Hepatitis C, Chronic
Conditions
Keywords
hepatitis C virus, hepatitis B virus, boceprevir, null responder, partial responder, relapser
Brief summary
The aim of this study is to explore the efficacy and safety of boceprevir -based triple therapy to rescue HCV genotype 1 (HCV GT1)/HBV dually infected patients refractory to previous peginterferon (PEG-IFN) plus ribavirin (RBV) combination therapy.
Detailed description
Liver disease, especially viral hepatitis, is an important public health issue, which frequent leads to liver cirrhosis, hepatocellular carcinoma (HCC) and liver-related death. Around 340 to 400 million persons are infected with hepatitis B virus (HBV) and 130 to 210 million persons are infected with hepatitis C virus (HCV) worldwide, In Taiwan, the prevalence of HBV infection is 15-20%, and the prevalence of HCV infection is 2-5% in general population. Moreover, there are some HCV-hyperendemic areas in southern Taiwan with anti-HCV prevalence rate of as high as 30-40%. HBV/HCV dual infections is not uncommon in HBV epidemic areas, such as Southeastern Asia, with a prevalence rate of 1.1% in southern Taiwan. Recent study showed that the risk of HCC incidence is even higher among HBV/HCV co-infected persons than those with HBV or HCV mono-infection, indicating the importance of disease control in this clinical setting. The PEG-IFN/RBV has been effective in the treatment of HCV-dominant, treatment-naïve patients with HCV/HBV dual infections. For treatment-naive HCV genotype 1 (HCV GT1)/HBV co-infected patients, 48 weeks of peginterferon (PEG-IFN) plus ribavirin (RBV) could achieve an HCV sustained virological response (SVR) rate of 72%, which was comparable to 77% for patients with HCV GT1 monoinfection. For treatment-naive HCV GT2 or GT3 /HBV co-infected patients, 24 weeks of PEG-IFN plus RBV could achieve an HCV SVR rate of 83%, which was comparable to 84% for patients with HCV GT2/3 monoinfection . Furthermore, PEG-IFN plus RBV combination therapy could enhance seroclearance of hepatitis B surface antigen (HBsAg) with an HBsAg loss rate of upto 11%. Nevertheless, there is about 30% of HCV GT1/HBV and 20% of HCV GT2 or 3/HBV co-infected patients refractory to current PEG-IFN/RBV combination therapy, which remains at high risk of HCC and liver-related death. Boceprevir is an oral antiviral drug, which is NS3/4A protease inhibitor. Boceprevir has been approved for treating HCV GT1 infection by Food and Drug Administration (FDA) on 11 May 2011. For HCV GT1 mono-infected patients who refractory to previous PEG-IFN plus RBV combination therapy, becoprevir combined with PEG-IFN/RBV triple therapy can improve the treatment efficacy. The SVR rate of becoprevir-based triple therapy is about 3 times when compared to patients who received PEG-IFN with RBV dual therapy \[14\].The investigators , therefore, hypothesize that boceprevir plus PEG-IFN/RBV is effective in treating HCV GT1/HBV dually infected patients who are refractory to previous PEG-IFN/RBV combination therapy.
Interventions
DRUGStop trial intervention for boceprevir, PEG-IFN and RBV
Stop trial intervention for patients with 32 week therapy (arm A): for all patients, if HCV RNA is more than 100 IU/ml at week 12 or HCV RNA is detectable at week 24, therapy will be stopped. Stop trial intervention for patients with 48 weeks therapy (arm B): for all patients, if HCV RNA is more than 100 IU/ml at week 12 or HCV RNA is detectable at week 24, therapy will be stopped. Stop trial intervention for for null responder or cirrhotic patients: (arm C) for all patients, if HCV RNA is more than 100 IU/ml at week 12 or HCV RNA is detectable at week 24, therapy will be stopped.
Sponsors
National Taiwan University Hospital
Kaohsiung Medical University Chung-Ho Memorial Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* 1\. Patient must be 20 years or older * 2\. Patient must have HCV GT1 infection combined with HBV infection. * 3\. Patients must be serum HCV RNA detectable, anti-HCV positive, HBsAg positive and HBeAg negative. * 4\. Patient has previously failed treatment with PEG-IFN-α 2a or 2b/RBV for minimum of 12 weeks of treatment. * 5\. Patient must have compensated liver disease consistent with CHC and/or CHB, and no other etiology. Note: patients with cirrhosis should have a liver imaging study (e.g. ultrasound, CT scan or MRI) within the preceding 6 months showing no evidence of hepatocellular carcinoma. * 6\. Patient meets all of the requirements and none of the contra-indications for treatment with PEG-IFN alpha-2b/RBV or boceprevir defined in the labels for the PEG-IFN/RBV to be used in combination with boceprevir. * 7\. Patient is able and willing to provide signed informed consent (prepared by and administered by the physician) as required by local country requirements.
Exclusion criteria
* 1\. Mixed genotypes including HCV genotype other than genotype 1. * 2\. Patient has received boceprevir, narlaprevir, telaprevir, or any other HCV protease inhibitor treatment. * 3\. Patient has evidence of decompensated liver disease including but not limited to, a history or presence of clinical ascites, bleeding varices, or hepatic encephalopathy. * 4\. Patient meets any of the following exclusionary hematologic and biochemical criteria (documentation required) Hemoglobin \<12 gm/dL for females and \<13 gm/dL for males Neutrophils \<1500/mm3 Platelets \<100,000/mm3 * 5\. Patient has an organ transplant other than cornea or hair. * 6\. Patient is co-infected with human immunodeficiency virus (HIV) * 7\. Patient requires or is anticipated to require any of the following prohibited medications: midazolam, pimozide, amiodarone, flecainide, propafenone, quinidine, and ergot derivatives * 8\. Patient with clinical diagnosis or evidence of substance abuse involving alcohol, intravenous drugs, inhalational psychotropics, narcotics, cocaine prescription or over-the-counter drugs. * 9\. Patient previously demonstrated clinically significant hypersensitivity or other contraindication to any component of the boceprevir formulation. This drug contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine. * 10\. Serious illness, including malignancy, active coronary artery disease or cardiac dysfunction within 24 weeks prior to study entry, that in the opinion of the site investigator may preclude completion of the treatment regimen. * 11\. Major hemoglobinopathy (e.g., thalassemia major), coagulopathy or any other cause of or tendency to hemolysis or bleeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Full Analysis Set Participants Who Received HCV Anti-viral Therapy With Sustained Virological Response (SVR) | week 24 | The methods used to assess this outcome measure is by full-analysis set (FAS), which is defined as undetectable HCV-RNA at follow-up Week 24 in subjects receiving ≥1 dose of any antiviral medication (Boceprevir/peginterferon/ribavirin) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Key Secondary Endpoint of This Clinical Trial-SVR in mITT | week 24 | The total 7 patients had SVR by mITT in this clincial-trial, which is defined as undetectable HCV-RNA at follow-up Week 24 in subjects receiving ≥1 dose of Boceprevir |
Other
| Measure | Time frame | Description |
|---|---|---|
| The Other Responses in the mITT Population/Safty- HBV Virologic Response | week 24 | HBV virologic response, defined as serum HBV DNA levels to \< 200 IU/mL at follow-up week 24 among patients with detectable HBV DNA at baseline |
Countries
Taiwan
Participant flow
Recruitment details
As protocol
Pre-assignment details
As protocol
Participants by arm
| Arm | Count |
|---|---|
| Patients With 32 Week Therapy For non-cirrhotic patients whose response of previous HCV therapy with PEG-IFN/RBV were relapse or partial response, PEG-IFN/RBV lead-in therapy is performed during 0-4 weeks, then add boceprevir from week 5 (boceprevir+ PEG-IFN/RBV). If HCV RNA is undetectable during 8-24 weeks, boceprevir+PEG-IFN/RBV triple therapy will be administered from week 5 to week 32. | 4 |
| Patients With 48 Weeks Therapy For non-cirrhotic patients whose response of previous HCV therapy with PEG-IFN/RBV were relapse or partial response, PEG-IFN/RBV lead-in therapy is performed during 0-4 weeks, then add boceprevir from week 5 (boceprevir+ PEG-IFN/RBV). If HCV RNA is detectable at week 8 and undetectable at week 24, boceprevir+ PEG-IFN/RBV triple therapy will be administered from week 5 to week 32, followed by additional 12 weeks of PEG-IFN/RBV therapy. | 0 |
| Null Responder or Cirrhotic Patients For null responder or cirrhotic patients, PEG-IFN/RBV lead-in therapy is performed during 0-4 weeks, then add boceprevir from week 5 to 48. | 8 |
| Total | 12 |
Baseline characteristics
| Characteristic | Patients With 32 Week Therapy | Null Responder or Cirrhotic Patients | Total |
|---|---|---|---|
| Age, Continuous | 42.9 years STANDARD_DEVIATION 16 | 50.6 years STANDARD_DEVIATION 9.2 | 48.0 years STANDARD_DEVIATION 11.7 |
| Sex: Female, Male Female | 0 Participants | 4 Participants | 4 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 0 | 0 / 8 |
| other Total, other adverse events | 4 / 4 | 0 / 0 | 8 / 8 |
| serious Total, serious adverse events | 0 / 4 | 0 / 0 | 1 / 8 |
Outcome results
Primary
Number of Full Analysis Set Participants Who Received HCV Anti-viral Therapy With Sustained Virological Response (SVR)
The methods used to assess this outcome measure is by full-analysis set (FAS), which is defined as undetectable HCV-RNA at follow-up Week 24 in subjects receiving ≥1 dose of any antiviral medication (Boceprevir/peginterferon/ribavirin)
Time frame: week 24
Population: For survey the total 12 chronic hepatitis C patients by FAS in different arms in this clinical- trial.~Outcome Measure Data Table: For survey the total 8 chronic hepatitis C patients had SVR by FAS in different arms in this clinical- trial.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients With 32 Week Therapy | Number of Full Analysis Set Participants Who Received HCV Anti-viral Therapy With Sustained Virological Response (SVR) | 4 participants |
| Null Responder or Cirrhotic Patients | Number of Full Analysis Set Participants Who Received HCV Anti-viral Therapy With Sustained Virological Response (SVR) | 4 participants |
p-value: 0.01Chi-squared
Secondary
Key Secondary Endpoint of This Clinical Trial-SVR in mITT
The total 7 patients had SVR by mITT in this clincial-trial, which is defined as undetectable HCV-RNA at follow-up Week 24 in subjects receiving ≥1 dose of Boceprevir
Time frame: week 24
Population: MITT population included subjects receiving ≥ 1 dose of boceprevir.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients With 32 Week Therapy | Key Secondary Endpoint of This Clinical Trial-SVR in mITT | 4 participants |
| Null Responder or Cirrhotic Patients | Key Secondary Endpoint of This Clinical Trial-SVR in mITT | 3 participants |
Other Pre-specified
The Other Responses in the mITT Population/Safty- HBV Virologic Response
HBV virologic response, defined as serum HBV DNA levels to \< 200 IU/mL at follow-up week 24 among patients with detectable HBV DNA at baseline
Time frame: week 24
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients With 32 Week Therapy | The Other Responses in the mITT Population/Safty- HBV Virologic Response | 0 participants |
| Null Responder or Cirrhotic Patients | The Other Responses in the mITT Population/Safty- HBV Virologic Response | 0 participants |