Original Article
Eltrombopag for the Treatment of Chronic Idiopathic Thrombocytopenic Purpura
N Engl J Med 2007; 357:2237-2247November 29, 2007
- Abstract
Background
The pathogenesis of chronic idiopathic thrombocytopenic purpura (ITP) involves antibody-mediated platelet destruction and reduced platelet production. Stimulation of platelet production may be an effective treatment for this disorder.
Methods
We conducted a trial in which 118 adults with chronic ITP and platelet counts of less than 30,000 per cubic millimeter who had had relapses or whose platelet count was refractory to at least one standard treatment for ITP were randomly assigned to receive the oral thrombopoietin-receptor agonist eltrombopag (30, 50, or 75 mg daily) or placebo. The primary end point was a platelet count of 50,000 or more per cubic millimeter on day 43.
Results
In the eltrombopag groups receiving 30, 50, and 75 mg per day, the primary end point was achieved in 28%, 70%, and 81% of patients, respectively. In the placebo group, the end point was achieved in 11% of patients. The median platelet counts on day 43 for the groups receiving 30, 50, and 75 mg of eltrombopag were 26,000, 128,000, and 183,000 per cubic millimeter, respectively; for the placebo group the count was 16,000 per cubic millimeter. By day 15, more than 80% of patients receiving 50 or 75 mg of eltrombopag daily had an increased platelet count. Bleeding also decreased during treatment in these two groups. The incidence and severity of adverse events were similar in the placebo and eltrombopag groups.
Conclusions
Eltrombopag increased platelet counts in a dose-dependent manner in patients with relapsed or refractory ITP. (ClinicalTrials.gov number, NCT00102739.)
Media in This Article
Figure 1
Enrollment, Group Assignments, and Outcome.Figure 2
Analyses of Platelet Counts and Responses.Article Activity
- Article
Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease in which antiplatelet antibodies accelerate the destruction of platelets. In addition, platelet production can be impaired1 because the antiplatelet antibodies can also damage megakaryocytes.2-4 Although the thrombocytopenia of ITP can be severe, signs of bleeding are usually only minor. Persistently low platelet counts (<20,000 per cubic millimeter), however, are associated with an increased risk of serious bleeding, such as intracranial hemorrhage.5,6 The goal of managing chronic ITP is to maintain platelet counts, with the least possible intervention, at levels that prevent bleeding, thereby reducing treatment-related toxicity.7
Glucocorticoids and intravenous immunoglobulins increase platelet counts in ITP primarily by reducing the extent of platelet destruction. However, the recognition that platelet production in ITP is often suboptimal has led to the use of treatments that enhance thrombopoiesis. This approach has focused on thrombopoietin, the growth factor underlying megakaryocytopoiesis. Thrombopoietin is the ligand for the thrombopoietin receptor on megakaryocytes and platelets.8-11 In many patients with ITP, however, serum levels of thrombopoietin are within the normal range despite the thrombocytopenia.12,13
Two recent studies showed that AMG 531, a subcutaneously administered thrombopoiesis-stimulating protein, can increase platelet counts in patients with chronic ITP.14,15 In one study, single doses increased platelet counts substantially in 7 of 12 patients, and multiple doses increased platelet counts in 12 of 16 patients.14 Eltrombopag (SB-497115) is an oral, small-molecule, nonpeptide thrombopoietin-receptor agonist. The drug initiates thrombopoietin-receptor signaling by interacting with the transmembrane domain of the receptor, thereby inducing proliferation and differentiation of cells in the megakaryocytic lineage. Administration of eltrombopag increased platelet production in preclinical studies, in volunteers with normal platelet counts,16-21 and in patients with thrombocytopenia secondary to hepatitis C virus infection.22 This study was designed to assess whether eltrombopag could safely increase platelet counts in adults with relapsed or refractory chronic ITP.
Methods
Patients
Patients at 44 clinical sites were enrolled between February and November 2005. The protocol was approved by the human subjects committee at each institution, and all patients gave written informed consent before enrollment. Participants were at least 18 years of age, had at least a 6-month history of ITP, had received at least one previous treatment for ITP, and had a platelet count of less than 30,000 per cubic millimeter at enrollment. Patients receiving maintenance immunosuppressive regimens, primarily glucocorticoids, were eligible if the dose had been stable for at least 1 month. The dose had to remain unchanged throughout the study. Other treatments for ITP must have been completed at least 2 weeks before enrollment.
Patients with the following conditions were excluded: secondary immune thrombocytopenia (e.g., patients infected with human immunodeficiency virus or hepatitis C virus or patients with systemic lupus erythematosus), hemoglobin levels of less than 10 g per deciliter, congestive heart failure, arrhythmia, thrombosis within 1 year before enrollment, or myocardial infarction within 3 months before enrollment; women who were nursing or pregnant were also excluded. Women of childbearing age agreed to use contraception throughout the study. Values within the normal range were required for neutrophils, reticulocyte count, creatinine, and liver enzymes.
Study Design
This multicenter, randomized, double-blind, placebo-controlled trial examined once-daily oral treatment with eltrombopag. Patients were randomly assigned (in a 1:1:1:1 ratio) to receive placebo or 30, 50, or 75 mg of eltrombopag per day for up to 6 weeks. Randomization was stratified according to concomitant ITP medication (yes or no), splenectomy (yes or no), and the baseline platelet count (>15,000 per cubic millimeter vs. ≤15,000 per cubic millimeter), with a block size of four within each stratum. To reduce the risk of thrombocytosis, treatment was discontinued when platelet counts exceeded 200,000 per cubic millimeter. Race was self-reported and recorded on the case report form by each participating center.
The primary end point was a platelet count of 50,000 or more per cubic millimeter on day 43 of the study. Secondary end points included safety and tolerability, signs of bleeding, serum thrombopoietin level (as measured by enzyme-linked immunosorbent assay, R&D Systems), and health-related quality of life (as measured by the Medical Outcomes Study 36-Item Short Form General Health Survey, version 2 [SF36v2]; QualityMetric). The incidence and severity of bleeding were assessed at every visit according to the World Health Organization (WHO) bleeding scale (grade 0, no bleeding; grade 1, petechiae; grade 2, mild blood loss; grade 3, gross blood loss; grade 4, debilitating blood loss).
All patients were assessed weekly for safety, tolerability, and efficacy of the treatment during the 6-week treatment period and at 2-week intervals for 6 weeks after the study medication had been discontinued. In preclinical studies, cataract formation was found in rodents but not dogs, and patients therefore received ophthalmic evaluations before treatment, at the end of treatment, and 6 months after the last dose of the study medication. An independent safety committee reviewed the ocular findings. The study was conducted in accordance with the provisions of the Declaration of Helsinki, Good Clinical Practice guidelines, and local laws and regulations.
The protocol was developed by the academic principal investigators at the study sites and employees of the sponsor (GlaxoSmithKline). Data were collected and analyzed by the sponsor. Decisions related to the content and publication of the manuscript were made by the academic principal investigator of the study in consultation with the coauthors. All academic and nonacademic authors had access to the primary data and vouch for the completeness and accuracy of the data.
Statistical Analysis
An adaptive sequential design was applied.23 Response to treatment was defined as achievement of the primary end point: a platelet count of 50,000 or more per cubic millimeter. All patients who were treated with at least one dose of study medication and who had a baseline platelet count of less than 30,000 per cubic millimeter were included in the analyses of the primary end point. Two interim analyses were planned when data were available for one third and two thirds of the maximum intended sample size of 272 patients (68 per group). The trial had 90% statistical power at the 2.5% level of significance (one-sided) to detect a 30% difference in the proportion of patients with a response (platelet count ≥50,000 per cubic millimeter) to patients without a response between the placebo group and each eltrombopag group, assuming that 30% of patients receiving placebo would have a response. A logistic-regression model with adjustment for the use or nonuse of concomitant medication for ITP, splenectomy status, and baseline platelet count (≤15,000 per cubic millimeter vs. >15,000 per cubic millimeter) was used to test the global null hypothesis that the odds of a response were equal across all four study groups. If the null hypothesis was rejected, the odds of a response in each eltrombopag group were compared with the odds of a response in the placebo group by means of a closed testing procedure to maintain the overall type 1 error at 2.5% (one-sided). The interactions between treatment response and stratification variables were evaluated at the 10% level of significance.
The primary end point was analyzed by use of a prospectively defined last-observation-carried-forward imputation in which the last platelet count during treatment was carried forward to day 43 for patients who withdrew prematurely because of a platelet count of more than 200,000 per cubic millimeter. Patients who withdrew prematurely for any other reason were counted as not having had a response, irrespective of the platelet count (Figure 1Figure 1
Enrollment, Group Assignments, and Outcome.). Additional supportive analyses were performed with the use of only observed data at day 43, with no imputations.For each planned interim analysis, critical boundaries for assessing efficacy and futility by means of step-down and step-up procedures, respectively, were derived with the use of EAST 3 software (Cytel Software). At the first interim analysis, performed by the study sponsor, a given dose of eltrombopag could be stopped for reasons of efficacy (one-sided P≤0.0113), futility (one-sided P≥0.333), or safety. In the first interim analysis, involving data from 104 patients, the groups receiving the two highest doses of eltrombopag met the predefined stopping criteria for efficacy under the closed testing procedure. The group receiving 30 mg of eltrombopag did not meet the stopping criterion for either efficacy or futility (two-sided P=0.340); however, this dose was not continued because of high response rates for doses of 50 mg and 75 mg and a similar incidence of adverse events among patients in all four study groups. After the decision was made to stop the study, the final analysis involving data from 118 patients, including 14 patients who enrolled after the interim cutoff date (September 2005), was performed and is presented here.
Descriptive statistics were used to summarize demographic and baseline clinical characteristics and safety data. All P values for these data were two-sided and were not adjusted for multiple testing.
Results
Study Population
Of 153 patients screened, 118 underwent randomization, and 117 were treated (Figure 1). The most common reasons for ineligibility were a platelet count of 30,000 or more per cubic millimeter (18 patients) and withdrawal of consent before randomization (7 patients). The median age of enrolled patients was 50 years; 62% were women, and 79% were white (Table 1Table 1
Demographic and Clinical Characteristics at Baseline.). Forty-seven percent of the patients had undergone splenectomy, 32% were receiving concomitant medication for ITP, and 48% had a platelet count of 15,000 or less per cubic millimeter. Seventy-four percent of the patients had previously received two or more treatments for ITP. Only 20 of the 117 patients had received therapy for ITP other than glucocorticoids or intravenous immune globulins within the 3 months preceding the start of the protocol treatment, and these 20 patients were equally distributed among the four treatment groups. Significant differences in median age and race (white vs. nonwhite) were observed between treatment groups at baseline (Table 1).Of the 117 patients who began the trial, 7 in the placebo group and 36 in the eltrombopag groups did not complete 6 weeks of the study treatment (Figure 1). Of these 43 patients, 28 withdrew early because they had a platelet count of more than 200,000 per cubic millimeter. Four additional patients had a platelet count of more than 200,000 per cubic millimeter but did not withdraw from the trial. Efficacy was evaluated in 109 patients (Figure 1); all 117 patients were evaluated for safety.
Platelet Counts
The primary end point, a platelet count of 50,000 or more per cubic millimeter on day 43, was achieved in 81% of patients (21 of 26) given 75 mg of eltrombopag, 70% of patients (19 of 27) given 50 mg, and 28% of patients (8 of 29) given 30 mg; 11% of patients (3 of 27) in the placebo group reached the end point (P<0.001 for the groups taking 50 mg and 75 mg of eltrombopag) (Figure 1). Results were similar in an analysis of data at day 43 with no last-observation-carried-forward imputation: 73% (8 of 11), 56% (9 of 16), and 22% (5 of 23) of patients given 75 mg, 50 mg, or 30 mg of eltrombopag, respectively, and 10% (2 of 21) of patients given placebo reached the primary end point (two-sided P=0.002 for the comparison of 50 mg with placebo and P=0.001 for the comparison of 75 mg with placebo). At the first visit (day 8), 44% of patients receiving 50 mg of eltrombopag and 62% of those receiving 75 mg had a platelet count of 50,000 or more per cubic millimeter. By day 15, 88% of patients receiving 50 mg and 81% of those receiving 75 mg had a response (Figure 2AFigure 2
Analyses of Platelet Counts and Responses.), with the median platelet count (last-observation-carried-forward data) approaching the normal range (i.e., 150,000 to 400,000 per cubic millimeter); at these two doses, the 25th percentile of the platelet counts was approximately 50,000 per cubic millimeter (Figure 2B). After the first interim analysis showed that the two highest eltrombopag doses met predefined stopping criteria for efficacy, the trial was stopped by the sponsor. The median platelet count for patients who continued treatment (Figure 1) was maintained at 50,000 or more per cubic millimeter at each subsequent visit during treatment in the groups receiving 50 mg or 75 mg of eltrombopag (observed data, Figure 2C).During the study, platelet counts rose to more than 200,000 per cubic millimeter in 4% of patients (1 of 27) in the placebo group and in 14% (4 of 29), 37% (10 of 27), and 50% (13 of 26) in the groups receiving 30, 50, and 75 mg of eltrombopag, respectively. The increase in the platelet count to more than 200,000 per cubic millimeter occurred earlier in the group receiving 75 mg of eltrombopag than in the other eltrombopag groups. After 1 week of treatment (day 8), more than 10% of patients in the groups receiving 50 mg or 75 mg of eltrombopag had platelet counts of more than 200,000 per cubic millimeter, and by day 15, more than 25% of patients in these two groups had a platelet count of more than 200,000 per cubic millimeter. Median platelet counts in these two groups returned to levels near baseline within 2 weeks after discontinuation of therapy (Figure 2C).
Further analyses showed no significant interaction between a response and prior splenectomy, age, or race (white vs. nonwhite). In all groups except those receiving 75 mg of eltrombopag, there was a higher percentage of responders among patients using concomitant ITP medication. Among patients who had a baseline platelet count of more than 15,000 per cubic millimeter, there was a substantially higher percentage of responders in all groups except for the group receiving 30 mg of eltrombopag (in which the overall percentage of responders was lowest) (two-sided P=0.093 for patients taking concomitant ITP medications and P=0.042 for patients with a baseline platelet count >15,000 per cubic millimeter) (Figure 2D).
Bleeding
During treatment with eltrombopag (50 mg or 75 mg), the incidence of bleeding (assessed according to the WHO bleeding scale) decreased (Figure 3Figure 3
Incidence of Bleeding Symptoms during and after Treatment According to Treatment Group.) as the platelet count increased and gradually returned to baseline levels during the 6 weeks of follow-up, as the platelet count returned to near-baseline levels. The incidence of bleeding events during treatment, regardless of grade and cause, was 14% in the placebo group and 17%, 7%, and 4% in the groups receiving 30, 50, and 75 mg of eltrombopag, respectively.Thrombopoietin Levels
Median baseline serum thrombopoietin levels were 54 ng per liter in the placebo group and 56, 57, and 54 ng per liter in the eltrombopag groups receiving 30, 50, and 75 mg, respectively — all within the range in healthy volunteers (26 to 209 ng per liter).11 Similar median serum thrombopoietin levels were observed at day 43 (59 ng per liter in the placebo group and 49, 52, and 45 ng per liter in the groups receiving 30, 50, and 75 mg of eltrombopag, respectively). Patients with a response generally had platelet counts within the normal range as well as normal thrombopoietin levels.
Quality of Life
Health-related quality of life, based on the physical and mental component scores of the SF36v2 survey, was similar at baseline and at the end of the study. Individual dimension scores, such as those for physical health and vitality, remained similar. The single exception was a significant decrease from baseline in the mean emotional-role score for the group receiving 75 mg of eltrombopag (P=0.02).
Safety and Adverse Events
The incidence and severity of adverse events were similar for all four study groups (Table 2Table 2
Adverse Events in 5% or More of Patients in Any Study Group.). The most common adverse event in each group, including the placebo group, was mild to moderate headache. The number of patients experiencing grade 3 or 4 adverse events24 during the study, or within 30 days after discontinuation of the study treatment, was similar among all four study groups. A single case of cataract progression was reported 181 days after the last dose of study medication in a 60-year-old woman with a history of glucocorticoid use and cigarette smoking who received 75 mg of eltrombopag daily for 8 days. The event was assessed by the investigator as not related to the study drug.The only death occurred in a 66-year-old man who had undergone a pneumonectomy for non–small-cell lung cancer and entered the study with chronic obstructive pulmonary disease, asthma, and peripheral edema. He received 50 mg of eltrombopag for 21 days and had grade 3 pneumonia, hepatitis, and renal insufficiency and grade 4 exacerbation of chronic obstructive pulmonary disease. Twenty-five days after entering the study, the patient died of cardiopulmonary failure, with clinical signs of sepsis. Thromboemboli were noted in the small vessels of the liver and kidneys on autopsy.
Discussion
This dose-ranging study of eltrombopag, an oral small-molecule nonpeptide platelet growth factor, showed that a daily dose of 50 or 75 mg of the drug is an effective short-term treatment for chronic ITP. At these doses, eltrombopag elevated platelet counts to 50,000 or more per cubic millimeter in more than 80% of patients within 2 weeks. Platelet counts rose above 200,000 per cubic millimeter in 37% of patients receiving 50 mg of eltrombopag and in 50% of patients receiving 75 mg — and this level was reached sooner in patients receiving the 75-mg dose. Patients with refractory disease after splenectomy responded in the same way as patients who had not undergone splenectomy. There was no significant difference between the placebo and eltrombopag groups in the incidence and severity of adverse events. The trial was stopped by the sponsor after the first interim analysis showed that the two highest doses (50 and 75 mg per day) met the predefined stopping criteria for efficacy. These data confirm that a treatment designed to increase platelet production in ITP can be effective, as was demonstrated with the thrombopoiesis-stimulating protein AMG 531.14,15
Our patients had normal thrombopoietin levels, a finding that has been reported in other patients with ITP.5,25,26 In this study, thrombopoietin levels were unaffected by treatment with eltrombopag.
At the two highest doses of eltrombopag, bleeding decreased as the platelet count increased, indicating the hemostatic efficacy of the newly produced platelets. Rates of adverse events were similar in the placebo group and the three groups receiving eltrombopag, with no evidence of dose-limiting toxicity. Cataracts had been observed in studies of eltrombopag in rodents, but no treatment-related cataracts were observed in this study. We are continuing to evaluate the risk of cataracts in our patients, who have multiple risk factors for cataracts (e.g., advanced age and long-term use of glucocorticoids).
Unanswered questions about the use of eltrombopag and other thrombopoietic growth factors concern their role and safety in long-term treatment and whether such agents are effective in patients receiving myelosuppressive chemotherapy. It is also not known whether patients whose platelet counts do not respond to 75 mg of eltrombopag would have a response to higher doses.
Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, June 2–6, 2006; at the 11th Congress of the European Hematology Association, Amsterdam, June 15–18, 2006; and at the 48th Annual Meeting of the American Society of Hematology, Orlando, FL, December 9–12, 2006.
Supported by GlaxoSmithKline (GSK).
Dr. Bussel reports receiving research grants from Amgen, Biogen–IDEC, Cangene, Genentech, GSK, and Sysmex; lecture fees from Baxter; and consulting fees from Amgen, Symphogen, GSK, and Baxter; and reports having equity ownership in Amgen and GSK. Dr. Psaila reports receiving consulting fees from Crofessionals. Dr. Provan reports receiving research grants from GSK and Baxter, consulting fees from GSK and Symphogen, and lecture fees from Amgen, GSK, and Baxter and reports having equity ownership in GSK. Dr. Hassani, Dr. Stone, Dr. Arning, Ms. Mayer, and Mr. Jenkins are full-time employees of GSK and report having equity ownership in the company. No other potential conflict of interest relevant to this article was reported.
We thank the patients who participated in the study and the physicians, nurses, and study coordinators who were involved; Karen Watkins, Robin Ball, Ruth Poulin, and Richard Steadman for their assistance in the analysis and conduct of the study; and the Phillips Group for technical assistance with an earlier version of the manuscript.
Source Information
From Weill Cornell Medical College of Cornell University, New York (J.B.B., B.P.); Prince of Wales Hospital, Shatin, Hong Kong (G.C.); Georgia Cancer Specialists, Tucker, GA (M.N.S.); Hematology Research Center, Moscow (L.K.); Hôpital La Rabta, Tunis, Tunisia (B.M.); Akademia Medyczna, Bialystok, Poland (J.K.); GlaxoSmithKline, Greenford, United Kingdom (H.H., B.M.), and Collegeville, PA (N.L.S., M.A., J.M.J.); and Barts and the London School of Medicine, London (D.P.).
Address reprint requests to Dr. Bussel at Weill Cornell Medical College of Cornell University, 525 E. 68th St., P695, New York, NY 10065, or at jbussel@med.cornell.edu.
Other study participants are listed in the Appendix.
Appendix
In addition to the authors, the following investigators participated in the TRA100773 Eltrombopag Study: QEII Health Sciences Centre, Halifax, NS, Canada — D. Anderson; Comprehensive Cancer Care Specialists, Boca Raton, FL — A. Berliner; Sunnybrook Regional Cancer Centre, Toronto — J. Callum; Ocala Oncology Center, Ocala, FL — T. Cartwright; Tri-Service General Hospital, Taipei, Taiwan — Y.C. Chen; Hematology and Oncology Specialists, New Orleans — T. Cosgriff; SPSK-1, Lublin, Poland — A. Dmoszynska; Hôpital Habib Bourguiba, Sfax, Tunisia — M. Elloumi; Hospital Gregorio Marañón, Madrid — A. Escudero Soto; Jeroen Bosch Ziekenhuis, Den Bosch, the Netherlands — R. Fijnheer; Minnesota Oncology Hematology, Minneapolis — P. Flynn; New Mexico Oncology–Hematology Consultants, Albuquerque, NM — R. Giudice; Utah Cancer Specialists, Salt Lake City — W. Harker; Cancer Center of Colorado Springs, Colorado Springs, CO — D. Headley; Hospital la Paz, Madrid — V. Jimenez Yuste; Hôpital Maisonneuve Rosemont, Montreal — J. Kassis; University of Minnesota, Minneapolis R. Kasthuri; Hôpital Farhat Hached, Sousse, Tunisia — A. Khelif; Jefferson City Medical Group, Jefferson City, MO — A. Khojasteh; Hematology Research Center, Moscow — N. Khoroshko, E. Pustovaya, and T. Safonova; Korea University Hospital, Seoul — S. Kim; Academisch Medisch Centrum, Amsterdam — H. Koene; University of Pennsylvania Medical Center–Presbyterian Hospital, Philadelphia — B. Konkle; Queen Mary Hospital, Pokfulam, Hong Kong — R. Liang; Kerckhoff-Klinik, Bad Nauheim, Germany — K. Madlener; Caritasklinik St. Theresia, Saarbruecken, Germany — A. Matzdorff; Arizona Clinical Research Center, Tucson — M. Modiano; Hôpital Militaire, Montfleury, Tunisia — F. M'Sadek; Royal London Hospital, London — A. Newland; General Hospital of Athens “Evagelismos,” Athens — E. Nikiforakis; UMC St. Radboud, Nijmegen, the Netherlands — V. Novotný; Centre Hospitalier de l'Université de Montreal, Hôpital Notre-Dame, Montreal — H. Olney; Uniwersytet Medyczny w Lodzi, Lodz, Poland — T. Robak; Justus-Liebig-Universität Giesen, Frankfurt, Germany — M. Rummel; Charité Universitätsmedizin Berlin, Berlin — A. Salama; Ziekenhuis Leyenburg, The Hague, the Netherlands — M. Schipperus; Johns Hopkins University School of Medicine Clinical Trials Unit, Baltimore — J. Segal; Spitalul Clinic Fundeni, Bucharest, Romania — R.A. Stoia, A.M. Vladareanu; Carolina Physicians Research, Raleigh, NC — S. Tremont; Virginia Cancer Institute, Richmond — D. Trent; Civic Parkdale Clinic, Ottawa — P. Wells; SoonChunHyang University Hospital, Seoul — J. Won; and Pomorska Akademia Medyczna, Szczecin, Poland — B. Zdziarska.
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