Boceprevir-based Therapy to Rescue HCV Genotype 1/HBV Infected Patients Refractory to Combination Therapy (BOLERO-CB)

March 12, 2018 updated by: Kaohsiung Medical University Chung-Ho Memorial Hospital

Boceprevir-based Triple Therapy to Rescue HCV Genotype 1/HBV Dually Infected Patients Refractory to Peginterferon Plus Ribavirin Combination Therapy

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

12

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Taiwan
      • Kaohsiung, Taiwan, 80787
        • Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

20 years to 80 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NON_RANDOMIZED
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: 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.

Dosage of drugs: Boceprevir 800mg tid po, PegIntron 1.5 mcg/kg im QW, and Ribavirin 800 to 1400 mg/day PO divided BID Regimen adjusted according to body weight.

Stop trial intervention for patients with 32 week therapy: 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 boceprevir, PEG-IFN and RBV for arm A).
Drug: Stop 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.

Other Names:
  • Stop trial intervention for arm A
  • Stop trial intervention for arm B
  • Stop trial intervention for arm C
EXPERIMENTAL: 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.

Dosage of drugs: as Patients with 32 week therapy Stop trial intervention for patients with 48 weeks therapy: 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 boceprevir, PEG-IFN and RBV for arm B).
Drug: Stop 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.

Other Names:
  • Stop trial intervention for arm A
  • Stop trial intervention for arm B
  • Stop trial intervention for arm C
EXPERIMENTAL: 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.

Dosage of drugs: as Patients with 32 week therapy Stop trial intervention for for null responder or cirrhotic patients: 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 boceprevir, PEG-IFN and RBV for arm C).
Drug: Stop 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.

Other Names:
  • Stop trial intervention for arm A
  • Stop trial intervention for arm B
  • Stop trial intervention for arm C

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Full Analysis Set Participants Who Received HCV Anti-viral Therapy With Sustained Virological Response (SVR)
Time Frame: 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)
week 24

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Key Secondary Endpoint of This Clinical Trial-SVR in mITT
Time Frame: 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
week 24

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
The Other Responses in the mITT Population/Safty- HBV Virologic Response
Time Frame: 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
week 24

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Kaohsiung Medical University Chung-Ho Memorial Hospital

Collaborators

National Taiwan University Hospital

Investigators

  • Study Chair: Ming-Lung Yu, Professsor, Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2013

Primary Completion (ACTUAL)

September 1, 2016

Study Completion (ACTUAL)

September 1, 2016

Study Registration Dates

First Submitted

January 27, 2014

First Submitted That Met QC Criteria

February 9, 2014

First Posted (ESTIMATE)

February 11, 2014

Study Record Updates

Last Update Posted (ACTUAL)

March 13, 2018

Last Update Submitted That Met QC Criteria

March 12, 2018

Last Verified

May 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • KMUHIRB-2013-10-03 (I)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

Until now if sharing data is not decided

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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