Hepatitis C
Conditions
Keywords
Hepatitis C Virus, Antiviral Agents, Hemolysis, Neutropenia, Cirrhosis, Hemolytic Anemia, Viral Hepatitis, Ribavirin, Alfa Interferon, Pegylated Interferon, Hepatitis C, HCV
Brief summary
This study will examine the effectiveness of low-dose peginterferon and ribavirin therapy for certain patients with chronic hepatitis C-a liver disease that, in some patients, can progress to cirrhosis of the liver, liver cancer, and liver failure.
Detailed description
Sixty patients with chronic hepatitis C infected with HCV genotype 2 or 3 will be treated using the combination of either low- or standard dose peginterferon and ribavirin for 24 weeks, with re-treatment using the standard doses and a longer duration (48 weeks) for those who do not respond to or relapse after initial low dose therapy. Adult patients with chronic hepatitis C who have HCV genotype 2 or 3 and previously have not received anti-viral treatment will be given peginterferon alfa-2a (90 or 180 micrograms weekly by injection) and ribavirin (800 mg daily by mouth). Patients will be monitored at 2- to 4-week intervals for side effects, compliance, complete blood counts, liver biochemical tests and HCV RNA. Patients becoming HCV RNA negative by week 12 will be considered on-treatment responders, continue therapy to week 24, and be monitored thereafter for another 24 weeks. Patients who do not become HCV RNA negative by week 12 as well as patients who relapse after therapy will be retreated with 180 micrograms of peginterferon weekly and 800 mg of ribavirin for another 48 weeks. The primary outcome will be sustained loss of HCV RNA at 24 weeks after low- or standard-dose combination therapy. Secondary outcomes include viral kinetics and side effects. Because of preliminary results in the initial 31 patients enrolled in this study, the dose of peginterferon was changed from 90 to 180 micrograms weekly for the remaining 29 patients to be enrolled, allowing for a direct comparison of efficacy, viral kinetics and side effects of standard- vs low-dose peginterferon therapy. This study will evaluate the relative efficacy and safety of the standard versus lower doses of peginterferon with ribavirin in patients with chronic hepatitis C and HCV genotype 2 or 3.
Interventions
DRUGPeginterferon alfa-2a
Peginterferon alfa-2a 90 mcg/week
DRUGRibavirin
800 mg/day
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: Age above 18 years, male or female. Presence of anti-HCV in serum. Positive HCV RNA determination in serum. HCV genotype 2 or 3 as determined by Inno LiPa assay or by direct sequencing. Patients with mixed genotypes will not be eligible if they have genotypes other than 2 or 3. Written informed consent.
Exclusion criteria
Previous treatment with interferon alpha or peginterferon. Decompensated liver disease, as marked by bilirubin greater than 4 mg/dL, albumin less than 3.0 g/dL, prothrombin time greater than 2 sec prolonged, or history of bleeding esophageal varices, ascites or hepatic encephalopathy. Patients with ALT levels greater than 1000 U/L (greater than 25 times ULN) will not be enrolled but may be followed until three determinations are below this level. Pregnancy or, in women of child-bearing potential or in spouses of such women, inability to practice adequate contraception, defined as vasectomy in men, tubal ligation in women, or use of condoms and spermicidal, or birth control pills, or an intrauterine device. Significant systemic or major illnesses other than liver disease, including congestive heart failure, renal failure (creatinine clearance less than 50 ml/min), organ transplantation, serious psychiatric disease not controlled by psychotropic agents, and angina pectoris. Evidence of coronary artery disease or cerebral vascular disease, including abnormalities on exercise stress testing in patients with defined risk factors who will be screened for evidence of underlying coronary artery disease. Pre-existing, severe bone marrow compromise; anemia (hematocrit less than 30%), neutropenia (less than 1000 neutrophils/microliter) or thrombocytopenia (less than 70,000 cells/microliter). History of hemolytic anemia. Evidence of another form of liver disease in addition to hepatitis C (for example hepatitis B, autoimmune liver disease, Wilson's disease, alcoholic liver disease). Active substance abuse, such as alcohol, inhaled or injection drugs within the previous six months. Evidence of hepatocellular carcinoma: either alfa-fetoprotein (AFP) levels greater than 50 ng/ml (normal less than 9 ng/ml) and/or ultrasound (or other imaging study) demonstrating a mass suggestive of liver cancer. Clinical gout. HIV infection. Quiescent or active, serious autoimmune disease such as lupus erythematosus, ulcerative colitis, Crohn's disease or rheumatoid arthritis that in the opinion of the investigators might be exacerbated by therapy with alfa interferon. The use of immunosuppressive medications, including corticosteroids in doses of 10 mg of prednisone or its equivalent and higher.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Virological Response (Intention to Treat) | 6 months after stopping therapy | Virological response category. Sustained virological response (SVR) is defined as negative serum HCV RNA at least 6 months after the end of treatment. Non-response is defined as serum HCV RNA positivity on week 12 of treatment. Breakthrough/relapse is defined as HCV RNA becoming negative and subsequently positive on treatment or after treatment is stopped. |
| Virological Response Category (Per Protocol) | 6 months after therapy | Virological response category. Sustained virological response (SVR) is defined as negative serum HCV RNA at least 6 months after the end of treatment. Non-response is defined as serum HCV RNA positivity on week 12 of treatment. Breakthrough/relapse is defined as HCV RNA becoming negative and subsequently positive on treatment or after treatment is stopped. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| First Phase Decline in Logarithm of HCV RNA Level | 2 days | The 1st phase decline is defined as the log difference between baseline HCV RNA level and the level on day 2 of treatment (see Neumann et al, Science, 1998). |
| Slope of Second Phase Decline in HCV Levels | day 7 to day 28 | The 2nd phase slope is defined as the slope of the logarithmic viral levels from week 1 to week 4 of treatment (see Neumann et al, Science, 1998). |
| Time to Negativity | 24 weeks | Time from treatment initiation to the first negative HCV RNA test during treatment |
Countries
United States
Participant flow
Recruitment details
Between Dec 2003 and Dec 2004, 31 patients were enrolled into the low-dose group and were treated with peginterferon alfa-2a 90ug/week and ribavirin 400 mg/twice daily for 24 week. From Feb 2005, all subsequent patients were enrolled into a standard-dose group and treated for 24 weeks with the doses of the approved regimen.
Participants by arm
| Arm | Count |
|---|---|
| Low Dose Group All patients receive peginterferon alfa-2a and ribavirin for 24 weeks with measurements of HCV RNA, routine liver tests, complete blood counts and side effects at regular intervals during therapy. Arm A receives a lower dose of peginterferon (90 mcg per week) but standard, recommended dose of ribavirin for chronic hepatitis C, genotype 2 and 3. | 30 |
| Standard Dose Group All patients receive peginterferon alfa-2a and ribavirin for 24 weeks with measurements of HCV RNA, routine liver tests, complete blood counts and side effects at regular intervals during therapy. Arm B receives the standard, recommended dose of peginterferon (180 mcg per week) and standard, recommended dose of ribavirin for chronic hepatitis c, genotype 2 and 3. | 27 |
| Total | 57 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 1 | 0 |
Baseline characteristics
| Characteristic | Low Dose Group | Standard Dose Group | Total |
|---|---|---|---|
| Age Continuous | 48 years | 47 years | 48 years |
| ALT | 91 U/L STANDARD_DEVIATION 69 | 97 U/L STANDARD_DEVIATION 85 | 94 U/L STANDARD_DEVIATION 77 |
| Genotype HCV Genotype 2 | 21 participants | 13 participants | 34 participants |
| Genotype HCV Genotype 3 | 9 participants | 14 participants | 23 participants |
| HCV RNA | 6.3 log IU/mL STANDARD_DEVIATION 0.82 | 5.9 log IU/mL STANDARD_DEVIATION 1.02 | 6.1 log IU/mL STANDARD_DEVIATION 0.92 |
| Race/Ethnicity, Customized African-American | 1 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized Asian | 2 participants | 5 participants | 7 participants |
| Race/Ethnicity, Customized Caucasian | 26 participants | 20 participants | 46 participants |
| Race/Ethnicity, Customized Hispanic | 1 participants | 0 participants | 1 participants |
| Region of Enrollment United States | 30 participants | 27 participants | 57 participants |
| Sex: Female, Male Female | 15 Participants | 14 Participants | 29 Participants |
| Sex: Female, Male Male | 15 Participants | 13 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 30 | 1 / 27 |
| serious Total, serious adverse events | 0 / 30 | 3 / 27 |
Outcome results
Primary
Virological Response Category (Per Protocol)
Virological response category. Sustained virological response (SVR) is defined as negative serum HCV RNA at least 6 months after the end of treatment. Non-response is defined as serum HCV RNA positivity on week 12 of treatment. Breakthrough/relapse is defined as HCV RNA becoming negative and subsequently positive on treatment or after treatment is stopped.
Time frame: 6 months after therapy
Population: Per protocol
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Low Dose Group | Virological Response Category (Per Protocol) | Nonresponse | 2 participants |
| Low Dose Group | Virological Response Category (Per Protocol) | SVR | 19 participants |
| Low Dose Group | Virological Response Category (Per Protocol) | Relapse/breakthrough | 7 participants |
| Standard Dose Group | Virological Response Category (Per Protocol) | SVR | 20 participants |
| Standard Dose Group | Virological Response Category (Per Protocol) | Relapse/breakthrough | 2 participants |
| Standard Dose Group | Virological Response Category (Per Protocol) | Nonresponse | 1 participants |
Primary
Virological Response (Intention to Treat)
Virological response category. Sustained virological response (SVR) is defined as negative serum HCV RNA at least 6 months after the end of treatment. Non-response is defined as serum HCV RNA positivity on week 12 of treatment. Breakthrough/relapse is defined as HCV RNA becoming negative and subsequently positive on treatment or after treatment is stopped.
Time frame: 6 months after stopping therapy
Population: Intention-to-treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Low Dose Group | Virological Response (Intention to Treat) | Relapse/breakthrough | 7 participants |
| Low Dose Group | Virological Response (Intention to Treat) | Treatment stopped for adverse event | 0 participants |
| Low Dose Group | Virological Response (Intention to Treat) | Nonresponse | 3 participants |
| Low Dose Group | Virological Response (Intention to Treat) | Lost to follow-up | 1 participants |
| Low Dose Group | Virological Response (Intention to Treat) | Sustained Virological Response (SVR) | 19 participants |
| Standard Dose Group | Virological Response (Intention to Treat) | Lost to follow-up | 0 participants |
| Standard Dose Group | Virological Response (Intention to Treat) | Sustained Virological Response (SVR) | 21 participants |
| Standard Dose Group | Virological Response (Intention to Treat) | Relapse/breakthrough | 2 participants |
| Standard Dose Group | Virological Response (Intention to Treat) | Nonresponse | 1 participants |
| Standard Dose Group | Virological Response (Intention to Treat) | Treatment stopped for adverse event | 3 participants |
Secondary
First Phase Decline in Logarithm of HCV RNA Level
The 1st phase decline is defined as the log difference between baseline HCV RNA level and the level on day 2 of treatment (see Neumann et al, Science, 1998).
Time frame: 2 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Group | First Phase Decline in Logarithm of HCV RNA Level | 1.15 logIU/mL | Standard Deviation 0.88 |
| Standard Dose Group | First Phase Decline in Logarithm of HCV RNA Level | 2.20 logIU/mL | Standard Deviation 1.14 |
Comparison: Null hypothesis: first phase decline in HCV RNA are the same for the two groupsp-value: 0.002t-test, 2 sided
Secondary
Slope of Second Phase Decline in HCV Levels
The 2nd phase slope is defined as the slope of the logarithmic viral levels from week 1 to week 4 of treatment (see Neumann et al, Science, 1998).
Time frame: day 7 to day 28
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose Group | Slope of Second Phase Decline in HCV Levels | 1.14 logIU/mL | Standard Deviation 0.69 |
| Standard Dose Group | Slope of Second Phase Decline in HCV Levels | 1.39 logIU/mL | Standard Deviation 0.64 |
Comparison: Null hypothesis: the second phase slopes of HCV RNA are the same for the two groupsp-value: 0.2Wilcoxon (Mann-Whitney)
Secondary
Time to Negativity
Time from treatment initiation to the first negative HCV RNA test during treatment
Time frame: 24 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Low Dose Group | Time to Negativity | 42 days |
| Standard Dose Group | Time to Negativity | 28 days |
Comparison: Null hypothesis: the time to negativity for the two groups are samep-value: 0.047Log Rank