks (85% versus 79%) in these patients who achieved RVR. While studies showed concordant results in SVR rates for patients with genotype 3 CHC who received peginterferon plus low dose or weight-based ribavirin for 16 or 24 weeks, the SVR rates stratified by RVR showed great differences in patients with genotype 2 CHC who received such treatment. Currently, there are no studies on the direct comparison of low dose versus weight-based ribavirin, and of 16 to 24 weeks of treatment stratified by RVR for patients with genotype 2 CHC. The investigators aimed to conduct a randomized trial to determine the optimal ribavirin dose and treatment duration of peginterferon plus ribavirin for patients with genotype 2 CHC based on RVR studies.

Detailed description: Treatment with peginterferon plus daily low dose (800 mg) or weight-based ribavirin (800-1400 mg) for 24 to 48 weeks has achieved 70-93% sustained virologic response (SVR) rates in patients with genotype 2 or 3 chronic hepatitis C (CHC). Recently, a large randomized study has shown that patients with genotype 2 or 3 CHC have comparable SVR rates for those who received peginterferon for 24 or 48 weeks, and who received daily low dose (800 mg) or standard dose (1000-1200 mg) ribavirin. Therefore, the currently recommended treatment for these patients is 24 weeks of peginterferon plus low dose ribavirin. Because of the high response rates, several studies have shown that when these patients had rapid virologic response (RVR), defined as undetectable hepatitis C virus (HCV) RNA levels, at week 4 of peginterferon plus weight-based ribavirin, 12-16 weeks of treatment could have 82-94% SVR rates. However, treatment with peginterferon plus low dose ribavirin for 24 weeks showed significantly higher SVR rates than that for 16 weeks (85% vs. 79%) in these patients who achieved RVR. While studies showed concordant results in SVR rates for patients with genotype 3 CHC who received peginterferon plus low dose or weight-based ribavirin for 16 or 24 weeks, the SVR rates stratified by RVR showed great differences in patients with genotype 2 CHC who received such treatment. Currently, there are no studies on the direct comparison of low dose versus weight-based ribavirin, and of 16 to 24 weeks of treatment stratified by RVR for patients with genotype 2 CHC. We aimed to conduct a randomized trial to determine the optimal ribavirin dose and treatment duration of peginterferon plus ribavirin for patients with genotype 2 CHC based on RVR studies.

Eligibility criteria: Inclusion Criteria:

* Treatment naïve
* Age older than 18 years old
* Anti-HCV (Abbott HCV EIA 2.0, Abbott Diagnostic, Chicago, IL) positive \> 6 months
* Detectable serum quantitative HCV-RNA (Cobas Taqman HCV Monitor v2.0, Roche Diagnostics) with dynamic range 25 \~ 391000000 IU/ml
* HCV genotype 2 (Inno-LiPA HCV II, Innogenetics, Ghent, Belgium)
* Serum alanine aminotransferase levels above the upper limit of normal with 6 months of enrollment
* A liver biopsy consistent with the diagnosis of chronic hepatitis C

Exclusion Criteria:

* Anemia (hemoglobin \< 13 grams per deciliter for men and \< 12 grams per deciliter for women)
* Neutropenia (neutrophil count \< 1,500 per cubic milliliter)
* Thrombocytopenia (platelets \< 90,000 per cubic milliliter)
* Co-infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV)
* Chronic alcohol abuse (daily consumption \> 20 grams per day)
* Decompensated liver disease (Child-Pugh class B or C)
* Serum creatinine level more than 1.5 times the upper limit of normal
* Autoimmune liver disease
* Neoplastic disease
* An organ transplant
* Immunosuppressive therapy
* Poorly controlled autoimmune diseases, pulmonary diseases, cardiac diseases, psychiatric diseases, neurological diseases, diabetes mellitus
* Evidence of drug abuse
* Unwilling to use contraception
* Unwilling to sign informed consent

Primary outcomes:
measure: Sustained virologic response (SVR)
timeFrame: 1.5 year
Secondary outcomes:
measure: Histologic response (HR)
timeFrame: 1.5 year
measure: Biochemical response (BR)
timeFrame: 1.5
Other outcomes:
Locations:
city: Douliou
country: Taiwan
facility: National Taiwan University Hospital, Yun-Lin Branch
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Municipal Hsiao-Kang Hospital
city: Pingtung
country: Taiwan
facility: Paochien Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Buddhist Xindian Tzu Chi General Hospital
city: Taipei
country: Taiwan
facility: Far Eastern Memorial Hospital
city: Taipei
country: Taiwan
facility: Ren-Ai Branch, Taipei Municipal Hospital
Study officials:
affiliation: National Taiwan University Hospital
name: Jia-Horng Kao, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Taiwan University Hospital
name: Ding-Shinn Chen, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Taiwan University Hospital
name: Ming-Yang Lai, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Taiwan University Hospital
name: Pei-Jer Chen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Taiwan University Hospital
name: Chun-Jen Liu, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Taiwan University Hospital
name: Chen-Hua Liu, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Taiwan University Hospital, Yun-Lin Branch
name: Shih-Jer Hsu, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Taipei City Hospital, Ren-Ai Branch
name: Chih-Lin Lin, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Far Eastern Memorial Hospital
name: Cheng-Chao Liang, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Buddhist Xindian Tzu Chi General Hospital
name: Ching-Sheng Hsu, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Taichung Veterans General Hospital
name: Sheng-Shun Yang, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Buddhist Xindian Tzu Chi General Hospital
name: Chia-Chi Wang, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Buddhist Xindian Tzu Chi General Hospital
name: Tai-Chung Tseng, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Kaohsiung Medical University
name: Ming-Lung Yu, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Kaohsiung Medical University
name: Wan-Long Chuang, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Kaohsiung Municipal Hsiao-Kang Hospital
name: Chia-Yen Dai, MD, Ms
role: PRINCIPAL_INVESTIGATOR
affiliation: Kaohsiung Municipal Hsiao-Kang Hospital
name: Jee-Fu Huang, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Paochien Hospital
name: Chang-Fu Chiu, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001 Sep 22;358(9286):958-65. doi: 10.1016/s0140-6736(01)06102-5.
citation: Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr, Haussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002 Sep 26;347(13):975-82. doi: 10.1056/NEJMoa020047.
citation: Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P, Ramadori G, Bodenheimer H Jr, Bernstein D, Rizzetto M, Zeuzem S, Pockros PJ, Lin A, Ackrill AM; PEGASYS International Study Group. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004 Mar 2;140(5):346-55. doi: 10.7326/0003-4819-140-5-200403020-00010.
citation: Zeuzem S, Hultcrantz R, Bourliere M, Goeser T, Marcellin P, Sanchez-Tapias J, Sarrazin C, Harvey J, Brass C, Albrecht J. Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol. 2004 Jun;40(6):993-9. doi: 10.1016/j.jhep.2004.02.007.
citation: Shiffman ML, Suter F, Bacon BR, Nelson D, Harley H, Sola R, Shafran SD, Barange K, Lin A, Soman A, Zeuzem S; ACCELERATE Investigators. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med. 2007 Jul 12;357(2):124-34. doi: 10.1056/NEJMoa066403.
citation: Strader DB, Wright T, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C. Hepatology. 2004 Apr;39(4):1147-71. doi: 10.1002/hep.20119. No abstract available.
citation: Dalgard O, Bjoro K, Hellum KB, Myrvang B, Ritland S, Skaug K, Raknerud N, Bell H. Treatment with pegylated interferon and ribavarin in HCV infection with genotype 2 or 3 for 14 weeks: a pilot study. Hepatology. 2004 Dec;40(6):1260-5. doi: 10.1002/hep.20467.
citation: von Wagner M, Huber M, Berg T, Hinrichsen H, Rasenack J, Heintges T, Bergk A, Bernsmeier C, Haussinger D, Herrmann E, Zeuzem S. Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology. 2005 Aug;129(2):522-7. doi: 10.1016/j.gastro.2005.05.008.
citation: Mangia A, Santoro R, Minerva N, Ricci GL, Carretta V, Persico M, Vinelli F, Scotto G, Bacca D, Annese M, Romano M, Zechini F, Sogari F, Spirito F, Andriulli A. Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2 or 3. N Engl J Med. 2005 Jun 23;352(25):2609-17. doi: 10.1056/NEJMoa042608.
citation: Yu ML, Dai CY, Huang JF, Hou NJ, Lee LP, Hsieh MY, Chiu CF, Lin ZY, Chen SC, Hsieh MY, Wang LY, Chang WY, Chuang WL. A randomised study of peginterferon and ribavirin for 16 versus 24 weeks in patients with genotype 2 chronic hepatitis C. Gut. 2007 Apr;56(4):553-9. doi: 10.1136/gut.2006.102558. Epub 2006 Sep 6.
citation: Liu CH, Huang CF, Liu CJ, Dai CY, Huang JF, Lin JW, Liang CC, Yang SS, Lin CL, Su TH, Yang HC, Chen PJ, Chen DS, Chuang WL, Kao JH, Yu ML. Peginterferon plus weight-based ribavirin for treatment-naive hepatitis C virus genotype 2 patients not achieving rapid virologic response: a randomized trial. Sci Rep. 2015 Jul 1;5:11710. doi: 10.1038/srep11710.