Hepatitis C Treatment Naive Genotype 1 Consensus Interferon Trial
|First Received Date ICMJE||September 13, 2005|
|Last Updated Date||February 17, 2011|
|Start Date ICMJE||July 2005|
|Primary Completion Date||July 2008 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||The primary endpoint would be the number who achieve a sustained virologic response.|
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT00211692 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||Secondary endpoints are the percentage of patients who complete therapy, have significant adverse events, and the relationship of early virologic response at each 4 week period between 4 and 24 weeks and those who achieve a sustained virologic response.|
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Hepatitis C Treatment Naive Genotype 1 Consensus Interferon Trial|
|Official Title ICMJE||Prospective Randomized Pilot Study of Daily Consensus Interferon (CIFN) and Ribavirin for 52 Wks vs Extended Duration 72 Wks Based on Virologic Response for the Initial Treatment of Difficult-to-treat Patients With Chronic HCV Genotype 1|
Data have suggested that consensus interferon (CIFN) has greater antiviral activity in vitro compared with interferon alfa-2a or alfa-2b. Several clinical studies also suggest that CIFN has greater antiviral activity in patients with genotype 1 hepatitis C infection, particularly if given as a daily injection. These data indicate that the use of a regimen of daily CIFN and ribavirin will lead to greater virologic response rates compared with pegylated interferon alfa-2b and ribavirin in patients with genotype 1 infection, with comparable adverse events. Emerging data indicate that HCV genotype 1 patients with a delayed virologic response to initial therapy may benefit from an extended duration of therapy. Therefore, the goals of this pilot study are to determine the tolerability and efficacy of daily CIFN plus ribavirin when given for 52 weeks or an extended duration of therapy. The target population will consist of "difficult-to-treat" patients, defined as having the following characteristics: genotype 1, a North American patient population, predominantly male gender, and no specific exclusions for pre-existing psychiatric or substance abuse co-morbidities.
Current treatment for hepatitis C is a pegylated interferon alfa plus ribavirin. This treatment is inadequate for patients with HCV genotype 1, since the majority of patients do not respond (termed non-responders) or respond but relapse (termed relapsers) following termination of these treatments. Data from the Veterans Health Administration (VHA) Hepatitis C Registry and community hospitals indicate that the large majority of patients identified with hepatitis C have characteristics associated with a poor treatment response and remain untreated at this time. Data have suggested that consensus interferon (CIFN, CIFN or interferon alfacon-1) has greater antiviral activity in vitro compared with interferon alfa-2a or alfa-2b. Preliminary data indicate that more patients with genotype 1 can respond to CIFN and ribavirin than current standard treatments, due to the fact that approximately 25% of patients who are nonresponders to pegylated interferon and ribavirin may have a sustained response to a regimen of daily CIFN and ribavirin. Furthermore, difficult to treat patients may benefit from a longer duration of therapy than the standard 48 week regimen based on when an initial virologic response to therapy occurs.
Aims: To determine the safety and efficacy of (A) daily CIFN (15 mcg/d sq) and ribavirin (1-1.2 gm/d PO) given for 52 weeks, vs (B) daily CIFN (15 mcg/d sq) and ribavirin (1-1.2 gm/d PO) given for 52 to 72 weeks for treatment-naïve patients with hepatitis C genotype 1, with treatment duration based on the virologic response during the initial 24 weeks.
Methods: Patients who meet eligibility criteria will be stratified by race and randomized to one of two treatment arms, and all patients will have viral kinetics measured by quantitative PCR at weeks 4,8,12,16,20 and 24. Patients in treatment arm A will follow "standard" stopping rules, i.e., if there is not a 2-log drop in viremia by 12 weeks the treatment will be discontinued, otherwise they will all receive 52 weeks of treatment if they also are qualitative PCR negative by week 24. In treatment arm B the patients will be monitored monthly until they have a virologic response (defined as >2 log drop in viral levels from baseline) by quantitative PCR for up to 24 weeks. Once they have a virologic response by quantitative PCR their treatment will be continued for an additional 48 weeks. In both groups, treatment will be stopped if the patients do not become negative for HCV RNA by qualitative PCR by 24 weeks on therapy. A total of 192 patients at up to 10-20 sites will be recruited. The primary endpoint would be the number who achieve a sustained virologic response; secondary endpoints are the percentage of patients who complete therapy, have significant adverse events, and the relationship of early virologic response at each 4 week period between 4 and 24 weeks and those who achieve a sustained virologic response.
Sample size determination: To detect an absolute difference of 20% or more in sustained virologic response between treatment arms A and B; the Log-rank test is performed at the alpha level of .05 and the test is maintained at least 80 percent statistical power; it is estimated that a total of 96 patients in each treatment arm will be required.
Analysis: Univariate and multivariate analysis will be used to determine factors associated with final endpoints. Subgroup analyses will be done based on time to early virologic response and duration of therapy each stratification. The primary and secondary endpoints will be determined on an intention-to-treat basis starting with all patients that receive at least one dose of study medications. The primary and secondary endpoints will also be determined in a per-protocol analysis on those patients who take 80% of the prescribed CIFN and 80% of the prescribed ribavirin for 80% of the time.
Significance: The current initial treatment of pegylated interferon alfa and ribavirin for patients with hepatitis C who are genotype 1 and have other "difficult-to-treat" characteristics is inadequate. The results of this trial are needed to demonstrate the safety and efficacy of two regimens of daily CIFN and ribavirin. Since the large majority of hepatitis C patients in VA and other community hospitals fall into this category, the results of this trial may influence the potential treatments recommended for these patients.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 3|
|Study Design ICMJE||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Condition ICMJE||Chronic Hepatitis C|
|Study Arm (s)||
|Publications *||Ho SB, Aqel B, Dieperink E, Liu S, Tetrick L, Falck-Ytter Y, Decomarmond C, Smith CI, McKee DP, Boyd W, Kulig CC, Bini EJ, Pedrosa MC. U.S. Multicenter Pilot Study of Daily Consensus Interferon (CIFN) Plus Ribavirin for "Difficult-to-Treat" HCV Genotype 1 Patients. Dig Dis Sci. 2011 Jan 11; [Epub ahead of print]|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Completion Date||September 2009|
|Primary Completion Date||July 2008 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
1. Chronic hepatitis C. This is defined as the documentation of the presence of circulating hepatitis C virus by a positive hepatitis C PCR test and a positive HCV genotype test for genotype 1, and a liver biopsy (within the previous 5 years) that is compatible with chronic hepatitis. (Note: no requirement is made for the presence of abnormal transaminases. Patients with persistently normal transaminases are allowed if they meet the definition of chronic hepatitis C above). Liver biopsy data is required on at least 90% of enrolled patients to allow for the potential refusal of patients for the liver biopsy test. In the case of patients that have refused liver biopsies a clinical diagnosis of chronic hepatitis C is required. In the absence of a liver biopsy within five years the clinical diagnosis requires a history compatible with a chronic hepatitis C infection with the documentation of the presence of circulating hepatitis C virus by a positive hepatitis C PCR test and a positive HCV genotype test for genotype 1, and biochemical evidence of prior abnormal transaminases at two times covering a time span of at least 6 months.
2. Positive HCV RNA by PCR, Genotype 1, treatment naive 3. Age 18-65 years. 4. Patient must be able to give informed consent. 5. Eligible for interferon alfa and ribavirin-based antiviral treatment:
1) CNS trauma or active seizure disorders requiring medication. 2) Significant cardiovascular dysfunction within the past 12 months 3) Poorly controlled diabetes mellitus (in the opinion of the site PI). 4) Moderate or severe chronic pulmonary disease 5) Clinically significant immunologically mediated disease 6) Hemoglobinopathies (e.g., Thalassemia) or any other cause of hemolytic anemia.
7) Evidence of decompensated liver disease such as a history of or presence of ascites, bleeding varices, or spontaneous encephalopathy or CHILD-PUGH scores B or C.
8) Any medical condition requiring, or likely to require during the course of the study, chronic systemic administration of steroids.
9) Hypersensitivity to interferon alfa or ribavirin 10) Known anti-HIV positive 11) Clinically significant retinopathy 12) Previous solid organ transplantation 13) Any condition that, in the opinion of the investigator, will prevent the patient from being compliant with study medications or appointments.
8. Patients who develop hepatic decompensation during the course of treatment. The PT/INR, total bilirubin, albumin will be repeated at the 24 week interval to allow for a re-calculation of the CHILD-PUGH score. Patients who have developed a score of 7 or greater (CHILD-PUGH class B or greater) be considered for discontinuation of the study.
|Ages||18 Years to 65 Years|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Location Countries ICMJE||Not Provided|
|NCT Number ICMJE||NCT00211692|
|Other Study ID Numbers ICMJE||MVRI001|
|Has Data Monitoring Committee||Yes|
|Responsible Party||Samuel B. Ho, M.D., VA San Diego Healthcare System|
|Study Sponsor ICMJE||Department of Veterans Affairs|
|Information Provided By||Minneapolis Veterans Affairs Medical Center|
|Verification Date||September 2005|
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