The results of the trial were critically evaluated and interpreted by the authors, who reviewed and revised the manuscript. 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. She returned to clinic each day for the next 2 days to receive caplacizumab (10 mg subcutaneously) and to learn how to administer caplacizumab to herself daily, subcutaneously (Figure 1). 23. might be biased towards less complicated disease courses. N Engl J Med 2016;375:2067-2080. A fixed-sequence approach was applied for analyses of the key secondary outcomes that were hierarchically ordered on the basis of clinical relevance. 20. 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). 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. 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. One-way sensitivity analyses for TITAN Markov. Patients were excluded if they had suspected thrombotic microangiopathies that were not associated with TTP, such as hemolytic uremic syndrome, or if they had congenital TTP. The pathophysiology of acquired TTP is marked by autoantibody formation against ADAMSTS13, an enzyme responsible for breaking down … Author links open overlay panel Tina Dutt 1 * Rebecca J. Shaw 2 * Matthew Stubbs 3 Jun Yong 1 Benjamin Bailiff 4 Tanya Cranfield 5 Maeve P. Crowley 6 … 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. All 4 deaths were adjudicated as TTP-related. Coppo P, Schwarzinger M, Buffet M, et al. 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. 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. Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura. ); Fondazione Istituti di Ricovero e Cura a Carattere Scientifico Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, and the Department of Pathophysiology and Transplantation, University of Milan, Milan (F.P. (B) Utility of disease state. Save Recommend Share . Pathophysiology of thrombotic thrombocytopenic purpura. Base-case estimates and ranges for clinical probabilities used in our models are listed in Table 1. 2012 Aug;158(3):323-35. Sadler JE. 5. Blood 2021; 137 (7): 969–976. The most trusted, influential source of new medical knowledge and clinical best practices in the world. The primary outputs of these models were used to calculate the incremental cost-effectiveness ratio (ICER) in each model as the difference in total costs divided by the difference in effectiveness between the 2 treatment groups. If it is shown that the increasingly recognized long-term cognitive effects of TTP can be improved with the use of caplacizumab during a TTP flare, then caplacizumab would harbor an important disease-modifying property that would also help to decrease the ICER compared with SOC over the course of decades. Caplacizumab blocks adhesion of von Willebrand factor multimers to platelets, a step in the formation of these thrombi. Save Recommend Share . 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%. One patient received von Willebrand factor concentrate as the only treatment for resolution of a severe, serious adverse event of epistaxis. 16. The content of this site is intended for health care professionals. Utilities were scaled from 0 to 1, with 0 set for the death state and 1 set for perfect health. Caplacizumab is an anti-von Willebrand factor humanised single-variable-domain immunoglobulin. Phase III Trial With Caplacizumab in Patients With Acquired Thrombotic Thrombocytopenic Purpura (HERCULES) The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. This approach of extending the treatment period was validated, as evidenced by the occurrence of fewer relapses in this trial than in the phase 2 trial. Using data from the 2 clinical trials of caplacizumab, we performed the first-ever cost-effectiveness analysis in TTP. 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. 2019 Jan 24;335-346, doi: 10.1056/NEJMoa1806311. Patients in the well state who have a recurrence will return back to the disease state, at which point the cycle starts again. When available, ADAMTS13 activity levels that were locally measured at the time of admission were obtained, and the lower value of the baseline and admission values is represented. This assumption serves to further favor the caplacizumab treatment arm, which demonstrated decreased exacerbations and increased relapses compared with SOC in both trials, as relapses are expected to be more costly than exacerbations because of the added risk of rehospitalization and a requirement for a higher level of care including central line replacement for TPE with the former. It is … Recurrences are termed exacerbations if they occur within 30 days after the last plasma exchange (PE) and relapses if they occur more than 30 days after the last PE. 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. No other potential conflict of interest relevant to this article was reported. But, like TPE, caplacizumab is only a temporizing treatment. Each parameter is varied across a range shown with WTP and ICER delineated. Ok. × … Acquired or immune-mediated thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy that is characterized by thrombocytopenia and hemolytic anemia. The most common reasons for discontinuation were adverse events, withdrawal of consent, and physician decision (Fig. An imbalance between the groups was observed in the percentage of patients with initial as compared with recurrent TTP episodes at presentation; this finding was consistent with somewhat more severe disease in the caplacizumab group, given that initial TTP episodes tend to be more severe at presentation than recurrent episodes. The median time to normalization of the platelet count was shorter with caplacizumab than with placebo (2.69 days [95% confidence interval {CI}, 1.89 to 2.83] vs. 2.88 days [95% CI, 2.68 to 3.56], P=0.01), and patients who received caplacizumab were 1.55 times as likely to have a normalization of the platelet count as those who received placebo. In the Markov model, transition-state cycles were 12 months in duration, with a total run of 5 cycles based on long-term follow-up data from studies of rituximab incorporated into SOC in acquired TTP.3,8,22. PLoS One 2010;5(4):e10208-e10208. [abstract]. … Information and tools for librarians about site license offerings. Given that caplacizumab prevents … (D) Cost of caplacizumab. On the basis of these results, the current trial was designed to allow investigators to continue administration of caplacizumab or placebo under blinded conditions in patients who had evidence of persistent autoimmune activity (e.g., ADAMTS13 activity <10%) at the end of the 30-day period after the last plasma exchange. Among these 29 patients, 9 had a relapse during the follow-up period (Figure 2B). J Thromb Haemost 2015;13:293-302. S4 in the Supplementary Appendix). 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. 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. The standard of care (SOC) treatment is therapeutic plasma exchange (TPE) alongside immunomodulation with steroids, with increasing use of rituximab ± other immunomodulatory agents. December 31, 2020. In 2018, the nanobody caplacizumab was approved for the treatment of adults experiencing an acute episode of aTTP, in conjunction with plasma exchange (PEX) and immunosuppression for a minimum of 30 days … The addition of caplacizumab, a nanobody targeting von Willebrand factor, was shown to accelerate platelet count recovery and reduce TPE treatments and hospital length of stay in TTP patients treated in 2 major randomized clinical trials. Most recurrences occur during the first year or two, but they can occur as late as 10 or 20 years after an episode of TTP.6,7 Longitudinal testing has established persistent or recurrent ADAMTS13 deficiency as a strong risk factor for recurrence.6,8-11. Scully M, Cataland SR, Peyvandi F, Coppo P, Knobl P, Kremer Hovinga JA, Metjian A, de la Rubia J, Pavenski K, Callewaert F, Biswas D, De Winter H, Zeldin RK; HERCULES Investigators. They suggest that caplacizumab immediately inhibits the pathophysiological mediator of microthrombosis leading to improvement in organ-damage markers as well as the numbers of exacerbations. Outcomes that were not part of the hierarchy included the number of days of plasma exchange and the volume of plasma exchanged, the duration of stay in an intensive care unit and in the hospital, mortality rate, pharmacodynamic and pharmacokinetic variables, and immunogenicity. We estimated that with a sample of 132 patients, the trial would have 80% power to detect a median time to normalization of the platelet count that was 40% shorter with caplacizumab than with placebo, using a log-rank test at a 5% significance level and assuming a 10% dropout rate. Journals & Books; Help Download PDF Download. Information, resources, and support needed to approach rotations - and life as a resident. 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). These utilities were selected because they provided the lowest ICER values, thereby minimizing bias against the caplacizumab arm and maximizing its cost effectiveness. 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. 3. Peyvandi F, Scully M, Kremer Hovinga JA, et al. ‖ Admission to the intensive care unit for administration of plasma exchange is standard practice at some centers and is not necessarily indicative of more severe clinical presentation. 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). Journal. (Because the time to normalization of the platelet count is linked with a positive outcome, “rate ratio” is used to describe the result instead of the typical “hazard ratio,” with similar interpretation.). Caplacizumab reduces the frequency of major thromboembolic events, exacerbations and death in patients with acquired thrombotic thrombocytopenic purpura. The rare blood disorder can be treated by plasma exchange and immunosuppressive therapy, but acute episodes are still associated with significant mortality (10–20%) and relapses are common. 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. About caplacizumab and the TITAN study results Caplacizumab is a highly potent and selective bivalent anti-von Willebrand Factor (vWF) Nanobody® that received Orphan Drug Designation in … ‡ Four of the six patients who had a relapse during the follow-up period had received the maximum allowed extension of treatment. Haematologica 2008;93:232-239. 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). Save Recommend Share . 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. Westwood JP, Webster H, McGuckin S, McDonald V, Machin SJ, Scully M. Rituximab for thrombotic thrombocytopenic purpura: benefit of early administration during acute episodes and use of prophylaxis to prevent relapse. The TITAN and HERCULES trials reported numerical ranges for number of TPE sessions and inpatient LOS; in our models, we chose the extremes of these ranges to maximize and minimize such costs in the SOC and caplacizumab groups, respectively. Concise summaries and expert physician commentary that busy clinicians need to enhance patient care. For the Markov model, in addition to a series of 1-way sensitivity analyses, we also performed a probabilistic sensitivity analysis (PSA), in which we varied all model parameters in numerous permutations and combinations, to assess the robustness of the model. Results from a phase II study show that this novel therapy leads to significantly … The guidance states … It has no effect on the autoimmune pathogenesis. In a Markov model based on the TITAN trial, over a 5-year time horizon, the addition of caplacizumab to SOC yielded a higher cost of treatment compared with SOC alone at the conclusion of the model simulation ($551 878 for caplacizumab vs $151 947 for SOC). Benhamou Y, Boelle PY, Baudin B, et al. Patients who received caplacizumab needed less plasma exchange and had a shorter hospitalization than those who received placebo. Contribution: G.G. You can find your saved items on your dashboard, … Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Acquired TTP is caused by the development of autoantibodies directed against the von Willebrand factor-cleaving metalloproteinase ADAMTS13, leading to accumulation of thrombogenic ultra-large von Willebrand factor multimers and microvascular occlusion. 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. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. The four key secondary outcomes, which were hierarchically ranked on the basis of clinical relevance, were the following: a composite of TTP-related death, recurrence of TTP, or a major thromboembolic event during the trial treatment period; recurrence of TTP at any time during the trial, including the follow-up period; refractory TTP (defined by the lack of a doubling of the platelet count after 4 days of treatment and a lactate dehydrogenase level that remained above the upper limit of the normal range); and the time to normalization (i.e., to a level below the defined upper limit of the normal range) of three organ-damage markers (lactate dehydrogenase, cardiac troponin I, and serum creatinine). Purple dashed line represents baseline estimate. Caplacizumab for acquired thrombotic thrombocytopenic purpura. (Funded by Ablynx; HERCULES ClinicalTrials.gov number, NCT02553317.). However, the analysis is a hypothetical best-case scenario in favor of caplacizumab (e.g., providing a cost-utility analysis without having any data on utility for patients with disease progression).