Epub 2019 Jan 9. The institutional review board or ethics committee at each participating site approved the protocol, which is available at NEJM.org, and all the patients provided written informed consent. Among these 29 patients, 9 had a relapse during the follow-up period (Figure 2B). The ICER range at which caplacizumab is favored in 0.03% to 100% of iterations is USD $1 037 405 to $2 142 668. capla, caplacizumab. J Thromb Haemost 2015;13:293-302. Blood. Joly BS, Coppo P, Veyradier A. Thrombotic thrombocytopenic purpura. This novel treatment may actually be the key to For 13 of the 20 patients who had ADAMTS13 activity of 10% or higher at baseline, the diagnosis was confirmed on the basis of a history of TTP or of ADAMTS13 activity below 10% at other time points during the trial. Br J Haematol 2012;158:323-335. Conflict-of-interest disclosure: The authors declare no competing financial interests. In all of our decision tree and Markov models, we assumed that the utility of either the well or the diseased state would be the same following treatment with SOC and caplacizumab vs SOC alone. Patients who received caplacizumab needed less plasma exchange and had a shorter hospitalization than those who received placebo. In 29 of the 120 patients (24%), ADAMTS13 was still severely deficient at the time that the caplacizumab or placebo was stopped. (Funded by Ablynx; HERCULES ClinicalTrials.gov number, NCT02553317.). What does the value of modern medicine say about the $50,000 per quality-adjusted life-year decision rule? Refractory disease, which develops in approximately one in six patients and is characterized by platelet counts that either do not increase at all or increase very slowly, is associated with poor outcomes. In a set of 1-way sensitivity analyses of the Markov model for the TITAN trial, the cost of caplacizumab itself again exerted a greater impact on the ICER of adding caplacizumab to SOC than any other factor analyzed, including number and cost of rituximab treatments, number of TPE days, and ICU and hospital LOS (Figure 4). We initially attempted to model utilities using existing resources including the comprehensive Cost Effectiveness Analysis Registry at Tufts (http://healtheconomicsdev.tuftsmedicalcenter.org/cear2/search/search.aspx), but there were no comparable reference diseases. Methods: A semi-mechanistic pharmacokinetic-pharmacodynamic (PKPD) population model has been developed describing the interaction between caplacizumab and von Willebrand factor antigen (vWF:Ag) … Serious adverse events of bleeding were reported in 8 patients (11%) in the caplacizumab group and in 1 patient (1%) in the placebo group. Facebook Twitter Print Email ×. Caplacizumab is an anti-von Willebrand factor humanised single-variable-domain immunoglobulin. From the Department of Haematology, University College London Hospitals, Cardiometabolic Program, National Institute for Health Research UCLH–UCL Biomedical Research Center, London (M.S. The purpose of this study is to evaluate the effectiveness and safety of caplacizumab treatment in more rapidly curtailing ongoing microvascular thrombosis when administered in addition to standard of care treatment in subjects with an acute episode of acquired thrombotic thrombocytopenic purpura. Variations in other parameters, such as changes in SOC arm costs, hospital or ICU LOS, TPE days, or rituximab use, have far less of an impact than caplacizumab cost on overall cost effectiveness of adding caplacizumab to SOC in both decision trees and in our Markov model, whereas a decrease in the utility of the well state significantly increases the ICER. We conducted this randomized, double-blind, placebo-controlled trial at 92 sites worldwide (see the Supplementary Appendix, available with the full text of this article at NEJM.org). ) is a life-threatening hematologic disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and end-organ damage involving the brain, heart, or kidneys.1 19. Callewaert, Biswas, De Winter, and Zeldin, being employed by Ablynx. 23. One-way sensitivity analyses of HERCULES trial with model parameters varied across ranges as shown. Data were collected retrospectively from 2018 to 2020 for 85 patients (4 children) receiving caplacizumab from 22 UK … 8. doi: https://doi.org/10.1182/blood.2020006052. No patient in either the phase 2 trial or the current trial died while receiving treatment with caplacizumab. With much interest we noted the manuscript ‘Cost effectiveness of caplacizumab in acquired thrombotic thrombocytopenic purpura’ by Goshua et al. Leebeek FWG, Eikenboom JCJ. In the latter instance, caplacizumab could be used as rescue therapy to offset some of the costs incurred from prolonged hospitalizations. Cablivi is the first FDA approved therapy specifically indicated for the treatment of aTTP. Exacerbations occurred up to 25 days after the end of plasma exchange, which supports the need for treatment with caplacizumab during the period in which a patient is at risk (i.e., for at least 30 days after normalization of the platelet count is achieved). Scully M, Cataland SR, Peyvandi F, et al. We calculated that this sample size would also provide 83% power to detect a rate of the first key secondary outcome (i.e., a composite of TTP-related death, recurrence of TTP, or a major thromboembolic event during the trial treatment period) that was 20% lower in the caplacizumab group than in the placebo group, using a chi-square test with a large sample approximation and a 5% significance level. ); the Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (J.A.K.H. Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura. Randomization was stratified according to neurologic involvement (baseline Glasgow Coma Scale score of ≤12 vs. >13, on a scale ranging from 3 to 15, with lower scores indicating worse mental status). 2018;132:1142. We appreciate the authors’ efforts in conducting an economic evaluation of caplacizumab in acquired thrombotic thrombocytopenic purpura (aTTP), however we wish to highlight important limitations of this analysis [1]. ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) is a von Willebrand factor–cleaving protease that leads to platelet consumption in von Willebrand factor–platelet aggregates and microvascular thrombosis. Callewaert F, Roodt J, Ulrichts H, et al. The trial also evaluated the potential of caplacizumab to reduce the risk of recurrence by allowing for treatment to continue until immunosuppressive therapy resolved the underlying autoimmune disease. Time to Confirmed Normalization of the Platelet Count in the Intention-to-Treat Population. 2016;127(24):3092 5. No effect on either clinical efficacy or ristocetin cofactor activity was observed, and no serious adverse events were reported in these patients. Autoantibodies inhibit activity of the von Willebrand factor–cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), which leads to platelet consumption in von Willebrand factor–platelet aggregates and microvascular thrombosis.1 The ensuing tissue ischemia and multiorgan dysfunction may result in thromboembolic events and death. Moreover, we used the absolute minimum and maximum total relapse rates for the caplacizumab and SOC arms, respectively. For cost of SOC, as previously published, we used the US average wholesale price for rituximab accounting for 4 inpatient doses ($7724 for each dose of 375 mg/m2 for a 170-cm, 70-kg individual) and our institution’s costs for number of TPE sessions ($6000 per TPE session), intensive care unit (ICU) length of stay (LOS) ($1043 per day for an ICU bed), and total hospital LOS ($490 per day for an inpatient general medicine bed).21 Because both clinical trials reported numerical ranges for number of TPE sessions and LOS, in our models we used the extremes of these ranges in order to maximize such costs in the SOC group and minimize costs in the caplacizumab group (supplemental Table, available on the Blood Web site). Blood. Caplacizumab, a bivalent Nb construct against von Willebrand factor, is the first EMEA and FDA-approved therapeutic that is life-saving in acquired thrombotic thrombocytopenic purpura patients []. J Thromb Haemost 2012;10:1556-1565. 2012 Aug;158(3):323-35. 2019. The relapses that did occur were all in patients who still had severely suppressed ADAMTS13 activity below 10%. Specific circumstances in which the addition of caplacizumab could potentially have a lower ICER would be in patients with severe (including cardiac and neurologic involvement) or refractory disease who are unable to leave the hospital because of a requirement for continued daily TPE. The percentage of patients who had a recurrence of TTP at any time during the trial was 67% lower with caplacizumab than with placebo (12% vs. 38%, P<0.001). (B) Utility of disease state. † The body-mass index is the weight in kilograms divided by the square of the height in meters. To be sure, because of the high price of many orphan drugs, in CEAs of different RDs, the calculated ICERs for orphan drugs vary widely. Bleeding-related adverse events were reported in 46 patients (65%) in the caplacizumab group and in 35 patients (48%) in the placebo group (Table S3 in the. ); the Department of Medicine 1, Division of Hematology and Hemostasis, Medical University of Vienna, Vienna (P.K. Safety assessments were performed throughout the course of the trial and included evaluation of vital signs, physical examinations, clinical laboratory testing, and 12-lead electrocardiography. Long-term outcomes of thrombotic microangiopathy treated with plasma exchange: a systematic review. In acquired thrombotic thrombocytopenic purpura (TTP), an immune-mediated deficiency of the von Willebrand factor–cleaving protease ADAMTS13 allows unrestrained adhesion of von Willebrand factor multimers to platelets and microthrombosis, which result in thrombocytopenia, hemolytic anemia, and tissue ischemia. Adding caplacizumab to standard of care for the treatment of acquired thrombotic thrombocytopenic purpura (aTTP) shortened the time to the normalization of platelet counts compared with standard care alone, according to a study published in the New England Journal of Medicine. The most trusted, influential source of new medical knowledge and clinical best practices in the world. In the week after daily plasma exchange ended, ADAMTS13 activity was still severely suppressed (i.e., <10%) in 57% of the patients overall (73 of 129 patients) — in 60% of the patients in the caplacizumab group (39 of 65 patients) and in 53% of the patients in the placebo group (34 of 64 patients). A phase 2 trial showed the efficacy of caplacizumab as compared with placebo with respect to the time to normalization of the platelet count, the incidence of recurrence of TTP during the treatment period,13 the percentage of patients in whom refractory disease developed,14 and the incidence of major thromboembolic events.15 A subgroup of patients who had persistent ADAMTS13 deficiency had a relapse soon after treatment with caplacizumab was stopped, which suggests that monitoring of ADAMTS13 could be useful to guide the continuation of therapy.13 In the phase 3 HERCULES trial (A Phase III Double-Blind, Randomized, Parallel Group, Multicenter Placebo-Controlled Trial to Study the Efficacy and Safety of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura), we sought to confirm the potential role of caplacizumab in the treatment of TTP by comparing caplacizumab with placebo with respect to the time to normalization of the platelet count and the risk of death and complications caused by thrombotic events and organ damage. Acquired thrombotic thrombocytopenic purpura: ADAMTS13 activity, anti-ADAMTS13 autoantibodies and risk of recurrent disease. The most effective and engaging way for clinicians to learn, improve their practice, and prepare for board exams. All the patients received the assigned caplacizumab or placebo, except for 1 patient assigned to the caplacizumab group who withdrew consent before receiving the first dose. For the probabilistic sensitivity analysis, we created distributions for clinical probabilities and health utilities using β-PERT distributions and used ɣ distributions for costs. The most common such events were epistaxis and gingival bleeding; all these events resolved, most without intervention. N Engl J Med. 33. … Multiple major morbidities and increased mortality during long-term follow-up after recovery from thrombotic thrombocytopenic purpura. Blood Advances; Citation. We also created a Markov model comparing cost effectiveness of SOC plus caplacizumab vs SOC in acquired TTP based on the TITAN trial (Figure 1); we selected the TITAN trial rather than HERCULES for building the Markov model because of the comparatively longer follow-up period in the TITAN trial. Already Have An Account? Several additional Nb constructs directed against a broad range of autoimmune … Caplacizumab-yhdp (Cablivi®) is the first Food and Drug Administration-approved treatment indicated for adult patients with acquired thrombotic thrombocytopenic purpura, in combination with plasma exchange and immunosuppressive therapy. An episode of TTP may result in long-term consequences, such as cognitive deficits, depression, arterial hypertension, and premature death.5 A major challenge is the persistent risk of life-threatening recurrences, which are termed exacerbations if they occur within 30 days after the last plasma exchange and relapses if they occur more than 30 days after the last plasma exchange. PARIS - January 9, 2019 - The New England Journal of Medicine (NEJM) today published positive results of the Phase 3 trial of Cablivi ® (caplacizumab) in adults with acquired thrombotic thrombocytopenic purpura (aTTP). Real-world experience with caplacizumab in the management of acute TTP. might be biased towards less complicated disease courses. Because only HERCULES reported details on hospital LOS and ICU stay, we used these parameters for TITAN. In a PSA of our Markov model for the TITAN trial, SOC was favored over SOC plus caplacizumab at a WTP of $195 330 in 100% of 10 000 iterations in a Monte Carlo simulation. Caplacizumab for acquired thrombotic thrombocytopenic purpura. Copyright ©2020 by American Society of Hematology, http://healtheconomicsdev.tuftsmedicalcenter.org/cear2/search/search.aspx, https://icer-review.org/wp-content/uploads/2017/02/ICER_Assessing-the-Value-of-Drugs-for-Rare-Conditions_051017.pdf, Probability of total recurrence, caplacizumab arm. Haematologica 2008;93:172-177. In addition, a lack of data was often handled by excluding details (e.g., costs of bleeding) or using extremes in favor of caplacizumab (e.g., usage of data on utility, number of PEX-sessions, lengths of hospital stay or recurrence rates), purportedly to avoid any bias towards the control group. Caplacizumab, a novel anti-von Willebrand factor nanobody trialed in 2 multicenter randomized controlled trials (RCTs) leading to European Union and US Food and Drug Administration approval, has been available in the United Kingdom (UK) through a patient access scheme. 1. Prepare to become a physician, build your knowledge, lead a health care organization, and advance your career with NEJM Group information and services. ‖ Normal ranges used in the trial were as follows: platelet count, 150,000 to 450,000 per mm3; lactate dehydrogenase, 120 to 246 U per liter; cardiac troponin I, 0 to 0.059 μmol per liter; serum creatinine, 44 to 97 μmol per liter (0.5 to 1.1 mg per deciliter) (women) and 62 to 115 μmol per liter (0.7 to 1.3 mg per deciliter) (men); and ADAMTS13 activity, 50 to 130%. Although in the 2 trials caplacizumab treatment was associated with increased TTP relapses and fewer exacerbations compared with SOC, in our models, we used a total recurrence rate representing the sum of relapses and exacerbations despite the former being more likely to incur greater costs as a result of hospital readmissions. (D) Cost of caplacizumab. De Winter and Zeldin contributed equally to this article. On December 16, 2020, the National Institute for Health and Care Excellence (NICE) published guidance 1 recommending caplacizumab combined with plasma exchange and immunosuppressive therapy as an option for treating acute episodes of acquired thrombotic thrombocytopenic purpura in adults and young patients aged 12 years and over. ** ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) is a von Willebrand factor–cleaving protease that leads to platelet consumption in von Willebrand factor–platelet aggregates and microvascular thrombosis. 7. We built decision tree models to evaluate the cost effectiveness of SOC plus caplacizumab vs SOC in acquired TTP based on the results of each of the phase 2 TITAN trial at 12-month follow-up and the phase 3 HERCULES trial at 1-month follow-up. N Engl J Med 2016;374:2497-2498. An independent data and safety monitoring board monitored the trial. Blood 2017;130:1181-1188. Adverse events were coded according to the Medical Dictionary for Regulatory Activities, version 20.0. In our study, we incorporated a number of factors designed to maximize the cost effectiveness of caplacizumab and avoid potential confounders that might inadvertently favor SOC. Caplacizumab in Acquired Thrombotic Thrombocytopenic Purpura Blood advances . 2019 Jan 24;335-346, doi: 10.1056/NEJMoa1806311. Kremer Hovinga JA, Vesely SK, Terrell DR, Lämmle B, George JN. Peyvandi F, Scully M, Kremer Hovinga JA, et al. Base-case estimates and ranges for clinical probabilities used in our models are listed in Table 1. The cause of death in the patient in the caplacizumab group was cerebral ischemia and was assessed by the investigator as unrelated to treatment; the cause of death in the patients in the placebo group was worsening massive ischemic attack with hemorrhagic transformation in 1 patient and refractory TTP (specifically, “worsening TTP with coma and death” and “hypoxia with bleeding in the lung”) in the 2 other patients. Blood 2016;128:2175-2178. Demographic and Baseline Disease Characteristics and Concomitant Treatments for TTP in the Intention-to-Treat Population. Data was collected retrospectively from 2018-2020 for 85 patients receiving caplacizumab, including 4 children, from 22 UK hospitals. Purple dashed line represents baseline estimate. ¶ These outcomes were assessed during the trial treatment period. This added value was associated with a higher incidence of low-grade mucosal bleeding than that with placebo. It is … Caplacizumab, a humanized, bivalent, variable-domain-only immunoglobulin fragment (Nanobody, Ablynx), targets the A1 domain of von Willebrand factor, preventing interaction with the platelet glycoprotein Ib-IX-V receptor12 and the ensuing microvascular thrombosis. thrombi. This finding suggests that monitoring of ADAMTS13 activity could be useful in guiding not only immunosuppressive treatment18-22 but also the continuation of caplacizumab treatment beyond 30 days after stopping plasma exchange. N Engl J Med. †† The Glasgow Coma Scale score is a measure of neurologic involvement; scores range from 3 to 15, with lower scores indicating worse mental status. The primary outcome was the time to a response, which was defined as the time from the first intravenous administration of caplacizumab or placebo to normalization of the platelet count (i.e., a platelet count of at least 150,000 per cubic millimeter), with discontinuation of daily plasma exchange within 5 days thereafter. You must be a member to content. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. Bresin E, Gastoldi S, Daina E, et al. Journal. Because utilities have not previously been established in acquired TTP patients, we calculated QALYs using hypothetical utility weights that augmented the difference between the well and diseased states to minimize the ICER and maximize the cost benefit of caplacizumab. However, for this strategy to be cost effective at the accepted US WTP and the current list price of caplacizumab, the added hospital LOS and added days of TPE would have to more than triple (Figures 2C and 3C). Drug-induced antibodies to caplacizumab developed in 3% of the patients who received caplacizumab. The median duration of exposure to caplacizumab was longer than the duration of exposure to placebo (35 days [range, 1 to 65] vs. 23 days [range, 2 to 66]). Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734. For each decision tree model, we performed 1-way sensitivity analyses varying the various model parameters individually to gauge their effects on the ICER. Cost-effectiveness analysis of brentuximab vedotin with chemotherapy in newly diagnosed stage III and IV Hodgkin lymphoma, Reforming the orphan drug act for the 21st century, Cost effectiveness of nusinersen in the treatment of patients with infantile-onset and later-onset spinal muscular atrophy in Sweden, Cost-effectiveness of enzyme replacement therapy for Fabry disease, Cost-effectiveness of enzyme replacement therapy with alglucosidase alfa in adult patients with Pompe disease, © 2021 by The American Society of Hematology, Response to Goshua et al (2020) "Cost effectiveness of caplacizumab in acquired thrombotic thrombocytopenic purpura", Laurence Pollissard (1) Sean D. Sullivan (2), (1) Sanofi, Chilly Mazarin, France; (2) CHOICE Institute, School of Pharmacy, University of Washington, Seattle, WA, USA. In total, 31 patients (3 in the caplacizumab group and 28 in the placebo group) had an exacerbation (i.e., recurrence within 30 days after the end of daily plasma exchange), 28 of whom (3 in the caplacizumab group and 25 in the placebo group) had unresolved underlying autoimmune disease, with ADAMTS13 activity levels below 10% (Figure 2A). Moreover, real-world data indicate that patients from a clinical trial settings like TITAN and HERCULES do not adequately reflect the reality because patients often have higher disease activities.3,4 Hence, the results of the analysis from Goshua et al. In this issue of Blood, Coppo et al 1 have documented that caplacizumab is an effective targeted immunotherapy for thrombotic thrombocytopenic purpura (TTP) that has the potential to change established clinical practice. We assessed costs from the health system perspective. In the phase 2 trial, when caplacizumab was stopped, early relapses occurred in a subgroup of patients who had persistent severe ADAMTS13 deficiency below 10%. Long-term management of acquired thrombotic thrombocytopenic purpura using serial plasma ADAMTS13 measurements. Acquired or immune-mediated thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy that is characterized by thrombocytopenia and hemolytic anemia. Blood 2021; 137 (7): 969–976. You can find your saved items on your dashboard, … Refractory disease developed in no patients in the caplacizumab group and in three patients in the placebo group. Because our models are designed to maximize the cost effectiveness of caplacizumab, it is very likely that the actual costs incurred by this medication will be much higher than what we report here. July 22, 2020. N Engl J Med 2016;375:2067-2080. analyzed the data and wrote the paper. Risk factors and manageability of the mainly mild mucocutaneous bleeding profile observed in aTTP patients treated with caplacizumab during the phase III hercules study. N Engl J Med 2016;374:511-522. Von Willebrand’s disease. No one who is not an author contributed to the writing of the manuscript. Caplacizumab is the first drug approved for this disease and the first to target von Willebrand factor (vWF), a key protein in the blood coagulation cascade. Adults (≥18 years of age) and, at some sites, children 2 to 18 years of age were eligible for participation if they had TTP that was diagnosed on the basis of clinical presentation (the presence of both thrombocytopenia and microangiopathic hemolytic anemia with schistocytes seen on blood smear) and if they had received exactly one plasma-exchange treatment. No temporal relationship between the occurrence of bleeding and the duration of exposure to caplacizumab was observed. To convert the values for creatinine to milligrams per deciliter, divide by 88.4. Subsequently, treatment with glucocorticoids could be tapered at the discretion of the investigator, with the aim of stopping glucocorticoid treatment completely within 30 days after the last plasma exchange. Doi: 10.1056/NEJMoa1806311. Medical costs for both treatment arms in both trials were calculated from the health system perspective; future costs and effectiveness in the Markov model were discounted at a standard annual rate of 3%, a principle universal to cost-effectiveness models and based on the concept that the value of money and health in the present is more than their value in the future.23 Effectiveness refers to the cumulative total of utilities for each health state within each arm of each trial and was measured using quality-adjusted life years (QALYs) with the latter a product of the utility value of the state at 1 year. Demographic and ADAMTS13 biomarker data as predictors of early recurrences of idiopathic thrombotic thrombocytopenic purpura. Already Have An Account? A total of 4 patients died during the trial, including 1 (1%) in the caplacizumab group (during the treatment-free follow-up period) and 3 (4%) in the placebo group (all during the treatment period). All 4 deaths were adjudicated as TTP-related. Her symptoms rapidly resolved as her platelet count recovered within 48 hours. In patients who had a recurrence of TTP while receiving caplacizumab or placebo, ADAMTS13 activity was measured at the time of the recurrence and then weekly beginning with the first day after plasma exchange during treatment with open-label caplacizumab. Other immunosuppressive therapy was allowed in accordance with clinical practice at each site. Background Acquired thrombotic thrombocytopenic purpura (aTTP) is a life-threatening autoimmune thrombotic microangiopathy. Page EE, Kremer Hovinga JA, Terrell DR, Vesely SK, George JN. December 31, 2020. Cost-Effectiveness of Caplacizumab in Acquired Thrombotic Thrombocytopenic Purpura Blood . According to this model, to meet the WTP, the cost of caplacizumab treatment of 1 episode of TTP would need to be $65 106, compared with its current list price of $270 000. New England Journal of Medicine Publishes Positive Results of the Pivotal Trial of Cablivi (caplacizumab) for Rare Blood Clotting Disorder 15/01/2019 PARIS, Jan. 9, 2019 /PRNewswire/ — The New England Journal of Medicine (NEJM) today published positive results of the Phase 3 trial of Cablivi® (caplacizumab) in adults with acquired thrombotic thrombocytopenic purpura (aTTP). Lämmle B, Kremer Hovinga JA, George JN. Finally, we did not include theoretical added costs that would be incurred with more frequent ADAMTS13 monitoring to help prevent possible underpheresis with caplacizumab treatment, which would further increase the ICER for adding caplacizumab to SOC treatment in acquired TTP. Shown are adverse events that occurred in at least 5% of the patients in either trial group, in decreasing order of the relative risk with caplacizumab as compared with placebo. In addition, treatment with caplacizumab prevented the development of refractory disease and consequently the negative outcomes that are commonly reported in patients with refractory TTP. An independent adjudication committee whose members were unaware of the trial-group assignments reviewed all potential major thromboembolic events and assessed the relatedness of deaths to TTP. Caplacizumab, a novel anti-von Willebrand factor nanobody, trialled in two multicentre, randomised-placebo-controlled trials leading to EU and FDA approval, has been available in the UK through a patient-access scheme.
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