Carcinoma, Hepatocellular
Conditions
Brief summary
This study aims to compare the role of peginterferon α-2b (50 μg/week) vs. control (no treatment) in the prevention of hepatocellular carcinoma, in adult patients with cirrhosis and initial signs of portal hypertension who did not respond to previous combined therapy with interferon alfa + ribavirin or peginterferon alfa + ribavirin or to interferon alfa monotherapy and with a high proliferation rate before entering the study. The duration of treatment will be 3 years, and the follow-up period will be 2 years.
Interventions
BIOLOGICALPeginterferon alfa-2b
Peginterferon alfa-2b, 50 μg, weekly, SC, for a period of 3 years.
OTHERObservation (no treatment)
No treatment was given to participants enrolled in the control arm (Arm B).
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Cirrhotic participants, both sexes, Child Pugh A, B, HCV-RNA positive, age \< 70 years * Participants non-responders to IFN + Ribavirin or PegIFN + Ribavirin or IFN monotherapy * Pre-therapy liver biopsy (\< 36 months) with PCNA-LI \> 2.0 * Fibrosis score 5-6 (Ishak) * Initial portal hypertension, such as gastroesophageal varices or one of the following US sign: * Collateral circles * Spleen longitudinal diameter \> 12 cm * Portal vein diameter at hilus \> 12 mm * Portal flow \> 12 cm/sec * Participants must have the following minimum hematologic and biochemical criteria: * Hemoglobin \>= 11 g/dL * Granulocyte count \> 1,000/mm\^3 * Platelets \> 70,000/mm\^3 * Prothrombin activity \> 50% * Total bilirubin \<3 mg/dL * Albumin \>= 3.5 g/dL * Serum creatinine within normal limits * Uric Acid within normal limits * Thyroid Stimulating Hormone (TSH), within normal limits * Antinuclear antibodies (ANA) \< 1:160 * Written informed consent * Women of childbearing potential must have a negative pregnancy test * Acceptance of patients of both sexes of proper contraceptive measures for the study period
Exclusion criteria
* Pregnant or breast-feeding women * Co-infection with HIV and/or HBV * Autoimmune hepatitis or history of autoimmune disease * Alcoholic liver disease * Metabolic disease * HCC * Participants with liver and kidney transplants * Evidence of decompensated liver disease such as history or presence of ascites, bleeding varices, spontaneous encephalopathy * Chronic renal failure or creatinine clearance \< 50 mL/min * Pre-existing thyroid disease unless it can be controlled with conventional treatment * History or presence of psychiatric condition, especially depression, or a history of severe psychiatric disorder, such as major psychoses, suicidal ideation and/or suicidal attempt * Epilepsy and/or compromised central nervous system (CNS) function * Significant cardiovascular dysfunction within the previous 6 months before the study starts (eg, angina, congestive heart failure, recent myocardial infarction, moderate or severe hypertension, significant arrhythmia) * Hemoglobinopathies * Poorly controlled diabetes mellitus * Chronic pulmonary disease (eg, chronic obstructive pulmonary disease) * Clinical gout * Hypersensitivity to interferons or any component of the drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With the Development of Hepatocellular Carcinoma (HCC) | During 3 years of treatment and 2 years of follow-up | Participants were tested for focal lesions by liver ultrasound and for AFP levels every 6 months the during study (treatment and follow-up). The development of hepatocellular carcinoma was determined by: 1. the appearance of a focal lesion detected by liver ultrasound with metastases confirmed by fine needle biopsy, or 2. the appearance of a focal lesion detected by ultrasound + alphafetoprotein (AFP) levels in blood \>400 ng/mL. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Development of Hepatic Decompensation | Baseline, During 3 years of treatment and 2 years of follow-up | The development of hepatic decompensation, defined as worsening of the hepatic function as measured by Child Pugh Score. The Child Pugh score was calculated based on biochemical changes (changes in serum albumin, serum bilirubin, prothrombin time) and clinical impairment (ascites, encephalopathies) or both. Each of the 5 parameters was scored from 1-3, and the Child Pugh Score represented the total score. The maximum score was 15, and a score of 10-15 represents the worst outcome and a life expectancy of 1-3 years. |
| Survival Time of Participants | During 3 years of treatment and 2 years of follow-up | Survival time was defined as time from screening visit to the death of the participant and was studied with Kaplan-Meier and Log-rank tests. If a participant did not die, he or she was censored with the last available date. |
| Number of Patients With a Virological Response Rate | Baseline and every year during 3 years of treatment | Virological Response rate was measured by the disappearance of Hepatitis C Virus from serum. Serum samples from participants were analyzed for the presence of HCV-RNA using a qualitative polymerase chain reaction (PCR). |
| Change in the Proliferating Cell Nuclear Antigen Labeling Index (PCNA-LI) | Baseline and at 18 months of treatment | PCNA-LI was measured at baseline and at 18 months of treatment, and the change in PCNA-LI was calculated. To measure PCNA-LI, liver tissue samples obtained from biopsies were fixed and immunostained to detect PCNA. PCNA-LI is the percentage of immunohistochemically stained (PCNA positive) cells in 1,000 HCC cells counted. A higher PCNA-LI indicates a worse outcome. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Proliferating Cell Nuclear Antigen Labeling Index (PCNA-LI) at Baseline | Baseline | Liver tissues obtained from biopsies were fixed and immunostained to detect PCNA. PCNA-LI is the percentage of immunohistochemically stained (PCNA positive) cells in 1,000 HCC cells counted. A higher PCNA-LI indicates a worse outcome. |
Participant flow
Pre-assignment details
The Intent-to-Treat (ITT) population included all randomized participants who took at least one dose of medication, and presented at least one further efficacy evaluation. No efficacy assessment post-baseline was obtained for 4 participants in the control group, therefore the ITT population included 146 (74 PegIntron + 72 Control) participants.
Participants by arm
| Arm | Count |
|---|---|
| Arm A - PegIntron Participants randomized to Arm A received peginterferon α-2b, 50 μg, weekly, for a period of 3 years. | 74 |
| Arm B - Control Participants randomized to Arm B were under observation and received no treatment. | 72 |
| Total | 146 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 17 | 12 |
| Overall Study | Death | 4 | 3 |
| Overall Study | HCV RNA negative | 1 | 0 |
| Overall Study | Inability to comply | 1 | 1 |
| Overall Study | Lost during study | 1 | 0 |
| Overall Study | Lost to Follow-up | 4 | 6 |
| Overall Study | Participant had a liver transplant | 0 | 1 |
| Overall Study | Participant moved to a different city | 0 | 1 |
| Overall Study | Started new therapy | 2 | 6 |
| Overall Study | Withdrawal by Subject | 9 | 5 |
Baseline characteristics
| Characteristic | Arm A - PegIntron | Arm B - Control | Total |
|---|---|---|---|
| Age, Continuous | 57 Years STANDARD_DEVIATION 8.7 | 59.7 Years STANDARD_DEVIATION 7.2 | 58.3 Years STANDARD_DEVIATION 8.1 |
| Sex: Female, Male Female | 22 Participants | 34 Participants | 56 Participants |
| Sex: Female, Male Male | 52 Participants | 38 Participants | 90 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 55 / 74 | 36 / 76 |
| serious Total, serious adverse events | 36 / 74 | 30 / 76 |
Outcome results
Primary
Number of Participants With the Development of Hepatocellular Carcinoma (HCC)
Participants were tested for focal lesions by liver ultrasound and for AFP levels every 6 months the during study (treatment and follow-up). The development of hepatocellular carcinoma was determined by: 1. the appearance of a focal lesion detected by liver ultrasound with metastases confirmed by fine needle biopsy, or 2. the appearance of a focal lesion detected by ultrasound + alphafetoprotein (AFP) levels in blood \>400 ng/mL.
Time frame: During 3 years of treatment and 2 years of follow-up
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A - PegIntron | Number of Participants With the Development of Hepatocellular Carcinoma (HCC) | 15 Participants |
| Arm B - Control | Number of Participants With the Development of Hepatocellular Carcinoma (HCC) | 11 Participants |
Secondary
Change in the Proliferating Cell Nuclear Antigen Labeling Index (PCNA-LI)
PCNA-LI was measured at baseline and at 18 months of treatment, and the change in PCNA-LI was calculated. To measure PCNA-LI, liver tissue samples obtained from biopsies were fixed and immunostained to detect PCNA. PCNA-LI is the percentage of immunohistochemically stained (PCNA positive) cells in 1,000 HCC cells counted. A higher PCNA-LI indicates a worse outcome.
Time frame: Baseline and at 18 months of treatment
Population: Participants with tissue biopsies at 18 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A - PegIntron | Change in the Proliferating Cell Nuclear Antigen Labeling Index (PCNA-LI) | -2.0 Score on a scale | Standard Deviation 3.2 |
| Arm B - Control | Change in the Proliferating Cell Nuclear Antigen Labeling Index (PCNA-LI) | -0.9 Score on a scale | Standard Deviation 2.4 |
Secondary
Number of Participants With Development of Hepatic Decompensation
The development of hepatic decompensation, defined as worsening of the hepatic function as measured by Child Pugh Score. The Child Pugh score was calculated based on biochemical changes (changes in serum albumin, serum bilirubin, prothrombin time) and clinical impairment (ascites, encephalopathies) or both. Each of the 5 parameters was scored from 1-3, and the Child Pugh Score represented the total score. The maximum score was 15, and a score of 10-15 represents the worst outcome and a life expectancy of 1-3 years.
Time frame: Baseline, During 3 years of treatment and 2 years of follow-up
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A - PegIntron | Number of Participants With Development of Hepatic Decompensation | 4 Participants |
| Arm B - Control | Number of Participants With Development of Hepatic Decompensation | 9 Participants |
Secondary
Number of Patients With a Virological Response Rate
Virological Response rate was measured by the disappearance of Hepatitis C Virus from serum. Serum samples from participants were analyzed for the presence of HCV-RNA using a qualitative polymerase chain reaction (PCR).
Time frame: Baseline and every year during 3 years of treatment
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A - PegIntron | Number of Patients With a Virological Response Rate | Baseline | 0 Participants |
| Arm A - PegIntron | Number of Patients With a Virological Response Rate | 1 year | 3 Participants |
| Arm A - PegIntron | Number of Patients With a Virological Response Rate | 2 years | 1 Participants |
| Arm A - PegIntron | Number of Patients With a Virological Response Rate | 3 years | 0 Participants |
| Arm B - Control | Number of Patients With a Virological Response Rate | 3 years | 0 Participants |
| Arm B - Control | Number of Patients With a Virological Response Rate | Baseline | 0 Participants |
| Arm B - Control | Number of Patients With a Virological Response Rate | 2 years | 0 Participants |
| Arm B - Control | Number of Patients With a Virological Response Rate | 1 year | 0 Participants |
Secondary
Survival Time of Participants
Survival time was defined as time from screening visit to the death of the participant and was studied with Kaplan-Meier and Log-rank tests. If a participant did not die, he or she was censored with the last available date.
Time frame: During 3 years of treatment and 2 years of follow-up
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - PegIntron | Survival Time of Participants | 5.2840 Years |
| Arm B - Control | Survival Time of Participants | 4.0602 Years |
Other Pre-specified
Proliferating Cell Nuclear Antigen Labeling Index (PCNA-LI) at Baseline
Liver tissues obtained from biopsies were fixed and immunostained to detect PCNA. PCNA-LI is the percentage of immunohistochemically stained (PCNA positive) cells in 1,000 HCC cells counted. A higher PCNA-LI indicates a worse outcome.
Time frame: Baseline
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A - PegIntron | Proliferating Cell Nuclear Antigen Labeling Index (PCNA-LI) at Baseline | 4.2 Score on a scale | Standard Deviation 2.1 |
| Arm B - Control | Proliferating Cell Nuclear Antigen Labeling Index (PCNA-LI) at Baseline | 3.9 Score on a scale | Standard Deviation 1.6 |