Original Article
Eltrombopag for Thrombocytopenia in Patients with Cirrhosis Associated with Hepatitis C
N Engl J Med 2007; 357:2227-2236November 29, 2007
- Abstract
Background
Eltrombopag is a new, orally active thrombopoietin-receptor agonist that stimulates thrombopoiesis. We evaluated its ability to increase platelet counts and facilitate treatment for hepatitis C virus (HCV) infection in patients with thrombocytopenia associated with HCV-related cirrhosis.
Methods
Seventy-four patients with HCV-related cirrhosis and platelet counts of 20,000 to less than 70,000 per cubic millimeter were randomly assigned to receive eltrombopag (30, 50, or 75 mg daily) or placebo daily for 4 weeks. The primary end point was a platelet count of 100,000 per cubic millimeter or more at week 4. Peginterferon and ribavirin could then be initiated, with continuation of eltrombopag or placebo for 12 additional weeks.
Results
At week 4, platelet counts were increased to 100,000 per cubic millimeter or more in a dose-dependent manner among patients for whom these data were available: in 0 of the 17 patients receiving placebo, in 9 of 12 (75%) receiving 30 mg of eltrombopag, in 15 of 19 (79%) receiving 50 mg of eltrombopag, and in 20 of 21 (95%) receiving 75 mg of eltrombopag (P<0.001). Antiviral therapy was initiated in 49 patients (in 4 of 18 patients receiving placebo, 10 of 14 receiving 30 mg of eltrombopag, 14 of 19 receiving 50 mg of eltrombopag, and 21 of 23 receiving 75 mg of eltrombopag) while the administration of eltrombopag or placebo was continued. Twelve weeks of antiviral therapy, with concurrent receipt of eltrombopag or placebo, were completed by 36%, 53%, and 65% of patients receiving 30 mg, 50 mg, and 75 mg of eltrombopag, respectively, and by 6% of patients in the placebo group. The most common adverse event during the initial 4 weeks was headache; thereafter, the adverse events were those expected with interferon-based therapy.
Conclusions
Eltrombopag therapy increases platelet counts in patients with thrombocytopenia due to HCV-related cirrhosis, thereby permitting the initiation of antiviral therapy. (ClinicalTrials.gov number, NCT00110799.)
Media in This Article
Figure 1
Randomization and Follow-up of the Study Patients.Figure 2
Median Platelet Counts and Percentages of Patients Who Completed the 12-Week Antiviral Treatment Phase.Article Activity
- Article
Thrombocytopenia is a frequent complication of chronic liver disease and is considered an indicator of advanced disease.1-3 The low platelet count is due partly to the effects of portal hypertension and hypersplenism,4 decreased thrombopoietin production,2,5,6 and virus-induced bone marrow suppression.7,8
Patients with chronic liver disease due to infection with the hepatitis C virus (HCV) who have thrombocytopenia (<75,000 platelets per cubic millimeter) have been routinely excluded from clinical trials of interferon and ribavirin, and few published reports have described the treatment of chronic HCV infection in patients with platelet counts of less than 50,000 per cubic millimeter. Although a reduced platelet count is not an absolute contraindication to treatment with pegylated interferon (peginterferon) and ribavirin, product labels advise that caution be used in treating patients with clinically significant thrombocytopenia. Furthermore, if thrombocytopenia develops during antiviral therapy, peginterferon may need to be delivered at a reduced dose or discontinued.9,10 Currently, there is no approved treatment for thrombocytopenia in patients with HCV infection.
Eltrombopag (SB-497115, GlaxoSmithKline) is a new, small-molecule, nonpeptide, oral platelet growth factor that acts as a thrombopoietin-receptor agonist. The drug interacts with the transmembrane domain of the thrombopoietin receptor and induces proliferation and differentiation of megakaryocytes and, as a result, an increase in platelet production. In preclinical and early clinical studies, eltrombopag therapy was shown to stimulate megakaryocyte proliferation and differentiation and to cause dose-dependent increases in platelet counts in chimpanzees and humans.11-14 Ex vivo experiments with platelets from humans and in vivo studies of healthy subjects have shown that treatment with eltrombopag does not adversely affect platelet function.15,16 Eltrombopag has also been shown to increase platelet counts in a dose-dependent manner in patients with chronic immune thrombocytopenic purpura.17
In this phase 2 study, we assessed whether the use of eltrombopag can increase platelet counts in patients with thrombocytopenia associated with cirrhosis due to chronic HCV infection. The safety and adverse-event profiles of eltrombopag were also evaluated.
Methods
Patients
Patients were enrolled from 22 centers in the United States and Europe. Eligible patients were 18 years of age or older and had chronic HCV infection (defined as the presence of anti-HCV antibodies and detectable serum HCV RNA levels, as determined with the use of a clinically available assay chosen by the investigator), compensated liver disease, and thrombocytopenia (defined as a platelet count of 20,000 to <70,000 per cubic millimeter). Patients were also required to have a liver-biopsy specimen indicative of cirrhosis, radiographic evidence of cirrhosis, or endoscopic evidence of portal hypertension. Patients were excluded if they were pregnant, had a history of thrombosis, or were coinfected with the human immunodeficiency virus or the hepatitis B virus.
Our study was approved by the institutional review board or ethics committee at each participating center and was conducted in accordance with the provisions of the Declaration of Helsinki, Good Clinical Practice guidelines, and local laws and regulations. All patients provided written informed consent.
Study Design and Organization
Our study was an international, multicenter, double-blind, randomized, placebo-controlled, phase 2 trial covering a range of doses of eltrombopag. After meeting the eligibility criteria, patients were randomly assigned to study groups in a 1:1:1:1 ratio with the use of permuted-block randomization and a block size of four. The random assignment was stratified according to the baseline platelet count (20,000 to <50,000 per cubic millimeter vs. 50,000 to <70,000 per cubic millimeter). Patients were assigned to an eltrombopag group or the placebo group by means of central randomization, which was independent of the study centers and involved an interactive voice system. In the initial treatment phase, patients received either eltrombopag tablets, once daily, at a dose of 30 mg, 50 mg, or 75 mg or matching placebo, once daily, for 4 weeks (Figure 1Figure 1
Randomization and Follow-up of the Study Patients.). Hematologic, biochemical, and other safety assessments were performed weekly. Treatment with eltrombopag was interrupted if the platelet count was 200,000 or more per cubic millimeter; treatment was then reinstated on an individual basis, generally when platelet counts returned to 100,000 or less per cubic millimeter.Patients who completed the initial treatment phase were eligible for antiviral treatment if they had attained a predefined platelet count: 70,000 or more per cubic millimeter for the use of peginterferon alfa-2a (Pegasys, Roche) or 100,000 or more per cubic millimeter for the use of peginterferon alfa-2b (Peg-Intron, Schering-Plough). The choice of interferon was not dictated by the protocol but rather was at the investigator's discretion.
In this antiviral treatment phase, peginterferon (180 μg of peginterferon alfa-2a per week or 1.5 μg of peginterferon alfa-2b per kilogram of body weight per week) and ribavirin (1000 to 1200 mg per day for patients receiving peginterferon alfa-2a and 800 mg per day for those receiving peginterferon alfa-2b) were administered for 8 weeks concomitantly with eltrombopag or placebo. Once additional preclinical safety data were available, the protocol was amended to extend this phase to 12 weeks, at which time eltrombopag was stopped and antiviral therapy was continued at the investigator's discretion. A follow-up visit was scheduled for 4 weeks after the last dose of eltrombopag or placebo had been received. Throughout the antiviral treatment phase, in accordance with the product labels for these approved therapies, the dose of peginterferon alfa-2a was reduced by half if the platelet count had decreased to 25,000 to 50,000 per cubic millimeter and was discontinued altogether if the platelet count was below 25,000 per cubic millimeter. The dose of peginterferon alfa-2b was reduced by half if the platelet count had decreased to 50,000 to 80,000 per cubic millimeter and was discontinued altogether if the platelet count was less than 50,000 per cubic millimeter.
An independent data monitoring committee was established to review data during the study. A separate independent committee reviewed all ophthalmic evaluations, because ocular findings in preclinical studies of immature rodents indicated a risk of cataract formation.
The sponsor, GlaxoSmithKline, and the academic principal investigator designed the study, developed the protocol, and prepared the first and subsequent drafts of the manuscript, with input from participating academic investigators. The sponsor and the academic principal investigator held and analyzed the data. Decisions related to the content of the final draft of the manuscript were made by the academic principal investigator in consultation with all coauthors. All authors, four of whom are employees of GlaxoSmithKline, had access to the data and contributed to the writing of the manuscript. The academic principal investigator vouches for the completeness and accuracy of this article.
Statistical Analysis
The primary efficacy end point was an increase in the platelet count from the baseline value (20,000 to <70,000 per cubic millimeter) to 100,000 or more per cubic millimeter after the 4-week initial treatment phase. Secondary end points included those related to safety, tolerability, and the ability to continue peginterferon therapy during the antiviral treatment phase. The analyses included all patients who were randomly assigned to a study group and who received at least one dose of the study medication. In the analysis of the primary end point, however, data for 5 of the 74 patients (7%) who entered the study but whose baseline platelet count was 70,000 or more per cubic millimeter were excluded; missing data were imputed with the use of the last-observation-carried-forward approach.
We planned to enroll 160 patients in the study, with 40 patients randomly assigned to each study group. We estimated the number of patients assuming a rate of response of 20% in the placebo group and 60% in the three active treatment groups. The power of our study to detect this anticipated treatment effect was 90% at an overall two-sided level of significance of 5%. The primary end point was analyzed with the use of multiple logistic-regression analysis. Each of the three eltrombopag groups was compared with the placebo group by means of a closed testing procedure. We tested the global null hypothesis of no significant difference among the four study groups and, if this global hypothesis was rejected, the null hypothesis of no significant difference between the placebo group and each eltrombopag group, with testing performed in the predetermined order of the highest dose (75 mg) to the lowest dose (30 mg). The sequential testing was continued until the null hypothesis could not be rejected.
The study was originally planned to be performed without interim analyses, except for a blinded review by the independent data monitoring committee of the safety and adverse-event profiles after 40 patients had completed the initial treatment phase. A subsequent amendment to the protocol stipulated the performance of formal interim analyses of efficacy data from the initial treatment phase.
The criterion for stopping the study early was a two-sided P value no greater than 0.0001, based on the O'Brien–Fleming adjustment for a group-sequential design, from an interim analysis of the efficacy data.18 The criterion was not met in the first interim analysis but was met in the second interim analysis (overall comparison for the four study groups, P<0.0001; 30 mg of eltrombopag vs. placebo, P=0.00067; 50 mg of eltrombopag vs. placebo, P=0.00015; and 75 mg of eltrombopag vs. placebo, P<0.0001).
Results
Characteristics of the Patients
Between April 5, 2005, and October 20, 2006, a total of 74 patients were randomly assigned to a study group and received the study drug or placebo (Figure 1): 18 patients received placebo, 14 received 30 mg of eltrombopag, 19 received 50 mg of eltrombopag, and 23 received 75 mg of eltrombopag. Since the 74 patients were distributed across 22 sites, some sites did not use a complete block, which caused a slight imbalance in the numbers of patients assigned to the four groups. The demographic and baseline clinical characteristics of the study groups were well balanced (Table 1Table 1
Baseline Characteristics of the Patients.). The median age was 51 years (range, 30 to 74), and more than two thirds of the patients were men.The median baseline platelet count was 55,000 per cubic millimeter (range, 26,000 to 94,000). The baseline platelet count was 20,000 to less than 50,000 per cubic millimeter in 35% of patients (26 of 74) and 50,000 to less than 70,000 per cubic millimeter in 58% (43 of 74) (Table 1). Seven percent of patients (5 of 74) who were successfully screened had baseline platelet counts of 70,000 or more per cubic millimeter just before administration of the study drug, which was considered a violation of the protocol. Therefore, the data for these five patients were excluded from the analysis of the primary efficacy end point, but they were included in the safety analysis because the patients received the study drug.
Efficacy
Initial Treatment Phase
The receipt of eltrombopag increased platelet counts to 100,000 or more per cubic millimeter at week 4, in a dose-dependent manner (P<0.001 for overall treatment effect) (Table 2Table 2
Median Platelet Counts at the End of the Initial Treatment Phase and the End of the Antiviral Treatment Phase.). The effect of each dose of eltrombopag was significant (P<0.001), as compared with the effect of placebo. No patient in the placebo group had an increase in the platelet count to 100,000 or more per cubic millimeter after 4 weeks. The results for the primary end point based on the observed data only (i.e., those obtained without the application of the last-observation-carried-forward approach) were similar to the results when the last-observation-carried-forward approach was used. Between 25 and 52% of patients receiving eltrombopag (primarily those receiving 50-mg or 75-mg doses daily) had platelet counts of 200,000 or more per cubic millimeter at any time during the initial treatment phase. Treatment with eltrombopag was interrupted in these patients until their platelet counts decreased to 100,000 or fewer per cubic millimeter.Antiviral Treatment Phase
Overall, two thirds of the patients (49 of 74) proceeded to the antiviral treatment phase: 4 of the 18 patients (22%) receiving placebo and 10 of the 14 (71%), 14 of the 19 (74%), and 21 of the 23 (91%) receiving 30 mg, 50 mg, and 75 mg of eltrombopag, respectively (Figure 1). Of these 49 patients, 48 had a platelet count that met the prespecified threshold for entry into the antiviral treatment phase (≥70,000 per cubic millimeter for the use of peginterferon alfa-2a or ≥100,000 per cubic millimeter for the use of peginterferon alfa-2b), and therefore peginterferon-based therapy could be initiated (Figure 1).
On an intention-to-treat basis, the first 12 weeks of antiviral therapy were completed by 5 of 14 patients receiving 30 mg of eltrombopag (36%), 10 of 19 receiving 50 mg (53%), and 15 of 23 receiving 75 mg (65%), as compared with 1 of 18 patients (6%) in the placebo group (Figure 2Figure 2
Median Platelet Counts and Percentages of Patients Who Completed the 12-Week Antiviral Treatment Phase.). Platelet counts in all eltrombopag groups decreased during the antiviral treatment phase, despite continued treatment with eltrombopag, but remained consistently above baseline values, with a nadir of more than 50,000 per cubic millimeter (Table 2 and Figure 2). Among the patients who completed the 12-week antiviral treatment phase and for whom platelet counts were available, a platelet count greater than the baseline value was maintained after completion of the antiviral treatment phase in 0 of 1 patient receiving placebo, 4 of 5 receiving 30 mg of eltrombopag, 4 of 5 receiving 50 mg of eltrombopag, and 10 of 12 receiving 75 mg of eltrombopag.At all time points during the antiviral treatment phase, platelet counts in all three eltrombopag groups were higher than those in the placebo group and remained higher than the level at which a reduction in the peginterferon dose is recommended (<50,000 per cubic millimeter). In the group receiving 75 mg of eltrombopag, 18 of 21 patients had platelet counts of 50,000 or more per cubic millimeter during this phase. No patient in the placebo group had a platelet count this high while receiving antiviral therapy. In the initial or antiviral treatment phase, platelet counts exceeded the protocol-specified upper limit of 200,000 per cubic millimeter in at least one visit in 4 of 14 patients (29%), 9 of 19 (47%), and 16 of 23 (70%) in the groups receiving 30 mg of eltrombopag, 50 mg of eltrombopag, and 75 mg of eltrombopag, respectively, necessitating a temporary interruption in eltrombopag therapy.
Safety
During the 4-week initial treatment phase, headache was reported in 36%, 16%, and 17% of patients who received 30 mg of eltrombopag, 50 mg of eltrombopag, and 75 mg of eltrombopag, respectively, as well as in 17% of patients who received placebo (Table 3Table 3
Most Common Adverse Events during the Initial Treatment Phase and the Antiviral Treatment Phase.). Other common adverse events in the three eltrombopag groups were dry mouth, abdominal pain, and nausea.During the subsequent antiviral treatment phase, the incidence of adverse events was similar in all three eltrombopag groups. The adverse events most commonly reported during this phase were influenza-like illness, fatigue, chills, and headache, all of which are known side effects of interferon-based therapy.19,20
Drug-related adverse events were reported for five patients receiving 30 mg of eltrombopag (36%), eight receiving 50 mg (42%), and eight receiving 75 mg (35%), as compared with three patients (17%) in the placebo group. The most frequent drug-related adverse events (all of low-grade severity) were dry mouth, headache, and nausea. After treatment had been discontinued, thrombocytopenia occurred in one patient receiving 30 mg of eltrombopag, decreased visual acuity occurred in another receiving 30 mg of eltrombopag, and petechiae occurred in one patient receiving 75 mg of eltrombopag.
During the entire study, 62 patients reported adverse events and 7 reported serious adverse events. These serious events included ascites (in the group receiving 30 mg of eltrombopag), which subsequently resolved, and retinal exudates (in the group receiving 75 mg of eltrombopag), which did not resolve and which were deemed by the investigator to be unrelated to treatment with eltrombopag. Thrombocytopenia in one patient receiving 30 mg of eltrombopag and myositis in one patient receiving 50 mg of eltrombopag were resolving at the end of the study. The thrombocytopenia occurred after eltrombopag therapy had been discontinued and peginterferon administration had begun; the platelet count fell below the patient's baseline count, and the event was considered by the investigator to be related to the study drug. One patient in the placebo group had two reported serious adverse events, abdominal pain and renal failure, and subsequently died. Adverse events led to the withdrawal of three patients receiving 30 mg of eltrombopag (owing to upper abdominal pain and ascites), one patient receiving 50 mg of eltrombopag (owing to neutropenia), and one patient receiving 75 mg of eltrombopag (owing to retinal exudates).
Discussion
Thrombocytopenia in patients with cirrhosis due to HCV can prevent or limit antiviral treatment, but there is little information concerning the eligibility for treatment of patients with platelet counts of less than 50,000 per cubic millimeter. In our study, 30 of 45 patients who had had a response to eltrombopag, with a rise in the platelet count to 70,000 or more per cubic millimeter (or ≥100,000 per cubic millimeter) during the initial treatment phase, completed the first 12 weeks of antiviral treatment with peginterferon, during which time the use of eltrombopag was continued; specifically, 65% of those receiving 75 mg of eltrombopag and 53% of those receiving 50 mg of eltrombopag completed the first 12 weeks of the treatment.
The most common side effects of eltrombopag during the initial treatment phase were headache, dry mouth, abdominal pain, and nausea; these effects were of insufficient severity to require discontinuation of the drug. In this small and therefore underpowered study, we did not find evidence of a dose–response relation with respect to the occurrence of adverse events in the antiviral treatment phase, during which the reported side effects were consistent with those associated with interferon-based therapy.
During the initial treatment phase, significant increases in platelet counts were observed in each of the three eltrombopag groups as compared with the placebo group. The primary end point (a platelet count ≥100,000 per cubic millimeter at week 4) was met in 75 to 95% of patients in the eltrombopag groups, in a dose-dependent manner. During the subsequent antiviral phase, platelet counts decreased, perhaps owing to the antiplatelet effect of peginterferon; nevertheless, platelet counts remained consistently above baseline levels. These results require confirmation in phase 3 trials involving standard-duration courses of peginterferon and ribavirin.
Supported by GlaxoSmithKline.
Drs. McHutchison, Dusheiko, Shiffman, Rodriguez-Torres, Sigal, Bourliere, Berg, Gordon, and Afdhal report receiving research and grant support from GlaxoSmithKline; Drs. McHutchison, Dusheiko, Shiffman, Rodriguez-Torres, Gordon, and Afdhal, research and grant support from Roche and Schering-Plough; Drs. McHutchison, Dusheiko, Rodriguez-Torres, Sigal, Gordon, and Afdhal, consulting or advisory fees from GlaxoSmithKline; Drs. Dusheiko, Shiffman, Rodriguez-Torres, and Bourliere, consulting fees from Roche; Drs. McHutchison, Dusheiko, and Afdhal, consulting fees from Schering-Plough; Drs. McHutchison and Gordon, lecture fees from GlaxoSmithKline, Schering-Plough, and Roche; Drs. Dusheiko and Bourliere, lecture fees from Schering-Plough and Roche; Drs. Shiffman and Rodriguez-Torres, lecture fees from Roche; and Dr. Afdhal, lecture fees from GlaxoSmithKline and Schering-Plough. Duke University has a funded academic alliance with GlaxoSmithKline that has also supported clinical and translational research by Dr. McHutchison and other Duke investigators. Dr. Theodore, Ms. Campbell, and Drs. Blackman and Jenkins report being employees of GlaxoSmithKline and holding stock therein. No other potential conflict of interest relevant to this article was reported.
We thank the study coordinators, nurses, and patients involved in the study; Steven Mangum, Dr. Valerie Kitchen, and Dawn Midwinter for their input and insights into the design of the study; Drs. Scott White, Helen Steel, Michael Arning, and Yizhe Wang from GlaxoSmithKline and Dr. James Bussel for their instructive comments and assistance during the preparation of an earlier version of the manuscript; and the staff of AOI Communications and Larry Rosenberg, Ph.D., for their editorial assistance with an earlier version of the manuscript.
Source Information
From Duke University and Duke Clinical Research Institute, Durham, NC (J.G.M.); Royal Free Hospital, London (G.D.); Virginia Commonwealth University Medical Center, Richmond (M.L.S.); Fundación de Investigación de Diego, San Juan, Puerto Rico (M.R.-T.); Weill Medical College of Cornell University, New York (S.S.); Hôpital Saint Joseph, Marseille, France (M.B.); Charité, Berlin (T.B.); Henry Ford Hospital and Health System, Detroit (S.C.G.); GlaxoSmithKline, Greenford, United Kingdom (F.M.C.); GlaxoSmithKline, Research Triangle Park, NC (D.T.); GlaxoSmithKline, Philadelphia (N.B., J.J.); and Beth Israel Deaconess Medical Center, Boston (N.H.A.).
Address reprint requests to Dr. McHutchison at Duke University and Duke Clinical Research Institute, P.O. Box 17969, Durham, NC 27705, or at mchut001@mc.duke.edu.
The members of the TPL102357 Study Group are listed in the Appendix.
Appendix
In addition to the authors, the participating investigators in the TPL102357 Study Group were as follows: Centre Hospitalier Universitaire de Nancy, Hôpital pour Adultes de Brabois, Vandoeuvre-lès-Nancy, France — J.P. Bronowicki; Hôpital du Haut Lévêque, Pessac, France — V. DeLédinghen; Hôpital Edouard Herriot, Lyon, France — J. Dumortier; Universitaetsklinikum Heidelberg, Innere Medizinische IV, Heidelberg, Germany — J. Encke; Papageorgiou General Peripheral Hospital, Thessaloniki, Greece — G. Germanidis; Alamo Medical Research, San Antonio, TX — E. Lawitz; Hôpital Beaujon, Clichy, France — P. Marcellin; Gartnavel General Hospital, Glasgow, United Kingdom — P. Mills; Hôpital Saint Antoine, Paris — R. Poupon; Metropolitan Research, Fairfax, VA — V. Rustgi; Klinikum der J.W. Goethe Universitaet-Medizinische Klinik III, Frankfurt, Germany — G. Teuber; Hôpital L'Archet, Nice, France — A. Tran; Centre Hospitalier Universitaire de Grenoble, Hôpital Nord Michallon, Grenoble, France — J.P. Zarski.
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