Haemophilia Outcomes Research Articles

Primary prophylaxis implementation and long-term joint outcomes in Swedish haemophilia A patients.

Primary prophylaxis is the gold standard in severe haemophilia A (SHA) but time to escalate the prophylaxis regimen varies. Assess prophylaxis implementation and long-term joint health outcomes in SHA with primary prophylaxis. Adult male patients born after 1980, with SHA on primary prophylaxis, started before the age of 3 years and second joint bleed, and no history of FVIII inhibitors, were enrolled. Repeated joint-health examinations were performed with HJHS or HEAD-US; VERITAS-PRO assessed adherence. Thirty patients were enrolled with, at inclusion, median age 33.5 years, annualized bleed rate and joint bleed rate 0, and FVIII consumption 4232IU/kg/year, respectively. The median age was 1.2 years, at prophylaxis start once weekly with a median FVIII dose of 47.7 IU/kg, and 1.7 years, by the time escalation to a final regimen had occurred, with a median infusion frequency of thrice weekly and FVIII dose 41.7 IU/kg, respectively. Older age correlated with later transition to escalated prophylaxis (p<.001). Longer time to escalated prophylaxis correlated to more bleeds (p<.001). Median HJHS increased slowly, reaching 4 at 35-40 years. HJHS at 15-20 years correlated with higher HJHS afterwards. Median total HEAD-US score was 1 and correlated with HJHS (p<.001). Median VERITAS-PRO score was 36, indicating good treatment adherence. Primary prophylaxis is effective but does not completely prevent the gradual development of arthropathy in SHA. Joint assessments with HJHS should start at an early age, as they correlate with arthropathy in later life. Prophylaxis escalation should proceed expeditiously to prevent bleeds.

Patients’ and health care providers’ perspectives on quality of hemophilia care in the Netherlands: a questionnaire and interview study

BackgroundHemophilia care has improved greatly because of advances in treatment options and comprehensive care. In-depth insight into the perspectives of persons with hemophilia and health care providers on their care may provide targets for further improvements. ObjectivesTo assess satisfaction of the hemophilia population with their care, to explore factors determining care satisfaction, and to identify areas for potential health care improvements, including digital health tools. MethodsFirst, to assess care satisfaction and factors determining satisfaction and health care improvements, data from a nationwide, cross-sectional questionnaire among 867 adult and pediatric Dutch persons with hemophilia A or B were analyzed. This included the Hemophilia Patient Satisfaction Scale questionnaire, Canadian Hemophilia Outcomes Kids’ Life Assessment Tool satisfaction questions, a visual analog scale satisfaction score, and open questions. Second, to further explore factors determining satisfaction and health care improvements, semistructured interviews were conducted with 19 persons with hemophilia or their parents and 18 health care providers. ResultsHigh care satisfaction was found, with an overall median Hemophilia Patient Satisfaction Scale score of 12 (IQR, 6-21). Participants in the interviews reported that patient-professional interactions, availability of care, and coordination of care were major factors determining satisfaction. Suggested health care improvements included improved information provision and coordination of care, especially shared care with professionals not working within comprehensive care centers. Participants suggested that digital health tools could aid in this. ConclusionSatisfaction with hemophilia care is high among persons with hemophilia in the Netherlands, although several potential improvements have been identified. Accentuating these is especially relevant in the current era of treatment innovations, in which we might focus less on other aspects of care.

Early immune tolerance induction is a unique predictor of favorable outcomes in hemophilia A children with intron 22 inversion and high-responding inhibitors

BackgroundThe predictors of immune tolerance induction (ITI) outcomes in hemophilia A (HA) patients with the same F8 genetic background have not yet been evaluated, although the F8 genotype is strongly associated with ITI response. This study aims to explore the predictors of ITI outcomes in the same F8 genetic background by focusing on intron 22 inversion (Inv22) patients with high-responding inhibitors. MethodsHA children with Inv22 and high-responding inhibitors who received low-dose ITI therapy over 24 months were included in this study. ITI outcomes were centrally assessed at the 24th month of treatment. The predictive ability of clinical variables to identify ITI success was determined using the receiver operating characteristic (ROC) curve, and the predictor of ITI outcomes was analyzed on the multivariable Cox model. ResultsAmong the 32 patients investigated, 23 (71.9 %) achieved success. In univariate analysis, interval time from inhibitor diagnosis to ITI start (interval-time) was significantly associated with ITI success (P = 0.001); however, inhibitor titers showed no significance (P > 0.05). The interval-time demonstrated a good predictive value for ITI success with the area under the ROC curve of 0.855 (P = 0.002), and the cutoff value was 25.8 months (sensitivity, 87.0 %; specificity, 88.9 %). In the multivariable Cox model which considered success rate and time to success, interval-time was the only independent predictor (<25.8 months vs. ≥25.8 months, P = 0.002). ConclusionsThe interval-time was first identified as a unique predictor of ITI outcomes in HA patients with high-responding inhibitors under the same F8 genetic background (Inv22). An interval-time of <25.8 months was associated with increased ITI success and reduced time to success.

Shorter Time Interval from Inhibitor Detection to Starting Low-Dose Immune Tolerance Induction Therapy Is Associated with Better Inhibitor Eradication Outcomes in Severe Hemophilia a Children with High-Titer Inhibitors in China

Background Shorter time from inhibitor detection to immune tolerance induction (ITI) start (interval-time) might play a critical role in ITI outcomes for severe Hemophilia A (SHA) children with high-titer inhibitors. However, the acceptable interval-time hasn't well been confirmed yet, especially for treatment-delay patients undergoing low-dose ITI therapy in China. Aim To explore the interval-time in Chinese SHA children with high-titer inhibitors, undergoing low-dose ITI strategy with outcomes. Methods A retrospective study in single center, 47 Chinese SHA children with high-titer inhibitors [> 10 Bethesda Unite (BU)/ml] undergoing low-dose ITI strategy with more than 24 months follow-up period. ITI outcomes were evaluated at the 24th month of treatment. The association between interval-time and outcomes was analyzed. Success was defined as negative inhibitor titer and FVIII recovery ≥ 66% of expected. The predictive ability of interval-time to identify ITI success was determined using receiver operating characteristic (ROC) curve. Results Forty-seven cases enrolled in this study, the median age of inhibitor detection was 2.4 (range, 0.6, 10.4) years and the interval-time was 5.8 (0, 61.1) months with the peak inhibitor titer of 55.8 (10.1, 512.0) BU/ml, 42.6% (20/47) using ITI-alone and 57.4% using ITI combined with Rituximab based immunosuppression (IS). Over a follow-up time of 31.3 (24.0, 69.5) months, 34 patients (72.3%) achieved success with the time to success of 11.0 (3.1, 23.0) months. (Table 1) The interval-time in ITI success group was shorter than in non-success group significantly [2.8 (0. 59.1) vs 28.1 (0, 61.1) months, p = 0.04]. Multivariate logistic regression model demonstrated the peak inhibitor titer and the interval-time were two independent predictors of ITI success (P < 0.05). The area under ROC curve (AUC) was 0.701 (95%CI: 0.507 - 0.896, p = 0.034) and reliable cut-off value of 22.3 months could be calculated in the prediction of ITI outcomes with the sensitivity of 0.853 and the specificity of 0.615. (Figure 1) Univariable linear regression demonstrated the relationship between the time to success and the interval-time, the equation y=0.1552*x+9.285 (R2 = 0.2252, p = 0.005). ROC curve describing the accuracy of the predictor of early-success (ITI time < 12 months); the AUC was 0.704 (95%CI: 0.521 - 0.887, p = 0.049); the cut-off value was 9.4 months with the sensitivity of 0.824 and the specificity of 0.533. (Figure 1) Conclusions Our study shows that shorter interval-time was associated with better inhibitor eradication outcomes in terms of ITI success rate and time to success in our SHA children with high-titer inhibitors (> 10BU/ml) undergoing low-dose ITI strategy. We showed that an interval-time of ≤ 22.3 months was associated with higher ITI success rate. And an interval-time of ≤ 9.4 months was related to shorter time to success. Our study on low-dose ITI in a developing country setting support the findings using higher dose ITI in developed countries setting that ITI should be started as soon as possible after inhibitor development. However, stronger evidence is needed from further clinical studies with better study design. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Postoperative bleeding adversely affects total knee arthroplasty outcomes in hemophilia

BackgroundHemophilic arthropathy can result in severe degenerative arthritis and functional limitations in the knees of relatively young patients. Total knee arthroplasty (TKA) provides pain relief and gain of function in advanced-stage hemophilic arthropathy cases. However, little is known about the long-term effects of early major postoperative bleeding (MPOB) in people with hemophilia (PWH). The aim of this study was to evaluate the effects of early MPOB on the final functional outcome, complications, and implant survival of TKA in a single-center hemophilia cohort. MethodPWH who underwent TKA between 1998 and 2019 in a single center were reviewed. Demographic data, clinical data, and radiographic images were evaluated. Hospital for Special Surgery (HSS), Knee Society Score (KSS), and Knee Society Function Score (KSS-F) scores were used to determine function. Patients with early bleeding complications (wound dehiscence, ecchymosis, hemarthrosis, hematoma formation, prolonged or recurrent bleeding attacks) were defined as the bleeding group. Patients who did not experience these complications were assigned to the control group. The bleeding group was compared with controls. Survival of the primary arthroplasty was analyzed by Kaplan–Meier curves. ResultsForty-five TKAs in 29 patients were included in the study. TKA led to an increase in the mean range of motion from 46.08° to 84.59° (P < 0.01). HSS scores increased from 48.33 preoperatively to 82.67 postoperatively (P < 0.01). There were improvements in both KSS and KSS-F scores from 34.22 and 53.3 preoperatively to 82.00 and 84.63 (P < 0.01), respectively. Ten patients (10 TKAs) (34%) experienced major bleeding during the postoperative period. Six of these patients had moderate hemophilia, and four had severe hemophilia. Three of these patients had hemarthroses (10.2%), one patient had a hematoma (3.4%), one patient had hemorrhagic bullae formation (3.4%), and five had excessive/prolonged bleeding from the wound (17%). The bleeding group (34%) had significantly worse HSS (63.78 vs 92.75, P < 0.001), KSS (61.78 vs 93.25, P < 0.001), and KSS-F (60.71 vs 96.25, P = 0.005) scores compared with controls. Preoperative and postoperative flexion contractures were positively correlated (+0.33, P = 0.003). One of the patients with postoperative hemarthrosis also had an accompanying transient common peroneal nerve palsy, and one patient (3.4%) had a periprosthetic fracture. Three knees (6.6%), two of whom were in the bleeding group, developed periprosthetic infections. Four knees (8.8%) in three patients underwent revision surgery, and two knees (4.4%) ended up in arthrodeses. Kaplan–Meier analysis revealed a mean survival duration of 17.04 years for the bleeding group and 22.15 years for the control group (P = 0.83). Survival rates were 80.0% for the bleeding group and 96.4% for the control group (P = 0.83). ConclusionsIn this study, MPOB after TKA in PWH was common and led to significantly worse function. MPOB after TKA in PWH was associated with a higher rate of complications and lower survival rates, although the differences were not statistically significant. Efforts must be made to avoid MPOB after TKA in PWH.

PREDICT: A Multicenter, Prospective, Open-Label, Clinical Study Using a New Risk Score Approach to Assess the Most Appropriate Prophylaxis Regimen to Reach Favorable Outcomes in Hemophilia A, When Switching from Standard-Half-Life Products to Damoctocog Alfa Pegol

PREDICT: A Multicenter, Prospective, Open-Label, Clinical Study Using a New Risk Score Approach to Assess the Most Appropriate Prophylaxis Regimen to Reach Favorable Outcomes in Hemophilia A, When Switching from Standard-Half-Life Products to Damoctocog Alfa Pegol

Emicizumab Outcomes in Hemophilia A Using Real-World Data from the Canadian Hemophilia Bleeding Disorder Registry

Background: The Canadian Hemophilia Bleeding Disorders Registry (CBDR) is a clinical database including data from all Canadian Hemophilia Treatment Centers (HTCs) to assist in the management of hemophilia and other bleeding disorders. The CBDR launched on July 1, 2015 and integrates the data entry platform for patients, myCBDR, allowing direct entry of treatments, bleeding events, and other patient reported outcomes (PRO) data. Health Canada approved emicizumab in August 2018 for the treatment of persons with hemophilia A (PwHA) with factor (F)VIII inhibitors, and for PwHA without FVIII inhibitors in 2019, enabling some patients without FVIII inhibitors to be provided compassionate access beginning November 2019.Our aim for this analysis was to use the CBDR data to describe the demographics of the emicizumab-treated PwHA population and assess its effectiveness, safety, treatment patterns, and the impact on disease burden.Methods: De-identified data were extracted from the CBDR database for all registered PwHA who had received emicizumab at least once up to December 31, 2020. Disease severity is defined by the level of endogenous clotting FVIII activity. Effectiveness outcomes include number of patients (%) with zero treated bleeds, joint bleeds, and spontaneous bleeds; annualized bleeding rates (ABR) for any bleeds and treated bleeds; Hemophilia Joint Health Score (HJHS); Patient Reported Outcomes Burdens and Experiences (PROBE); and EQ-5D-5L index and visual analog scale (VAS). ABRs were calculated as (total number of bleeds/duration of follow-up [days])*365.25. All analyses were performed based on the observed values, without imputation. This study was approved by the research ethics board of McMaster University and other participating centers, and abides by the guiding principles of the Declaration of Helsinki.Results: 73 PwHA who received emicizumab at least once up to December 31, 2020 were identified. Demographic characteristics, severity, inhibitor status, and treatments are described in Table 1. Median (IQR) age for the entire cohort was 19.7 (10.0, 40.6) years with 45.2% ≤18 years. There were 64 PwHA with severe disease, 7 with moderate disease and 2 with mild disease; both cases with mild disease had current FVIII inhibitors. 49 PwHA had current FVIII inhibitors, 12 had a history of FVIII inhibitors, and 12 had no FVIII inhibitors. 5/73 (6.8%) received immune tolerance induction (ITI) treatment while on emicizumab. Two cases of rash (allergic or acute reactions) were reported (2/73, 2.7%) of which one (reported 6 days after administration) was possibly related to emicizumab according to the reporting HTC. No thromboembolisms or thrombotic microangiopathies were observed.Median ABR (IQR) for the entire study population was 0.0 (0, 0) and 59/73 (80.8%) had no recorded bleeds. In the 14/73 (19.2%) with recorded bleeds, median ABR (IQR) was 2 (1, 3); 8 of those 14 had joint bleeds and 7 had spontaneous bleeds. HJHS was recorded for 23, PROBE Score for 9, EQ-5D-5L for 9 and EQ-5D-5L VAS for 4 PwHA (Table 2).Conclusions: The Canadian population treated with emicizumab had severe disease and current or historical FVIII inhibitors. The bleed outcomes are consistent with earlier publications, showing 80.8% had no recorded bleeds. The CBDR will allow for longitudinal follow-up of this patient population. Our results can inform healthcare practitioners and regulatory authorities on the real-world safety and effectiveness outcomes of emicizumab in PwHA with and without FVIII inhibitors. [Display omitted] DisclosuresPoon: Roche: Honoraria; Pfizer: Honoraria; Novo Nordisk: Honoraria; Bioverativ/Sanofi: Honoraria; CSL-Behring: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; University of Calgary: Current Employment; Takeda: Honoraria. Lee: Roche: Honoraria; Pfizer: Honoraria, Speakers Bureau; Novo Nordisk: Honoraria, Speakers Bureau; CSL Behring: Honoraria; Biovertiv/Sanofi: Honoraria, Research Funding; Bayer: Research Funding, Speakers Bureau; Takeda: Honoraria. Keepanasseril: McMaster University: Current Employment; NovoNordisk Canada: Consultancy. Ibrahim: McMaster University: Current Employment. Nissen: F. Hoffmann-La Roche Ltd: Current Employment, Current holder of stock options in a privately-held company; Novartis: Consultancy; Actelion: Consultancy. Sanabria: F. Hoffmann-La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Santos: F. Hoffmann-La Roche Ltd.: Current Employment; Roche: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Baxter: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Takeda: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Iorio: McMaster University: Current Employment; Bayer (funding to the institution): Research Funding; BioMarin (funding to the institution): Research Funding; NovoNordisk (funding to the institution): Research Funding; Octapharma (funding to the institution): Research Funding; Pfizer (funding to the institution): Research Funding; Roche (funding to the institution): Research Funding; Sanofi (funding to the institution): Research Funding; Sobi (funding to the institution): Research Funding; Takeda (funding to the institution): Research Funding.

Spk-8011: Preliminary Results from a Phase 1/2 Dose Escalation Trial of an Investigational AAV-Mediated Gene Therapy for Hemophilia a

▪Background: Hemophilia A therapy is currently based on intravenous administration of exogenous FVIII protein either on demand to treat bleeding or prophylactically to prevent bleeding. Prophylaxis has revolutionized health outcomes in hemophilia by significantly reducing the frequency of bleeding, preventing the development of arthropathy, improving health-related quality of life and enabling affected individuals to increase participation in physical activities enhancing psychosocial outcomes. The burden of repetitive infusions and the time required to perform them may be partially responsible for a strikingly high rate of non-compliance. A recent multi-center study revealed only 43% of individuals with hemophilia adhered to their prophylactic regimen (Schrijvers 2016) putting improved outcomes in jeopardy. Recombinant adeno-associated viral (rAAV) vectors have been in development for >25 years. No major safety concerns have emerged in the >100 previously conducted rAAV gene transfer clinical trials. A single administration of rAAV vector encoding human coagulation F8 or F9 gene may result in sustained expression of therapeutic factor activity levels sufficient to reduce or eliminate the need for exogenous factor infusions (Pasi 2017; George 2017).Objectives: 1) To safely obtain consistent, predictable and sustained FVIII activity (FVIII:C) >12% adequate to prevent spontaneous bleeding without the need for prophylactic FVIII infusions, manipulation of normal coagulant or anticoagulant pathways or increased thrombotic risk; 2) Minimize a dose-dependent capsid immune response by using the lowest possible vector dose that produces clinically relevant improvements in FVIII:C.Methods: SPK-8011 is a recombinant AAV vector composed of a bio-engineered capsid (AAV-Spark200) with liver specific enhanced tropism and a codon-optimized expression cassette that encodes the SQ-FVIII variant of a B-domain-deleted (BDD) human F8 gene (Lind 1995). This Phase 1/2 study is an open-label, non-randomized, dose-escalation study of SPK-8011 with a starting dose of 5x1011 vg/kg. The study is evaluating the safety, tolerability and efficacy of a single intravenous infusion of SPK-8011 in up to 18 adult men with hemophilia A (endogenous FVIII activity levels ≤2% of normal). Data on bleeding and factor infusions in the year prior to enrollment are retrospectively compiled. Laboratory values, bleeding frequency, and FVIII consumption are prospectively evaluated following vector infusion.Results: As of 8/1/17, we infused 3 subjects with SPK-8011, two at a dose of 5 x1011 vg/kg and one at a dose of 1x1012 vg/kg. Infused subjects were adult males ages 34-52 years with baseline FVIII:C <1% and Spark200 NAb titer of <1:1. The two participants infused with a vector dose of 5x1011 vg/kg have FVIII:C of 11% and 14% at 23 and 12 weeks, respectively, after infusion (Figure 1). Subject 3 is two-weeks post infusion with 1x1012 vg/kg and has not yet reached peak steady-state transgene expression. No subjects have experienced hepatic transaminase elevation, a decline in FVIII:C or required steroid intervention. ELISPOT reactivity to Spark200 capsid peptides revealed a transient low-level positivity to two different AAV peptides at week 3 and 4 in the second subject. By week 5 all ELISPOTs were negative. The positive ELISPOTs were not associated with a decrease in FVIII:C or increase in hepatic transaminases. No participants have developed a FVIII inhibitor. All subjects have discontinued FVIII prophylaxis. In the cumulative 258 days of follow up, there have been no vector or procedure-related adverse events.Conclusion: Our preliminary results from the ongoing Phase 1/2 study of SPK-8011 demonstrate FVIII:C levels in the range of 12%, sufficient in the trial to date to prevent spontaneous bleeding without the need for exogenous factor infusions, and with no evidence of a cellular immune response to transduced hepatocytes. Therapeutic transgene-derived FVIII:C was achieved at a 120-fold lower vector dose than that previously reported (Pasi 2017) in another ongoing AAV gene transfer trial for hemophilia A. Transduction in the participant dosed at 1x1012 vg/kg tracks at higher levels than observed at the same time point for participants in the low dose cohort, providing early evidence of a dose-response. No adverse events or safety concerns have been observed in the first 258 days of subject exposure to SPK-8011. [Display omitted] DisclosuresGeorge:Spark Therapeutics: Other: Principal Investigator of Ongoing Phase I/II Gene Therapy Trials for Hemophilia A and B; Pfizer: Consultancy. Ragni:Alnylam, CSL Behring, BAYER, Biomarin, Biomarin, Bioverativ, Genetech/Roche, Pfizer, Shire, SPARK: Research Funding; A Anylam, Biomarin, Bioverativ, Shire: Honoraria. Cuker:Spark Therapeutics: Research Funding; T2 Biosystems: Research Funding. Cole:Spark Therapeutics: Employment. Wright:Spark Therapeutics: Employment, Equity Ownership, Patents & Royalties. Chen:Spark Therapeutics: Employment. Hui:Spark Therapeutics: Employment, Equity Ownership. Wachtel:Spark Therapeutics: Employment. Takefman:Spark Therapeutics: Employment. Couto:Spark Therapeutics: Employment. Reape:Spark Therapeutics: Employment. Carr:Spark Therapeutics: Employment. Anguela:Spark Therapeutics: Employment, Equity Ownership, Patents & Royalties. High:Spark Therapeutics: Employment, Equity Ownership, Patents & Royalties.

Patient-Reported Outcomes in Hemophilia B Patients Treated with IB1001 [Coagulation Factor IX (recombinant)

INTRODUCTION. Hemophilia B is a rare bleeding disorder caused by missing or defective factor IX, a clotting protein in the coagulation cascade. Patients with hemophilia B are treated with infusion of concentrated factor IX to replace the deficiency. As a chronic disease, patient quality of life and treatment satisfaction is a fundamental component of overall patient care in hemophilia B. Anecdotal evidence has suggested that some patients experience improved clinical outcomes and increased satisfaction when treated with IB1001, approved in the US as IXINITY®, [coagulation factor IX (recombinant)] (current factor treatment) as compared to their previous treatment. The objective of this study was to undertake a systematic assessment of IB1001 patient responses to measures of clinical care and quality of life that are relevant in hemophilia B in order to provide a more comprehensive description. METHODS. This was a cross-sectional study of hemophilia B patients in the United States currently being treated with IB1001. The study protocol was reviewed and approved by a central IRB. A survey was developed to capture patient-reported responses to clinical and quality of life questions of interest, including demographic characteristics, disease status, bleeding events, treatment, quality of life, and patient satisfaction. Where possible, patients were asked to compare responses on current factor treatment to those while on previous treatment with other available products. Patients were invited to complete the survey online. This was a pilot study to generate a descriptive analysis of patient experience. RESULTS. A total of 17 patients completed the survey. Most patients were male (76.5%) with a mean age of 43.8 years (range 16-73), and had been taking IB1001 for a mean 18 months at the time of this study. The elements most important for patient treatment choice were a high recovery rate, 24-hour half-life, no inhibitor development, and few side effects. Fewer annualized bleeding events were reported with the current factor treatment (mean 3.3 vs 6.7). Joint bleeds were most commonly reported, and most patients stated their bleed frequency was less (41%) or about the same (35%) on their current factor treatment compared to their previous treatment. Most patients reported their activity level as either ‘very active’ (23%), or ‘somewhat active’ (53%), and 47% of patients indicated they are more active now than on prior treatment. Overall, patients were either ‘very satisfied’ (76%) or ‘somewhat satisfied’ (12%) with their current factor treatment, compared with 12% and 23%, respectively, on prior treatment. Patients reported more mobility (29%), less pain (41%), and less anxiety or depression (18%) now than on prior treatment. CONCLUSIONS. In this study, we showed the utility of an online, survey-based instrument in characterizing patient experience with factor replacement products in hemophilia B. This study quantified the details of the patient experience that may have been driving the anecdotes of improved patient satisfaction and quality of life with IB1001. Overall, patients reported increased satisfaction, and improved clinical outcomes on their current factor treatment compared to products they had used in the past. While the data from this pilot study are encouraging, further study is warranted such as linking patient-reported outcomes to medical chart data to validate the clinical response and to better understand the variables that most influence patient satisfaction and quality of life. DisclosuresSchaaf:Aptevo Therapeutics: Employment, Equity Ownership. Lockhart:Aptevo Therapeutics: Consultancy. Fritz:Aptevo Therapeutics: Employment, Equity Ownership. Stromatt:Aptevo Therapeutics: Employment, Equity Ownership.

Comparative analysis of the pivotal studies of extended half-life recombinant FVIII products for treatment of haemophilia A.

The need to reduce the burden of injections, and improve adherence and clinical outcomes in haemophilia A led to the development of recombinant FVIII products endowed with an extended plasma half-life (EHL-rFVIII) in comparison with standard half-life products (SHL-rFVIII). Lack of head-to-head studies makes difficult to grasp the relative value of each treatment option. We conducted a combined evaluation of the individual pivotal trials in order to assess between-product differences regarding the reported efficacy results and FVIII consumption. We evaluated 4 EHL-rFVIII products available to treat patients with haemophilia A without inhibitors and also a SHL-rFVIII as a comparator. In the frame of these clinical studies, all the EHL-rFVIII products showed a decrease in the injection burden coupled with good clinical efficacy, even though there were between-product differences in terms of reduction in injection frequencies. Further, between-product differences in terms of weekly/yearly consumption of rFVIII expressed in IU/Kg were identified, suggesting a different economic impact for the different EHL-rFVIII products in the context of comparable clinical efficacy. The present findings based upon the review of pivotal studies done in the frame of a highly selected clinical scenario should be integrated with real-life data.

Updating the Canadian Hemophilia Outcomes–Kids’ Life Assessment Tool (CHO‐KLAT) in the era of extended half‐life clotting factor concentrates

IntroductionThe purpose of this study was to review and update the content of the Canadian Hemophilia Outcomes–Kids’ Life Assessment Tool version 2.0 (CHO‐KLAT), in the context of extended half‐life (EHL) factor concentrates (FCs) and to establish the validity and reliability of the updated CHO‐KLAT. MethodsFocus groups were conducted with boys with hemophilia, their parents, and health care providers across Canada to review the CHO‐KLAT v2.0 and determine if any modifications were required. The validity of the revised CHO‐KLAT (version 3.0) was then determined in a sample of boys with hemophilia and their parents by calculating its correlation with the Pediatric Quality of Life Core Module (PedsQL‐Core). Test‐retest reliability was assessed using an intraclass correlation coefficient (ICC). ResultsThirteen focus groups at 5 pediatric hemophilia treatment centers (HTCs) (n = 71) resulted in 19 changes to the CHO‐KLAT v2.0, generating a revised 40‐item CHO‐KLAT, the CHO‐KLAT v3.0. Thirty‐five boys with hemophilia (median age, 14; range, 7–17 years) and 47 parents participated in the validation of the CHO‐KLAT v3.0. There was a moderate correlation between the CHO‐KLAT v3.0 child self‐report and PedsQL‐Core (r = 0.56, P = .01), and a strong correlation between the CHO‐KLAT v3.0 parent‐proxy and PedsQL‐Core (r = .79, P = .0007). The test‐retest reliability ICC was 0.90 for the child self‐report CHO‐KLAT v3.0 and 0.68 for the parent‐proxy CHO‐KLAT v3.0. ConclusionThe CHO‐KLAT v3.0 is a reliable and valid child‐centric tool that effectively measures health‐related quality of life in boys with hemophilia who are receiving standard half‐life or EHL FCs.

Evidence of a disability paradox in patient‐reported outcomes in haemophilia

IntroductionPeople with inherited and long‐term conditions such as haemophilia have been shown to adapt to their levels of disability, often reporting better quality of life (QoL) than expected from the general population (the disability paradox).AimTo investigate the disability paradox in people with haemophilia in the United States by examining preference differences in health state valuations versus the general population.MethodsWe conducted a discrete choice experiment including duration to capture valuations of health states based on patient‐reported preferences. Participants indicated their preferences for hypothetical health states using the EQ‐5D‐5L, where each participant completed 15 of the 120 choice tasks. Response inconsistencies were evaluated with dominated and repeated scenarios. Conditional‐logit regressions with random sampling of the general population responses were used to match the sample of patients with haemophilia. We compared model estimates and derived preferences associated with EQ‐5D‐5L health states.ResultsAfter removing respondents with response inconsistencies, 1327/2138 (62%) participants remained (177/283 haemophilia; 1150/1900 general population). Patients with haemophilia indicated higher preference value for 99% of EQ‐5D‐5L health states compared to the general population (when matched on age and gender). The mean health state valuation difference of 0.17 indicated a meaningful difference compared to a minimal clinically important difference threshold of 0.07. Results were consistent by haemophilia type and severity.ConclusionOur findings indicated the presence of a disability paradox among patients with haemophilia, who reported higher health states than the general population, suggesting the impact of haemophilia may be underestimated if general population value sets are used.

Analysis of Hemophilia a Outcomes and Treatment Patterns Using Real-World Data from the Canadian Hemophilia Bleeding Disorder Registry

Analysis of Hemophilia a Outcomes and Treatment Patterns Using Real-World Data from the Canadian Hemophilia Bleeding Disorder Registry

Clinical outcomes in hemophilia: Towards development of a core set of standardized outcome measures for research

IntroductionA lack of uniformity in the choice of outcome measurement in hemophilia care and research has led to studies with incomparable results. We identified a need to define core outcome measures for use in research and clinical care of persons with hemophilia. ObjectiveTo move toward a core set of outcome measures for the assessment of persons with hemophilia in research and practice. MethodsA modified nominal groups process was conducted with an international group of hemophilia experts, including persons with hemophilia as follows. Step 1: item generation for all potential outcome measures. Step 2: survey where respondents voted on the relative importance and usefulness of each item. Steps 3/4: 2‐day meeting where attendees voted for items they valued, followed by open discussion and a second round of voting. Step 5: survey where respondents selected their top five items from those with >50% agreement at the meeting. ResultsThe highest ranked items for the pediatric core set (% agreement) are treatment satisfaction (92.7%), joint health (83.3%), a measure of access to treatment (82.5%), a measure of treatment adherence (72.5%), and generic performance based physical function (72.1%). The highest ranked items for the adult core set (% agreement) are total bleeding events (88.1%), EuroQol five dimensions (85.4%), treatment adherence (82.1%), joint health (79.1%), and number/location of bleeds per unit time (78.6%). ConclusionThis process generated a list of preferred outcome measures to consider for assessment in persons with hemophilia. This information now requires refinement to define optimal core sets for use in different clinical/research contexts.

Assessing prophylactic use and clinical outcomes in hemophilia A patients treated with rVIII-SingleChain and other common rFVIII products in Germany.

ObjectiveTo evaluate real‐world outcomes with rVIII‐SingleChain and other commonly used recombinant FVIII (rFVIII) products.MethodsHemophilia treatment centers in Germany (n = 21) contributed patient chart data. Inclusion criteria were prophylactic treatment with one of five rFVIII products for ≥8 weeks.ResultsMale patients (n = 225) were included: rVIII‐SingleChain (n = 40), rFVIIIFc (n = 47), octocog alfa (rFVIII; n = 58), octocog alfa (BAY 81‐8973; n = 40), or moroctocog alfa (n = 40). In patients with severe disease (n = 76), 66.6%, 70.0%, 20.0%, 7.7%, and 27.3% were dosed ≤2×/week, respectively. Irrespective of dosing frequency, mean annualized bleed rates (ABRs)/annualized spontaneous bleed rates (AsBRs) were 0.3/0.1, 0.8/0.4, 1.1/0.5, 1.5/0.8, and 1.4/0.6, and mean FVIII consumption (IU/kg/week) was 83.2, 97.2, 92.5, 104.0, and 102.1, respectively. Results for all patients were similar. Of the patients on prophylaxis with prior therapy and after switching to rVIII‐SingleChain (n = 21), mean ABR/AsBRs were 0.7/0.3 and 0.2/0.0, respectively. After switching to rVIII‐SingleChain, mean FVIII consumption reduced (109.4 vs 74.5 IU/kg/week), and percentage of patients dosed ≤2×/week increased (0% to 71.4%).ConclusionsrVIII‐SingleChain prophylaxis provides excellent bleeding protection, with potentially lowest factor consumption among the products assessed. Patients who switched to rVIII‐SingleChain prophylaxis reduced dosing frequency and consumption compared with prior treatment, with similar or potentially lower bleeding rates.

Impact of prophylaxis on health‐related quality of life of boys with hemophilia: An analysis of pooled data from 9 countries

BackgroundProphylaxis reduces the frequency of bleeds in boys with severe hemophilia and is the standard care for their management in resource‐abundant countries. The effect of prophylaxis on Health‐Related Quality of Life (HRQoL) has not been established, because the sample sizes of most studies are too small to explore the relationship of multiple factors that influence HRQoL.MethodsThe aim of this study was to assess the impact of hemophilia severity and treatment regimen on HRQoL and to establish the minimum important difference (MID) using the international level of score distributions. HRQoL data were pooled from 7 studies across 9 countries. HRQoL was measured using the Canadian Hemophilia Outcomes–Kids’ Life Assessment Tool (CHO‐KLAT). A mixed‐effect linear regression analysis was employed to assess the impact of prophylaxis on the CHO‐KLAT score.ResultsData from 401 boys with hemophilia were analyzed (57.6% severe hemophilia and 57.6% receiving prophylaxis). The model revealed that receiving prophylaxis was significantly associated with higher HRQoL (regression coefficient 8.5, 95% confidence interval [CI] 3.9‐13.1). Boys with severe hemophilia had a significantly lower HRQoL as compared to boys with moderate and mild hemophilia whose CHO‐KLAT scores were 7.0 and 6.6 points higher, respectively. There was a significant interaction between treatment and disease severity (P = 0.023), indicating prophylaxis has the most significant impact in boys with severe hemophilia. Based on these pooled data, the MID of the CHO‐KLAT was established at 6.5.ConclusionsThis study confirms the positive effect of prophylaxis on HRQoL in boys with hemophilia in a real‐world setting and provides initial benchmarks for interpreting HRQoL scores based on use of the CHO‐KLAT instrument.

The effect of emicizumab regimen on haemophilia outcomes

The effect of emicizumab regimen on haemophilia outcomes

Health-related quality of life in children with haemophilia in China: a 4-year follow-up prospective cohort study

BackgroundHealth-related quality of life (HRQoL) has been brought up for decades in haemophilia patients. However, no data to date are available about HRQoL in children with haemophilia using long-term follow up data. This nearly 4-year follow-up study aimed to assess the long-term HRQoL of haemophilia children.MethodsA prospective cohort study among 42 children with haemophilia and their parents was conducted in August 2014 in a children’s hospital; follow-up was completed in January 2018. Primary endpoint was the change in patient HRQoL evaluated by Canadian Haemophilia Outcomes–Kids’ Life Assessment Tool (CHO-KLAT) from baseline to year 4; secondary endpoint was the impact of bleeding rates, physical activity restriction, financial burden and treatment (prophylaxis vs on-demand treatment) on HRQoL, as well as the impact of treatment on event-free survival.ResultsTotally 42 patients (mean age, 5.48[SD, 4.63] years) and 42 parents were included. 38 families completed 4-year follow up. Patients reported a small increase in HRQoL from baseline to year 4. The mean scores of child self-report and parent proxy report of CHO-KLAT at baseline were 60.69 (SD = 20.28) and 61.01 (SD = 12.14), respectively. Scores at follow-up were 64.69 (SD = 13.71) and 65.33 (SD = 15.78), respectively. Haemophilia patients without physical activity restriction, living in urban areas, and receiving prophylactic treatment and home injection, had higher average values for HRQoL scores than the others. Bleeding rates were proportionally negatively correlated with HRQoL. Patients who had received prophylactic treatment had better event-free survival.ConclusionsHaemophilia decreased HRQoL of patients, but this effect weakened after 4 years. HRQoL of children is influenced by severity of haemophilia, bleeding rates, physical activity restriction, financial burden and treatment. Prophylactic treatment is a key factor contributing to event-free survivor prognosis and the optimal form of therapy for childhood haemophilia.

Clinical outcomes in hemophilia A patients undergoing tailoring of prophylaxis based on population-based pharmacokinetic dosing

IntroductionStandard prophylaxis dosing based on bodyweight may result in over- or under-dosing due to interpatient variability. Adopting individual pharmacokinetic (PK) based tailoring may improve adherence to treatment guideline, and consequently clinical outcomes. Here we report clinical observations performed across the adoption of individual PK based tailoring in a single center in Japan. MethodsAn individual PK study on sparse samples was modeled on myPKFiT or WAPPS-Hemo, depending on concentrate, and used to optimize treatment regimens. Adherence to prophylaxis and bleeding rate were calculated from patient diaries. Radiological joint scores were used to assess arthropathy, and SPSS to perform all the analyses. ResultsThirty-nine patients underwent PK profiling, and 20 required and accepted a modification of their treatment (8 increases in dose, 5 reductions in frequency, 5 switches to extended half-life (EHL)). Adherence to prophylaxis remained the same in those increasing the dose, whilst increased in all the other groups. Annualized bleeding rate (ABR) and annualized joint bleeding rate (AjBR) decreased in all the groups but reached statistical significance only in those switched to EHL and showed a larger reduction in those patients without baseline arthropathy. Longer time spent above a 1% or 5% threshold was associated with a decrease in the ABR/AjBR. ConclusionsOur study results suggest that PopPK based tailoring supported changing treatment regimen in nearly half of the patients, and may have contributed to an improvement in the adherence and a reduction in the ABR/AjBR.

Treatment regimens and outcomes in severe and moderate haemophilia A in the UK: The THUNDER study.

The THUNDER study provides an analysis of treatment patterns and outcomes in UK patients with severe or moderate haemophilia A (SHA/MHA) in 2015. Patients with SHA or MHA registered with the UK National Haemophilia Database (NHD) were segregated by severity, inhibitor status and age. Haemophilia joint health score (HJHS) was derived from NHD records and treatment regimen and annualized bleed/joint-bleed rate (ABR/AJBR) from Haemtrack (HT) in HT-compliant patients. We report 1810 patients with SHA and 864 with MHA. Prophylaxis was used in 94.9% (n=130/137) of HT-compliant children <12years with SHA, falling to 74.1% (n=123/166) aged ≥40years. Median ABR increased with age (1.0, IQR 0.0-5.0, <12years; 3.0 IQR, 1.0-8.0, ≥40years). Inhibitors were present in 159 (8.8%) SHA and 34 (3.9%) MHA. Median ABR increased from 2.0 (<12years) to 21.0 (≥40years) in SHA inhibitor patients using prophylaxis. Prophylaxis was used by 68.8% of HT-compliant MHA patients (n=106) (median FVIII baseline 0.01IU/mL) associated with a median (IQR) ABR of 3.0 (1.0-7.0). Median HJHS (n=453) increased with age in SHA and MHA. Median (IQR) HJHS was higher in SHA inhibitor (17.0, 0.0-64.5) than non- or past inhibitor patients (7.0, 0.0-23.0). Increasing ABR with age persists despite current prophylaxis regimens. SHA and MHA had similar ABR/AJBR and HJHS, leading to a suspicion that a subgroup of MHA may be relatively undertreated. More intensive prophylaxis may improve outcomes, but this requires further study.