Clinical trial NCT00006164: Long Term Interferon for Patients Who Did Not Clear Hepatitis C Virus With Standard Treatment
Official title: Hepatitis C Antiviral Long-term Treatment Against Cirrhosis Trial (HALT-C)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Hepatitis c
Cirrhosis, Liver
Fibrosis, Liver
Hepatic Cirrhosis
Keywords: liver disease
hepatitis c virus
antiviral agent
cirrhosis
Lead sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor class: NIH
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
name: National Institute on Minority Health and Health Disparities (NIMHD)
name: National Cancer Institute (NCI)
name: Hoffmann-La Roche
First posted: 2000-08-09
Enrollment: 1050
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The HALT-C Trial is a National Institute of Diabetes and Digestive and Kidney Diseases sponsored, randomized clinical trial of long-term use of Peginterferon alfa-2a (pegylated interferon) in patients who failed to respond to prior interferon treatment. All patients who enter the trial will be treated for 6 months with Peginterferon alfa-2a and Ribavirin. Patients who respond to this 6 month treatment will continue to be treated for an additional 6 months.

Patients who do not respond to this treatment will be eligible for the long-term maintenance phase of this study where patients will be randomly selected to be treated with Peginterferon alfa-2a or to discontinue treatment for 3.5 years. Patients in both arms of this study will be followed closely with quarterly study visits.

The combination of peginterferon plus ribavirin has recently been approved by the FDA for treatment of chronic hepatitis C. Patients who remain HCV-RNA positive after being treated for at least 6 months with peginterferon and ribavirin outside of this study may be eligible to directly enter the randomized portion of the HALT-C Trial.

The HALT-C study is designed to determine if continuing interferon long-term over several years will suppress Hepatitis C virus, prevent progression to cirrhosis, prevent liver cancer and reduce the need for liver transplantation.


Eligibility criteria: Inclusion Criteria:

* Age at entry at least 18 years.
* Positive for Hepatitis C.
* Previous treatment with any interferon or interferon and ribavirin for at least 3 months.
* Documented non-response to treatment with interferon.
* A liver biopsy demonstrating significant liver scarring.

Exclusion Criteria:

* No other liver disease.
* No unstable major medical diseases or conditions.
* No major complications of cirrhosis.
* No recent abuse of alcohol or illicit drugs.

Primary outcomes:
measure: Progression of Liver Disease as Indicated by Death, Hepatic Decompensation, Hepatocellular Carcinoma, or for Patients With Noncirrhotic Fibrosis at Baseline, an Increase in the Ishak Hepatic Fibrosis Score of 2 or More Points
timeFrame: 1400 days (3.85 years) post randomization
measure: Increase in Ishak Fibrosis Score by 2 Points or More at 2 or 4 Year Biopsies
timeFrame: 1400 days (3.85 years) post randomization
measure: Death From Any Cause
timeFrame: 1400 days (3.85 years) post randomization
measure: Development of Hepatocellular Carcinoma (HCC)
timeFrame: 1400 days (3.85 years) post randomization
measure: Child-Turcotte-Pugh (CTP) Score of 7 or Higher at Two Consecutive Study Visits
timeFrame: 1400 days (3.85 years) post randomization
measure: Variceal Hemorrhage
timeFrame: 1400 days (3.85 years) post randomization
measure: Ascites
timeFrame: 1400 days (3.85 years) post randomization
measure: Spontaneous Bacterial Peritonitis
timeFrame: 1400 days (3.85 years) post randomization
measure: Hepatic Encephalopathy
timeFrame: 1400 days (3.85 years) post randomization
Secondary outcomes:
measure: Serious Adverse Events
timeFrame: 1400 days (3.85 years) post randomization
measure: Changes in Fibrosis From Baseline at Year 2 or Year 4 Biopsy.
timeFrame: 1400 days (3.85 years) post randomization
measure: Presumed Hepatocellular Carcinoma (HCC)
timeFrame: 1400 days (3.85 years) post randomization
measure: SF-36 Vitality Summary Score
timeFrame: 0.5, 1.5, 2.5, and 3.5 years after randomization
measure: SF-36 Physical Function Summary Score
timeFrame: 0.5, 1.5, 2.5, and 3.5 years after randomization
measure: SF-36 Mental Health Summary Score
timeFrame: 0.5, 1.5, 2.5, and 3.5 years after randomization
Other outcomes:
Locations:
city: Long Beach
country: United States
facility: University of California-Irvine/VA Medical Center-Long Beach
state: California
city: Los Angeles
country: United States
facility: USC School of Medicine
state: California
city: Denver
country: United States
facility: UCHSC (University of Colorado)
state: Colorado
city: Farmington
country: United States
facility: University of Connecticut Health Center
state: Connecticut
city: Bethesda
country: United States
facility: Lds, Niddk, Nih
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Worcester
country: United States
facility: UMass Memorial HealthCare, University Campus
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Saint Louis
country: United States
facility: Saint Louis University
state: Missouri
city: Dallas
country: United States
facility: University of Texas Southwestern - Dallas
state: Texas
city: Richmond
country: United States
facility: Medical College of Virginia
state: Virginia
Study officials:
affiliation: UCHSC (University of Colorado)
name: Gregory T. Everson, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: St. Louis University
name: Adrian M. Di Bisceglie, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Texas, Southwestern Medical Center at Dallas
name: William M. Lee, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: LDS, NIDDK, NIH
name: Marc Ghany, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Massachusetts General Hospital
name: Jules L. Dienstag, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical College of Virginia
name: Mitchell Shiffman, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Michigan
name: Anna Lok, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California-Irvine/VA Medical Center-Long Beach
name: Tim Morgan, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: USC School of Medicine
name: Karen Lindsay, M.D., M.M.M.
role: PRINCIPAL_INVESTIGATOR
affiliation: UMass Medical School
name: Gyongyi Szabo, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lee WM, Dienstag JL, Lindsay KL, Lok AS, Bonkovsky HL, Shiffman ML, Everson GT, Di Bisceglie AM, Morgan TR, Ghany MG, Morishima C, Wright EC, Everhart JE; HALT-C Trial Group. Evolution of the HALT-C Trial: pegylated interferon as maintenance therapy for chronic hepatitis C in previous interferon nonresponders. Control Clin Trials. 2004 Oct;25(5):472-92. doi: 10.1016/j.cct.2004.08.003.
citation: Di Bisceglie AM, Shiffman ML, Everson GT, Lindsay KL, Everhart JE, Wright EC, Lee WM, Lok AS, Bonkovsky HL, Morgan TR, Ghany MG, Morishima C, Snow KK, Dienstag JL; HALT-C Trial Investigators. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. N Engl J Med. 2008 Dec 4;359(23):2429-41. doi: 10.1056/NEJMoa0707615.
citation: Donlin MJ, Lomonosova E, Kiss A, Cheng X, Cao F, Curto TM, Di Bisceglie A, Tavis JE. HCV genome-wide genetic analyses in context of disease progression and hepatocellular carcinoma. PLoS One. 2014 Jul 31;9(7):e103748. doi: 10.1371/journal.pone.0103748. eCollection 2014.
citation: Snow KK, Bell MC, Stoddard AM, Curto TM, Wright EC, Dienstag JL. Processes to manage analyses and publications in a phase III multicenter randomized clinical trial. Trials. 2014 May 7;15:159. doi: 10.1186/1745-6215-15-159.
citation: Morishima C, Shiffman ML, Dienstag JL, Lindsay KL, Szabo G, Everson GT, Lok AS, Di Bisceglie AM, Ghany MG, Naishadham D, Morgan TR, Wright EC; HALT-C Trial Group. Reduction in Hepatic Inflammation Is Associated With Less Fibrosis Progression and Fewer Clinical Outcomes in Advanced Hepatitis C. Am J Gastroenterol. 2012 Sep;107(9):1388-98. doi: 10.1038/ajg.2012.137. Epub 2012 Jun 12.
citation: Morishima C, Di Bisceglie AM, Rothman AL, Bonkovsky HL, Lindsay KL, Lee WM, Koziel MJ, Fontana RJ, Kim HY, Wright EC; HALT-C Trial Group. Antigen-specific T lymphocyte proliferation decreases over time in advanced chronic hepatitis C. J Viral Hepat. 2012 Jun;19(6):404-13. doi: 10.1111/j.1365-2893.2011.01562.x. Epub 2011 Dec 16.
citation: Fontana RJ, Litman HJ, Dienstag JL, Bonkovsky HL, Su G, Sterling RK, Lok AS; HALT-C Trial Group. YKL-40 genetic polymorphisms and the risk of liver disease progression in patients with advanced fibrosis due to chronic hepatitis C. Liver Int. 2012 Apr;32(4):665-74. doi: 10.1111/j.1478-3231.2011.02686.x. Epub 2011 Nov 22.
citation: Everson GT, Shiffman ML, Hoefs JC, Morgan TR, Sterling RK, Wagner DA, Lauriski S, Curto TM, Stoddard A, Wright EC; HALT-C Trial Group. Quantitative liver function tests improve the prediction of clinical outcomes in chronic hepatitis C: results from the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis Trial. Hepatology. 2012 Apr;55(4):1019-29. doi: 10.1002/hep.24752. Epub 2012 Mar 1.
citation: Sterling RK, Wright EC, Morgan TR, Seeff LB, Hoefs JC, Di Bisceglie AM, Dienstag JL, Lok AS. Frequency of elevated hepatocellular carcinoma (HCC) biomarkers in patients with advanced hepatitis C. Am J Gastroenterol. 2012 Jan;107(1):64-74. doi: 10.1038/ajg.2011.312. Epub 2011 Sep 20.
citation: O'Bryan JM, Potts JA, Bonkovsky HL, Mathew A, Rothman AL; HALT-C Trial Group. Extended interferon-alpha therapy accelerates telomere length loss in human peripheral blood T lymphocytes. PLoS One. 2011;6(8):e20922. doi: 10.1371/journal.pone.0020922. Epub 2011 Aug 4.
citation: Rakoski MO, Brown MB, Fontana RJ, Bonkovsky HL, Brunt EM, Goodman ZD, Lok AS, Omary MB; HALT-C Trial Group. Mallory-Denk bodies are associated with outcomes and histologic features in patients with chronic hepatitis C. Clin Gastroenterol Hepatol. 2011 Oct;9(10):902-909.e1. doi: 10.1016/j.cgh.2011.07.006. Epub 2011 Jul 23.
citation: O'Brien TR, Everhart JE, Morgan TR, Lok AS, Chung RT, Shao Y, Shiffman ML, Dotrang M, Sninsky JJ, Bonkovsky HL, Pfeiffer RM; HALT-C Trial Group. An IL28B genotype-based clinical prediction model for treatment of chronic hepatitis C. PLoS One. 2011;6(7):e20904. doi: 10.1371/journal.pone.0020904. Epub 2011 Jul 8.
citation: Hoefs JC, Shiffman ML, Goodman ZD, Kleiner DE, Dienstag JL, Stoddard AM; HALT-C Trial Group. Rate of progression of hepatic fibrosis in patients with chronic hepatitis C: results from the HALT-C Trial. Gastroenterology. 2011 Sep;141(3):900-908.e1-2. doi: 10.1053/j.gastro.2011.06.007. Epub 2011 Jun 12.
citation: Dienstag JL, Ghany MG, Morgan TR, Di Bisceglie AM, Bonkovsky HL, Kim HY, Seeff LB, Szabo G, Wright EC, Sterling RK, Everson GT, Lindsay KL, Lee WM, Lok AS, Morishima C, Stoddard AM, Everhart JE; HALT-C Trial Group. A prospective study of the rate of progression in compensated, histologically advanced chronic hepatitis C. Hepatology. 2011 Aug;54(2):396-405. doi: 10.1002/hep.24370. Epub 2011 Jun 23.
citation: Freedman ND, Curto TM, Lindsay KL, Wright EC, Sinha R, Everhart JE; HALT-C TRIAL GROUP. Coffee consumption is associated with response to peginterferon and ribavirin therapy in patients with chronic hepatitis C. Gastroenterology. 2011 Jun;140(7):1961-9. doi: 10.1053/j.gastro.2011.02.061. Epub 2011 Mar 2.
citation: Lok AS, Everhart JE, Di Bisceglie AM, Kim HY, Hussain M, Morgan TR; HALT-C Trial Group. Occult and previous hepatitis B virus infection are not associated with hepatocellular carcinoma in United States patients with chronic hepatitis C. Hepatology. 2011 Aug;54(2):434-42. doi: 10.1002/hep.24257.
citation: Lambrecht RW, Sterling RK, Naishadham D, Stoddard AM, Rogers T, Morishima C, Morgan TR, Bonkovsky HL; HALT-C Trial Group. Iron levels in hepatocytes and portal tract cells predict progression and outcomes of patients with advanced chronic hepatitis C. Gastroenterology. 2011 May;140(5):1490-500.e3. doi: 10.1053/j.gastro.2011.01.053. Epub 2011 Feb 15.
citation: Fontana RJ, Sanyal AJ, Ghany MG, Bonkovsky HL, Morgan TR, Litman HJ, Reid AE, Lee WM, Naishadham D; HALT-C Trial Study Group. Development and progression of portal hypertensive gastropathy in patients with chronic hepatitis C. Am J Gastroenterol. 2011 May;106(5):884-93. doi: 10.1038/ajg.2010.456. Epub 2010 Dec 7.
citation: Lok AS, Everhart JE, Wright EC, Di Bisceglie AM, Kim HY, Sterling RK, Everson GT, Lindsay KL, Lee WM, Bonkovsky HL, Dienstag JL, Ghany MG, Morishima C, Morgan TR; HALT-C Trial Group. Maintenance peginterferon therapy and other factors associated with hepatocellular carcinoma in patients with advanced hepatitis C. Gastroenterology. 2011 Mar;140(3):840-9; quiz e12. doi: 10.1053/j.gastro.2010.11.050. Epub 2010 Dec 1.
citation: Freedman ND, Curto TM, Morishima C, Seeff LB, Goodman ZD, Wright EC, Sinha R, Everhart JE; HALT-C Trial Group. Silymarin use and liver disease progression in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis trial. Aliment Pharmacol Ther. 2011 Jan;33(1):127-37. doi: 10.1111/j.1365-2036.2010.04503.x. Epub 2010 Nov 2.
citation: Kronfol Z, Litman HJ, Back-Madruga C, Bieliauskas LA, Lindsay KL, Lok AS, Fontana RJ; HALT-C Trial Group. No increase in depression with low-dose maintenance peginterferon in prior non-responders with chronic hepatitis C. J Affect Disord. 2011 Mar;129(1-3):205-12. doi: 10.1016/j.jad.2010.09.010.
citation: Fontana RJ, Dienstag JL, Bonkovsky HL, Sterling RK, Naishadham D, Goodman ZD, Lok AS, Wright EC, Su GL; HALT-C Trial Group. Serum fibrosis markers are associated with liver disease progression in non-responder patients with chronic hepatitis C. Gut. 2010 Oct;59(10):1401-9. doi: 10.1136/gut.2010.207423. Epub 2010 Jul 30.
citation: Morgan TR, Ghany MG, Kim HY, Snow KK, Shiffman ML, De Santo JL, Lee WM, Di Bisceglie AM, Bonkovsky HL, Dienstag JL, Morishima C, Lindsay KL, Lok AS; HALT-C Trial Group. Outcome of sustained virological responders with histologically advanced chronic hepatitis C. Hepatology. 2010 Sep;52(3):833-44. doi: 10.1002/hep.23744.
citation: Seeff LB, Everson GT, Morgan TR, Curto TM, Lee WM, Ghany MG, Shiffman ML, Fontana RJ, Di Bisceglie AM, Bonkovsky HL, Dienstag JL; HALT-C Trial Group. Complication rate of percutaneous liver biopsies among persons with advanced chronic liver disease in the HALT-C trial. Clin Gastroenterol Hepatol. 2010 Oct;8(10):877-83. doi: 10.1016/j.cgh.2010.03.025. Epub 2010 Apr 1.
citation: Fontana RJ, Sanyal AJ, Ghany MG, Lee WM, Reid AE, Naishadham D, Everson GT, Kahn JA, Di Bisceglie AM, Szabo G, Morgan TR, Everhart JE; HALT-C Trial Group. Factors that determine the development and progression of gastroesophageal varices in patients with chronic hepatitis C. Gastroenterology. 2010 Jun;138(7):2321-31, 2331.e1-2. doi: 10.1053/j.gastro.2010.02.058. Epub 2010 Mar 6.
citation: Snow KK, Bonkovsky HL, Fontana RJ, Kim HY, Sterling RK, Di Bisceglie AM, Morgan TR, Dienstag JL, Ghany MG; HALT-C Trial Group. Changes in quality of life and sexual health are associated with low-dose peginterferon therapy and disease progression in patients with chronic hepatitis C. Aliment Pharmacol Ther. 2010 Apr;31(7):719-34. doi: 10.1111/j.1365-2036.2010.04235.x. Epub 2010 Jan 12.
citation: Lok AS, Sterling RK, Everhart JE, Wright EC, Hoefs JC, Di Bisceglie AM, Morgan TR, Kim HY, Lee WM, Bonkovsky HL, Dienstag JL; HALT-C Trial Group. Des-gamma-carboxy prothrombin and alpha-fetoprotein as biomarkers for the early detection of hepatocellular carcinoma. Gastroenterology. 2010 Feb;138(2):493-502. doi: 10.1053/j.gastro.2009.10.031. Epub 2009 Oct 20.
citation: Ghany MG, Lok AS, Everhart JE, Everson GT, Lee WM, Curto TM, Wright EC, Stoddard AM, Sterling RK, Di Bisceglie AM, Bonkovsky HL, Morishima C, Morgan TR, Dienstag JL; HALT-C Trial Group. Predicting clinical and histologic outcomes based on standard laboratory tests in advanced chronic hepatitis C. Gastroenterology. 2010 Jan;138(1):136-46. doi: 10.1053/j.gastro.2009.09.007. Epub 2009 Sep 18.
citation: Shiffman ML, Morishima C, Dienstag JL, Lindsay KL, Hoefs JC, Lee WM, Wright EC, Naishadham D, Everson GT, Lok AS, Di Bisceglie AM, Bonkovsky HL, Ghany MG; HALT-C Trial Group. Effect of HCV RNA suppression during peginterferon alfa-2a maintenance therapy on clinical outcomes in the HALT-C trial. Gastroenterology. 2009 Dec;137(6):1986-94. doi: 10.1053/j.gastro.2009.08.067. Epub 2009 Sep 10.
citation: Freedman ND, Everhart JE, Lindsay KL, Ghany MG, Curto TM, Shiffman ML, Lee WM, Lok AS, Di Bisceglie AM, Bonkovsky HL, Hoefs JC, Dienstag JL, Morishima C, Abnet CC, Sinha R; HALT-C Trial Group. Coffee intake is associated with lower rates of liver disease progression in chronic hepatitis C. Hepatology. 2009 Nov;50(5):1360-9. doi: 10.1002/hep.23162.
citation: Everhart JE, Lok AS, Kim HY, Morgan TR, Lindsay KL, Chung RT, Bonkovsky HL, Ghany MG; HALT-C Trial Group. Weight-related effects on disease progression in the hepatitis C antiviral long-term treatment against cirrhosis trial. Gastroenterology. 2009 Aug;137(2):549-57. doi: 10.1053/j.gastro.2009.05.007. Epub 2009 May 13.
citation: Lok AS, Everhart JE, Chung RT, Kim HY, Everson GT, Hoefs JC, Greenson JK, Sterling RK, Lindsay KL, Lee WM, Di Bisceglie AM, Bonkovsky HL, Ghany MG, Morishima C; HALT-C Trial Group. Evolution of hepatic steatosis in patients with advanced hepatitis C: results from the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial. Hepatology. 2009 Jun;49(6):1828-37. doi: 10.1002/hep.22865.
citation: Lok AS, Seeff LB, Morgan TR, di Bisceglie AM, Sterling RK, Curto TM, Everson GT, Lindsay KL, Lee WM, Bonkovsky HL, Dienstag JL, Ghany MG, Morishima C, Goodman ZD; HALT-C Trial Group. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease. Gastroenterology. 2009 Jan;136(1):138-48. doi: 10.1053/j.gastro.2008.09.014. Epub 2008 Sep 18.
citation: Lindsay KL, Morishima C, Wright EC, Dienstag JL, Shiffman ML, Everson GT, Lok AS, Bonkovsky HL, Lee WM, Morgan TR, Ghany MG; HALT-C Trial. Blunted cytopenias and weight loss: new correlates of virologic null response to re-treatment of chronic hepatitis C. Clin Gastroenterol Hepatol. 2008 Feb;6(2):234-41. doi: 10.1016/j.cgh.2007.11.020.