December 6, 2013

Gastroenterology

A Randomized Trial

Fred Poordad, Eric Lawitz, K. Rajender Reddy, Nezam H. Afdhal, Christophe Hézode, Stefan Zeuzem, Samuel S. Lee, Jose Luis Calleja, Robert S. Brown, JR., Antonio Craxi, Heiner Wedemeyer, Lisa Nyberg, David R. Nelson, Lorenzo Rossaro, Luis Balart, Timothy R. Morgan, Bruce R. Bacon, Steven L. Flamm, Kris V. Kowdley, Weiping Deng, Kenneth J. Koury, Lisa D. Pedicone, Frank J. Dutko, Margaret H. Burroughs, Katia Alves, Janice Wahl, Clifford A. Brass, Janice K. Albrecht, and Mark S. Sulkowski

Gastroenterology. 2013;145(5):1035-1044.

Abstract and Introduction

Abstract

Background & Aims Treatment of hepatitis C virus (HCV) infection with boceprevir, peginterferon, and ribavirin can lead to anemia, which has been managed by reducing ribavirin dose and/or erythropoietin therapy. We assessed the effects of these anemia management strategies on rates of sustained virologic response (SVR) and safety.
Methods Patients (n = 687) received 4 weeks of peginterferon and ribavirin followed by 24 or 44 weeks of boceprevir (800 mg, 3 times each day) plus peginterferon and ribavirin. Patients who became anemic (levels of hemoglobin approximately ≤10 g/dL) during the study treatment period (n = 500) were assigned to groups that were managed by ribavirin dosage reduction (n = 249) or erythropoietin therapy (n = 251).
Results Rates of SVR were comparable between patients whose anemia was managed by ribavirin dosage reduction (71.5%) vs erythropoietin therapy (70.9%), regardless of the timing of the first intervention to manage anemia or the magnitude of ribavirin dosage reduction. There was a threshold for the effect on rate of SVR: patients who received <50% of the total milligrams of ribavirin assigned by the protocol had a significantly lower rate of SVR (P < .0001) than those who received ≥50%. Among patients who did not develop anemia, the rate of SVR was 40.1%. Eleven thromboembolic adverse events were reported in 9 of 295 patients who received erythropoietin, compared with 1 of 392 patients who did not receive erythropoietin.
Conclusions Reduction of ribavirin dosage can be the primary approach for management of anemia in patients receiving peginterferon, ribavirin, and boceprevir for HCV infection. Reduction in ribavirin dosage throughout the course of triple therapy does not affect rates of SVR. However, it is important that the patient receives at least 50% of the total amount (milligrams) of ribavirin assigned by response-guided therapy. ClinicalTrials.gov number, NCT01023035.

Introduction

Anemia is a well-established adverse event with both pegylated interferon alfa (peginterferon) and ribavirin (RBV) in the treatment of chronic hepatitis C virus (HCV), particularly when these compounds are used in combination.[1-3] The mechanism of anemia with RBV is hemolysis-associated, peginterferon suppresses bone marrow, and the mechanism of anemia with boceprevir is unknown. The relative contribution of each to the degree of anemia varies by patient, and depends on renal function, RBV exposure, body mass, and degree of liver fibrosis. Roughly 30% of patients in the large phase 3 clinical trials of peginterferon/RBV experienced hemoglobin declines below 10 g/dL[4,5] and this threshold has been largely recommended in practice guidelines as defining clinically meaningful anemia and the threshold for anemia management.[6,7]

Chief among the clinical management paradigms that had been developed based on peginterferon/RBV therapy was the dosage-reduction scheme for RBV because data supported the concept that a minimum of 60%−80% of intended RBV dosing and duration was required to achieve optimal rates of sustained virologic response (SVR).[8,9] These various reports that probability of response was correlated with RBV dosing and that higher dosages of RBV were more effective led many to speculate that RBV dosing should be maintained at all cost. This led to the use of erythropoietin (EPO) and blood transfusions to support anemic patients on therapy to allow for minimal and brief reductions in RBV dosing.

The contribution of EPO in achieving SVR has never been formally studied in a randomized manner in HCV therapy, including its use with the newly approved protease inhibitors.[10-13] In a phase 3 clinical trial of boceprevir in previously untreated patients with HCV genotype-1, it was noted that patients who became anemic but did not receive EPO had similar SVR rates to those patients who were given the growth factor.[14] Given the high cost of EPO and potential safety concerns with its off-label use with HCV treatment-induced anemia, there remains a need to assess the utility of EPO vs RBV dosage reduction as the primary anemia-management intervention with current HCV therapy. This study was designed to determine the relative efficacy and safety of RBV dosage reduction vs EPO as the primary anemia management strategy among previously untreated patients with chronic HCV genotype-1 infection who were treated with boceprevir plus peginterferon/RBV.

Methods

Study Design

This randomized, multi-center, open-label clinical trial was designed to compare 2 strategies for the management of anemia (RBV dosage reduction vs EPO use) in adult patients with previously untreated chronic HCV genotype-1 infection who became anemic (hemoglobin ≤10 g/L) during therapy with boceprevir (VICTRELIS, 800 mg 3 times daily; Merck Sharp & Dohme Corp., Whitehouse Station, NJ) plus peginterferon alfa-2b (PegIntron, 1.5 μg/kg/wk; Merck Sharp & Dohme Corp.)/RBV (600−1400 mg/d, based on weight). The study was conducted between December 2009 and October 2011 in accordance with the principles of good clinical practice and was approved by the appropriate Institutional Review Boards and regulatory agencies. All patients provided written informed consent. Patients (n = 687) were enrolled into this study and received 4 weeks of peginterferon/RBV followed by 24 or 44 weeks of boceprevir plus peginterferon/RBV (Supplementary Figure 1). Patients in cohort 1 (n = 111) received 44 weeks of boceprevir/peginterferon/RBV. After a protocol amendment, patients in cohort 2 (n = 576) were eligible to receive response-guided therapy due to the equivalent efficacy, which had been demonstrated in an earlier pivotal phase 3 trial (either 24 weeks of boceprevir/peginterferon/RBV if HCV RNA was undetectable at treatment week 8 and below the lower limit of quantitation [<25 IU/mL] at all subsequent time points, or 44 weeks of boceprevir/peginterferon/RBV if HCV RNA was detectable at treatment week 8 or ≥25 IU/mL at any subsequent time point). Patients with detectable HCV RNA (≥25 IU/mL) and a <2 log10 decline from baseline HCV RNA levels at treatment week 12 discontinued treatment, as did patients with HCV RNA ≥25 IU/mL at treatment week 24. Patients (n = 500) who became anemic (hemoglobin ≤10 g/dL, or if the rate of hemoglobin decline suggested that the value would be ≤10 g/dL before the next protocol-specified visit and the value was <11 g/dL) during the 4-week lead-in phase with peginterferon/RBV or during study treatment with boceprevir/peginterferon/RBV were randomized in a 1:1 ratio to RBV dosage reduction or EPO use for primary anemia management. The randomized treatment was stratified by time to development of anemia (≤16 vs >16 weeks after starting peginterferon/RBV) and by race (black vs non-black). Patients remained in the Treated/Not Randomized arm (n = 187) if they never met the protocol definition of anemia, discontinued treatment before randomization, or if their first hemoglobin value was ≤8.5 g/dL and treatment was continued at the investigator's discretion.

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Supplementary Figure 1. Supplementary Figure 1 Study design and patient disposition. Patients (N = 1154) were assessed for eligibility. Eligible patients (n = 687) received 4 weeks of peginterferon/RBV followed by 24 or 44 weeks of boceprevir (800 mg 3 times a day) plus peginterferon/RBV. The study was projected to enroll a sample size of 660 patients to be treated with boceprevir/peginterferon/RBV. Approximately 60% (400 patients) were expected to develop anemia. The precision of the 95% CI for the true difference in SVR rates between the treatments was expected to be approximately ±10%. Patients with detectable HCV RNA (≥25 IU/mL) and a <2 log10 decline from baseline HCV RNA levels at treatment week 12 discontinued treatment, as did patients with HCV RNA ≥25 IU/mL at treatment week 24. Patients remained in the Treated/Not Randomized arm (n = 187) if their hemoglobin values remained >10 g/dL throughout the 28-week or 48-week treatment period or they discontinued treatment before randomization. Patients with hemoglobin ≤10 g/dL during the lead-in phase with peginterferon/RBV or who became anemic (hemoglobin ≤10 g/dL) during study treatment were randomized in a 1:1 ratio to RBV dosage reduction (RBV DR) or EPO use. If the rate of hemoglobin decline suggested that the value would be ≤10 g/dL before the next protocol-specified visit and the value was <11g/dL, then the patient could be randomized to RBV dosage reduction or EPO use. Patients randomized during the lead-in period with peginterferon/RBV might have delayed initiation of boceprevir for up to 2 weeks at the discretion of the investigator if the anemia was significant.

The initial dosage reduction of RBV was 200 mg/d (or 400 mg/d if initial RBV dosage was 1400 mg/d) with a follow-up assessment at 2 weeks. If further dosage reduction of RBV was required, additional steps of RBV dosage reduction (by 200 mg/d) were performed. EPO was provided by the sponsor and was administered subcutaneously at 40,000 IU/wk. Secondary interventions for anemia (use of EPO in the RBV dosage-reduction arm; RBV dosage reduction in the EPO arm) were permitted for hemoglobin ≤8.5 g/dL. Packed red cell transfusions were allowed at the investigators' discretion. Patients were discontinued from the study if the hemoglobin level was ≤7.5 g/dL.

Selection of Patients

Eligibility criteria included no previous treatment for HCV infection, age older than 18 years, weight of 40−125 kg, HCV genotype-1, plasma HCV RNA level ≥10,000 IU/mL, hemoglobin ≤15 g/dL, and no contraindications for the use of EPO. Exclusion criteria were liver disease of cause other than HCV, decompensated liver disease, renal insufficiency, HIV or hepatitis B infection, pregnancy or current breastfeeding, diabetes, hypertension, pre-existing psychiatric conditions, and active or suspected malignancy. Laboratory exclusion criteria were hemoglobin <12 g/dL for females (males: <13 g/dL), neutrophils <1500/mm3 (blacks/African Americans: <1200/mm3), and platelets <100,000/mm3.

Efficacy

The primary efficacy end point was SVR (undetectable plasma HCV RNA at 24 weeks after the end of treatment) for both the RBV dosage-reduction and EPO arms. Plasma HCV RNA levels were measured with the TaqMan 2.0 assay (Roche Diagnostics, Indianapolis, IN), which had a lower limit of quantification of 25 IU/mL and lower limit of detection of 9.3 IU/mL. The lower limit of detection was used for decision making at various points throughout the study.

Safety

Safety analyses were based on all patients who were treated with any study medication. The proportion of patients with dosage modification/discontinuation due to adverse events, treatment-related serious adverse events, World Health Organization grade 3/4 neutropenia, and hemoglobin <10 g/dL were summarized by treatment. An adverse event was considered common if it occurred in a frequency ≥25% in either study arm. An exploratory analysis also examined safety in cirrhotic patients.

Statistical Analysis

The primary objective was to compare the effect on SVR of the 2 anemia management strategies. Key secondary objectives were to determine the safety and tolerability of EPO use vs RBV dosage reduction and to define predictors of SVR.

For the primary efficacy comparison, a 95% confidence interval (CI) for the difference in the SVR rates between the 2 treatment arms was computed using a Mantel-Haenszel approach adjusting for stratification factors as well as protocol amendment cohort. SVR rates were summarized for various subgroups using descriptive statistics (number and percentage) and exact 95% CIs. Exploratory analyses included calculation of P values using the χ2 test to compare SVR rates in some subgroups and the proportions of requiring secondary anemia intervention, and the Cochran-Armitage trend test for SVR rates by total RBV dosage. For safety analyses, adverse events were summarized using descriptive statistics (number and percentage).

All authors were involved in the collection, analysis, or interpretation of the data; revision of the manuscript; and the decision to submit the manuscript for publication. All authors had access to the study data, and reviewed and approved the final manuscript. All authors vouch for the completeness and accuracy of the data and analyses, as well as the fidelity of the study to the protocol.

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