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1
Vanover, Kimberly, Gretchen Snyder, Joseph Hendrick, Allen Fienberg, Lawrence Wennogle, Sharon Mates, and Robert Davis. "ITI-007." International Clinical Psychopharmacology 26 (September 2011): e56. http://dx.doi.org/10.1097/01.yic.0000405728.69382.1e.
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Zendel, Benjamin Rich, Bernhard Ross, and Takako Fujioka. "The Effects of Stimulus Rate and Tapping Rate on Tapping Performance." Music Perception 29, no. 1 (September 1, 2011): 65–78. http://dx.doi.org/10.1525/mp.2011.29.1.65.
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when finger taps are synchronized with an isochronous click, it is known that tap-click asynchrony and its variability increase with the interonset interval (IOI). It remains unclear whether these results are due to the IOI or the intertap interval (ITI) duration. The present study examines how these two factors influence tapping performance by altering the tap-click ratio (i.e., 1:n tapping). It has been shown that holding the ITI constant while decreasing the IOI—so that extra clicks subdivide each tap—results in a reduction of tapping variability, described as a subdivision benefit (Repp, 2003). Two questions remain: Does asynchrony and variability increase with the ITI while holding the IOI constant? Does asynchrony decrease with the IOI while holding ITI constant? Using linear regression, both asynchrony and variability decreased with the IOI, with little additional effect of ITI. In contrast, when using ITI as a predictor, the contribution of IOI was significant, suggesting that IOI is the main determinant of tapping performance. In addition, an ANOVA revealed a disadvantage for 1:3 tapping, supporting a categorical distinction between duple and triple meters since 1:n tapping can engender the subjective feel of different metric structures.
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Patterson, C. J. W. "ITI dental implants." Journal of Dentistry 23, no. 3 (June 1995): 191. http://dx.doi.org/10.1016/s0300-5712(95)90083-7.
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Tosta, Mauro. "Seção ITI México." Dental Press Implantology 9, no. 4 (2015): 16–20. http://dx.doi.org/10.14436/2358-2553.9.4.016-020.int.
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Schwarz, M. S. "Why ITI Implants?" Implant Dentistry 5, no. 1 (1996): 53. http://dx.doi.org/10.1097/00008505-199600510-00021.
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Escuriola-Ettingshausen, Carmen, Vladimir Vdovin, Nadezhda Zozulya, Olga Plyushch, Wolfhart Kreuz, and Bruce A. Schwartz. "ITI with a VWF-Stabilised FVIII Concentrate in Haemophilia A Patients with Inhibitors and a Poor Prognosis for ITI Success: Progress Report on octanate® in the Observational ObsITI Study,." Blood 118, no. 21 (November 18, 2011): 3310. http://dx.doi.org/10.1182/blood.v118.21.3310.3310.
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Abstract Abstract 3310 FVIII inhibitors that neutralise FVIII efficacy are the most serious complication of FVIII replacement therapy in patients with haemophilia A (HA) and can be overcome with high-dose FVIII (Bonn protocol) during immune tolerance induction (ITI) therapy. The ongoing investigator-initiated Observational Immune Tolerance Induction (ObsITI) study systematically documents the tolerisation process, retrospectively and prospectively, in patients with HA and inhibitors, including those with a poor prognosis for ITI success. Here we report interim data on Octanate®, a human plasma-derived, von Willebrand factor-stabilised FVIII product. Data were analysed for a subgroup of 18 prospective patients who received octanate® as the sole FVIII replacement therapy for a treatment/follow-up period of 36 months. ITI success was determined by fulfilment of three stringent criteria: (I) inhibitor titre < 0.6 Bethesda Units, (II) incremental in vivo recovery ≥ 80% of 1.5% per IU/kg body weight reference and (III) FVIII half-life ≥ 7 hours. According to the criteria fulfilled, patients achieved the following: partial response (I), partial success (I, II), complete success (I, II, III) or failure. Following complete success, patients received prophylaxis with octanate® every second day. Of 18 patients, with at least one risk factor for a poor ITI outcome, 14 patients (77.8%) achieved complete success; 2 patients (11.1%) had partial response and 2 patients (11.1%) failed the ITI. Cox regression analysis of time to achievement of treatment outcome, suggested that both commencing ITI at ≤ 7 years of age and having had no prior ITI attempt appear to be positive prognostic factors for earlier ITI success in this population. Despite the stringent success criteria, complete or partial ITI success was achieved in 77.8 % of the patients. Treatment with octanate® administered according to the Bonn protocol is safe and effective in the induction of immune tolerance, even in patients with a poor-prognosis for ITI success. Disclosures: Schwartz: Octapharma usa: Employment.
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Ødum, Lars, Torben E. Jessen, and Claus Yding Andersen. "Glycosaminoglycan-bound and free inter-α-trypsin inhibitor components of follicular fluid." Zygote 9, no. 4 (November 2001): 283–88. http://dx.doi.org/10.1017/s0967199401001319.
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The proteinase inhibitor inter-α trypsin inhibitor (ITI) is a blood-derived protein necessary for normal female fertility. Absence of ITI leads to ovulation of naked oocytes that cannot fertilise. ITI consists of two heavy chains (ITI-HC) and bikunin linked by a chrondroitin sulphate. By binding to hyaluronate, ITI-HC stabilises the extracellular matrix, but ITI-HC also binds to proteoglycans in follicular fluid. In vivo concentrations of ITI components in preovulatory follicular fluid, free as well as bound to hyaluronate or proteoglycan, are unknown. In order to quantify these components, 58 follicular fluids and 13 blood samples were collected in connection with in vitro fertilisation and embryo transfer treatment of 13 women. Quantitation of glycosaminoglycan-bound ITI-HC was performed after separation from free ITI in agarose gel. ITI components were determined by immunoelectrophoresis and hyaluronate by an ELISA method. The follicular fluid concentration of ITI was on average 70% of that in plasma and the concentration of hyaluronate remained low despite follicular production, suggesting that the production of hyaluronate is the rate-limiting step in the formation of the extracellular matrix of the oocyte-cumulus complex. In follicular fluid, the concentration of free ITI-HC was higher than that of glycosaminoglycan-bound ITI-HC. Addition of exogeneous hyaluronate doubled the amount of hyaluronate-bound ITI-HC, further supporting the notion that ITI in follicular fluid is not rate-limiting for cumulus expansion in vivo.
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Guo, Jin, Meng Chen, Xialing Sun, Zhanzhao Wang, and Jinli Xue. "Leveraging industrial-technological innovation to achieve sustainable development: A systems thinking perspective." PLOS ONE 15, no. 12 (December 21, 2020): e0242981. http://dx.doi.org/10.1371/journal.pone.0242981.
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Industrial-technological innovation (ITI) has become an important requirement for the sustainable development of China. ITI development requires a comprehensive understanding of the dynamic complexity associated with ITI systems. Previous research into ITI systems is based primarily on static methods that isolate system components, and ignore feedback on adjustments made. Based on systems thinking, this paper develop six archetypes (“Limit to Growth,” “Success to the Successful,” “Tragedy of the Commons,” “Fixes that Fail,” “Accidental Adversaries,” and “Shifting the Burden”) and an ITI system integration model. The model visualizes the ITI system as a whole and identifies bottlenecks that may affect ITI development. This conceptual model provides a more effective method of judgment, which can better explain the operational mechanism of the ITI system and improve the system’s operational characteristics. Finally, we evaluate the ITI system and propose that self-organization is a key lever of a systemic intervention framework for ITI.
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Callaghan, Michael U., Indira Warrier, Madhvi Rajpurkar, and Jeanne Lusher. "Immune Tolerance Induction in 28 Children with Hemophilia Awith Inhibitors." Blood 108, no. 11 (November 16, 2006): 1046. http://dx.doi.org/10.1182/blood.v108.11.1046.1046.
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Abstract Aim: To study the characteristics, treatment, and outcome of patients with hemophilia with inhibitors who have undergone immune tolerance induction (ITI) at the Children’s Hospital of Michigan over the past 14 years. Methods: In compliance with local IRB regulations, patient charts and laboratory databases were reviewed and salient data extracted. 28 boys underwent 29 attempts at immune tolerance induction. Results: Hemophilia A 26 boys with severe hemophilia A with inhibitors underwent 27 trials of ITI. In this cohort of 26 patients the average age at which patients developed an inhibitor was 22 months and the average age at start of ITI was 5 years 4 months (range 2 months to 17 years 5 months). The average number of exposure days prior to inhibitor development was 10 (1–47). The average time between development of an inhibitor and initiation of ITI was 43 months, with no difference between those who successfully completed ITI and those who did not. Six patients had low titer inhibitors (0.8–6.5 BU) and successfully completed ITI using a modified low dose ITI regimen of factor infusions 3–7 times per week. 20 of the patients with high titer inhibitors (6.4–1280 BU) were treated with daily infusions of 50–200 units/kg/d of factor VIII (FVIII) products. For ITI, 4 patients received high purity plasma derived FVIII (PD-FVIII) and 21 received recombinant FVIII (rFVIII) and one received both. In patients who became tolerized to FVIII, the average time to achieve an inhibitor titer of 0 Bethesda Units (BU) was 211 days. In those who were unable to achieve tolerance, the average length of the trial was 263 days. 21 of the ITI trials employed a central venous catheter and in 5 patients ITI was stopped after removal of the line because of recurrent infections. 14 boys received FEIBA, rFVIIa, or porcine FVIII for bleeding episodes during ITI; 8 of them failed ITI and one is still on therapy. Seven trials of ITI were in Caucasian patients (26 %), 17 in African American (AA) (63 %), and 3 in Middle Eastern patients (11 %). 19 patients achieved complete tolerance (73 %), 6 patients failed (23 %), one failed twice, and one patient continues on therapy. All but 2 patients who successfully completed ITI went on prophylaxis with FVIII. All patients who successfully completed ITI have maintained tolerance with a mean follow-up of 101 months (range 7–168). Table I: Hemophilia A Failed ITI Successful ITI *One still ongoing Number of trials* 7 (23 %) 19 (73 %) African Americans 7 (41 %) 10 (59 %) Non-AA 0 10 (100 %) Historical Peak Titer (mean) 345 BU 47 BU Titer at Start of ITI (mean) 62 BU 5 BU Peak Titer on ITI (mean) 168 BU 46 BU Age at inhibitor development (mean) 26 months 12 months ITI with PD-FVIII 1 4 ITI with rFVIII 7 15 Hemophilia B During this time period, 2 boys with severe hemophilia B underwent ITI. Both had severe allergic reactions at the time of inhibitor development; both underwent desensitization successfully but both failed ITI. Both started ITI with plasma derived factor nine at age 15 months. One developed nephrotic syndrome while on ITI. Conclusions: Most patients with Hemophilia A were able to achieve and maintain tolerance (73%). Higher titer inhibitors, hemophilia B, younger age at development of inhibitor, AA race and treatment of bleeds with bypass agents or porcine factor while on ITI were risk factors for ITI failures. Loss of central venous access with recurrent infections was also a common reason for ITI failure.
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Lorenzana, Eduardo, Dean Morton, Gregory Philips, and William Martin. "Interview ITI Section USA." Dental Press Implantology 9, no. 3 (2015): 8–11. http://dx.doi.org/10.14436/2358-2553.9.3.008-011.oar.
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&NA;. "ITI World Symposium 2005." Implant Dentistry 12, no. 1 (March 2003): 103. http://dx.doi.org/10.1097/00008505-200312010-00033.
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Li, Nanxin, Koo Wilson, Marc Botteman, Daniel Nicoloso, Sangeeta Krishnan, and Jun Su. "Economic Impact of Immune Tolerance Induction (ITI) with Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) Compared to Conventional Recombinant Factor VIII (rFVIII)." Blood 132, Supplement 1 (November 29, 2018): 3520. http://dx.doi.org/10.1182/blood-2018-99-114993.
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Abstract Introduction: Hemophilia A results from a clotting protein factor VIII (FVIII) deficiency, which leads to the need for the use of exogenous FVIII. Such therapy is effective unless alloantibodies (inhibitors) develop and render FVIII replacement ineffective. Patients with high-titer inhibitors may try to eradicate the presence of these inhibitors by undergoing ITI, an often costly process that requires the prolonged use of frequent doses of FVIII to induce FVIII antigen-specific tolerance. There is no consensus on the best approach to achieve tolerance and no product has been approved by any regulatory agency for ITI treatment in hemophilia A patients with inhibitors. The Fc portion of rFVIIIFc has shown immunomodulatory properties in mice, and chart reviews and case reports suggest that tolerization with rFVIIIFc in first-attempt ITI patients can potentially be achieved rapidly (i.e., ≤18 months) and therefore may possibly offer cost savings compared to conventional rFVIII. This analysis assessed the economic consequences and budget impact of using rFVIIIFc vs. conventional rFVIII for first-attempt immune tolerance induction (ITI) in hemophilia A patients with inhibitors. Methods: A literature-based model was developed to estimate the effect of rFVIIIFc vs conventional rFVIII on drug cost of first-attempt ITI, based on modelled ITI duration and outcome (rates and time to ITI success or failure) for US patients with varying clinical profiles (e.g., historical peak titer, FVIII dose) over a 3-year period. In the model, at any given time after ITI initiation (on either rFVIIIFc or rFVIII), a patient was categorized as ongoing ITI, post-ITI as success, or post-ITI as failure. The duration and outcomes for patients treated with rFVIIIFc ITI were based on observed data for first-attempt ITI patients with varied clinical profiles and ITI regimens from in chart reviews and case reports (n = 9). In the absence of direct head-to-head observations, the duration and outcome of ITI for the exact same patients in a scenario in which they received rFVIII (instead of rFVIIIFc) at the same doses were estimated indirectly using a previously published regression model (Bojke et al. 2009, Value in Health, 12(7), A378-A379) based on data for 113 patients from international and national registries that adjusts for historical and pre-ITI titer levels, time from inhibitor diagnosis to ITI start, and ITI factor dose. To place the cost comparison results in the perspective of a third-party US payer, a budget impact analysis was undertaken on a population of typical hemophilia A patients (after adjusting for patient characteristics) who are embarking on first-attempt ITI in a plan of 10 million insured members. In this analysis, the number of patients starting ITI each year was assumed constant, and patients who successfully eradicated inhibitors with ITI would transition back to FVIII prophylaxis. Results: The model predicted that, compared to rFVIII, rFVIIIFc would result in a reduction in estimated time to ITI success (rFVIIIFc: 9.43 months, rFVIII: 16.80 months), increased success probability at 20 months (rFVIIIFc: 67%, rFVIII: 25%), and lower 3-year per-patient costs (rFVIIIFc: $1,709,000, rFVIII: $3,630,000), respectively. In the budget impact analysis for a US health plan of 10 million insured members, 11.2 patients were expected to be newly diagnosed hemophilia A patients, among whom 1.17 patients were expected to develop inhibitors to FVIII and initiate ITI each year. By year 3, the predicted number of successful ITI patients increased by 23% and the budget savings for the plan were $103,738 per patient per year (for the ~1 patient who started ITI each year) after the inclusion of rFVIIIFc for ITI and subsequent prophylaxis when patients successfully eradicated inhibitors. Conclusions: Based on this mathematical economic model of first-attempt ITI patients, the modeled faster time to tolerization with rFVIIIFc vs. rFVIII, resulted in estimated per-patient and overall budget savings in ITI from a US payer perspective. Current prospective studies (e.g. verITI-8) will provide additional evidence on the efficacy of rFVIIIFc for ITI in Hemophilia A patients with inhibitors. Disclosures Li: Bioverativ: Employment. Wilson:SOBI: Employment. Botteman:Daiichi Sankyo Incorporated: Research Funding; BMS: Research Funding; Pharmerit International: Employment, Equity Ownership, Research Funding; Celgene: Research Funding; Bioverativ: Consultancy, Other: Provided consulting to Bioverativ, Research Funding. Nicoloso:Bioverativ: Other: an employee of Pharmerit, which provided consulting to Bioverativ. Krishnan:Bioverativ: Employment. Su:Bioverativ: Employment.
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Prezotti, Alessandra Nunes Loureiro, Silmara Aparecida De Lima Montalvão, Cláudia Lorenzato, Andrea Maia Oliveira, Maria do Perpétuo Socorro Vendramini Orletti, Maria Do Rosario Ferraz Roberti, Luiz Ivando Ferreira Filho, et al. "Immune Tolerance Induction Treatment Is Cost-Effective in Adult Patients with Long-Standing High-Responding Inhibitors." Blood 126, no. 23 (December 3, 2015): 3530. http://dx.doi.org/10.1182/blood.v126.23.3530.3530.
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Abstract Introduction: Despite treatment of hemophilia having achieved considerable improvement over the last decades, inhibitor development remains a major complication for these patients. Inhibitors are alloantibodies that neutralize factor (F) VIII coagulation activity, and occur in approximately 25% of hemophilia A patients. Immune tolerance induction (ITI) is the choice therapy to eradicate these antibodies. There are several ITI protocols with similar success rates, approximately 70%. The presence of long-standing inhibitors in the adult population has usually been associated with poor ITI outcome. In Brazil, as in other countries with constrained resources, limited access to factor concentrates prevented the use of ITI. Thus, almost all patients with inhibitors remained a long time with this complication. Only after 2013 with increased availability of factor concentrates in the country, has assured long-term prophylaxis and ITI treatment been possible. Objective: This study aimed to describe the Brazilian experience in managing ITI in adult patients from seven Hemophilia Treatment Centers with long-standing inhibitor using bypassing agents to control bleeding episodes, considering bleeding frequency, treatment barriers and economic impact of therapy. Patients and Methods: We retrospectively analyzed clinical and laboratory data of hemophilia A patients with high-responding inhibitors (peak titer > 5 Bethesda Unit (BU), anamnestic response to FVIII) over 18 yo who underwent ITI treatment and were using bypass agents before ITI. The initial ITI protocol used was low-dose FVIII concentrate (25-50 IU/kg 3x/week) Results: In Brazil, since the availability of ITI, 39 adult hemophilia A patients with inhibitors, have been submitted to ITI for the first time. In this study, we accessed data from 26 patients, of these 13 (50%) already achieved complete ITI success criteria (inhibitor titer < 0.6 BU; FVIII recovery ≥ 66%, and half-live ≥ 6 h). Another 4 patients with ongoing ITI achieved inhibitor titer < 5 BU and are no longer using bypassing agents. Thus, 17/26 (65%) patients discontinued the bypassing agents in a median period of 2 mo (range 0 to 18 mo) after starting ITI. After 24 months of irregular treatment 2 patients abandoned ITI protocol. Analyses of the 13 patients with complete success revealed mean age at first reported inhibitor of 16.21y (SD ± 11.6; median 21y, range 0.7 to 37y), and mean age at ITI onset of 31.2y (SD ± 10.6; median 27y, range 19 to 47y). The mean period from the first inhibitor detected until starting ITI was 15y (SD ± 5.1), with a 16y median (range 7 to 22y). The historical peak inhibitor mean was 53.1 BU (SD ± 49.5; median 39.4 BU, range 5.5 to 163 BU). The mean pre ITI inhibitor titer was 6.6 BU (SD ± 5.5; median 5.5 BU, range 0.6 to 20.8 BU). Low-dose ITI protocol was initially used for all patients, however 3 patients had the dose increased during treatment (100 IU/kg from 3 to 7 x/week). During ITI, 10/13 patients received prophylaxis with bypassing agents, and 9 began prophylaxis before ITI started. The mean time to achieve inhibitor titer < 0.6 BU was 11.6 mo (SD ± 12.5; median 7 mo, range 0.5 to 44 mo). All 13 patients achieved other ITI success criteria. However, a delay was observed in the majority of patients in FVIII recovery and half-life. Regarding clinical outcome, we observed a significant reduction in both, annualized bleeding rate (ABR), and annualized joint bleeding rate (AJBR), comparing 12 months before ITI, during ITI, and after achieving complete success (figure 1). Regarding economic evaluation, we observed a significant reduction in the median cost of clotting factor consumption, comparing 12 months before starting ITI, and the following years after achieving ITI success. No significant difference was observed between the median cost of 12 months before, and ITI period (figure 2). Conclusion: This study indicated that this treatment is worthwhile even for inhibitor patients with poor prognostic factors for ITI considering both effectiveness to control and prevent bleeding episodes, and economic impact. In this group, 65% of adult hemophilia A high-responding inhibitors patients stopped using bypassing agents after a median period of 2 months after starting ITI. Despite being a high cost treatment, ITI can be cost-effective, especially for patients using bypassing agents. These results reinforce the positive impact of the ITI even in long time inhibitor adult patients. Disclosures Ozelo: Baxter: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Research Funding, Speakers Bureau; Biogen: Research Funding.
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Nakar, Charles T., Marilyn J. Manco-Johnson, Alice Lail, Sharyne M. Donfield, Jennifer Maahs, Young Chong, Taylor A. Blades, and Amy D. Shapiro. "Prompt Immune Tolerance Induction at Inhibitor Diagnosis Regardless of Titer May Increase Overall Success in Hemophilia A With Inhibitors: Experience of Two US Centers." Blood 122, no. 21 (November 15, 2013): 575. http://dx.doi.org/10.1182/blood.v122.21.575.575.
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Abstract Introduction Immune tolerance induction (ITI) for patients (pts) with hemophilia A with inhibitors is the only modality known to effectively eradicate inhibitors with an overall reported success of ∼60-80%. One debate concerns the optimal time to start ITI; recent guidelines recommend delaying ITI until inhibitor titer is <10 Bethesda units (BU). Aim We report results of an analytic project to determine the success of ITI relative to time from inhibitor detection to ITI initiation. Methods Data was collected retrospectively at 2 US hemophilia centers on pts with severe/moderate (≤5%) factor VIII (FVIII) deficiency undergoing ITI including time interval from inhibitor detection to ITI start, inhibitor titer and outcome. High-dose ITI was practiced by both centers (i.e. ≥100 IU/kg/day). Success, partial success and failure were defined practically with success as a negative inhibitor titer and ability to use FVIII concentrate routinely for treatment and prevention of bleeding; partial success was an inhibitor titer <5 BU with ability to use FVIII concentrate to treat bleeding episodes; failure as ongoing ITI >3 years without achieving success/partial success or discontinuation of ITI. IRB approvals were obtained at both centers for this data analysis. Pts were first divided into low responding inhibitor (LRI) and high responding inhibitor (HRI) based on peak inhibitor titer; the HRI subgroup was further subdivided based on time to start ITI, including within 1 month, 1-6 months and greater than 6 months. The HRI subgroup starting ITI within 1 month was analyzed based on pre-ITI inhibitor titer. Results Fifty eight male pts with adequate ITI history documentation were included; 55 (95%) were severe (<1%), 3 moderately deficient (1-3%). Forty-seven pts (48%) were Caucasian, 6 Hispanic, 2 African American, 2 Asian and 1 Native American. Outcome is summarized in Table 1. Overall, 49 of 58 pts (84%) underwent successful ITI. Low responding Inhibitors: Among 19 (33%) pts with LRI, ITI success was 100%. Most pts with LRI 15/19 (79%) started ITI within 1 month from inhibitor detection. High responding inhibitors: Among 39 (67%) pts with HRI, 30/39 (77%) achieved tolerance, 1 achieved partial success and continued ITI, 1 was ongoing, 7 pts failed. The 39 pts with HRI were further subdivided based on time to ITI start. ITI start within 1 month of detection: Twenty three pts started ITI within 1 month from detection; 21 achieved success (91%), 1 partially succeeded and 1 failed. Eight of 10 pts (80%) with a pre-ITI titer <10 BU achieved success, 1 partially succeeded and 1 failed. All 13 pts (100%) starting ITI with pre-ITI inhibitor titer ≥ 10 BU achieved success. ITI start > 6 months: Eleven pts had an interval > 6 months until ITI start; 7 (64%) achieved success and 4 (36%) failed. Conclusions These results suggest that the time interval from inhibitor detection to start of ITI may play a critical role in outcome. A titer ≥10 BU did not influence outcome in pts where ITI was utilized within 1 month, supporting this approach in contrast to the commonly accepted practice of delaying ITI start until a titer <10 BU is achieved. Pts may benefit from prompt ITI regardless of current inhibitor titer and are not subjected to wait periods where bleeding is more likely to occur. Prompt ITI should be considered a viable therapeutic option in newly identified inhibitor pts regardless of current inhibitor titer. Disclosures: Manco-Johnson: Bayer HealthCare: Membership on an entity’s Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees; Biogen Idec: Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees; Eisai: Research Funding. Maahs:Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Biogen Idec: Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Shapiro:Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novo Nordisck: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bayer Healthcare: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Biogen Idec: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Chugai Pharma: Consultancy; Kedrion Biopharma: Consultancy, Research Funding; Cangene Pharmaceuticals: Research Funding; CSL Behring: Research Funding; Octopharma: Research Funding; PTC Therapeutics: Research Funding; Eli Lilly: Research Funding.
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Nogami, Keiji, Masashi Taki, Tadashi Matsushita, Shouichi Ohga, Hideji Hanabusa, Toshiaki Oka, Yasuo Horikoshi, Kagehiro Amano, and Midori Shima. "Outcome of the Japanese Immune Tolerance Induction (ITI) Registry and Predictors of Successful ITI." Blood 126, no. 23 (December 3, 2015): 3526. http://dx.doi.org/10.1182/blood.v126.23.3526.3526.
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Abstract [Background] Immune tolerance induction (ITI) therapy is the only therapeutic approach that can eradicate factor (F)VIII and FIX inhibitors in patients with hemophilia A (HA) and B (HB), respectively. Although results of several retrospective cohort studies have been published, predictors of successful outcome are still debated. Nonetheless, little information is so far available in terms of large ITI cohort in non-Caucasian countries. [Aim] In this study, we performed a retrospective cohort study on ITI therapy carried out for Japanese hemophilia patients with inhibitors to understand the status of practice on this therapy in Japan and to study the predictors of successful outcome. [Methods] As of March 31, 2015, the registry of ITI therapy in Japanese hemophilia patients had received reports on 155 HA patients (140 severe type, high responder 69.1%) and 7 HB patients (7 severe type, high responder 42.5%) who have undergone this therapy from 45 hospitals including Hemophilia Treatment Centers since 2000. The ITI outcome was centrally reviewed. The success of ITI was defined as an undetectable inhibitor for 2 successive measurements, and the salvage ITI was defined as any rescue ITI regimen by using von Willebrand factor-containing FVIII concentrates. [Results] Among the completed ITI courses, the overall success rate of ITI therapy was 71.2% (94/132) and 83.3% (5/6) for HA and HB patients, respectively. Cumulated ITI success rates of 50% and 80% for HA patients were achieved at 1.6 and 4.3 years after the inhibitor diagnosis, and 0.6 and 2.3 years after the initiation of ITI, respectively. Significant predictors for success of ITI in HA were (i) low responding inhibitors (success 35/37 (94.5%)) compared to high responding inhibitors (59/93 (63.4%); p <0.0001), (ii) shorter intervals from inhibitor diagnosis to the initiation of ITI (success (S): 1.85±3.52 vs failure (F): 3.38±3.77 years; p =0.02), (iii) lower historical peak titers on pre-ITI (S: 24.9±55.2 vs F: 132±295 BU/ml; p =0.04), and (iv) lower peak inhibitor titers on-ITI (S: 72.4±231 vs F: 916±1,307 BU/ml; p <0.01). However, outcome was not significantly different (p =0.77) between high dose regimens (>90 IU/kg, 7 days/wk) and low dose regimens (<75 IU/kg, 3 days/wk). Also, either FVIII products (plasma-derived or recombinant) at the initiation or the insertion of central venous access devise (CVAD) did not affect the outcome (p =0.32 and 0.85). Although the outcome prediction was difficult for HB because of low number of the cases registered, success rate was much higher than those of previous reports. The success rate of salvage ITI was 50% (6/12) for HA. The significant predictive parameter for outcome was only the age at the initiation of salvage ITI (p =0.03). The inhibitor relapsed in 6 cases, and all cases were HA patients (4.5% 6/140). In 86 cases with insertion of CVAD, the catheter-related infection was complicated in 21 cases (12.9%). [Conclusion] This study underscores the importance of initiating the ITI as early as possible after the diagnosis of inhibitor and the low response of inhibitor titer before and during the ITI to maximize the success of the treatment for Japanese hemophilia patients. Disclosures Nogami: Chugai: Membership on an entity's Board of Directors or advisory committees; Bayer, NovoNordisk, Baxalta, Chugai, Kaketsuken, Pfizer, Biogen: Honoraria; Bayer, Novo Nordisk, Baxalta. Biogen: Research Funding. Taki:Biogen, Baxalta, Bayer, Novo, Pfizer: Honoraria; Biogen, Baxalta, NovoNordisk, CSL-Behring, Kaketsuken, Chugai: Research Funding. Matsushita:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CLS-Behling: Research Funding; Japan Blood Products Organization: Honoraria, Research Funding; Kyowa-Kirin: Honoraria, Research Funding; Octapharma AG: Honoraria; Sysmex: Speakers Bureau; Seamens: Speakers Bureau; Nihon Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Kaketsuken: Honoraria, Research Funding, Speakers Bureau; Asahi Kasei Pharma: Honoraria, Research Funding, Speakers Bureau; Eisai: Research Funding; Novartis Pharma: Honoraria, Speakers Bureau; Bayer Healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai Pharmaceutical Co., Ltd.: Research Funding. Hanabusa:Novo Nordisk, Baxalta, Bayer, Pfizer, Biogen, and KaketsuKen: Honoraria; Novo Nordisk, Baxalta, KaketsuKen, and Biogen: Membership on an entity's Board of Directors or advisory committees. Shima:Pfizer: Honoraria, Research Funding; Kaketsuken: Honoraria; Biogen: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Baxalta: Honoraria, Research Funding.
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Ragni, Margaret V., Lynn M. Malec, and Janna M. Journeycake. "Durability of ITI Utilizing Rfviiifc." Blood 128, no. 22 (December 2, 2016): 3793. http://dx.doi.org/10.1182/blood.v128.22.3793.3793.
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Introduction: The eradication of inhibitors using immune tolerance induction (ITI) remains the mainstay of therapy in patients with severe hemophilia A who develop inhibitors. The long-acting recombinant factor VIII Fc fusion protein, rFVIIIFc (Eloctate™), which is safe and effective in the prevention and treatment of bleeding events, may promote tolerance to FVIII as shown in preclinical animal models and an inhibitor prone child, as Fc suppresses immunoregulatory Tcells to proteins to which Fc is attached. We therefore previously hypothesized rFVIIIFc would provide effective ITI, specifically shortening and simplifying ITI, and have previously described successful inhibitor eradication in three patients. Long-term follow-up data after successful ITI in patients with severe hemophilia remains limited. In the International Immune Tolerance Induction study, at 1-year follow-up, 6 of 66 subjects who had achieved tolerance demonstrated evidence of relapse at a median of 9.5 months. Of these 6 subjects, 1 had a measurable inhibitor titer and 5 had reduced FVIII recovery. We aim to provide follow-up data on our cohort of patients who had successful inhibitor eradication utilizing rFVIIIFc for ITI. Methods: Immune tolerance induction was initiated in three patients with severe hemophilia A and anti-VIII >5 B.U., in two as initial ITI (Pt. 1, 3), and one as salvage (Pt. 2) after failing to achieve ITI with standard rFVIII due to poor compliance. Follow-up was scheduled every 6-8 weeks, with planned determination of FVIII half-life once the anti-FVIII fell to <0.6 B.U. Tolerance was a priori defined as achieving anti-FVIII <0.6 B.U., FVIII recovery of at least 60%, and half-life (t½) >6 hours. Once a t½ >6 hours was documented, incremental reduction to rFVIIIFc occurred. Patients continued to be followed by their local HTC as per standard of care. Results: ITI was initiated with rFVIIIFc at a dose of 100-200 IU/kg rFVIIIFc every other day or three times weekly per MD discretion. The time to initial anti-FVIII <0.6 B.U. was 4-12 weeks. Patient 1 and 2 were able to achieve tolerance, with a FVIII recovery of at least 60%, and half-life (t½) >6 hours, at weeks 18 and 17, respectively, after initiation of ITI. Patient 3 has improved but is not yet fully tolerized, as evidenced by 57% recovery and a t½ of approximately 7 hours. Anti-VIII inhibitor titers remain negative at 15, 16 and 15 months, from the initiation of ITI in patients 1, 2, and 3 respectively. Patients 1 and 2 have been able to decrease their post ITI prophylaxis dosing regimen to 80 IU/kg and 65 IU/kg three times a week while maintaining a FVIII trough of >1%. No patients were maintained on bypassing prophylaxis during ITI and no patients have experienced hemarthroses or other major bleeding event since the initiation of ITI. Discussion: Immune tolerance induction was successful in three children with inhibitors using rFVIIIFc, including a child previously failing rFVIII ITI. The time to anti-FVIII=0 was 4-12 weeks, significantly shorter than with current rFVIII ITI. At a mean duration of follow up of 15.3 months, all patients achieved an anti-VIII inhibitor titer of 0 B.U. Repeat pharmacokinetics studies will be available at planned subsequent follow-up visit. To date, these data indicate that rFVIIIFc safely and effectively induced immune tolerance to FVIII in three children with inhibitors, and has provided durable and continuing immune tolerance to FVIII. Whether rFVIIIFc ITI will be successful and durable in a larger cohort of children with severe hemophilia A will require prospective studies. A prospective observational study of rFVIIIFc ITI pre- and post-ITI T cell responses in children with hemophilia and inhibitors, the Hemophilia Inhibitor Response to Eloctate (HIRE) Study, has begun recruitment. Disclosures Ragni: SPARK: Research Funding; Shire: Consultancy; Novo Nordisk: Research Funding; Genentech: Research Funding; CSL Behring: Research Funding; Biomarin: Consultancy; Biogen: Consultancy, Research Funding; Baxalta: Research Funding; Alnylam Pharmaceuticals: Consultancy, Research Funding; Tacere Benitec: Consultancy; Vascular Medicine Institute: Research Funding; OPKO: Research Funding. Malec:Vascular Medicine Institute: Research Funding; Biogen: Research Funding; Baxalta: Research Funding; Biogen: Consultancy. Journeycake:CSL: Consultancy; Biogen: Consultancy; Baxalta/Shire: Consultancy.
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Abraham, Aby, Shashikant Apte, Chandrakala Shamukhaiah, Fouzia N., Kannan Subramaniam, Akshata Rahate, Abraham Sunder Singh, et al. "Outcome of Immune Tolerance Induction Using an Extended Half-Life Clotting Factor Concentrate — Recombinant Factor VIII Fc (Eloctate™) — a Report from India." Blood 132, Supplement 1 (November 29, 2018): 2494. http://dx.doi.org/10.1182/blood-2018-99-119279.
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Abstract The development of inhibitors is the most serious adverse effect of replacement theray with clotting factor concentrates (CFC) in hemophilia. Its eradication is also difficult, usually requiring months of frequent exposure to high doses of the CFC - immune tolerance induction (ITI). There is limited data on use of extended half-life (EHL) CFC for ITI. A limited program of ITI was made possible in India with some of the rFVIIIFc (Eloctate™) provided through the humanitarian aid program of the World Federation of Hemophilia. This report summarizes the interim outcome of ITI in these patients treated at three centers participating in this program. ITI with rFVIIIFc was offered to patients with hemophilia A and significant inhibitors. The CFC dose used ranged from 50 IU/kg, 3x/week, to 200 IU/kg per day, depending on the weight, convenience and early response as well as availability of rFVIIIFc. All patients completing at least 10 weeks of ITI are included in this analysis. Bethesda assay was done every 2-4 weeks. Successful ITI was defined as a negative Bethesda assay with a FVIII recovery of >60%. Patients received either FEIBA or rVIIa for breakthrough bleeds. Thirty eight patients were included in this analysis. The median age at initiation of ITI was 15 years (range:2 -39). Nine (24%) patients had a family history of inhibitors. The median age at which inhibitors developed was 11 years (range:0.6 -38). Nine (24%) patients had history of surgery prior to onset of inhibitor. Ten patients (26%) had exposure to only plasma derived factors. All patients were on episodic CFC replacement therapy except two (5%) who were receiving low-dose prophylaxis prior to inhibitor development. The median exposures to FVIII was 20 (range:2-80) and duration of inhibitors prior to ITI was 2 years (range:0.1 - 20). The median highest inhibitor titre recorded prior to ITI was 19 BU (range:4-1177). Only 3 patients had their maximum inhibitor titer below 5BU. The median inhibitor titre at the time of starting ITI was 10.4 BU (range: 0.6-1177). The median peak inhibitor titer after starting ITI was 40.4 BU (range:3.5-13933). Out of the 38, 17 (45%) patients achieved a negative inhibitor status after ITI for a median duration of 23 weeks (range: 10-64). Among the 17 patients who had successful ITI, the median duration of ITI required to achieve negative inhibitor status was 20 weeks (range:10-60). Among the other 21 patients who had persistence of inhibitors, 4 were included in other clinical trials, 3 discontinued due to personal reasons while the other 14 are continuing ITI based on availability of appropriate EHL CFC. Among these patients with persistence of inhibitors, the last inhibitor titer was 6.4 BU (range:0.9-9240) after a median of 26 weeks of ITI (range:11-64). The median number of breakthrough bleeds during ITI was 1 (range:0-12), being 1 (range:0-6) among responders and 1 (range:0-12) among those with persistence of inhibitors. A comparison of the group which responded within this duration of ITI and those who did not respond is shown in the table. Older age and the peak inhibitor titer prior to ITI were the two significant variables which affected early outcome of ITI. These data show that EHL rFVIIIFc can be effective in ITI with nearly 45% of patients achieving a negative inhibitor titer within 1 year and with responses starting as early as 1 month and nearly half of them within 4 months. There was also a relatively low median annualized bleed rate during ITI. More patients need to be treated with different doses of rFVIIIFc to assess its potential in ITI and to determine the optimal protocols but the initial data is promising. Disclosures No relevant conflicts of interest to declare.
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Sakurai, Yoshihiko, Takaji Matsutani, Takeshi Yoshioka, Tomohiro Takeda, Akira Yoshioka, and Midori Shima. "Alterations of T cell receptor Vβ repertoire of CD8 T lymphocytes in immune tolerance induction in two hemophilia A patients with inhibitors." Vojnosanitetski pregled 68, no. 12 (2011): 1047–50. http://dx.doi.org/10.2298/vsp1112047s.
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Background/Aim. Hemophilia A patients with inhibitors are treated effectively with immune tolerance induction (ITI) therapy. Although anti-idiotypic antibodies may play a certain role in the underlying mechanism, the detailed mechanism by which ITI produces a curative effect remains unknown. The aim of this study was to clarify the immunological aspect of ITI. Methods. Longitudinal T-cell receptor (TCR) analysis was performed during ITI. TCR variable region ?-chain and ?-chain repertoires were serially analyzed for peripheral blood mononuclear cells (PBMCs), CD4 T cells, and CD8 T cells from 2 hemophilia inhibitor patients treated with ITI (Patients 1 and 2). Furthermore, to see whether skewing observed in TCR analysis resulted from clonality alterations, T-cell clonality was investigated using complementarity-determining region 3 (CDR3) size spectratyping. Results. In the patient 1, inhibitor titer remained to be 19.6 BU/mL for 596 days after ITI commencement, and ITI was unsuccessful. In the patient 2, inhibitor titer disappeared 434 days after ITI commencement, and ITI was successful. In both cases, skewing of TCR variable region ?/?-chain repertoires was observed in CD8 T cell subset, whereas not in CD4 T cell subset. Conclusion. Alteration of TCR repertoires, especially TCR variable region ?-chain repertoire of CD8 T cells, was distinct between successful and unsuccessful cases, suggesting that immunological response in the early phase affected the ITI outcomes.
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Zozulya, N. I., V. V. Vdovin, P. V. Svirin, T. A. Andreeva, E. E. Shiller, N. I. Konyashina, I. A. Lavrichenko, et al. "Results of a prospective observation on the use of a coagulation factor concentrate VIII concentrate (Octanate®) for the induction of immunological tolerance in patients with an inhibitory form of hemophilia A." Russian Journal of Pediatric Hematology and Oncology 7, no. 2 (July 4, 2020): 54–63. http://dx.doi.org/10.21682/2311-1267-2020-7-2-54-63.
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Relevance. Immune tolerance induction (ITI) is the only approach proven to eradicate inhibitors in hemophilia A patients. ITI with Octanate® (human VWF-stabilized FVIII) has been shown to be effective at eradicating inhibitors, even in poor-prognosis patients. Here we report interim data from two observational, prospective studies on the use of Octanate® for ITI in patients in Russia.Purposes of research. The primary objective was to assess the efficacy of ITI. Secondary objectives included assessment of time to ITI success and inhibitor eradication.Patients and methods. Patients of any age with any severity of hemophilia A and a FVIII inhibitor 0.6 BU/mL were eligible. The ITI regimen was at the discretion of the treating physician.Results. The analysis included 73 patients. ITI outcomes were assessed in 63 patients who had completed the study, of whom 56 (89 %) had 1 poor prognostic factors. Inhibitor eradication was achieved by 77.1 % (37/48) of primary ITI patients and 71.4 % (45/63) of all patients, in a median of 2.4 months (range – 0.0–27.4) for both groups. Complete success was achieved by 72.9 % (35/48) of primary ITI patients in a median of 8.9 months (range – 2.4–28.0) and 66.7 % (42/63) of all patients in a median of 10.5 months (range – 2.4–28.0). No relapses were reported after complete or partial ITI success. Of the patients with 1 poor prognostic factors, 67.9 % achieved inhibitor eradication and 62.5 % complete success.Conclusions. ITI with Octanate® in a real-world setting showed rapid and sustained success, even in patients with poor prognostic factors.
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Bhatnagar, Neha, Kate Khair, Ri Liesner, Alice Wilkinson, and Larisa Belyanskaya. "Immune Tolerance Induction with Simoctocog Alfa (Nuwiq®) in Six Patients with Severe Haemophilia a and FVIII Inhibitors." Blood 132, Supplement 1 (November 29, 2018): 5037. http://dx.doi.org/10.1182/blood-2018-99-118041.
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Abstract Introduction and Objective: Inhibitors to coagulation factor VIII (FVIII) are the most serious complication of haemophilia A treatment. Previously untreated patients (PUPs) are at the greatest risk of inhibitors, which generally occur within the first 20 exposure days (ED) to FVIII. Immune tolerance induction (ITI) is the only clinically proven strategy for eradication of inhibitors. We present a case series of six PUPs with severe haemophilia A and inhibitors who underwent ITI with simoctocog alfa (Nuwiq®), a 4th generation human cell-line-derived recombinant FVIII approved for treatment of haemophilia A. Materials and Methods: Six male PUPs with severe haemophilia A who developed FVIII inhibitors after treatment with simoctocog alfa were started on ITI with simoctocog alfa. Primarily, we assessed the success of simoctocog alfa in patients with inhibitors. Success of ITI was determined based on undetectable inhibitor titre (< 0.6 BU/ml), FVIII recovery ≥ 66% and half-life ≥ 6 hours. Secondary objectives were to assess bleeding rate, tolerability and safety in patients with inhibitors treated with simoctocog alfa ITI. Results: The age of the patients at the start of ITI ranged from 8 to 186 months. Four of the patients were Caucasian, and two were African. All patients had a F8 mutation associated with high risk of ITI failure and two patients had an additional risk factor for ITI failure. The number of EDs prior to inhibitor development ranged from 9 to 33, and the peak inhibitor titre ranged from 0.9 to 114 BU. For ITI, five patients were treated with 100 IU/kg simoctocog alfa daily, and one with 90 IU/kg every other day. One patient achieved complete tolerisation and is now on prophylaxis at normal doses, having achieved an undetectable inhibitor titre after 9 months. This was despite an inhibitor titre ≥ 10 BU/mL at ITI start, which is considered a poor prognosis factor for ITI success. Three other patients achieved an undetectable inhibitor titre after 1, 6 and 18 months of ITI, and FVIII recovery has normalised but half-life remains short and they are on weaning doses as the half-life extends. One patient discontinued ITI with simoctocog alfa after 15 months due to an increasing inhibitor level. This patient was 15 years old at ITI start, and older age is associated with poor ITI outcome. Additionally, his haemophilia A was untreated for 15 years, during which time he developed severe arthropathy. One patient, who started ITI 3 months ago, has an ongoing inhibitor titre and continues on ITI with simoctocog alfa. Conclusions: In a case series of six patients treated with simoctocog alfa for ITI, who all had poor prognosis factors for ITI success, four patients (67%) to date have achieved an undetectable inhibitor titre. These data suggest that ITI with simoctocog alfa may be an effective treatment approach in haemophilia A patients with inhibitors. Disclosures Khair: Shire, SOBI, Pfizer, Roche, Novo Nordisk, Octapharma: Speakers Bureau; shire, SOBI, Pfizer, Roche: Research Funding. Liesner:Roche: Research Funding; Novo Nordisk: Research Funding, Speakers Bureau; Baxalta: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Octapharma: Consultancy, Other: Clinical study investigator for NuProtect Study (Octapharma sponsored), Research Funding, Speakers Bureau; Sobi: Speakers Bureau. Belyanskaya:Octapharma AG: Employment.
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Spotts, Gerald, Brigitt E. Abbuehl, Huong D. Luu, Clara K. Song, Jacqueline A. Dyck-Jones, Norma Guzman-Becerra, LieLing Wu, et al. "Safety and Efficacy Profile of rAHF-PFM for Immune Tolerance Induction as Assessed In 3 Clinical Trials (PUP ITI, PRE-PAIR, and PAIR)." Blood 116, no. 21 (November 19, 2010): 3670. http://dx.doi.org/10.1182/blood.v116.21.3670.3670.
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Abstract Abstract 3670 Introduction: Development of neutralizing antibodies to FVIII is the most serious complication in the management of hemophilia A today. Eradication of the inhibitor with ITI therapy is a common treatment practice however, there are few reports of controlled studies, and much of the current ITI experience is reported from international registries and small site-based case studies. A previous case-series demonstrated successful tolerance in 9/12 (75%) patients using ADVATE [Antihemophilic Factor (Recombinant) Plasma/Albumin Free Method] (rAHF-PFM). Data on the safety and efficacy of rAHF-PFM in ITI therapy have now been formally captured in the recently completed Previously Untreated Patient (PUP-ITI) study, a retrospective chart review (PRE-PAIR), and an ongoing Prospective ADVATE ITI Registry (PAIR). Objectives: To provide a critical assessment of the safety and efficacy of rAHF-PFM in ITI therapy through a review of the cumulative data from PUP-ITI, PRE-PAIR, and PAIR. Methods: PUP study was a prospective, multicenter, open-label, clinical study in PUPs <6 years of age with severe or moderately severe hemophilia (FVIII level ≤2%) who underwent on-demand or prophylactic treatment with rAHF-PFM. Subjects who developed inhibitors against rAHF-PFM could enter the PUP-ITI study and receive ITI. PRE-PAIR was a multicenter, retrospective, chart review of PTPs of any age and any severity of hemophilia A with history of ITI with rAHF-PFM. PAIR is an ongoing non-interventional safety surveillance registry of subjects prescribed rAHF-PFM for ITI. In all three studies, the choice of ITI regimen was at the discretion of the investigator; however, for the PUP-ITI study, the ITI regimen was based on site-specific ITI data and/or institutional guidelines, or as described in peer reviewed literature. The primary endpoints for PUP-ITI and PRE-PAIR were the success rate of ITI. The PAIR report was an interim safety assessment that did not examine efficacy endpoints. For PUP-ITI and PRE-PAIR, the definitions of success required the subject to have achieved 2 consecutive negative inhibitor test results and if data available, demonstrated normalized FVIII recovery. For PRE-PAIR, partial success was defined as achieving negative titer but without normalized recovery. Results: In PUP-ITI, a total of 11 subjects initiated ITI; 3 withdrew and 8 completed ITI. In PRE-PAIR, 35 subjects were enrolled, 30 of which were evaluable per protocol. Of these 30 subjects, 20 had moderately severe to severe hemophilia A (FVIII ≤2%), and high-titer (>5 BU) inhibitor. As of Sept 4, 2010, 18 subjects had been enrolled in PAIR and were included in an interim safety assessment. Over all 3 studies, most commonly prescribed initial dose regimen in subjects with high inhibitor titer prior to initiation of ITI was 100 IU/kg QD (17/37 [46%]), followed by 200 IU/kg QD (11/37 [30%]), and any dose at a frequency of <1/day (9/37 [24%]). In the low titer inhibitor subjects the most commonly prescribed regimen were various doses with a frequency of <1/day (13/22 [59%] subjects). Of the 11 subjects in the PUP study who participated in the PUP-ITI study, 3 withdrew and 8 (72.7%) achieved success (95% CI: 43.4%, 90.3%). All 8 subjects (100%) achieved success, with 1st negative titer at a median time of 1.8 months (0.0 - 4.1 months) and the 2nd negative titer at 3.0 months (1.1 – 9.0 months). In PRE-PAIR, sum of complete and partial success rates gave a total success rate of 76.7% (23/30) in subjects who met inclusion criteria (95% CI: 59.1, 88.2%). During these 3 studies, there were no SAEs related to rAHF-PFM ITI therapy and 6 non-serious AEs in 3 subjects considered to be related to rAHF-PFM (diarrhea, vomiting, pain following bleed, mild urticaria, and mild fever). Conclusions: In 2 clinical studies of rAHF-PFM therapy in ITI treatment, rAHF-PFM was found to be efficacious in a variety of dosing regimens reflective of current standards of practice in hemophilia care. Overall success rates ranged from 72.7% in PUP-ITI to 76.7% in PRE-PAIR. Success rates in these 2 rAHF-PFM studies are similar to those reported in published literature. In all 3 ITI studies, there were no product related SAEs and 6 non-serious AEs in 3 subjects considered to be related to rAHF-PFM, suggesting that rAHF-PFM used for ITI has a similar risk profile established in routine clinical use. These data suggest that ITI treatment with rAHF-PFM was both effective and safe. Disclosures: Spotts: Baxter Bioscience: Employment. Off Label Use: ADVATE [Antihemophilic Factor (Recombinant) Plasma/Albumin Free Method] (rAHF-PFM)use in ITI therapy. Abbuehl:Baxter Bioscience: Employment. Luu:Baxter Bioscience: Employment. Song:Baxter Bioscience: Employment. Dyck-Jones:Baxter Bioscience: Employment. Guzman-Becerra:Baxter Bioscience: Employment. Wu:Baxter Bioscience: Employment. Oh:Baxter Bioscience: Employment. Zoerer:Baxter Bioscience: Employment. Sosa:Baxter Bioscience: Employment. Stephens:Baxter Bioscience: Employment. Yamamoto:Baxter Bioscience: Employment. Ewenstein:Baxter Bioscience: Employment.
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Li, Zekun, Zhenping Chen, Xiaoling Cheng, Xinyi Wu, Li Gang, Zhen Yingzi, Cai Siyu, Man-Chiu Poon, and Runhui Wu. "Low-Dose Immune Tolerance Induction for Hemophilia a Children with Poor-Risk High-Titer Inhibitors." Blood 134, Supplement_1 (November 13, 2019): 1122. http://dx.doi.org/10.1182/blood-2019-132021.
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Background: Low-dose immune tolerance induction (ITI) +/- immunosuppression as a practical ITI strategy in China showed a relatively satisfactory success rate and economic advantages in pilot study. However, the outcome still needs to be verified by larger cohort. Aim: To report the efficacy of this low-dose ITI +/- immunosuppression strategy in hemophilia A children ≥ 10 BU. Methods: This was a single center, prospective study in 53 hemophilia A subjects from Sep 2016 to Apr 2019. All subjects having ≥ 10 BU receiving ~50IU/kg FVIII every other day using domestic intermediate purity pdFVIII/VWF products, either alone or in combination with rituximab and prednisone judging by inhibitors and ITI response. Results: Finally, 46 subjects received this strategy at a median of 3.2 (IQR, 2.3-6.5) years old, their pre-ITI inhibitor titer was median 30.0 (range, 10.1-416) BU. Analysis at median 15.1 (range 3.0-34.4) months follow-up, success (inhibitor <0.6BU) was achieved in 32 (69.6%) subjects, partial success (inhibitor <5BU but >0.6BU) in 11 (23.9%) subjects, and failure in 5 (10.9%) subjects. Between subjects administered ITI-alone and ITI- immunosuppression, no significant difference was observed in time to success (median 8.5; IQR 6.7-11.7 vs 10.2; IQR 5.1-25.1, P=0.164). The mean monthly bleeding rate on ITI was 0.49 which declined 59.3% compared with pre-ITI period. Subjects administered ITI-immunosuppression (0.54 ± 0.46) was higher than ITI-alone (0.42 ± 0.69) although with no significantly difference (P=0.089). Seven (21.9%) subjects experienced inhibitor recurrence, 4 subjects treated with ITI-alone, 3 with ITI-immunosuppression. Recurrence occurred at a median of 4.8 (range, 2.8-10.8) months after successful ITI with inhibitor titer transiently rising to median 0.7 (range, 0.7-1.5) BU. Conclusion: This low-dose ITI +/- immunosuppression therapy in subjects with pre-ITI inhibitor ≥ 10 BU showed a success rate similar to other high/intermediate-dose regimen for the whole inhibitor patients. The subjects treated with ITI-immunosuppression did not showed higher recurrence at present, while a longer time follow-up is still needed. Disclosures Poon: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bioverativ/Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; World Federation of Hemophilia: Other: Not-for-profit organization affiliation: volunteer ; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participation in sponsored research; CSL-Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Grant Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Grant Funding; Takeda/Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees.
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Vincent, Anne-Marie, Anthony Chan, Sara J. Israels, Man-Chiu Poon, John K. Wu, and Georges E. Rivard. "Use of Factor VIII/Von Willebrand Factor Complex for Inducing Immune Tolerance in Hemophilia a Patients Who Have Failed with Recombinant Fviii: Recent Canadian Experience." Blood 112, no. 11 (November 16, 2008): 4520. http://dx.doi.org/10.1182/blood.v112.11.4520.4520.
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Abstract Immune tolerance induction (ITI) is effective in approximately 63–83% of hemophilia patients with inhibitors. Poor prognostic factors are age > 18 years, ITI started > 4 years after inhibitor development, inhibitor peaks > 200 BU, inhibitor titre > 10 BU at ITI initiation, and previously failed ITI. It has been reported that patients who have failed ITI with a recombinant FVIII concentrate achieved and maintained immune tolerance when VWF/FVIII complex concentrates were used. We present our Canadian experience with a factor VIII/von Willebrand factor concentrate (Humate-P) for inducing immune tolerance in patients who have previously failed ITI. A questionnaire was sent to all Hemophilia Treatment Centers of Canada. Data collected included baseline FVIII level, mutation, date at initial diagnosis of inhibitor, peak titer, concentrate associated with development of inhibitor, inhibitor titer at initiation of first ITI, concentrate and regimen used, and concentrate, dosing and outcome of secondary ITI with Humate-P. All Hemophilia Centers agreed to participate. 5 Centers submitted data about 8 patients. One patient resistant to initial ITI with Kogenate FS achieved good partial response with Humate-P, with titers going down from 40 to values between 0,6 and 4 BU. One patient who responded to initial ITI with Kogenate FS with peaking of inhibitor to 380 BU was remaining above 100 BU and lowered to 28 BU on Humate-P. In three patients, Humate-P induced an anamnestic response. Two of those patients had a concomitant line infection at time of switching to Humate-P. The third of those three patients had a transient anamnestic response after introduction of Humate-P. One patient had successfull induction of immune tolerance using multiple therapies (cyclophosphamide, Immunate, IVIG, Rituximab) and maintained remission under Humate-P. One patient was on ITI for 27 months using Recombinate and switched to Humate-P when Recombinate was withdrawn from the market. After 12 months, the inhibitor had gone from 12 to 7.3 BU. One patient attained complete remission during primary ITI using recombinant FVIII concentrate (Advate) and maintained remission when switched to Humate-P. In subjects failing ITI with recombinant factor VIII concentrates, Humate-P may be considered as a second line for inducing immune tolerance.
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Odeyemi, Isaac, and Anne D. Møller. "The Economic Impact of Anamnestic Response in the Management of Hemophilia Patients with Inhibitors Undergoing Immune Tolerance Induction in Germany." Blood 110, no. 11 (November 16, 2007): 5161. http://dx.doi.org/10.1182/blood.v110.11.5161.5161.
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Abstract The aim of this analysis was to estimate the economic impact of bleed control treatments prior to immune tolerance induction (ITI) in patients with hemophilia with inhibitors in Germany. “Poor risk” hemophilia patients presenting at ITI are more costly to manage as they require higher-dose factor VIII treatment over a longer period, compared to “good risk” patients. Thus, factors that improve patient risk status for ITI, and permit the lowering of factor usage during ITI while maintaining clinical efficacy, are expected to result in cost-effective outcomes. The phenomenon of anamnestic response (AR) which occurs following treatment of hemophilia bleeds with immunogenic products results in significant elevation of titer levels, conferring a “poor risk” status on these patients at ITI. We therefore hypothesize that the prevention of AR pre-ITI, by avoiding immunogenic agents, would result in fewer “poor risk” patients requiring high-dose regimen during ITI, resulting in a cost-effective outcome. A cost-minimization model compared two strategies for the management of patients with severe hemophilia A with inhibitors. One strategy involved management of bleeds with a bypassing agent (activated prothrombin complex concentrates; aPCC) prior to ITI, while the other involved management of bleeds by use of a product which does not provoke AR (recombinant activated factor VII; rFVIIa) prior to ITI. Data on resource use and probabilities of clinical outcomes were derived from published literature, and the model validated by clinical experts with experience in managing inhibitor patients. The mean cost of ITI in inhibitor patients previously treated with rFVIIa is €1,073,327 compared to €1,420,825 for patients previously treated with aPCC. The model also estimated the incremental cost attributable to anamnesis in the management of a hemophilia patient who has undergone ITI to be €186,665. Sensitivity analyses suggest that the model is robust to the price of aPCC, but sensitive to the proportion of patients with AR post-aPCC treatment and the cost and dosage of FVIII at ITI. Anamnestic response is an unpredictable but avoidable consequence of managing bleeding episodes in inhibitor patients and confers significant additional costs to the management of high-responding inhibitor patients undergoing ITI. Avoiding AR prior to ITI by managing spontaneous bleeding episodes with bypassing agents which do not provoke AR has the potential for significant cost savings.
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Stillman, Amy Ku'uleialoha, and Pascal Nabet-Meyer. "The Tahitian Choir--Rapa Iti." Ethnomusicology 40, no. 2 (1996): 362. http://dx.doi.org/10.2307/852079.
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Mirfazaelian, Ali. "A screwdriver for ITI abutments." Journal of Prosthetic Dentistry 86, no. 3 (September 2001): 326. http://dx.doi.org/10.1067/mpr.2001.114514.
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Syono, Y., and T. Yagi. "Syun-iti Akimoto (1925–2004);." Eos, Transactions American Geophysical Union 86, no. 46 (2005): 465. http://dx.doi.org/10.1029/2005eo460007.
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Letowska, Magdalena Katarzyna, Krystyna Zawilska, Anna Klukowska, Krzysztof Chojnowski, Joanna Zdziarska, Ewa Stefanska-Windyga, and Jerzy Windyga. "Immune Tolerance Induction (ITI) in Paediatric and Adult Patients with Haemophilia a (HA) and High-Titre (HT) Factor VIII (FVIII) Inhibitor - Real Life Data." Blood 134, Supplement_1 (November 13, 2019): 4942. http://dx.doi.org/10.1182/blood-2019-122422.
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Introduction: In Poland, the principles for the management of rare bleeding disorders as well as financing of medication are regulated by the National Program for the Management of Haemophilia and Related Bleeding Disorders. One objective of the Program for 2012-2018 was to include the financing of ITI for all haemophilia patients with inhibitor. The qualification for ITI was performed by a physician from a Haemophilia Treatment Centre (HTC). Goal: the aim of the study is/was prospective assessment of the efficacy of ITI in real life setting. Patients and Methods: The study comprised 30 patients with severe and one with moderate HA and HT FVIII inhibitors. Factor VIII activity (FVIII:C) was measured by one-stage clotting assay and Factor VIII inhibitors by a modified Nijmegen-Bethesda assay and expressed in Bethesda Units/ml (BU/ml). Cut-off level for positive inhibitor was ≥0.5BU/ml. The following data was collected: historical peak inhibitor titre (HPT), pre-ITI titre (measured 1 month prior to ITI), peak titre recorded during the course of ITI, time between inhibitor detection and ITI start, and ITI duration. During ITI course blood samples were collected every 4 weeks. Treatment regimen with dosing and type of FVIII concentrate was at the discretion of the physician in each HTC. ITI success was defined as inhibitor titre below 0.5 BU/ml with FVIII half-life ≥6h and FVIII recovery ≥66% of normal. Partial response to ITI was defined as clinical response to FVIII therapy with no anamnestic response despite the presence of FVIII inhibitor or FVIII half-life <6h and FVIII recovery <66% of normal. Results: 31 patients with HA and inhibitor were divided into two groups: Group 1 comprised 12 adults with severe HA, median age 36 years (mean 40.1±15.1 and Group 2 included 19 boys, (<18 years) (18 with severe, one with moderate HA), median age 8 years (mean 8.1±4.3) The median (mean) duration time between inhibitor detection and ITI start was 108 months (102±91) in Group 1 and 10 months (9±10) in Group 2. The median (mean) HPT before ITI was 68 BU/ml (156±193) and 50 BU/ml (126±242) in Group 1 and 2, respectively. ITI is still ongoing in one patient (Group 1) and in 3 boys (Group 2); these 4 patients were excluded from outcome analysis. Two adult patients (16,6%) of Group 1 and 2 boys (10,5%) of group 2 discontinued ITI therapy for a variety of reasons such as death (one patient), poor compliance or loss to follow-up; those patients were however included in the outcome analysis. The median (mean) duration of ITI was 24 months (30.8±31.7) (1-120) in Group 1 and 28 months (33.4±21.4) (6-84) in Group 2. The median (mean) peak titre during ITI was 40 BU/ml (225.7±185.7) in Group 1 and 85 (160±171.7) in Group 2. Immune tolerance to FVIII (success) was achieved in 3/11 adult (27.3%) and in 6/16 paediatric patients (37.5%). Median HPT, median time between inhibitor detection and ITI start, median peak inhibitor titre during ITI and median duration of ITI in patients who achieved immune tolerance were 380 BU/ml, 120 months, 8 BU/ml, 33 months in Group 1 and 22.5 BU/ml, 9.5 months, 205 BU/ml, 25 months in Group 2, respectively. No partial response to ITI was observed in our patients. The most common initial ITI regimen in both groups was 100 IU/kg/d of FVIII (50 - 200 IU/kg/d). In 28/31 (90.3%) patients only plasma derived FVIII concentrates were used which contained various amounts of von Willebrand factor. In two patients recombinant FVIII was administered. Recombinant, plasma derived and EHL FVIII concentrates were used in the case of one boy. In two patients immunosuppressive therapy (prednisone or rituximab) was concomitantly applied. Conclusions: it is our belief that the presented real-life data reflects i) the challenge of ITI therapy in clinical practice and ii) wide variety of approaches to ITI strategy in individual haemophilia treatment centres. Disclosures Windyga: Octapharma: Honoraria, Research Funding; Rigel Pharmaceuticals: Honoraria, Research Funding; Ferring Pharmaceuticals: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Alnylam: Honoraria, Research Funding; Alexion: Honoraria, Research Funding; Werfen: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Baxalta/Shire (a Takeda company): Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Siemens: Honoraria, Research Funding; Sobi: Honoraria, Research Funding.
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Kruse-Jarres, Rebecca, Maria Elisa Mancuso, Eva Mingot Castellano, and Johnny Mahlangu. "Immune Tolerance Induction (ITI) in Adults with Congenital Hemophilia: A Multicenter Experience." Blood 120, no. 21 (November 16, 2012): 1123. http://dx.doi.org/10.1182/blood.v120.21.1123.1123.
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Abstract Abstract 1123 Introduction Most inhibitors developing in adulthood are low titer inhibitors [Eckhardt 2012], however high titer inhibitors have been described [Kruse-Jarres 2010, Hay 2011]. The role of ITI in the management of adult inhibitors has not been established. Two large registries have suggested that age at ITI initiation could be a predictor of success. The North American ITI registry showed a trend toward a younger age in the ITI success group [DiMichele 2002], while the International ITI group showed a more definitive difference, where patients receiving ITI at age > 20 years had a 40 % success rate compared to a much higher success rate of 70 t0 78% in younger individuals [Mariani 2001]. Prospective therapy trials in an adult congenital hemophilia inhibitor population are difficult to conduct, as the number of patients is limited. The aim of the this multicenter retrospective review was to document our experience in the management of adult hemophilia inhibitor patients with ITI Methods Twelve hemophilia treatment centers which are part of the Globally Emerging Hemophilia Expert Panel (GEHEP) with centers in Canada, Europe, South Africa and the US, who collectively look after over 3000 hemophilia patients, participated in this study. Each center obtained ethics approval prior to data collection. Retrospective record review was undertaken at each center to identify congenital hemophilia patients treated with ITI as an adult (started at ≥ 17 years of age)and who completed the treatment course between 1980 and 2012. The treatment course was defined as any of the accepted ITI regimens. Treatment success was defined as inhibitor eradication or >66% factor recovery. Results Of 21 patients who received ITI as an adult, 71% had partial (<5BU and FVIII was able to be reinstated) or complete success. All patients had hemophilia A and most were severe (One patient in the ITI failure group had a level of 2% and in the success group, one had a level of 1% and on of 3%). Of the 13 patients achieving complete success, 38% relapsed (mean follow up of 9.4 years, range 3 months to 29 years). Age at start of ITI did not seem to be a predictor of success: mean age in the success group was 32.0 years (range 17 –55) and in the failure group was 33.5 years (range 22 – 57). All patients in the failure group were white, where 3 patients in the success group were non-white. The success group included one low responding inhibitor and had an overall lower peak inhibitors (mean 89.75 BU, range 3 – 270 BU) than the failure group (mean 353.8 BU, range 89–600 BU). Fifty percent of the failure patients had received a prior ITI attempt, where only 8% of the success group had. More patients in the failure group had received plasma derived factor VIII product for their ITI (83%) than in the success group (69%) but dosing was not significantly different (mean of 416 units/kg/week in failure group, 455 U/kg/week in success group). Overall, patient who failed stayed on ITI slightly longer (mean 20 months) than the patients who succeeded (mean 16 months). Conclusion In this limited series of adult inhibitor hemophilia patients treated with ITI, the success rate was high and comparable to that obtained in the pediatric population. Age at start of ITI did not seem to be a predictor of success, but prior ITI and historical peak inhibitor were negative predictors. Prospective clinical studies are required to expand on these preliminary findings. Disclosures: Kruse-Jarres: Bayer: Administrative and meeting support Other, Honoraria, Research Funding.
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Aledort, Louis M., Johannes Oldenburg, Elena Santagostino, and Victor Jimenez Yuste. "Rescue and Primary ITI in Children and Adults with a Single FVIII/VWF Product." Blood 120, no. 21 (November 16, 2012): 1174. http://dx.doi.org/10.1182/blood.v120.21.1174.1174.
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Abstract Abstract 1174 Introduction Inhibitors are the most serious complication of hemophilia A (HA) treatment. Current optimal intervention for inhibitor eradication is immune tolerance induction (ITI), the goal of which is for the patient to resume therapy with FVIII. Basic and clinical research have strongly supported that VWF containing FVIII concentrates may be less immunogenic and are effective in primary ITI as well as for rescue ITI for those who fail to develop tolerance with recombinant proteins. Objective To assess the outcome of rescue and primary ITI in children (<18 years old) and adults with a single FVIII/VWF product (Fanhdi®, Grifols, Barcelona, Spain). Methods Retrospective data from HA patients (FVIII< 2%) with inhibitors from 22 centers in Spain, Italy and Germany, who underwent primary or rescue ITI with FVIII/VWF concentrate were evaluated. Success, partial success and failure were defined based on the criteria of the consensus recommendations of the 2006 International ITI Workshop. Results The largest international multicenter study on ITI using a single product has evaluated 41 cases of primary ITI (32 children and 9 adults) and 19 cases of rescue ITI (17 children and 2 adults). Conclusion The response rate of 87% (CS+PS) in primary ITI exceeds that previously reported with any product class. The response rate (CS+PS) of 74% in the higher risk profile of rescue ITI is what one might expect for primary ITI. These excellent results, using a single VWF containing FVIII product, should encourage the use of this class of product for immune tolerance. Acknowledgments: The authors acknowledge Grifols financial support of the study. The authors also acknowledge Drs Jeffrey Spears and Roser Peiro, Grifols, for their editorial assistance in preparation of the abstract. Disclosures: Aledort: Grifols: Advisory Board Other, Honoraria; Kedrion: Advisory Board, Advisory Board Other; Baxter: DSMB, DSMB Other; Octapharma: DSMB, DSMB Other. Off Label Use: This FVIII is not licensed for ITI - nor is any other product. Oldenburg:d and e: Baxter, Bayer, Biotest, CSL-Behring, Grifols, Inspiration, NovoNordisk, Octapharma, Pfizer e: Biogen IDec, Swedish Orphan Biovitrum: Honoraria, Research Funding. Santagostino:Bayer, Baxter, Pfizer, CSL Behring, Novo Nordisk, Biotest, Kedrion and Grifols: Speakers Bureau; Pfizer, Baxter, Bayer, CSL Behring, Kedrion, Grifols and Novo Nordisk: Consultancy; Novo Nordisk and Pfizer: Research Funding. Jimenez Yuste:Grifols, Baxter, Pfizer, NovoNordisk: Advisory Board Other, Consultancy.
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Zanon, Ezio, Samantha Pasca, Renato Marino, and Angelo Claudio Molinari. "Successful of Immune Tolerance Induction (R-ITI) with Simoctocog Alfa (rhFVIII) in Hemophilia a Patients and High-Titer Inhibitors." Blood 132, Supplement 1 (November 29, 2018): 5036. http://dx.doi.org/10.1182/blood-2018-99-114615.
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Abstract Backgroud: The appearance of inhibitors (INH) is the most serious complication in hemophilia A (HA) patients. The primary objective is their eradication. Usually the primary ITI was performed with the same concentrate causing INH development, but which replacement factor to be use in case of ITI-R is still debatable. We report two successful cases of ITI-R with simoctocog alfa (rhFVIII) performed in two different Italian Hemophilia Centers, while three other cases are still ongoing. Case Report: Case-1: Adult man with moderate HA who developed INH after surgery and concomitant switch to another concentrate (octocog-alfa 2nd gen). The patient refused the ITI treatment immediately after the inhibitors appearance, and was then put on prophylaxis with bypassing agents for several months. First ITI was then started with pdFVIII/vWF at 200 IU/kg/day, inhibitor titer reached its historical peak (134 BU/ml) two months later and progressively decreased to 15 BU/ml, but without ever disappearing. This ITI was stopped after nineteen months. A second ITI was then tried with high dose regimen of morocotocog-alfa, but also in this case the mean INH titer remained steadily high (21 BU/ml) and this treatment was considered failed after fifteen months from the onset. A new ITI-R was then started when the INH titer was 74 BU/ml, with simoctoctocog-alfa (rhFVIII), at 200 IU/kg/day. INH progressively decreased and 7 months later disappeared (<0.6 BU/ml). Subsequent laboratory analysis confirmed this value. Case-2: A child, with severe hemophilia A, diagnosed at 12 months, was initially treated with moroctocog alfa only on demand, but he developed a transient low titer inhibitor (3 BU/ml) after 18 exposure days (ED), subsequently disappeared. At age of 42 months the young child was put on prophylaxis at dosage of 40 IU/kg three times a week. One year later he developed a new low titer inhibitor. A first ITI was then started with morocotocog alfa 100 IU/kg/day, reduced to 50 IU/kg three times a week when the inhibitor disappeared. Subsequently the ITI dose was increased to 200 IU/kg/day due to inhibitor recurrence and to frequent bleeds. During this treatment the inhibitor titer reached its historical peak of 103 BU/ml. This ITI was considered failed after 57 months of treatment. An ITI Rescue was then started with simoctocog alfa 200IU/kg/day, at the onset of this treatment the inhibitor titer was 2.8 BU/ml, it reached a peak of 10 BU/ml two months later, and disappeared 22 months from the start of ITI-R. During treatment with simoctocog alfa no haemorrhagic events were reported. Conclusions: Our cases showed that simoctocog alfa (rhFVIII) can be an important option in treating patients with HA and high-titer INH who previously underwent one or more failed ITI. Our cases proved the efficacy of this concentrate in two very poor risk patients. This result may suggest the use of simoctocog alfa also for first-line ITI, more real-world data are requested to confirm it. Important results are now awaited by the remaining three ITI-R still ongoing in three other Italian Hemophilia Centers. Backgroud: The appearance of inhibitors (INH) is the most serious complication in hemophilia A (HA) patients. The primary objective is their eradication. Usually the primary ITI was performed with the same concentrate causing INH development, but which replacement factor to be use in case of ITI-R is still debatable. We report two successful cases of R-ITI with simoctocog alfa (rhFVIII) performed in two different Italian Hemophilia Centers, while three other cases are still ongoing. Case Report: Case-1: Adult man with moderate HA who developed INH after surgery and concomitant switch to another concentrate (octocog-alfa 2nd gen). The patient refused the ITI treatment immediately after the inhibitors appearance, and was then put on prophylaxis with bypassing agents for several months. First ITI was then started with pdFVIII/vWF at 200 IU/kg/day, inhibitor titer reached its historical peak (134 BU/ml) two months later and progressively decreased to 15 BU/ml, but without ever disappearing. This ITI was stopped after nineteen months. A second ITI was then tried with high dose regimen of morocotocog-alfa, but also in this case the mean INH titer remained steadily high (21 BU/ml) and this treatment was considered failed after fifteen months from the onset. A new ITI-R was then started when the INH titer was 74 BU/ml, with simoctoctocog-alfa (rhFVIII), at 200 IU/kg/day. INH progressively decreased and 7 months later disappeared (<0.6 BU/ml). Subsequent laboratory analysis confirmed this value. Case-2: A child, with severe hemophilia A, diagnosed at 12 months, was initially treated with moroctocog alfa only on demand, but he developed a transient low titer inhibitor (3 BU/ml) after 18 exposure days (ED), subsequently disappeared. At age of 42 months the young child was put on prophylaxis at dosage of 40 IU/kg three times a week. One year later he developed a new low titer inhibitor. A first ITI was then started with morocotocog alfa 100 IU/kg/day, reduced to 50 IU/kg three times a week when the inhibitor disappeared. Subsequently the ITI dose was increased to 200 IU/kg/day due to inhibitor recurrence and to frequent bleeds. During this treatment the inhibitor titer reached its historical peak of 103 BU/ml. This ITI was considered failed after 57 months of treatment. An ITI Rescue was then started with simoctocog alfa 200IU/kg/day, at the onset of this treatment the inhibitor titer was 2.8 BU/ml, it reached a peak of 10 BU/ml two months later, and disappeared 22 months from the start of ITI-R. During treatment with simoctocog alfa no haemorrhagic events were reported. Conclusions: Our cases showed that simoctocog alfa (rhFVIII) can be an important option in treating patients with HA and high-titer INH who previously underwent one or more failed ITI. Our cases proved the efficacy of this concentrate in two very poor risk patients. This result may suggest the use of simoctocog alfa also for first-line ITI, more real-world data are requested to confirm it. Important results are now awaited by the remaining three R-ITI still ongoing in three other Italian Hemophilia Centers. Disclosures No relevant conflicts of interest to declare.
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Wu, John K., Celina Woo, and Erica Crilly. "Immune Tolerance Induction in Severe Hemophilia a Patients Using Wilate®, a Von Willebrand Factor/Factor VIII Concentrate." Blood 124, no. 21 (December 6, 2014): 5057. http://dx.doi.org/10.1182/blood.v124.21.5057.5057.
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Abstract Introduction: To prevent and treat bleeding episodes, hemophilia A patients undergo factor VIII (FVIII) replacement therapy with either recombinant FVIII (r-FVIII) or plasma-derived FVIII (pd-FVIII). Approximately 32% of patients develop neutralizing antibodies to the FVIII protein rendering FVIII therapy ineffective (Gouw et al. N Engl J Med. 2013; 368:231-239). Development of these neutralizing antibodies, or ‘inhibitors’ is the most serious and challenging complication in the treatment of hemophilia A patients and represents the highest economic burden for a chronic disease (Gringeri et al. Blood 2003; 102:2358-2363). The standard approach for eradicating inhibitors is to tolerize the patient to FVIII through prolonged, daily exposure to high-dose FVIII – a process termed immune tolerance induction (ITI). Although costly, ITI can successfully eliminate inhibitors in a large proportion of low-risk patients, however there are several risk factors that reduce the likelihood of ITI success. For high-risk patients, the choice of drug product (r-FVIII versus pd-FVIII) may be particularly important. Several small studies have demonstrated the superiority of pd-FVIII for ITI, as these products contain the FVIII stabilizing protein, von Willebrand Factor (VWF) (Gringeri et al., Haemophilia 2007; 13:373-379). Wilate® (Octapharma) is a high-purity pd-FVIII complex that contains the two proteins (VWF and FVIII) in a 1:1 ratio. In this retrospective study, we present the patient history and outcome for four severe hemophilia A patients that have undergone ITI with Wilate®. Patients and Methods. All patients presented with severe FVIII deficiency (<1%). Only 1/4 patients had undergone and failed a previous ITI attempt using a rFVIII product. The Wilate ITI dosing regimen ranged from 90 U/Kg to 100 U/Kg daily. Three of the four patients presented with high-risk factors for poor ITI outcome: 1 patient had 1, 1 patient had 3 and 1 patient had 5 poor prognostic factors. The definition of ITI success and failure were consistent with the definitions described in the consensus recommendations of the 2006 International ITI workshop (DiMichele et al. Haemophilia 2007;13 Suppl. 1: 1-22). Complete success (CS) was defined as having an undetectable inhibitor titer, FVIII recovery ≥66% and half-life ≥6 hours; partial success (PS) was defined as having a clinical response allowing for commencement of FVIII therapy associated with an inhibitor titer of <5 BU/mL (and with FVIII recovery <66% and/or half-life <6 hours). Results. ITI with Wilate was found to be well tolerated, with no reported drug-related adverse events. Although 75% of the patients presented with high-risk factors for poor ITI outcome, Wilate ITI reduced inhibitor levels below 5 BU/mL for 3 out of 4 patients. The clinical outcome of Wilate ITI correlated with the presence and number of high-risk factors. Patient 1 did not respond to Wilate, and was considered a failure. This patient had 3 high risk factors for poor ITI outcome including FVIII gene mutation type, peak historical titer >50, and inhibitor titer at ITI onset > 10 BU/mL. Of the three patients that responded to Wilate ITI, patient 4 experienced a CS to Wilate ITI in 4 months. For the remaining 2 patients, Wilate ITI is currently ongoing. Despite the presence of high risk factors, these two patients have thus far achieved a PS with inhibitor levels stable for several months at or below 1 BU/mL. One of these patients (patient 2) presented with 5 high-risk factors, including having failed a previous ITI attempt. The frequency of bleeding episodes were significantly reduced upon commencement of Wilate ITI, allowing for the eventual cessation of FEIBA prophylaxis. Conclusion. Despite the presence of high-risk factors, 3 out of 4 patients (75%) experienced a clinical response to Wilate ITI. The patients experienced improved quality of life. Wilate ITI resulted in a significant reduction in bleed episodes in a high-risk patient. The type of FVIII product to use during ITI has been debated, however, some have observed a higher success rate when plasma-derived FVIII products containing VWF are used. From our experience, we conclude that Wilate for ITI in patients with inhibitors is effective and produces high rates of ITI success in high-risk patients. Disclosures Wu: Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees. Woo:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Crilly:Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxter: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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Carcao, Manuel, Amy Shapiro, Nina Hwang, Steven Pipe, Sanjay Ahuja, Kenneth Lieuw, Janice Staber, et al. "Real-World Data of Immune Tolerance Induction Using rFVIIIFc in Subjects With Severe Hemophilia A With Inhibitors at High Risk for ITI Failure." Blood 132, Supplement 1 (November 29, 2018): 2500. http://dx.doi.org/10.1182/blood-2018-99-110467.
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Abstract Introduction: Immune tolerance induction (ITI) is the standard of care for eradication of inhibitors in subjects with severe hemophilia A. ITI is not always effective and can require a lengthy and burdensome treatment regimen. Those who have previously failed ITI are more likely to fail subsequent ITI. The successful use of recombinant factor VIII Fc fusion protein (rFVIIIFc) for ITI was described in our initial retrospective review of 19 high-risk subjects, including first-time and rescue ITI subjects (Carcao et al, Haemophilia, 2018). These findings indicated that time to tolerization appears to be faster with rFVIIIFc, despite a high-risk profile. It has been postulated that the Fc domain of rFVIIIFc may promote tolerization due to immunomodulatory properties. We report characteristics and ITI outcomes of 6 newly identified subjects, as well as follow-up data from 12 of the 19 subjects included in the original analysis. Methods: A follow-up of subjects enrolled in the original retrospective chart review and clinical outcomes of newly identified males with severe hemophilia A and historical high-titer inhibitors (≥5 BU) treated with rFVIIIFc for ITI is reported from 12 sites in the US and Canada. De-identified data were collected via electronic surveys. This interim analysis was performed on aggregated data collected through July 6, 2018. Data collection is ongoing, with 29 subject charts (19 original subjects and an additional 10) expected by October. Results: Of 25 charts reviewed to date, 9 were first-time ITI and 16 were rescue ITI subjects. Of 9 first-time ITI charts, 7 subjects were from the original study (4 had follow-up data), and 2 subjects were newly identified. Of 16 rescue ITI charts, 12 subjects were from the original study (8 with follow-up data), and 4 subjects were newly identified. All but 1 subject in the first-time ITI group had ≥1 high-risk feature. The median (range) age (n=9) at initiation of rFVIIIFc ITI was 1.4 (0.8-4.3) years and the median (range) time from inhibitor detection to initiation of rFVIIIFc ITI was 1.5 (0-9.4) months (Table 1). The median (range) inhibitor titer at rFVIIIFc ITI initiation was 32 (3-1126) BU/mL, and the dosing regimen of rFVIIIFc ranged from 50 IU/kg 3 times per week (TIW) to 200 IU/kg daily. All 16 rescue ITI subjects had high-risk features. The median (range) age at rFVIIIFc ITI initiation was 7.8 (1.6-48.9) years, with a median (range) time from inhibitor detection to initiation of rFVIIIFc ITI of 7.1 (0.6-43) years (Table 1). The median (range) number of prior ITI courses was 2.5 (1-7). The median (range) inhibitor titer at rFVIIIFc ITI start was 24.2 (0.6-237) BU/mL, and the dosing regimen of rFVIIIFc ranged from 43 IU/kg TIW to 200 IU/kg daily. Eight of 9 first-time ITI subjects achieved a negative Bethesda titer in a median (range) time of 27.2 (3-64.1) weeks and mean (standard deviation [SD]) time of 25.9 (20.7) weeks. All 8 were subsequently tolerized with a median (range) time to tolerization of 29.7 (3-64.1) weeks and a mean (SD) time to tolerization of 33.4 (20.4) weeks (Table 2). One of the 8 subjects, although he achieved a negative Bethesda titer and ultimately was tolerized (time to tolerization: 59 weeks), did so after a complicated course of ITI: he was initially on rFVIIIFc ITI for 15 weeks then was switched to plasma-derived FVIII ITI for 12 weeks. Owing to lack of reduction in inhibitor titer, the subject was switched back to rFVIIIFc ITI. Fourteen weeks later he became Bethesda titer‒negative and achieved tolerance 18 weeks after that. The 9th subject had a reduced titer and continues on rFVIIIFc ITI. Eight of 16 rescue ITI subjects reached negative Bethesda titer in a median (range) time of 29.6 (3-70) weeks (Table 2) and a mean (SD) of 34.9 (25.6) weeks. Of these, 2 subjects were tolerized at 23.1 and 35 weeks, respectively; both have transitioned to rFVIIIFc prophylaxis. Eight subjects continue on rFVIIIFc ITI and 6 transitioned to other ITI treatment regimens. Conclusions: A rapid time to tolerization was achieved in high-risk first-time ITI subjects in a real-world setting. ITI with rFVIIIFc led to rapid negative inhibitor titer in most first-time ITI subjects and many rescue ITI subjects. Faster time to tolerization is expected to improve subject's quality of life, joint health, and healthcare utilization. Findings from this study are being tested in 2 prospective trials using rFVIIIFc for ITI in subjects with hemophilia A with inhibitors (first time and rescue). Disclosures Carcao: Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL-Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shapiro:Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sangamo Biosciences: Consultancy; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bio Products Laboratory: Consultancy; Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioMarin: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prometic Life Sciences: Consultancy, Research Funding; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; Octapharma: Research Funding; Daiichi Sankyo: Research Funding; OPKO: Research Funding; Kedrion Biopharma: Consultancy, Research Funding. Hwang:Bioverativ: Other: PI in clinical research study; Shire: Consultancy; Hema Biologics: Consultancy; Bayer: Consultancy; BPI: Consultancy. Pipe:Catalyst Biosciences: Consultancy; Shire: Consultancy, Research Funding; Spark Therapeutics: Consultancy; Freeline: Consultancy; Bayer: Consultancy; uniQure: Consultancy; Biomarin: Consultancy; Apcintex: Consultancy; Ainylam: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy; Genentech: Consultancy; Pfizer: Consultancy; CSL Behring: Consultancy; Bioverativ: Consultancy; Nove Nordisk: Consultancy; Siemens: Research Funding; HEMA Biologics: Consultancy; R2 Diagnostics: Research Funding. Ahuja:Shire: Honoraria, Speakers Bureau; Bayer: Honoraria; Bioverativ: Honoraria, Speakers Bureau. Staber:uniQure: Honoraria; Bayer: Honoraria; NovoNordisk: Consultancy. Sun:Octapharma: Research Funding; Novo Nordisk: Consultancy. Ding:Bioverativ: Other: Site PI for clinical research study. Wang:Bayer: Consultancy; Bayer, Novo Nordisk, Octapharma, Genentech, HEMA Biologics, Shire, CSL Behring: Honoraria; Bayer, Bioverative, Novo Nordisk, Octapharma, Shire, Genentech, Biomarain, Pfizer, CSL Behring, HEMA Biologics, Daiichi Sankyo: Research Funding; CSL Behring: Consultancy; Terumo BCT: Other: CPC Clinical Research; Novo Nordisk: Consultancy. Steele:Baxter/SHIRE: Other: Travel, Hotel; Bayer: Honoraria; Roche: Honoraria. Tsao:Bioverativ: Employment. Feng:Bioverativ: Employment. Al-Khateeb:Bioverativ: Other: Consultancy (via Trinity Partners, LLC). Dumont:Bioverativ: Employment. Jain:Bioverativ: Employment.
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Guo, Jin, Bingmei Gu, Xialing Sun, Jinli Xue, and Baiyun Yuan. "Communication Barrier, Spillover Effect and Industrial-Technological Innovation." Sustainability 11, no. 18 (September 5, 2019): 4841. http://dx.doi.org/10.3390/su11184841.
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Industrial-technological innovation (ITI) has far-reaching significance for China’s sustainable development. In this study, we construct an ITI model to analyze the impact of communication barrier and spillover effects in ITI system from the perspective of system by means of system dynamics. Statistical data of smartphone industry were collected to verify the authenticity of the model, which show that the model has higher goodness of fit with the real-world. Simulation experiments were carried out and the results showed that: (1) Spillover effects have obvious effects on ITI in both positive and negative radiation directions, and deeper exchanges and cooperation should be encouraged to carry out among firm. (2) Communication barrier play an important role in regulating ITI. Under the condition of non-barrier and complete-barrier, the completion time of the whole process has increased by 76.5%, it is urgent to reduce communication carrier. The research puts forward suggestions to help improve ITI from institutional, market, and government.
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Bourguignon, J., R. Sesboüé, M. Diarra-Mehrpour, M. Daveau, and J. P. Martin. "Human inter-α-trypsin inhibitor. Synthesis and maturation in hepatoma HepG2 cells." Biochemical Journal 261, no. 1 (July 1, 1989): 305–8. http://dx.doi.org/10.1042/bj2610305.
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In hepatoma HepG2 cells, human inter-alpha-trypsin inhibitor (ITI) was synthesized as three heavy chains, H-1 (100 kDa), H-2 (110 kDa) and H-3 (113 kDa), and light hybrid chain (49.5 kDa) composed of alpha 1-microglobulin and HI-30 (ITI derivative, human inhibitor of 30 kDa). The association of at least two heavy chains, H-1 and H-3, with the HI-30 part of the light chain gave rise to a molecule similar to serum ITI. A composite protein (approximately 250 kDa) including heavy and light chains was also secreted, while alpha 1-microglobulin and ITI H-2 protein were released as separate entities. Light chain synthesis could be the limiting factor for ITI maturation.
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Su, Jun, Jia Zhou, Brieana Buckley, Tom Rising, Qiang Hou, and Nisha Jain. "The Immune Tolerance Induction Factor Utilizations and Costs for the Management of Male Hemophilia-a Patients Who Developed Inhibitors." Blood 128, no. 22 (December 2, 2016): 4758. http://dx.doi.org/10.1182/blood.v128.22.4758.4758.
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Abstract Background: Hemophilia-A is a chronic inherited bleeding disorder that results from deficiencies in factor VIII. Prophylactic replacement of coagulation factor VIII (FVIII) is the standard of care. However, about 20-30% of patients with severe hemophilia A may develop neutralizing antibodies (inhibitors) against the coagulation factor VIII. The Immune Tolerance Induction (ITI) method, consist in the regular infusion of variable FVIII doses to induce FVIII antigen-specific tolerance. It has proven the most effective inhibitor eradication treatment in patients with high-titer inhibitors. Current published studies reported wide range of findings on the factor usage and cost of treatment. The objective of this study is to describe the consumption, duration, and cost of ITI treatment in US healthcare settings. Methods: This retrospective analysis used MarketScan, an US health insurance claim database from January 2010 to September 2015. Eligible patients were: male hemophilia-A inhibitor patients who received ITI treatment. ITI treatment was identified as patients who tested Bethesda/Nijmegen assays between 30 days prior to an ITI index date and the end of study period; and used high dose of factor therapy (>3 times of the median IU factors dispensed for patients in the same age group for more than 5 consecutive months, allowing one month gap). Conclusion of ITI treatment was defined as when the amount of IU dispensed has fallen under 1.5 times of the median amount dispensed, or remaining in ITI treatment at the end of study period. Patients, who used by-pass agents to treat bleeding without undergoing ITI, were excluded. The total cost of ITI treatment was focused only on the cost of factor therapy. The treatment duration, cost, and IU consumption were further stratified by age groups and specific factor therapies. Results: Of the 2,302 hemophilia-A patients, 231 inhibitor patients were identified. A total of 72 patients used high dose short-acting factors for ITI treatment. No patient receiving long-acting factor was captured in the inhibitor population. Table 1 lists the patient counts, duration and cost of ITI treatment by age groups. Higher percentages of younger patient groups developed inhibitor compared with older age groups. About 14% of hemophilia-A patients aged 7 and under had ITI treatment. The older groups (aged 16 and older) had higher total costs as they required higher IU of factor therapy. The average duration of ITI treatment was 18.7 months, and the average total cost was $1,463,668 per patient regardless of the type of short acting factor therapy used. Conclusions: This US health insurance claim database study reflects that the current utilization of short acting factor for ITI treatment is associated with high cost burden. Products that decrease or eliminate inhibitor formation should be developed. Disclosures Su: Novartis Pharmaceuticals Corporation: Employment; Biogen: Employment, Equity Ownership. Zhou:Biogen: Employment, Equity Ownership. Buckley:Biogen: Employment, Equity Ownership. Rising:Biogen: Employment, Equity Ownership. Hou:Biogen: Employment, Equity Ownership. Jain:Biogen: Employment, Equity Ownership.
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Myint, Lin Min Min, and Chanon Warisarn. "Equalizer Design for Bit-Patterned Media Recording System Based on ISI and ITI Estimations by Cross Correlation Functions." Applied Mechanics and Materials 781 (August 2015): 223–26. http://dx.doi.org/10.4028/www.scientific.net/amm.781.223.
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Due to ultra-high density, a bit-patterned media recording (BPMR) system experiences two-dimensional (2D) interference--inter-symbol interference (ISI) and inter-track interference (ITI)--which degrades the overall performance of a recording systems. Therefore, we propose a novel single-track equalization and a single track detection that can perform these duties almost equally well. Our novel equalizer design uses ISI and ITI estimation schemes with the help of cross-correlation functions. The simulation result shows that our proposed method is able to achieve a significant performance gain over the one-dimensional (1D) equalization method and the conventional joint-track equalization, especially at higher recording density.
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Jiménez-Yuste, Víctor, Johannes Oldenburg, Savita Rangarajan, Roser Peiró, and Elena Santagostino. "Long-Term Follow-up of Hemophilia a Patients Who Previously Showed Complete or Partial Success in Immune Tolerance Induction Therapy with a Single Plasma-Derived FVIII/VWF Product: Long-Term ITI Study." Blood 126, no. 23 (December 3, 2015): 2282. http://dx.doi.org/10.1182/blood.v126.23.2282.2282.
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Abstract Introduction Inhibitor development against infused FVIII is a serious complication in hemophilia A that greatly increases the risk of developing major bleeding episodes. Immune tolerance induction (ITI) is the standard therapy for the management and eradication of inhibitors and return to effective FVIII therapy. Little evidence exists on the long-term status of patients who eradicated the inhibitor totally or partially by ITI. Therefore, the aim of this study is to investigate the clinical status and sustainability of tolerance in patients who succeeded on ITI therapy. Methods The Long-term ITI study was an international, multicenter, observational, retrospective study performed on hemophilia A patients who received primary or rescue ITI therapy using a single pdFVIII/VWF concentrate (Fanhdi®, Grifols, Spain) and who showed partial or total success in the Grifols-ITI study (Oldenburg J et al. Haemophilia 2014;20:83, Rangarajan S et al. J Thromb Haemost 2013;11 suppl 2;1081). In the G-ITI study, 60 patients from Germany, Italy and Spain showed a success rate of 85% and nine other G-ITI patients from UK obtained a 78% of ITI success. Demographics and clinical data relevant for the Long-term ITI study were extracted from the medical records of eligible patients. Primary endpoints were to describe the long-term status and post-ITI outcomes (including comorbidities, joint status, bleeding episodes, inhibitor relapses, venous access complications, hospitalizations and surgeries). Secondary endpoints included regular hemophilia therapy as well adjuvant and concomitant therapy used. Statistical analysis performed was descriptive. Results Forty-four out of the 57 eligible patients signed the informed consent and were included in the study. The mean follow up period after ITI success was 9.3 ±3.3 years (range: 2.1-17.7). At least one co-morbidity was reported in 17 (38.6%) patients, which included liver and lung cancer, hypertension, liver disease, hepatitis C and HIV infection. Twenty-one (47.7%) patients had a total of 37 affected -joints of which 5 patients had 2 affected joints, 1 patient had 3 affected joints and 3 patients had 4 affected joints. In 38 (86.4%) patients at least 1 bleeding episode was reported (mean annual bleeding rate: 1.0±1.2; range 0.1-3.9). A total of 330 bleeding episodes were described, of which 271 were treated with Fanhdi. Four (9.0%) patients had inhibitor relapse. Of those, 2 patients did not attempt rescue ITI because in one case the inhibitor (0.5 BU) disappeared after the next infusion with Fanhdi, and the other was considered of low titer (3.5 BU). The 2 patients who attempted rescue ITI (one under prophylaxis with Kogenate and the other treated on demand with Emoclot at the time of inhibitor relapse) were both successfully tolerized, one completely after 3.9 months of ITI with Fanhdi and the other partially after 9.1 months of ITI with Haemate P. Twenty venous access complications were reported in 10 (22.7%) patients. Thirty-nine surgical/invasive procedures were reported in 22 (50.0%) patients, 37 procedures requiring extra treatment with FVIII (Fanhdi), 25 of them for more than 3 days and 14 for more than 5 days. Hospitalizations reported were 79, 17 of them due to bleeding, 18 due to venous access complications, 33 due to surgical/invasive procedures, and 11 due to other reasons. Treatment product for hemophilia after ITI success was always Fanhdi in 29 (65.9%) patients, while 13 (29.5%) other patients were first treated with Fanhdi and then switched to other FVIII products, and 2 patients were immediately switched post-ITI to other FVIII products. The most common regimen used was prophylaxis (42 patients, 95.4%), and the most common treatment frequency was every 48 hours (16 patients, 36.4%). The FVIII dose ranged from 20 to 85 IU/Kg. Use of NSAIDs was reported for 6 patients and immunesuppressors for 5 patients. Conclusions After an average of more than 9 years of post-ITI success follow up of patients participating in the G-ITI Study, all of them continue with regular FVIII treatment for hemophilia. The few inhibitor relapses were successfully overcome. Disclosures Jiménez-Yuste: Baxter, Bayer, CSL-Behring, Grifols, Novo Nordisk, Octapharma and Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Oldenburg:Baxter, Bayer, Biogen Idec, Biotest, CSL-Behring, Grifols, Novo Nordisk, Octapharma, Swedish Orphan Biovitrum and Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rangarajan:Baxter, Grifols, Biotest and Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Peiró:Grifols: Employment. Santagostino:Bayer, Baxter, Pfizer, CSL Behring, Novo-Nordisk, Sobi/Biogen, Octapharma, Kedrion, Roche and Grifols: Consultancy, Honoraria, Research Funding, Speakers Bureau.
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Mankia, Kulveer, Maria-Antonietta D'Agostino, Emma Rowbotham, Elizabeth MA Hensor, Laura Hunt, Ingrid Möller, Misabel Miguel, et al. "MRI inflammation of the hand interosseous tendons occurs in anti-CCP-positive at-risk individuals and may precede the development of clinical synovitis." Annals of the Rheumatic Diseases 78, no. 6 (March 23, 2019): 781–86. http://dx.doi.org/10.1136/annrheumdis-2018-214331.
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Interosseous tendon inflammation (ITI) has been described in rheumatoid arthritis (RA). Whether ITI occurs in at-risk individuals before the onset of clinical synovitis is unknown.ObjectivesTo investigate, by MRI, ITI in anti-cyclic citrullinated peptide (CCP)-positive at-risk individuals (CCP +at risk) and to describe the anatomy, prevalence and clinical associations across the RA continuum.MethodsHand MRI was performed in 93 CCP + at risk, 47 early RA (ERA), 28 established ‘late’ RA (LRA) and 20 healthy controls (HC) and scored for ITI, flexor tenosynovitis (TSV) and RA MRI scoring at the metacarpophalangeal joints (MCPJs). Cadaveric and histological studies were performed to explore the anatomical basis for MRI ITI.ResultsThe proportion of subjects with ITI and the number of inflamed interosseous tendons (ITs) increased along the disease continuum (p<0.001): 19% of CCP +at risk, 49% of ERA and 57% of LRA had ≥1 IT inflamed . ITI was not found in any HC. ITI was more frequently identified in tender MCPJs compared with nontender MCPJs (28% vs 12%, respectively). No IT tenosynovial sheath was identified in cadavers on dissection or histological studies suggesting MRI findings represent peritendonitis. Dye studies indicated no communication between the IT and the joint.ConclusionsITI occurs in CCP + at-risk individuals and can precede the onset of clinical synovitis. The ITs may be important nonsynovial extracapsular targets in the development and progression of RA.
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Batsuli, Glaivy M., Karen L. Zimowski, Kelly Tickle, Shannon L. Meeks, and Robert F. Sidonio. "The Atlanta Protocol: Immune Tolerance Induction in Pediatric Patients with Hemophilia a and Inhibitors on Emicizumab." Blood 132, Supplement 1 (November 29, 2018): 634. http://dx.doi.org/10.1182/blood-2018-99-114249.
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Abstract Introduction: The formation of neutralizing anti-factor VIII (fVIII) antibodies, called inhibitors, is a challenging complication in hemophilia A care. While novel non-factor therapies significantly reduce bleeding symptoms in patients with hemophilia A and inhibitors, the absence of fVIII tolerance remains unchanged. Additionally, there are concerns regarding the hemostatic efficacy and safety of bypassing agents necessary for the management of breakthrough bleeds in patients with inhibitors on these novel therapies. Immune tolerance induction (ITI) remains the primary method for eradicating inhibitors and restoring the hemostatic response to fVIII. Here we report on the response to ITI in pediatric patients following initiation of the bispecific humanized monoclonal antibody Emicizumab. Methods: Patients between the ages of 1 - 11 years old with hemophilia A and an active inhibitor (≥0.6 Bethesda Units (BU)/mL) treated at the Emory Pediatric Hemophilia Treatment Center were included in this analysis. In general, ITI was initiated after four weekly loading doses of Emicizumab with standard or extended half-life recombinant (rfVIII) or plasma-derived (pdfVIII) fVIII at 100 units/kg three times per week. Factor choice was determined by the fVIII product used for the ITI attempt prior to initiation of Emicizumab or a standard half-life third generation rfVIII product if no prior ITI attempts. FVIII pharmacokinetics during ITI including the estimated fVIII half-life, fVIII incremental recovery of expected, and inhibitor titers were measured with chromogenic-based assays using bovine reagents. Bleeding symptoms and treatment regimens for bleeds/procedures were also monitored. Results: Eight patients are currently receiving ITI according to this Atlanta Protocol. Details regarding this cohort are outlined in Table 1. Three of the 8 patients required central venous access for ITI fVIII infusions. These eight patients have historical peak inhibitor titers, defined as the highest inhibitor titer prior to this ITI regimen, ranging from 2.0 - 198 BU/mL. Four patients have just recently started ITI. The other 4 patients (patients 1, 2, 4, and 5) have been treated with Emicizumab and ITI for a median duration of 15 weeks (range 13-18 weeks). Two of the 4 patients are on ITI with a standard half-life third generation rfVIII product, 1 is on a standard half-life third generation B domain deleted (BDD) rfVIII product, and 1 is on an extended half-life (EHL) rfVIII-Fc fusion product. Their last measured inhibitor titers after initiation of ITI range from 0.3 - 3.7 chromogenic BU (CBU). All inhibitor titers declined with the start of ITI, and none of the 4 patients experienced an amnestic response (Figure 1). The fVIII incremental recovery improved in 3 of the 4 patients from a median of 30% of expected (range 17-69%) prior to Emicizumab with ITI to 85% of expected (range 67-85%) at the last clinical evaluation. The 1 patient remaining has an fVIII incremental recovery <10% of expected at the last clinical evaluation. Only one patient has required treatment with a single dose of recombinant activated factor VII (rfVIIa) for a right knee hemarthrosis during ITI without complication. There were 3 additional mild bleeding symptoms in 2 patients that did not require intervention including 1 trauma-induced forehead hematoma that self-resolved and 2 episodes self-resolving epistaxis lasting <5 minutes. Two of the 4 patients reported no bleeding symptoms. There were no episodes of thrombosis or thrombotic microangiopathy. Conclusions: This is the first report detailing the Atlanta Protocol for ITI in hemophilia A patients with inhibitors receiving Emicizumab prophylaxis. Although early, these results suggest that ITI can be safely administered in these patients and is able to achieve continued improvement in clinical indicators of tolerance. Disclosures Batsuli: Bayer: Other: Advisory Board; Genentech: Other: Advisory Board; Octapharma: Other: Advisory Board. Zimowski:National Hemophilia Association/Shire: Other: Funding for clinical fellowship in Hemostasis/Thrombosis. Meeks:Bioverativ: Other: Advisory Board; Bayer: Other: Advisory Board; CSL Behring: Other: Advisory Board; Catalyst Biosciences: Other: Advisory Board; Genentech: Other: Advisory Board; HEMA Biologics: Other: Advisory Board; Shire: Other: Advisory Board; Pfizer: Research Funding. Sidonio:Genentech: Other: Advisory Board, Research Funding; Bioverativ: Other: Advisory Board, Research Funding; Biomarin: Other: Advisory Board; Novo Nordisk: Other: Advisory Board; Octapharma: Other: Advisory Board; Grifols: Other: Advisory Board, Research Funding; Uniqure: Other: Advisory Board; CSL Behring: Other: Advisory Board; Shire: Other: Advisory Board, Research Funding; Kedrion: Research Funding.
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Belletrutti, Mark J., Roxanne Seiferman-Nelson, and Bonny Granfield. "A Case Series Evaluating the Use of a Von Willebrand Factor/Factor VIII Concentrate (Wilate®) for Immune Tolerance Induction (ITI) in Children with Severe Factor VIII Deficiency." Blood 124, no. 21 (December 6, 2014): 5050. http://dx.doi.org/10.1182/blood.v124.21.5050.5050.
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Abstract Introduction: Development of circulating anti-factor VIII antibodies (inhbitors) is the most serious and challenging complication in the treatment of hemophilia A. Up to 38% of hemophilia patients develop inhibitors with recombinant FVIII (rFVIII) products (Gouw et al. N Engl J Med. 2013; 368:231-239). The presence of inhibitors leads to an increased risk of bleeding, poor physical functioning and quality of life (Benson et al., Eur. J. Haematol. 2012; 88:371-379). Immune tolerance induction (ITI) is the most common method for eliminating inhibitors, historically performed with high dose, and prolonged treatment with plasma-derived (pd), or recombinant FVIII (rFVIII) concentrates. Although ITI for the eradication of inhibitors has become standard of care for hemophilia patients the therapeutic superiority of a particular product type (rFVIII vs. pd-FVIII) has not yet been conclusively demonstrated. In accordance with its role in stabilizing FVIII, the presence of von Willebrand factor (VWF) in pd-FVIII concentrates has been shown to improve the outcome of ITI. Wilate® (Octapharma) is a high-purity human plasma derived complex containing two proteins (VWF and FVIII) in a 1:1 ratio. The aim of this study was to determine the effectiveness of Wilate for primary ITI therapy for six patients with severe hemophilia A. Patients and Methods: The case history for six pediatric hemophilia A patients prior to and during primary Wilate ITI was reviewed. For 5/6 patients, inhibitors developed during rFVIII factor replacement therapy. For the sixth patient, inhibitors were detected at the time of hemophilia diagnosis. ITI began once patients achieved an inhibitor titer of less than 10 BU/mL. The ITI dosing regimen ranged from 50-60 IU/Kg of Wilate three times per week to 200 IU/Kg once daily. Inhibitor titers were measured regularly, prior to and during ITI using the Nijmegen-Bethesda assay. The number of port-a-cath infections and bleeding episodes were also monitored. ITI success was defined as: an undetectable inhibitor level (<0.6 BU/mL), FVIII plasma recovery ≥ 66% of predicted, and FVIII half-life ≥6 hours. Results: Wilate ITI was well tolerated in all patients, with no product-related adverse events. All patients had a port-a-cath device inserted for Wilate injections. Two port-a-cath infections occurred during ITI. Five of six patients had poor prognostic factors for ITI outcome. These poor prognostic factors included a high-risk FVIII gene mutation, historical peak inhibitor titer greater than 50 BU/mL, age of ITI onset greater than 6 years, and ITI onset more than 12 months from inhibitor development. The frequency of these poor prognostic factors varied amongst the patients: 1 patient had 4, 1 patient had 2, and 3 patients presented with 1 poor prognostic factor. Despite the presence of these high-risk factors, Wilate was successful at reducing the inhibitor titers to undetectable levels in all patients. Furthermore, inhibitor titers have remained low or undetectable without significant spikes for the duration of treatment. Patient plasma recovery and FVIII half-life results have also indicated that patients are progressing towards successful ITI. Importantly, for 6/6 patients (including 3 patients who had previously been treated with Anti-Inhibitor Coagulant Complex (FEIBA) prophylaxis therapy) - Wilate therapy was successful at reducing the number of bleeding episodes allowing for the cessation of FEIBA prophylaxis. Since commencing Wilate ITI, 6/6 patients have not reported any major bleeding episodes. The improved clinical outcome was perceived by the patients as an improved well-being, and quality of life. Conclusion: Wilate ITI was found to be well tolerated, safe, and successful at reducing inhibitor levels to below the detectable range for six severe hemophilia A patients. Patients experienced no treatment related adverse events, had a low rate of port-a-cath infections, and did not present with any major bleeding episodes while on Wilate ITI. In light of the 3-5 fold increase in overall treatment costs of immune tolerance induction, careful consideration should be given to choice of product (rFVIII versus pd-FVIII) – especially for patients at high-risk of failure. (Dimichele et al. Haemophilia 2004: 10 Suppl 4;140-145). The present data suggest that Wilate, a pd-FVIII product, is effective in managing patients with inhibitors. Disclosures Belletrutti: Baxter Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring Canada: Honoraria.
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Kowalska, Iwona. "Integrated Territorial Investments in the Formula of Cohesion Policy 2014 - 2020." Economic and Regional Studies / Studia Ekonomiczne i Regionalne 10, no. 1 (March 1, 2017): 36–50. http://dx.doi.org/10.2478/ers-2017-0003.
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Abstract Subject and purpose of work: EU regional policy aims to increase the economic and social cohesion of the Member States. For the programming period of 2014 - 2020 a new tool has been planned, which will contribute to the effective implementation of the cohesion policy - Integrated Territorial Investment (ITI). The aim of this article is to determine whether the direction of measures arising from the assumptions of the cohesion policy 2014 - 2020, implemented in the ITI strategy, addresses actual problems in the area covered by the ITI strategy (on the example of Kalisz-Ostrów Agglomeration - KOA). Materials and methods: The study was based on the analysis and synthesis of EU and Polish regulatory provisions on the cohesion policy 2014 - 2020, data on financial allocation for the implementation of the ITI and literature on the subject of EU regional policy. Results: The direction of measures arising from the assumptions of the cohesion policy 2014 - 2020 in the ITI strategy addresses real problems in the development of the area covered by the KOA strategy. EU funds have been planned for: promoting entrepreneurship; promoting low-carbon strategies; the development of an educated society and investments in modern infrastructure. Conclusions: Solving the problems of the areas covered by the ITI strategy will depend on the realization of the development goals. Therefore, the synergy of conditions associated with the transformation of the postulated stage into the executive stage of the cohesion policy under ITI is necessary. This synergy is associated with both the quality of human capital and the amount of financial resources as well as the competences of those involved in the implementation of the ITI concept.
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Morgan, David L., and Andreea Nica. "Iterative Thematic Inquiry: A New Method for Analyzing Qualitative Data." International Journal of Qualitative Methods 19 (January 1, 2020): 160940692095511. http://dx.doi.org/10.1177/1609406920955118.
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Because themes play such a central role in the presentation of qualitative research results, we propose a new method, Iterative Thematic Inquiry (ITI), that is guided by the development of themes. We begin by describing how ITI uses pragmatism as a theoretical basis for linking beliefs, in the form of preconceptions, to actions, in the form of data collection and analysis. Next, we present the four basic phases that ITI relies on: assessing beliefs; building new beliefs through encounters with data; listing tentative themes; and, evaluating themes through coding. We also review several notable differences between ITI and existing methods for qualitative data analysis, such as thematic analysis, grounded theory, and qualitative content analysis. The use of ITI is then illustrated through its application in a study of exiters from fundamentalist religions. Overall, the two most notable features of ITI are that it begins the development of themes as early as possible, through an assessment of initial preconceptions, and that it relies on writing rather than coding, by using a continual revision of tentative results as the primary procedure for generating a final set of themes.
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Jain, Paras. "INCREASING JOB PROSPECTS IN THE FIELD OF INDUSTRIAL EDUCATION." International Journal of Research -GRANTHAALAYAH 5, no. 6 (June 30, 2017): 255–60. http://dx.doi.org/10.29121/granthaalayah.v5.i6.2017.2024.
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The students are turning down the engineering courses which result in lakhs of seats remaining vacant every year whereas the trend of ITI education is increasing. The reason behind the huge demand for ITI students as there is a great demand from industry for electrician, fitter, machinist, turners and mechanics in diesel as well as in motor. All these courses are offered at ITI. A few years back, the situation was different as students were attracted to engineering and management courses and very few people used to join ITI branch. Due to economical shut down the opportunities in Engineering and Management branches saw a dip.
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Thom, K., J. Falger, I. Pabinger, and C. Male. "Spontaneous disappearance of high titre factor VIII inhibitor 15 years after unsuccessful ITI." Hämostaseologie 29, no. 02 (2009): 149–50. http://dx.doi.org/10.1055/s-0037-1617023.
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SummaryThe most serious complication of haemophilia A is development of a high-titre factor VIII (FVIII) inhibitor which renders the patient unresponsive to FVIII replacement. Bleeding complications can only be controlled using FVIII-inhibitor bypassing agents but their effect is less certain. The ultimate goal is to eliminate the inhibitor by immune tolerance induction therapy (ITI) using daily high doses of FVIII. The success rate of ITI using various protocols is between 56 and 79% (1, 2). If ITI is unsuccessful, the inhibitor usually persists throughout life.We report on a patient with a high titre FVIII inhibitor that persisted after ITI but spontaneously disappeared 15 years later.
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Kovintavewat, Piya. "Investigation of Graph-Based Detection in Iterative Decoding for Bit-Patterned Media Recording." Advanced Materials Research 979 (June 2014): 58–61. http://dx.doi.org/10.4028/www.scientific.net/amr.979.58.
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High-density bit-patterned media recording (BPMR) can be obtained by reducing the spacing between data bitislands in both the along-and across-track directions, thus leading to severe intersymbol interference (ISI) and intertrack interference (ITI) because of small bit and track pitches, respectively. Here, we propose to use the graph-based detector, instead of the trellis-based detector, in iterative decoding to combat the ISI and the ITI for a multi-head multi-track BPMR system. Specifically, the readback signal is sent to the graph-based detector before iteratively exchanging the soft information with a decoder. Experimental results indicate that at low to moderate complexity, the proposed scheme outperforms the existing schemes, especially at high recording density.
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Rezaieyazdi, Zahra, and Hassan Mansouritorghabeh. "Clinical Care of Bone Health in Patients on the Immune Tolerance Induction’s Protocols With an Immunosuppressive Agent for Inhibitor Eradication in Hemophilia." Clinical and Applied Thrombosis/Hemostasis 26 (January 1, 2020): 107602962091395. http://dx.doi.org/10.1177/1076029620913951.
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Nowadays, the development of factor VIII and IX inhibitors in patients with hemophilia is considered as the most challenging in the treatment of hemophilia. Immune tolerance induction (ITI) therapy is an approach for eradication of inhibitors. Some ITI protocols are routinely in use for the eradication of inhibitors in patients with hemophilia. Moreover, such a therapeutic regimen may facilitate the tendency to reduced bone density in patients with inhibitor. This study scheduled to investigate whether that predisposing role of ITI protocols with an immunosuppressive agent has considered or not. By a literature review, published ITI protocols in hemophilia with inhibitors were evaluated. Among them, 51 papers found and studied thoroughly. None of them had performed the bone mineral examination in patients with hemophilia and inhibitor under treatment. Since there are 2 coexisting facilitating factors in these protocols, considering the bone mineral density study for patients with inhibitor who are undergoing ITI protocols with an immunosuppressive agent is recommended.
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Escuriola Ettingshausen, Carmen, and Robert F. Sidonio. "Design of an international investigator-initiated study on MOdern Treatment of Inhibitor-positiVe pATiEnts with haemophilia A (MOTIVATE)." Therapeutic Advances in Hematology 12 (January 2021): 204062072110324. http://dx.doi.org/10.1177/20406207211032452.
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Background: Inhibitor development is the most serious treatment-related complication of replacement coagulation factor VIII (FVIII) therapy for patients with haemophilia A. Immune tolerance induction (ITI), which involves intensive and prolonged treatment with plasma-derived or recombinant FVIII, is the only clinically proven strategy for eradication of inhibitors. The bispecific antibody emicizumab is approved for use in patients with and without inhibitors to prevent bleeding but does not eliminate inhibitors. MOTIVATE ( www.motivate-study.com ) aims to capture different approaches to the treatment and management of patients with haemophilia A and inhibitors, document current ITI approaches from real-world clinical experience, and evaluate the efficacy and safety of ITI, emicizumab prophylaxis and ITI with emicizumab prophylaxis. Methods: The investigator-initiated MOTIVATE study [ClinicalTrials.gov identifier: NCT04023019; EudraCT 2019-003427-38] will investigate in real-life clinical practice the management of patients with haemophilia A of any severity who have developed inhibitors to FVIII. All treatment is at the investigator’s discretion. The following treatment approaches will be evaluated: Group 1 – ITI with Nuwiq®, octanate® or wilate® and aPCC/rFVIIa if needed to treat bleeding episodes (BEs) or during surgery or for prophylaxis; Group 2 – ITI with Nuwiq®, octanate® or wilate® and emicizumab prophylaxis and aPCC/rFVIIa if needed to treat BEs or during surgery; Group 3 – routine prophylaxis with emicizumab, aPCC or rFVIIa without ITI and aPCC/rFVIIa if needed to treat BEs or during surgery. Patients will not be randomised to a treatment group and may change groups during the study. Conclusions: It is planned to enrol 120 patients who will be followed for up to 5 years. Optional sub-studies will explore factors that may influence ITI results as well as the impact of different treatment approaches on important aspects of patient health, including joint and bone health and the risk of thrombotic events.
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Arhangelʼskii, Alexander, Yasunao Hattori, and Jan van Mill. "Professor Jun-iti Nagata (1925–2007)." Topology and its Applications 159, no. 6 (April 2012): 1497. http://dx.doi.org/10.1016/j.topol.2011.12.022.
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Minno, G. D., E. Santagostino, K. Pratt, and C. Königs. "New predictive approaches for ITI treatment." Haemophilia 20 (June 26, 2014): 27–43. http://dx.doi.org/10.1111/hae.12467.
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