Hepatitis C, Chronic
Conditions
Brief summary
The current trial is designed to prospectively explore the safety of erythropoietin use for the treatment of anemia during boceprevir plus peginterferon alfa-2b/Ribavirin (PEG2b/RBV) therapy and to assess its relationship to efficacy. All participants in this trial will be treated with the triple combination of boceprevir plus PEG2b/RBV. If a participant becomes anemic during treatment, the participant will be randomized to one of two therapeutic strategies for management of anemia (erythropoietin use versus RBV dose reduction).
Interventions
DRUGBoceprevir
800 mg given three times a day (TID), orally (PO)
DRUGPeginterferon alfa-2b (PEG2b)
1.5 µg/kg/week given subcutaneously (SC)
DRUGRibavirin (RBV)
Ribavirin weight-based dosing (WBD), 600 to 1400 mg/day given twice daily (BID), orally (PO)
DRUGErythropoietin
Initial dose of 40,000 Units given subcutaneously (SC) once weekly (QW), with dose adjustment as necessary to achieve and maintain serum hemoglobin levels of 10-12 g/dL
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant must have previously documented Chronic Hepatitis C (CHC) genotype 1 infection. * Hemoglobin concentration at Screening must be ≤15 g/dL for both females and males. * Participant must have a liver biopsy with histology consistent with CHC and no other etiology. * Participant with bridging fibrosis (F3) or cirrhosis (F4) must have an ultrasound within 6 months of the Screening Visit (or between Screening and Day 1) with no findings suspicious for hepatocellular carcinoma. * Participant's weight must be ≥40 kg and ≤125 kg. * Participant and participant's partner(s) must each agree to use acceptable methods of contraception for at least 2 weeks prior to Day 1 and continue until at least 6 months after last dose of study medication, or longer if dictated by local regulations. * Participant must be willing to give written informed consent. * Participant must be willing to attend frequent site visits for the duration of the trial. * Participant must not have any contraindications for the use of erythropoietin.
Exclusion criteria
* Participants known to be coinfected with the human immunodeficiency virus (HIV) or hepatitis B virus. * Participants who received prior treatment for hepatitis C. * Treatment with any investigational drug within 30 days of the screening visit in this trial. * Participants receiving any of the following medication(s) within 2 weeks prior to the Day 1 visit: alfuzosin, antiarrhythmics (amiodarone, bepridil, flecainide, propafenone, and quinidine), ergot derivatives, cisapride, lovastatin, simvastatin, pimozide, triazolam, and orally administered midazolam. * Participation in any other clinical trial within 30 days of the screening visit in this trial or intention to participate in another clinical trial during participation in this trial. * Evidence of decompensated liver disease. * Diabetic and/or hypertensive participants with clinically significant ocular examination findings. * Pre-existing psychiatric condition(s). * Clinical diagnosis of substance abuse of specified drugs within specified timeframes. * Any known pre-existing medical condition that could interfere with the participant's participation in and completion of the trial. * Evidence of active or suspected malignancy, or a history of malignancy, within the last 5 years (except adequately treated carcinoma in situ and basal cell carcinoma of the skin). * Participants who are pregnant or nursing. Participants who intend to become pregnant during the trial period. Male participants with partners who are, or intend to become, pregnant during the trial period. * Any other condition which, in the opinion of a physician, would make the participant unsuitable for enrollment or could interfere with the participant participating in and completing the trial. * Participant who had a life-threatening serious adverse event during the screening period. * A participant must not be a member or a family member of the personnel of the investigational or sponsor staff directly involved with this trial. * Protocol-specified hematologic, biochemical, and serologic criteria (growth factors may not be used to achieve trial entry requirements). * Serum albumin below the lower limit of normal (LLN) of laboratory reference range. * Thyroid-stimulating hormone (TSH) \>1.2 x Upper Limit of Normal (ULN) or \<0.8 x LLN of laboratory reference. * Serum creatinine \>ULN of the laboratory reference. * Protocol-specified serum glucose concentrations. * Prothrombin time/partial thromboplastin time (PT/PTT) values \>10% above laboratory reference range. * Protocol-specified alpha fetoprotein concentrations.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Virologic Response (SVR) | At Follow-up Week 24 | SVR was defined as undetectable plasma Hepatitis C Virus ribonucleic acid (HCV-RNA) at Follow-up Week 24 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Discontinued Treatment | From Study Day 1 up to Study Treatment Week 48 | Cumulative discontinuation was defined as the sum of discontinuations due to adverse events, viral breakthrough/resistance, detectable HCV-RNA and futility rules (\<2-log10 decline in HCV-RNA at Treatment Week 12, ≥ Lower Limit of Quantification \[LLQ\] HCV-RNA at Treatment Week 24), and other (noncompliance, withdrawal of consent, lost to follow-up). |
Participant flow
Pre-assignment details
687 Participants enrolled and were treated with Peginterferon/Ribavirin (PEG2b/RBV) followed by PEG2b/RBV + boceprevir. 500 participants became anemic during treatment and were randomized to either the RBV Dose Reduction Arm (n=249) or the Erythropoietin Use Arm (n=251).
Participants by arm
| Arm | Count |
|---|---|
| Ribavirin Dose Reduction Arm After the initiation of treatment with 4 weeks with PEG2b/RBV followed by 24 or 44 weeks of boceprevir, participants who became anemic (serum hemoglobin = ≤10 g/dL) within the 28- or 48-week treatment period and who were randomized to the Ribavirin (RBV) Dose Reduction Arm received reduced doses of RBV for management of the anemia in combination with PEG2b and boceprevir therapies. | 249 |
| Erythropoietin Use Arm After the initiation of treatment with 4 weeks with PEG2b/RBV followed by 24 or 44 weeks of boceprevir, participants who became anemic (serum hemoglobin = ≤10 g/dL) within the 28- or 48-week treatment period and who were randomized to the Erythropoietin Use Arm received erythropoietin for management of the anemia in addition to PEG2b/RBV and boceprevir therapies. | 251 |
| Treated/Not Randomized Participants received 4 weeks of PEG2b/RBV followed by 24 or 44 weeks of boceprevir plus PEG2b/RBV depending on Hepatitis C Virus RNA (HCV-RNA) levels. Participants continued with this treatment if their serum hemoglobin remained \>10 g/dL throughout the 28- or 48-week treatment period. | 187 |
| Total | 687 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Follow-up Period (up to Week 72) | Adverse Event | 2 | 0 | 1 |
| Follow-up Period (up to Week 72) | Non-medical Reason | 26 | 28 | 38 |
| Treatment Period | Adverse Event | 27 | 32 | 50 |
| Treatment Period | Non-Medical Reasons | 19 | 22 | 44 |
| Treatment Period | Treatment Failure | 26 | 31 | 24 |
Baseline characteristics
| Characteristic | Ribavirin Dose Reduction Arm | Erythropoietin Use Arm | Treated/Not Randomized | Total |
|---|---|---|---|---|
| Age, Continuous | 50.2 years STANDARD_DEVIATION 9.9 | 49.7 years STANDARD_DEVIATION 9.7 | 47.5 years STANDARD_DEVIATION 10.1 | 49.3 years STANDARD_DEVIATION 10.1 |
| Sex: Female, Male Female | 171 Participants | 164 Participants | 99 Participants | 434 Participants |
| Sex: Female, Male Male | 78 Participants | 87 Participants | 88 Participants | 253 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 247 / 249 | 248 / 251 | 180 / 187 |
| serious Total, serious adverse events | 39 / 249 | 33 / 251 | 15 / 187 |
Outcome results
Primary
Percentage of Participants With Sustained Virologic Response (SVR)
SVR was defined as undetectable plasma Hepatitis C Virus ribonucleic acid (HCV-RNA) at Follow-up Week 24
Time frame: At Follow-up Week 24
Population: The primary efficacy analysis was performed on all participants who were randomized to either the RBV Dose Reduction Arm or the EPO Use Arm for anemia management (i.e. the Full Analysis Set of patients requiring anemia management \[FAS, n=500\]).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ribavirin Dose Reduction Arm | Percentage of Participants With Sustained Virologic Response (SVR) | 71.5 percentage of participants |
| Erythropoietin Use Arm | Percentage of Participants With Sustained Virologic Response (SVR) | 70.9 percentage of participants |
Comparison: The modified Koch method was used to calculate the stratum-adjusted Mantel-Haenszel (MH) difference between the SVR rates for the Erythropoietin Use Arm versus the Ribavirin Dose Reduction Arm and corresponding 95% confidence interval with continuity correction.95% CI: [-8.6, 7.2]Mantel-Haenszel, modified Koch method
Secondary
Percentage of Participants Who Discontinued Treatment
Cumulative discontinuation was defined as the sum of discontinuations due to adverse events, viral breakthrough/resistance, detectable HCV-RNA and futility rules (\<2-log10 decline in HCV-RNA at Treatment Week 12, ≥ Lower Limit of Quantification \[LLQ\] HCV-RNA at Treatment Week 24), and other (noncompliance, withdrawal of consent, lost to follow-up).
Time frame: From Study Day 1 up to Study Treatment Week 48
Population: All Treated Participants, defined as all participants who were treated with any study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ribavirin Dose Reduction Arm | Percentage of Participants Who Discontinued Treatment | 29 percentage of participants |
| Erythropoietin Use Arm | Percentage of Participants Who Discontinued Treatment | 34 percentage of participants |
| Treated/Not Randomized | Percentage of Participants Who Discontinued Treatment | 63 percentage of participants |