Hepatology Research News

Volume 5, Issue 1 May 2001
University of Washington

Inside This Issue
Update on Pegylated Interferon
Currently Enrolling Clinical Trials at the University of Washington
NIH Workshop on Living Donor Liver Transplants
Understanding Clinical Trials
Upcoming Educational Events

Update on Pegylated Interferons

By Anne Larson, M.D.

Interferon alfa has a powerful but transient antiviral effect on Hepatitis C virus (HCV). Viral levels drop within 12 hours of dosing but rebound within 24-48 hours to near baseline values. Newer interferon's with a longer half-life (pegylated interferon's or PEG) recently have been developed. These interferon's offer the advantage of once weekly injection while achieving the pharmacologic equivalent of daily therapy. Reports from clinical trials reveal that pegylated monotherapy is 2-3 times as effective as interferon given 3 times a week (39% vs. 19%). Early reports using pegylated interferon in conjunction with ribavirin show an overall sustained response rates of 54%.

Pegasys Monotherapy Data (peg interferon alfa-2a)
General.   Peg interferon alfa-2a (PegasysTM) is a product of Roche Pharmaceuticals. The original monotherapy trial was done to compare Pegasys to standard interferon alfa-2a(Roferon). Efficacy and Safety:   Overall end of treatment response (ETR) was 69% and sustained responses (SR) was 39% The investigators did not determine response based upon viral genotype. Adverse events (AEs) were similar between standard Roferon and Pegasys with regard to both dose reductions and discontinuation of drug.

Peg Intron Monotherapy Data (peg interferon-2b)
General.   Peg interferon Alfa-2b (Peg-Intron) is a product of Schering-Plough Biotech. This data has not yet been published. This trial was done to assess which dose of Peg-Intron was most effective in obtaining a sustained virological response. Efficacy and Safety:   Overall end of treatment response (ETR) 41% and sustained responses (SR) 25%. PEG-Intron was tolerated fairly well, although overall adverse event profile requiring discontinuation of drug was worse than that reported for interferon monotherapy.

PEG-Intron plus Ribavirin
General.   These trials have recently been completed, and results were reported at the AASLD Liver Meetings in October, 2000. Efficacy:   Efficacy was measured as sustained virological response (SVR) at 6 months after treatment (as in other trials). The investigators for this study reported the data based upon genotype. The data based upon body weight was done retrospectively after the trial was completed The retrospective review of the data using weight as a criteria for ribavirin dose revealed a SVR of 61% overall, 48% in Genotype 1 and 88% in Genotype 2/3. Dose Adjustments.   Adjustments for hematologic and other side effects of the drugs were the same across all groups. There were more adjustments made for hematologic effects in the high dose Peg-Intron arm, but discontinuation due to other adverse events was similar between the groups.

Issues not Addressed.
Standard dosing of ribavirin was not used with the higher dose of Peg-Intron (1.5 mg/kg). Had the "usual" dose of ribavirin been used, a greater improved sustained response rate may have been seen. In genotype 2/3 patients, the issue of whether 6 months rather than 12 months of therapy is adequate was not addressed. All genotypes were treated for 12 months. The "weight-based" findings are all retrospective. Prospective data regarding this issue is not available

Currently Enrolling Clinical Trials

The following is a list of upcoming or currently enrolling clinical trials at the University of Washington

Hepatitis C:

We will soon be enrolling previously untreated, previously treated relapsed and refractory patients into protocols using pegylated interferon plus ribavirin. These trials involve both high doses (3.0 mcg/kg) and standard doses (1.5 mcg/kg) of pegylated interferon in combination with weight based ribavirin. The criteria for these studies are as follows: Male/Female any gender, any race, HCV-RNA positive with compensated liver disease, Liver biopsy within 36 months prior to first dose of study drug, (unless cirrhotic then no repeat biopsy required) consistent with chronic hepatitis C, negative tests for HbsAg, anti HIV Ab, Wilson’s disease, and alpha-1 antitrypsin deficiency, No history of organ transplantation, and not currently pregnant or breastfeeding. In addition they must have a neutrophil count > 1500/mm, platelet count > 70,000/mm3, albumin > 3.0, and no alcohol or drug abuse within the previous 6 months. For more information please call (206) 221-4655.

Hepatitis B:

We are currently enrolling patients with Lamivudine resistant chronic hepatitis B into a research protocol involving a new study drug combination. We are looking for patients that are currently being treated with Lamivudine for their hepatitis B, and have been taking it for at least 6 months. In addition these patients must have initially had a response to the Lamivudine, but then developed breakthrough, with increased ALT and return of HBV-DNA. For more information please call (206) 221-4538.

NIH Workshop on Living Donor Liver Transplants

     The greatest benefit of the living donor transplant ( LDT ) is that it helps to alleviate the shortage of organs, curtails waiting time and decreases the waiting list for patients. As of March 31, 2001 there were 17,376 patients on the waiting list for a liver transplant. In December , the National Institutes of Health (NIH), American Association for the Study of Liver disease ( AASLD), and the American Society for Transplant Surgeons (ASTS) sponsored a workshop to discuss and share information surrounding the transplant procedure and to outline the most important areas for future research.
     The development of living donor pediatric transplants was a response to the rise of the number of child deaths due to waiting for cadaveric livers. In 1998, 12% of all pediatric liver transplants were living donor type. The procedure consists of removing a portion of the left lobe of a healthy donor liver, and transplanting it into the child recipient. This form of LDT (adult liver to a child) is now routinely accomplished with minimal morbidity to the donor. The success of LDTs is due to the ability of liver tissue to regenerate. In most adult donors, the liver will completely regenerate within approximately 2 months.
     Adult to Adult LDTs were also initiated to combat the shortage of cadaveric livers. Although outcomes are generally better in children than in adults, the number of adult to adult LDTs has tripled since their development. Adults require a much more rigorous selection of matching donor to recipient and the liver tissue grafts have to be larger in adult transplantation.
     Acute rejection overall appears no different in LDTs than in cadaveric liver transplants, but the long term success of LDTs has not been established . Although the living donor transplant has changed dramatically over the past 3 to 4 years we must remember that only about one-quarter to one-third of patients will have a suitable living donor. People need to be conscious of the importance of organ donation.

American Liver Foundation

Understanding Clinical Trials

What is a clinical trial?   Most Americans have never heard this term. But for many, understanding what a clinical trial is and how to find out about one can have life saving or life extending implications. In the following pages there are descriptions of different types of clinical trials, including the three phases through which a drug must pass before it is judged to be safe and effective. The Food and Drug Administration (FDA) is the government agency with the responsibility for overseeing the clinical trial process.
     At the time of enrollment in a clinical trial, people are usually assured that they will receive either the standard of treatment known for their condition or a treatment that is hoped will be an improvement. Some people considering a clinical trial fear they might receive a placebo, which is not treatment at all. In some cases it is preferable to postpone treatments, therefore "no treatment" can be a standard of care. Each treatment approach in a trial is referred to as an "arm" of the trial. If you enter a clinical trial often you will be told that you will be randomized to one arm of the study. This means that you will be assigned, generally by a computer so the selection is unbiased, to one of the arms or treatment groups of the study. If during the course of a clinical trial it is discovered that the treatment in one arm is superior to the other arm or arms, the trial is stopped and people in each arm are given the superior treatment. When you first arrive for a visit regarding a clinical trial, the staff will carefully explain the clinical trial to you, and then give you an explanation in writing, which you will be asked to sign. This process is called Informed Consent.
Why should people participate in clinical trials?   The answer is simple. Clinical trials are the only road to progress in improving treatments. When researchers come up with a new treatment, they must prove to their colleagues and patients that the new treatment is better or at least equal to existing treatments. The only way to prove it is to run a clinical trial to demonstrate how the new treatment fares when compared to the standard treatment.

Clinical Trials

Most clinical trials are carried out in steps called phases. Each phase is designed to find different information. People may be eligible for studies in different phases, depending on their general condition, the type and stage of their disease and what therapy, if any they have already had.
Phase I Clinical Trials:   The purpose of phase I clinical trials is to find the best way to give a new treatment and how much of it can be given safely. In this phase, a new treatment is given to a small number of patients starting with a very small dose and increasing as more people enter the trial. People are watched closely for any harmful side effects. Although the research treatment has been well tested in the laboratory and in animals, the side effects in humans cannot be completely known ahead of time. Often participants in these trials are those who cannot be helped by any other treatment.
Phase II Clinical Trials:   The purpose of Phase II clinical trials are to find out if the treatment controls the disease in humans. If a significant amount of people in the Phase II trial responded (usually about one fifth) then the treatment is judged to be active against that condition or disease. In addition to monitoring people for response, any side effects of the treatment are carefully recorded and assessed. Phase II studies involve larger number of patients than did the Phase I trial.
Phase III Clinical Trials:   Phase III clinical trials usually compare to standard treatments (the treatment most accepted) with treatments that appeared to be good in the small Phase II studies. Phase III studies require large numbers of participants; some trials use thousands of patients. Participants are usually randomized, which means that they are assigned by chance to one of the treatments being studied. The group that receives the standard treatment is the "control" group. Phase III studies look for longer life, better quality of life, fewer side effects and fewer cases of the disease returning.
Supportive Care Studies:   Clinical trials also try to find better ways of caring for the side effects caused by certain treatments and diseases. Some supportive studies use drugs to treat side effects, some look at support groups, and support innovations.
Group C and Treatment Referral Center Studies   These types of studies make drugs available to some doctors. These drugs have been through clinical trials, have been shown to work, and may soon be approved by the FDA for sale.

Upcoming Accredited Educational Programs

Conducting Clinical Research in 2001
July 16 –17 2001
UW campus   Kane Hall

This conference is for new and experienced clinical researchers, including nurse researchers, research nurses, research coordinators, principal investigators, managers, and other interested health care professionals. 14.2 contact hours will be awarded. For copy of conference brochure, please go to the website uwcne.org or call (206) 543-1047.

Hepatitis C: The Latest Word
September 22, 2001
Four Seasons Hotel

This conference is for physicians, nurse practitioners and other interested health care professionals that are currently treating or actively involved in the management of patients with chronic hepatitis C. CME will be awarded. For more information please go to the website: http://depts.washington.edu/uwhep/ or call (206) 598-4956.

Hepatology Research News
Volume 5, Issue 1     May 2001
Paula Cox, R.N.
Anne Larson, M.D.
Medical Editor
Robert Carithers, Jr., M.D.
Medical Editor
Kris Kowdley, M.D.
Medical Editor
Judy Kaiser, R.N.
Kelly Worrell, R.N.
K.P Smith
Tamsin Sarich
Hao Do
Website: http://depts.washington.edu/uwhep/