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Background We tested the safety and efficacy of eculizumab, a humanized monoclonal antibody against terminal complement protein C5 that inhibits terminal complement activation, in patients with paroxysmal nocturnal hemoglobinuria (PNH).
Methods We conducted a double-blind, randomized, placebo-controlled, multicenter, phase 3 trial. Patients received either placebo or eculizumab intravenously; eculizumab was given at a dose of 600 mg weekly for 4 weeks, followed 1 week later by a 900-mg dose and then 900 mg every other week through week 26. The two primary end points were the stabilization of hemoglobin levels and the number of units of packed red cells transfused. Biochemical indicators of intravascular hemolysis and the patients' quality of life were also assessed.
Results Eighty-seven patients underwent randomization. Stabilization of hemoglobin levels in the absence of transfusions was achieved in 49% (21 of 43) of the patients assigned to eculizumab and none (0 of 44) of those assigned to placebo (P<0.001). During the study, a median of 0 units of packed red cells was administered in the eculizumab group, as compared with 10 units in the placebo group (P<0.001). Eculizumab reduced intravascular hemolysis, as shown by the 85.8% lower median area under the curve for lactate dehydrogenase plotted against time (in days) in the eculizumab group, as compared with the placebo group (58,587 vs. 411,822 U per liter; P<0.001). Clinically significant improvements were also found in the quality of life, as measured by scores on the Functional Assessment of Chronic Illness Therapy-Fatigue instrument (P<0.001) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Of the 87 patients, 4 in the eculizumab group and 9 in the placebo group had serious adverse events, none of which were considered to be treatment-related; all these patients recovered without sequelae.
Conclusions Eculizumab is an effective therapy for PNH. (ClinicalTrials.gov number, NCT00122330
[ClinicalTrials.gov]
.)
Intravascular hemolysis is a prominent feature of PNH and is the consequence of the absence of the GPI-linked complement regulatory protein CD59.3,4 CD59 blocks the formation of the terminal complement complex (also called the membrane-attack complex) on the cell surface, thereby preventing erythrocyte lysis and in vitro platelet activation.5,6,7,8 Excessive or persistent intravascular hemolysis in patients with PNH causes anemia, hemoglobinuria, and complications related to the presence of plasma free hemoglobin, including thrombosis, abdominal pain, dysphagia, erectile dysfunction, and pulmonary hypertension.9,10,11,12 Indeed, the symptoms in PNH are often disproportionate to the degree of anemia. Many patients with this disease are dependent on transfusions. Currently, there is no therapy that effectively reduces intravascular hemolysis or improves the symptoms in patients with PNH.
Eculizumab (Soliris, Alexion Pharmaceuticals) is a humanized monoclonal antibody directed against the terminal complement protein C5.13 In a preliminary, 12-week, open-label clinical study involving 11 patients with PNH, eculizumab reduced intravascular hemolysis and the patients' transfusion requirements.14 However, this two-center, uncontrolled study did not have a control group or predefined criteria for the administration of a transfusion, such as a predefined hemoglobin level at which transfusions were administered or a prespecified number of units of packed red cells for a given hemoglobin level.
We report the results of the phase 3 Transfusion Reduction Efficacy and Safety Clinical Investigation, a Randomized, Multicenter, Double-Blind, Placebo-Controlled, Using Eculizumab in Paroxysmal Nocturnal Hemoglobinuria (TRIUMPH) study, which investigated whether eculizumab stabilized hemoglobin levels and reduced transfusion requirements in 87 transfusion-dependent patients with PNH during 6 months of treatment. Intravascular hemolysis and the quality of life were also assessed.
Methods
Patients
The trial consisted of a 2-week screening period, an observation period of up to 3 months, and a 26-week treatment period. Patients 18 years of age or older who had received at least four transfusions during the previous 12 months were eligible. A PNH type III erythrocyte proportion of 10% or more, platelet counts of at least 100,000 per cubic millimeter, and lactate dehydrogenase levels that were at least 1.5 times the upper limit of the normal range were also required. Concomitant administration of erythropoietin, immunosuppressive drugs, corticosteroids, coumarins, low-molecular-weight heparins, iron supplements, and folic acid were permitted, provided that the doses were constant before and throughout the study. Because persons who have a genetic deficiency of terminal complement proteins have an increased risk of neisserial infections, all patients were vaccinated against Neisseria meningitidis with the use of locally approved vaccines. The protocol was approved by the institutional review board at each center, and all patients gave written informed consent.
Patients receiving transfusions who had a mean hemoglobin level greater than 10.5 g per deciliter before transfusion during the 12 months before entry into the study or who had received another investigational drug within 30 days before the first visit were excluded. Patients who had a complement deficiency, an active bacterial infection, or a history of meningococcal disease and those who had undergone bone marrow transplantation were also excluded.
An individualized transfusion algorithm was calculated for each patient on the basis of the history of transfusions during the previous 12 months; the written algorithm documented the number of units of packed red cells to be transfused for given hemoglobin values and served as a prospectively determined guide for transfusion during the observation and treatment periods. Before randomization, eligible patients were observed for up to 13 weeks. Patients who did not require a transfusion during the observation period were considered ineligible. A transfusion administered to a patient who had a hemoglobin level of 9 g per deciliter or less with symptoms or 7 g per deciliter or less with or without symptoms qualified the patient for the study (qualifying transfusion) and established the hemoglobin set point. This set point was required for the primary efficacy variable and was individualized for each patient.
Study Design
Randomization was performed centrally in a 1:1 ratio without blocking and with stratification according to the number of units of packed red cells transfused during the past year; patients were assigned, by means of an interactive voice–response system, to receive either placebo or eculizumab within 10 days after the administration of the qualifying transfusion. Patients received infusions of 600 mg of eculizumab or placebo every week (±2 days) for 4 weeks, followed 1 week (±2 days) later by 900 mg of eculizumab or placebo, and then by a maintenance dose of 900 mg of eculizumab or placebo every 2 weeks (±2 days) through week 26.
Clinical Efficacy
The two primary end points were the stabilization of hemoglobin levels, defined as a hemoglobin value that was maintained above the level at which the qualifying transfusion was administered, in the absence of transfusions during the 26-week treatment period, and the number of units of packed red cells transfused during that period. The trigger for the administration of transfusions during the study remained unchanged: patients received transfusions when they had symptoms resulting from anemia and their hemoglobin levels reached the individualized, predetermined set point. Prespecified secondary end points included transfusion independence; hemolysis, as measured by the lactate dehydrogenase value for the area under the curve from baseline to 26 weeks; and changes in the level of fatigue, as assessed from baseline to 26 weeks with the use of the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) instrument (scores can range from 0 to 52, with higher scores indicating improvement in fatigue).15 Prespecified exploratory analyses included assessment of the quality of life with the use of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) (scores can range from 0 to 100, with higher scores on the global health status and functioning scales and lower scores on the symptom scales and single-item measures indicating improvement)16; changes in lactate dehydrogenase levels from baseline through week 26; and the presence of thrombosis. Other prespecified measurements included the pharmacokinetics, pharmacodynamics, and immunogenicity of eculizumab. The time to the first transfusion during the treatment period and the proportion of PNH type III blood cells were assessed.
Safety
Adverse events related to study infusions and vital signs (assessed at each of the 17 study visits during treatment), the results of biochemical analyses and blood counts (assessed at 9 visits), and findings on electrocardiograms (assessed at 3 visits) were documented. Adverse events were coded with the use of preferred terms from the Medical Dictionary for Regulatory Activities (MedDRA) (www.msso.org/MSSOWeb/index.htm) and tabulated as incidence rates in the two study groups.
Statistical Analysis
The planned sample size of 75 patients provided the study with a statistical power of 82%, at an alpha level of 0.05, to detect an increase of 35 percentage points (i.e., a change from 20% to 55%) in the rate of the stabilization of hemoglobin levels and a reduction in the median number of units of packed red cells transfused from 6 to 2 (±2). For the two primary end points, the analyses were performed according to the intention-to-treat principle with the use of data on all 87 patients who underwent randomization; stabilization of hemoglobin levels was analyzed with the use of Fisher's exact test, and the total number of units of packed red cells transfused was analyzed with the use of the Wilcoxon rank-sum test. To assess the effect of treatment on whether or not transfusions were required, Fisher's exact test was used. The log-rank test was used to compare the time to the first transfusion in the two groups. The area under the curve for lactate dehydrogenase was compared between the two groups with the use of the Wilcoxon rank-sum test.
Fatigue was assessed according to the scoring guidelines for the FACIT-Fatigue instrument.17 The assessment of the quality of life was based on the EORTC QLQ-C30 scores and was conducted as described previously.18 Changes in scores on the FACIT-Fatigue instrument and the EORTC QLQ-C30 instrument from baseline through week 26 were analyzed with the use of a mixed model, with baseline scores as the covariate, treatment and time as fixed effects, and the patient identifier as a random effect. Changes in the levels of lactate dehydrogenase, PNH type III erythrocytes, and hemoglobin from baseline through week 26 were analyzed with the use of the same mixed model. All reported P values are two-sided and were not adjusted for multiple analyses. The incidence rates of adverse events were compared with the use of Fisher's exact test. No interim analyses were performed, and blinding regarding the results was maintained until the end of the study.
The authors and the sponsor were jointly responsible for the trial design and the development of the protocol. Data were collected by an electronic case-report form with the use of InForm software (version 4.0, Phase Forward) and were analyzed by the sponsor. The decision to publish the trial data and final decisions on the content of the manuscript rested with Dr. Hillmen in consultation with the other authors. The manuscript was prepared by Dr. Hillmen, with substantial review and comments by the other authors. All authors had access to the primary data and take responsibility for the veracity and completeness of the data reported.
Results
Patients' Characteristics
Of a total of 115 patients with PNH who underwent screening, 87 (35 men and 52 women) at 34 sites in the United States, Canada, Europe, and Australia who received a qualifying transfusion, met the inclusion criteria and did not meet any of the exclusion criteria were randomly assigned to eculizumab (43 patients) or placebo (44 patients) between October 2004 and June 2005. At each of 16 sites one patient underwent randomization, at each of 6 sites two patients underwent randomization, and at each of 12 sites 3 or more patients underwent randomization. There were no significant differences in the baseline characteristics of the patients in the two groups (Table 1).
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Pharmacokinetics and Pharmacodynamics
In 42 of 43 patients in the eculizumab group, a 900-mg dose of eculizumab every 2 weeks (±2 days) completely blocked serum hemolytic activity, as assessed by a presensitized erythrocyte hemolytic assay,14 throughout the study period. In one patient, therapeutic trough levels of eculizumab were not maintained.
Effect on Hemolysis
The effect of eculizumab on chronic intravascular hemolysis was demonstrated by an immediate (1 week) and sustained decrease in lactate dehydrogenase levels (Figure 1A). In the eculizumab group, the mean (±SE) lactate dehydrogenase level decreased from 2199.7±157.7 U per liter at baseline to 327.3±67.6 U per liter at 26 weeks, whereas in the placebo group the levels remained elevated, with values of 2258.0±154.8 U per liter at baseline and 2418.9±140.3 U per liter at 26 weeks (P<0.001). The median value of the areas under the curve for lactate dehydrogenase plotted against time (in days) was 85.8% lower in the eculizumab group than in the placebo group (58,587 vs. 411,822 U per liter; P<0.001). A second biochemical measure of hemolysis, the serum level of aspartate aminotransferase, also showed significant improvement with eculizumab, as compared with placebo (data not shown).
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Clinical Efficacy
Primary End Points
The two primary efficacy end points were the stabilization of hemoglobin levels and the number of units of packed red cells transfused. At the end of the treatment period, 49% of patients in the eculizumab group (21 of 43) had levels of hemoglobin that remained above the prespecified set point (median, 7.7 g per deciliter for both groups) in the absence of transfusions, whereas stabilization of hemoglobin levels did not occur in any patient in the placebo group (P<0.001) (Table 2). By week 26, the median number of units of packed red cells transfused per patient was 0 in the eculizumab group and 10 in the placebo group (P<0.001), whereas the mean number of units of packed red cells transfused was 3.0±0.7 and 11.0±0.8, respectively. In the 6-month period before the study, the median number of units of packed red cells transfused per patient was 9.0 in the eculizumab cohort and 8.5 in the placebo cohort, and the mean number of units of packed red cells transfused was 9.6±0.6 and 9.7±0.7, respectively. The mean hemoglobin levels changed from 10.0±0.2 g per deciliter and 9.7±0.2 g per deciliter in the eculizumab group and the placebo group, respectively, at baseline to 10.1±0.2 g per deciliter and 8.9±0.2 g per deciliter, respectively, at week 26 (P<0.001, by mixed-model analysis).
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Assessments of the quality of life were performed with the use of two instruments, the FACIT-Fatigue instrument and the EORTC QLQ-C30 instrument. Patients in the eculizumab group had a mean increase (improvement) in scores on the FACIT-Fatigue instrument of 6.4±1.2 points from baseline to week 26, whereas in the placebo group the mean score decreased by 4.0±1.7 points during this period, for a total difference between the two groups of 10.4 points (Figure 3). A mixed-model analysis of covariance was performed that showed a significant difference between the two groups (P<0.001).
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0.01 for each scale and measure) (Table 3).
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No patients died during the study. Serious adverse events were reported in 13 patients: 4 in the eculizumab group and 9 in the placebo group (Table 4). No serious adverse events were considered to be treatment-related; all these patients recovered without sequelae. The most common adverse events reported in the eculizumab group were headache, nasopharyngitis, back pain, and nausea. Headache and back pain occurred more frequently in the eculizumab group than in the placebo group. The number of headaches that occurred was similar in the two groups after the first 2 weeks of therapy. There were no significant differences in the incidence rates between the two groups for any reported adverse event. A single thrombosis occurred in a patient in the placebo group.
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Discussion
Patients with PNH have chronic intravascular hemolysis with acute exacerbations. Anemia and the need for transfusions to sustain hemoglobin levels occur frequently, as does deterioration of the patient's quality of life. In this study, in approximately half the patients treated with eculizumab, the end points of stabilization of hemoglobin levels and transfusion independence were reached, whereas none of the patients in the placebo group reached either of these end points. The median time to the first transfusion was 4 weeks in the placebo group and more than 6 months in the eculizumab group. The overall rate of transfusion was reduced by 73% in the eculizumab group. Even among patients receiving eculizumab in whom transfusion independence was not reached, the number of units of packed red cells transfused was reduced by 44%, as compared with patients in the placebo group (data not shown).
Intravascular hemolysis is central to the occurrence of serious coexisting conditions in patients with PNH and contributes to the risk of death among these patients.9,12 Lactate dehydrogenase, a biochemical marker of hemolysis, was immediately reduced from approximately 10 times the upper limit of the normal range to normal levels or to just above normal levels in all patients in the eculizumab group. Residual low-level hemolysis in some patients despite terminal-complement blockade may be caused by an inherent decrease in the survival of PNH type III erythrocytes19 or may be due to the fact that these cells are opsonized with C3b, which mediates extravascular clearance through the reticuloendothelial system.
Before treatment with eculizumab, the hemoglobin levels were maintained by transfusion. Therefore, the stabilization of hemoglobin levels with a concomitant cessation of or reduction in the number of transfusions indicates an increase in endogenous erythrocyte mass. The reduction in hemolysis with eculizumab results in a new steady-state hemoglobin level, as determined by a balance of the underlying bone marrow dysfunction, the increased half-life of PNH erythrocytes because of eculizumab therapy, and the new level of transfusions (if any) required.
For most patients with PNH, the quality of life is impaired, and the impairment has been attributed not only to anemia but also to excessive intravascular hemolysis and the scavenging of nitric oxide by cell-free hemoglobin.9,10,11 In this study, the reduction in intravascular hemolysis with eculizumab, as compared with placebo, was associated with a significant improvement in fatigue, as assessed by scores on the FACIT-Fatigue instrument. Eculizumab increased the baseline score for fatigue by 6.4 points. A change of three or more points in scores on this instrument represents a clinically important difference.20 Improvement with eculizumab in the fatigue component of the EORTC QLQ-C30 instrument provides additional evidence for the benefit shown by scores on the FACIT-Fatigue instrument. These improvements with eculizumab occurred without complete resolution of the anemia, providing further evidence of the contribution of hemolysis, in contrast to anemia, to the diminishing quality of life of patients with PNH. Clinical assessment of additional symptoms related to the quality of life of such patients, including abdominal pain, dysphagia, and erectile dysfunction, have also been reported to improve during eculizumab therapy.21
There were no deaths during the study, and only a single thrombotic event occurred in a patient in the placebo group. There were four serious adverse events in the eculizumab group and nine in the placebo group; all these patients recovered. The issue of possible protection against the risk of thrombosis through terminal complement inhibition with eculizumab is being evaluated in ongoing clinical studies of PNH. All 85 patients who completed the study elected to receive eculizumab in an open-label extension study.
The results of this randomized, double-blind, controlled study show that terminal complement inhibition with eculizumab reduces intravascular hemolysis, reduces or eliminates the need for transfusion, and improves anemia, fatigue, and the quality of life in patients with PNH. The data provide support for the central role of intravascular hemolysis in the pathogenesis of the disease and indicate that eculizumab is an effective treatment in patients with PNH.
Funded by Alexion Pharmaceuticals.
Dr. Hillmen reports having received consulting fees, lecture fees, and grant support from Alexion Pharmaceuticals; Dr.Schubert, consulting and lecture fees from Alexion Pharmaceuticals; Drs. Brodsky, Socié, Hill, Schrezenmeier, and Luzzatto, lecture fees from Alexion Pharmaceuticals; and Drs. Nakamura and Maciejewski, consulting fees from Alexion Pharmaceuticals. Dr. Young reports having received support from an unrestricted donation for this study from Alexion Pharmaceuticals to the National Heart, Lung, and Blood Institute, National Institutes of Health. Drs. Rollins, Mojcik, and Rother report being employees of Alexion Pharmaceuticals and holding equity ownership in it. Drs. Rollins and Rother report having assigned to Alexion Pharmaceuticals their inventions made as employees and receiving no royalties from the company for these inventions. Dr. Rollins reports having received royalties for inventions he made before becoming an employee of Alexion Pharmaceuticals. No other potential conflict of interest relevant to this article was reported.
We are indebted to Michael Bombara and Dr. Henk-Andre Kroon for trial oversight; to Dr. Jason Chan for the statistical analysis; to Drs. Kerry Quinn-Senger and Lisa De Boer for assistance with technical writing; and to Dr. Leonard Bell for critical review of the manuscript.
Source Information
From Leeds General Infirmary, Leeds, United Kingdom (P.H., A.H.); National Heart, Lung, and Blood Institute, Bethesda, MD (N.S.Y.); Saarland University Medical School, Homburg-Saarland, Germany (J. Schubert); Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore (R.A.B.); Hôpital Saint-Louis and INSERM, Paris (G.S.); Radboud University Medical Center, Nijmegen, the Netherlands (P.M.); University Hospital of Essen, Essen, Germany (A.R.); Royal Melbourne Hospital, Parkville, Melbourne, Australia (J. Szer); St. George Hospital, London (M.O.E.); City of Hope National Medical Center and Beckman Research Institute, Duarte, CA (R.N.); St. James' Hospital, Trinity College Dublin, Dublin (P.B.); Federico II University, Naples (A.M.R.); the Institute of Transfusion Medicine, University Hospital, Ulm, Germany (H.S.); Cleveland Clinic Florida, Weston, FL (C.-L.F.); Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland (J.M.); Alexion Pharmaceuticals, Cheshire, CT (S.A.R., C.F.M., R.P.R.); and Istituto Toscano Tumori, Florence, Italy (L.L.).
Address reprint requests to Dr. Hillmen at the Department of Haematology, Leeds General Infirmary, Great George St., Leeds LS1 3EX, United Kingdom, or at peter.hillmen{at}nhs.net.
References
In addition to the authors, the following investigators and institutions participated in the TRIUMPH study: Australia — Princess Alexandra Hospital, Woolloongabba: A. Mills; Queen Elizabeth Hospital, Woodville South: J. Norman; Royal Melbourne Hospital, Parkville; Royal Perth Hospital, Perth, WA: R. Herrmann; Belgium — St. Luc University Hospital, UCL, Brussels: E. Van Den Neste; Canada — University of Alberta, Cross Cancer Institute, Edmonton, AB.: L. Larratt, A. Turner, M.A. Hamilton; Germany — Universitätsklinikum Essen, Essen: U. Dührsen; Medizinische Hochschule Hanover, Hanover: A. Ganser; Universitätsklinik Greifswald, Greifswald: M. Montemurro; Institut für Klinische Transfusionsmedizin and Immungenetik, University Hospital Ulm, Ulm; Saarland University Medical School, Hamburg; France — Hospital de l'Hotel-Dieu, Paris: B. Rio; Hospital St. Louis and INSERM, Paris; Ireland — St. James Hospital, Dublin; Italy — Ospedale San Martino, Genoa: A. Bacigalupo; Azienda-Ospedaliera Universitaria Careggi, Florence: E. Antonioli, G. Gianfaldoni, F. Mannelli, A. Bosi; Ospedale San Bortolo, Vicenza: F. Rodeghiero; Federico II University, Naples: B. Rotoli, F. Alfinito; Ospedale Maggiore di Milano, Milan: A. Zanella, C. Boschetti; Istituto Toscana Tumori, Florence; the Netherlands — Radboud University Medical Center, Nijmegen; Sweden — Lund University Hospital, Lund: P.-G. Nillson; Umea University Hospital, Umea: A. Wahlin; Stockholm South Hospital, Stockholm: J. Samuelsson, L.G. Lundberg, P. Andersson; United Kingdom — St. George's Hospital, London; Leeds General Infirmary, Leeds; Belfast City Hospital, Belfast: M.F. McMullin; United States — Washington University School of Medicine, St. Louis: M. Bessler, L. Andritsos, M. Blinder, S. Devine; Johns Hopkins University Medical Center, Baltimore; Memorial Sloan-Kettering Cancer Center, New York: H. Castro-Malaspina, D. Araten; Stanford University Medical Center, Stanford, CA: S. Coutre; Duke University Medical Center, Durham, NC: C. de Castro III; Cleveland Clinic Florida, Weston, FL: E. Stone; University of Pennsylvania, Philadelphia: B. Konkle; Massachusetts General Hospital, Boston: D. Kuter; Cleveland Clinic Foundation, Cleveland: A. Lichtin; New York University Clinical Cancer Center, New York: T. Moskovits, B.G. Raphael, E. Amorosi, K.B. Hymes, P. Cook; City of Hope National Medical Center, Duarte, CA; Indiana University Cancer Center, Indianapolis: R. Nelson; University of California at Los Angeles, Los Angeles: R. Paquette; Hartford Hospital, Hartford, CT: R. Siegel; National Heart, Lung, and Blood Institute, Bethesda, MD: B. Savani.
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Related Letters:
Eculizumab in Paroxysmal Nocturnal Hemoglobinuria
Kathula S. K., Singh J., Malani A. K., Pabla M., Takita M., Matsumura T., Kami M., Pride Y. B., Hillmen P.
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N Engl J Med 2006;
355:2786-2788, Dec 28, 2006.
Correspondence
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