The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial was designed to determine whether maintenance interferon therapy could slow disease progression in patients who had failed to eradicate hepatitis C virus (HCV) during prior interferon treatment (nonresponders). Ten clinical sites, a virological testing center, and a data coordinating center (DCC) were selected to collaborate in the design and implementation of the final protocol. Eligible patients had been treated previously with interferon for at least 12 weeks, with or without another antiviral, ribavirin, but still had persistent viremia. Because patients had received a variety of prior treatments, and as a perceived benefit of enrollment, we incorporated a Lead-in period of treatment with long-acting pegylated interferon alfa-2a plus ribavirin into the study design, a combination believed to be more effective but not approved by the Food and Drug Administration at the Trial's inception. If patients failed to achieve clearance of virus from the blood after 20 weeks of this Lead-in therapy, they were entered into the main trial at week 24 and randomized to receive either a lower dose of pegylated interferon weekly alone or no further therapy for an additional 3 1/2 years. The original protocol was amended later in three respects to improve enrollment and to adapt to Food and Drug Administration approval of the Lead-in therapy, including allowing patients to proceed directly to the randomized part of the study if treatment resembling the Lead-in had been completed. The protocol changes enhanced enrollment while upholding the original goals of the study and its integrity.
"The publications committee assigned a writing group to develop the HALT-C trial design manuscript in study year 3 . The paper provided detailed information on study design, hypotheses, outcomes, inclusion and exclusion criteria, sample size and power calculations, study execution, and numbers of patients screened, randomized, and followed. "
[Show abstract][Hide abstract] ABSTRACT: The timely publication of findings in peer-reviewed journals is a primary goal of clinical research. In clinical trials, the processes leading to publication can be complex from choice and prioritization of analytic topics through to journal submission and revisions. As little literature exists on the publication process for multicenter trials, we describe the development, implementation, and effectiveness of such a process in a multicenter trial.
The Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial included a data coordinating center (DCC) and clinical centers that recruited and followed more than 1,000 patients. Publication guidelines were approved by the steering committee, and the publications committee monitored the publication process from selection of topics to publication.
A total of 73 manuscripts were published in 23 peer-reviewed journals. When manuscripts were closely tracked, the median time for analyses and drafting of manuscripts was 8 months. The median time for data analyses was 5 months and the median time for manuscript drafting was 3 months. The median time for publications committee review, submission, and journal acceptance was 7 months, and the median time from analytic start to journal acceptance was 18 months.
Effective publication guidelines must be comprehensive, implemented early in a trial, and require active management by study investigators. Successful collaboration, such as in the HALT-C trial, can serve as a model for others involved in multidisciplinary and multicenter research programs.
The HALT-C Trial was registered with clinicaltrials.gov (NCT00006164).
"Study design & patient population—The overall study design as well as inclusion and exclusion criteria have been published elsewhere (Di Bisceglie et al., 2008; Fontana et al., 2010; Lee et al., 2004). Briefly, hepatitis C patients with advanced fibrosis or cirrhosis (Ishak fibrosis score ≥ 3 on a scale of 0 to 6) failing to achieve a sustained virological response with peginterferon and ribavirin treatment, and with no history of hepatic decompensation or hepatocellular carcinoma were eligible for enrollment into the randomized phase of the HALT-C Trial. "
[Show abstract][Hide abstract] ABSTRACT: Peginterferon and ribavirin treatment of chronic hepatitis C (CHC) is frequently associated with dose-limiting neuropsychiatric toxicity. The purpose of this study is to determine whether prolonged administration of low-dose peginterferon-α2a is associated with an increase in the rate and severity of depression compared to untreated controls.
129 non-responders to full-dose peginterferon and ribavirin treatment were randomized to low-dose maintenance treatment with peginterferon-α2a 90 μg/week or no treatment for 3.5 years. Depression was assessed using the Beck Depression Inventory (BDI-II) and the Composite International Diagnostic Interview (CIDI) at baseline and at 12, 24, 36, and 48 months. "Clinical depression" was defined as BDI-II ≥11 and/or meeting DSM-IV criteria for major depression on the CIDI. Serial cortisol and serotonin plasma concentrations were obtained in a subgroup of patients.
Rates of clinical depression did not significantly differ over time or between treatment groups. Baseline clinical depression was the only significant predictor of clinical depression over time (p<0.001). Rates of clinical depression were also significantly higher in patients experiencing liver disease progression (p=0.016). Antidepressant use did not significantly differ between groups. Adjusted whole blood serotonin levels dropped significantly over time (p=0.04), but there was no group by time effect.
Lack of significant group differences in antidepressant use does not completely preclude significant mood changes masked by antidepressants. Results may differ in treatment naïve CHC patients or in those receiving full-dose peginterferon.
Prolonged low-dose peginterferon-α2a treatment is not associated with an increase in the frequency or severity of clinical depression in prior non-responder patients with chronic hepatitis C.
"The National Institutes of Health sponsored HALT-C trial (Hepatitis C Antiviral Long Term Treatment against Cirrhosis), is a multicenter study of the potential benefit of prolonged peginterferon therapy in mitigating the progression of fibrotic liver disease. 8 In this study, 391 of the 1045 patients enrolled into the initial “lead-in” phase had biopsy proven cirrhosis. Preliminary results show that cirrhosis alone impaired response to therapy, with lower SVR rates compared to non-cirrhotic patients. "
[Show abstract][Hide abstract] ABSTRACT: Despite the improved efficacy of peginterferons, the rate of sustained virologic response is suboptimal in cirrhotic patients, relative to non-cirrhotic patients. However, the treatment of patients with compensated cirrhosis has recently been encouraged by expert panels. Interferon-based therapy may provide additional benefit by reducing the risk of hepatocellular carcinoma in cirrhotic patients as suggested in preliminary studies. Results of two ongoing prospective studies are awaited to answer the important question of the effectiveness of suppressive interferon therapy, even in the absence of sustained virologic response. Given the importance of recurrent HCV following liver transplantation, attention has been directed toward the antiviral treatment of patients with advanced liver disease. This approach needs to be pursued with caution given the potential morbidity of the therapy. Recently, a low accelerating dosage regimen has provided excellent results and is the subject of additional inquiry.
International journal of medical sciences 02/2006; 3(2):75-8. DOI:10.7150/ijms.3.75 · 2.00 Impact Factor
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