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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm A - PegIntron | Experimental | Participants randomized to Arm A received peginterferon α-2b (PegIntron), 50 μg, weekly, subcutaneously (SC), for a period of 3 years. |
|
| Arm B - Control | Other | Participants randomized to Arm B were under observation and received no treatment. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Peginterferon alfa-2b | Biological | Peginterferon alfa-2b, 50 μg, weekly, SC, for a period of 3 years. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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:
| During 3 years of treatment and 2 years of follow-up |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline |
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:
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:
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Arm A - PegIntron | Participants randomized to Arm A received peginterferon α-2b, 50 μg, weekly, for a period of 3 years. |
| FG001 | Arm B - Control | Participants randomized to Arm B were under observation and received no treatment. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Observation (no treatment) | Other | No treatment was given to participants enrolled in the control arm (Arm B). |
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| Baseline, During 3 years of treatment and 2 years of follow-up |
| 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. | During 3 years of treatment and 2 years of follow-up |
| 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). | Baseline and every year during 3 years of treatment |
| 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. | Baseline and at 18 months of treatment |
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| ID | Title | Description |
|---|---|---|
| BG000 | Arm A - PegIntron | Participants randomized to Arm A received peginterferon α-2b, 50 μg, weekly, for a period of 3 years. |
| BG001 | Arm B - Control | Participants randomized to Arm B were under observation and received no treatment. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | ITT Population | Mean | Standard Deviation | Years |
| ||||||||||||||
| Sex: Female, Male | ITT Population | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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:
| ITT population | Posted | Number | Participants | During 3 years of treatment and 2 years of follow-up |
|
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| |||||||||||||||||||||||||||||
| 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. | ITT population | Posted | Number | Participants | Baseline, During 3 years of treatment and 2 years of follow-up |
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| 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. | ITT population | Posted | Median | 95% Confidence Interval | Years | During 3 years of treatment and 2 years of follow-up |
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| 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). | ITT population | Posted | Number | Participants | Baseline and every year during 3 years of treatment |
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| 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. | Participants with tissue biopsies at 18 months. | Posted | Mean | Standard Deviation | Score on a scale | Baseline and at 18 months of treatment |
|
| |||||||||||||||||||||||||||||
| 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. | ITT population | Posted | Mean | Standard Deviation | Score on a scale | Baseline |
|
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A total of 15 serious adverse events resulted in death.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Arm A - PegIntron | Participants randomized to Arm A received peginterferon α-2b, 50 μg, weekly, for a period of 3 years. | 36 | 74 | 55 | 74 | ||
| EG001 | Arm B - Control | Participants randomized to Arm B were under observation and received no treatment. | 30 | 76 | 36 | 76 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| ANAEMIA | Blood and lymphatic system disorders | MedDRA 13.0 | Systematic Assessment |
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| THROMBOCYTOPENIA | Blood and lymphatic system disorders | MedDRA 13.0 | Systematic Assessment |
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| ACUTE MYOCARDIAL INFARCTION | Cardiac disorders | MedDRA 13.0 | Systematic Assessment |
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| ATRIAL FIBRILLATION | Cardiac disorders | MedDRA 13.0 | Systematic Assessment |
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| CONGESTIVE CARDIOMYOPATHY | Cardiac disorders | MedDRA 13.0 | Systematic Assessment |
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| PERICARDIAL EFFUSION | Cardiac disorders | MedDRA 13.0 | Systematic Assessment |
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| VENTRICULAR TACHYCARDIA | Cardiac disorders | MedDRA 13.0 | Systematic Assessment |
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| ABDOMINAL PAIN | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
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| ASCITES | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
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| DIARRHOEA | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
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| GASTRIC DYSPLASIA | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
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| HAEMATEMESIS | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
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| INGUINAL HERNIA | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
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| INTESTINAL ISCHAEMIA | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
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| MELAENA | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
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| OESOPHAGEAL VARICES HAEMORRHAGE | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
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| VARICES OESOPHAGEAL | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
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| VOMITING | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
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| DEATH | General disorders | MedDRA 13.0 | Systematic Assessment |
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| HYPERPYREXIA | General disorders | MedDRA 13.0 | Systematic Assessment |
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| PYREXIA | General disorders | MedDRA 13.0 | Systematic Assessment |
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| BILIARY DILATATION | Hepatobiliary disorders | MedDRA 13.0 | Systematic Assessment |
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| CHOLECYSTITIS | Hepatobiliary disorders | MedDRA 13.0 | Systematic Assessment |
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| CHOLELITHIASIS | Hepatobiliary disorders | MedDRA 13.0 | Systematic Assessment |
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| HEPATIC FAILURE | Hepatobiliary disorders | MedDRA 13.0 | Systematic Assessment |
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| HEPATORENAL SYNDROME | Hepatobiliary disorders | MedDRA 13.0 | Systematic Assessment |
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| PORTAL VEIN THROMBOSIS | Hepatobiliary disorders | MedDRA 13.0 | Systematic Assessment |
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| CRYOGLOBULINAEMIA | Immune system disorders | MedDRA 13.0 | Systematic Assessment |
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| BRONCHITIS | Infections and infestations | MedDRA 13.0 | Systematic Assessment |
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| BRONCHOPNEUMONIA | Infections and infestations | MedDRA 13.0 | Systematic Assessment |
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| CYSTITIS | Infections and infestations | MedDRA 13.0 | Systematic Assessment |
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| MUSCLE ABSCESS | Infections and infestations | MedDRA 13.0 | Systematic Assessment |
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| PERITONITIS BACTERIAL | Infections and infestations | MedDRA 13.0 | Systematic Assessment |
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| SALMONELLOSIS | Infections and infestations | MedDRA 13.0 | Systematic Assessment |
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| CLAVICLE FRACTURE | Injury, poisoning and procedural complications | MedDRA 13.0 | Systematic Assessment |
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| FEMUR FRACTURE | Injury, poisoning and procedural complications | MedDRA 13.0 | Systematic Assessment |
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| HAND FRACTURE | Injury, poisoning and procedural complications | MedDRA 13.0 | Systematic Assessment |
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| HUMERUS FRACTURE | Injury, poisoning and procedural complications | MedDRA 13.0 | Systematic Assessment |
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| LOWER LIMB FRACTURE | Injury, poisoning and procedural complications | MedDRA 13.0 | Systematic Assessment |
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| RIB FRACTURE | Injury, poisoning and procedural complications | MedDRA 13.0 | Systematic Assessment |
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| THORACIC VERTEBRAL FRACTURE | Injury, poisoning and procedural complications | MedDRA 13.0 | Systematic Assessment |
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| UPPER LIMB FRACTURE | Injury, poisoning and procedural complications | MedDRA 13.0 | Systematic Assessment |
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| ULTRASOUND LIVER ABNORMAL | Investigations | MedDRA 13.0 | Systematic Assessment |
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| HYPOALBUMINAEMIA | Metabolism and nutrition disorders | MedDRA 13.0 | Systematic Assessment |
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| BREAST CANCER | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 13.0 | Systematic Assessment |
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| GASTRIC CANCER | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 13.0 | Systematic Assessment |
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| HEPATIC NEOPLASM MALIGNANT | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 13.0 | Systematic Assessment |
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| LYMPHOMA | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 13.0 | Systematic Assessment |
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| PANCREATIC NEOPLASM | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 13.0 | Systematic Assessment |
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| PROSTATE CANCER | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 13.0 | Systematic Assessment |
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| BRAIN MASS | Nervous system disorders | MedDRA 13.0 | Systematic Assessment |
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| CEREBRAL HAEMORRHAGE | Nervous system disorders | MedDRA 13.0 | Systematic Assessment |
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| COMA HEPATIC | Nervous system disorders | MedDRA 13.0 | Systematic Assessment |
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| EPILEPSY | Nervous system disorders | MedDRA 13.0 | Systematic Assessment |
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| HAEMORRHAGE INTRACRANIAL | Nervous system disorders | MedDRA 13.0 | Systematic Assessment |
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| NORMAL PRESSURE HYDROCEPHALUS | Nervous system disorders | MedDRA 13.0 | Systematic Assessment |
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| QUADRIPLEGIA | Nervous system disorders | MedDRA 13.0 | Systematic Assessment |
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| SYNCOPE | Nervous system disorders | MedDRA 13.0 | Systematic Assessment |
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| TRANSIENT ISCHAEMIC ATTACK | Nervous system disorders | MedDRA 13.0 | Systematic Assessment |
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| ANURIA | Renal and urinary disorders | MedDRA 13.0 | Systematic Assessment |
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| GLOMERULONEPHRITIS | Renal and urinary disorders | MedDRA 13.0 | Systematic Assessment |
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| NEPHROTIC SYNDROME | Renal and urinary disorders | MedDRA 13.0 | Systematic Assessment |
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| BREAST PAIN | Reproductive system and breast disorders | MedDRA 13.0 | Systematic Assessment |
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| ACUTE RESPIRATORY FAILURE | Respiratory, thoracic and mediastinal disorders | MedDRA 13.0 | Systematic Assessment |
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| DYSPNOEA | Respiratory, thoracic and mediastinal disorders | MedDRA 13.0 | Systematic Assessment |
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| EPISTAXIS | Respiratory, thoracic and mediastinal disorders | MedDRA 13.0 | Systematic Assessment |
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| PLEURAL EFFUSION | Respiratory, thoracic and mediastinal disorders | MedDRA 13.0 | Systematic Assessment |
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| PNEUMONITIS | Respiratory, thoracic and mediastinal disorders | MedDRA 13.0 | Systematic Assessment |
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| PULMONARY EMBOLISM | Respiratory, thoracic and mediastinal disorders | MedDRA 13.0 | Systematic Assessment |
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| VOCAL CORD POLYP | Respiratory, thoracic and mediastinal disorders | MedDRA 13.0 | Systematic Assessment |
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| HYPERHIDROSIS | Skin and subcutaneous tissue disorders | MedDRA 13.0 | Systematic Assessment |
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| PSORIASIS | Skin and subcutaneous tissue disorders | MedDRA 13.0 | Systematic Assessment |
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| RASH | Skin and subcutaneous tissue disorders | MedDRA 13.0 | Systematic Assessment |
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| COLON POLYPECTOMY | Surgical and medical procedures | MedDRA 13.0 | Systematic Assessment |
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| GASTRECTOMY | Surgical and medical procedures | MedDRA 13.0 | Systematic Assessment |
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| INGUINAL HERNIA REPAIR | Surgical and medical procedures | MedDRA 13.0 | Systematic Assessment |
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| KNEE ARTHROPLASTY | Surgical and medical procedures | MedDRA 13.0 | Systematic Assessment |
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| BLEEDING VARICOSE VEIN | Vascular disorders | MedDRA 13.0 | Systematic Assessment |
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| HYPERTENSIVE CRISIS | Vascular disorders | MedDRA 13.0 | Systematic Assessment |
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| SYSTOLIC HYPERTENSION | Vascular disorders | MedDRA 13.0 | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| ANAEMIA | Blood and lymphatic system disorders | MedDRA 13.0 | Systematic Assessment |
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| THROMBOCYTOPENIA | Blood and lymphatic system disorders | MedDRA 13.0 | Systematic Assessment |
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| ABDOMINAL PAIN | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
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| ASCITES | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
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| DIARRHOEA | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
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| DYSPEPSIA | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
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| GASTRITIS | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
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| NAUSEA | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
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| ASTHENIA | General disorders | MedDRA 13.0 | Systematic Assessment |
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| INFLUENZA LIKE ILLNESS | General disorders | MedDRA 13.0 | Systematic Assessment |
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| OEDEMA PERIPHERAL | General disorders | MedDRA 13.0 | Systematic Assessment |
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| PYREXIA | General disorders | MedDRA 13.0 | Systematic Assessment |
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| WEIGHT DECREASED | Investigations | MedDRA 13.0 | Systematic Assessment |
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| ARTHRALGIA | Musculoskeletal and connective tissue disorders | MedDRA 13.0 | Systematic Assessment |
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| BACK PAIN | Musculoskeletal and connective tissue disorders | MedDRA 13.0 | Systematic Assessment |
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| PAIN IN EXTREMITY | Musculoskeletal and connective tissue disorders | MedDRA 13.0 | Systematic Assessment |
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| HEADACHE | Nervous system disorders | MedDRA 13.0 | Systematic Assessment |
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| DEPRESSION | Psychiatric disorders | MedDRA 13.0 | Systematic Assessment |
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| EPISTAXIS | Respiratory, thoracic and mediastinal disorders | MedDRA 13.0 | Systematic Assessment |
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| PRURITUS | Skin and subcutaneous tissue disorders | MedDRA 13.0 | Systematic Assessment |
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| HYPERTENSION | Vascular disorders | MedDRA 13.0 | Systematic Assessment |
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The disclosure restriction on the principal investigator (PI) is that the PI agrees not to publish or publicly present any results of the study without the prior written permission of the sponsor. The PI further agrees to allow the sponsor to review, 30 days prior to submission for publication or presentation, copies of abstracts or manuscripts for publication (including texts of oral presentations) which report any results of the study.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Senior Vice President,Global Clinical Development | Merck Sharp and Dohme Corp. | ClinicalTrialsDisclosure@merck.com |
| ID | Term |
|---|---|
| D006528 | Carcinoma, Hepatocellular |
| ID | Term |
|---|---|
| D000230 | Adenocarcinoma |
| D002277 | Carcinoma |
| D009375 | Neoplasms, Glandular and Epithelial |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D008113 | Liver Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D004066 | Digestive System Diseases |
| D008107 | Liver Diseases |
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| ID | Term |
|---|---|
| C417083 | peginterferon alfa-2b |
| D019370 | Observation |
| ID | Term |
|---|---|
| D008722 | Methods |
| D008919 | Investigative Techniques |
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| Male |
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