scholarly journals Simoctocog Alfa (Nuwiq) in Previously Untreated Patients with Severe Haemophilia A: Final Results of the NuProtect Study

2021 ◽  
Author(s):  
Ri J. Liesner ◽  
Aby Abraham ◽  
Carmen Altisent ◽  
Mark J. Belletrutti ◽  
Manuel Carcao ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Human Cell Line ◽  
High Titre ◽  
Phase Iii ◽  
Fourth Generation ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Open Label ◽  
Inhibitor Development ◽  
Fviii Inhibitor

Abstract Introduction FVIII inhibitor development is the most serious contemporary treatment complication in haemophilia A, particularly in previously untreated patients (PUPs). No inhibitors developed in clinical trials in previously treated patients treated with simoctocog alfa (Nuwiq), a fourth-generation recombinant FVIII produced in a human cell line. Methods The NuProtect study investigated the immunogenicity of simoctocog alfa in PUPs. NuProtect was a prospective, multinational, open-label, non-controlled, phase III study. PUPs with severe haemophilia A (FVIII:C <1%) of any age and ethnicity were treated with simoctocog alfa for 100 exposure days or a maximum of 5 years. Patients were true PUPs without prior exposure to FVIII concentrates or blood components. Inhibitor titres were measured with the Nijmegen-modified Bethesda assay; cut-off for positivity was 0.6 BU mL−1 (≥0.6 to <5 low-titre, ≥5 high titre). Results A total of 108 PUPs with a median age at first treatment of 12.0 months (interquartile range: 8.0–23.5) were treated with simoctocog alfa. F8 mutation type was known for 102 patients (94.4%) of whom 90 (88.2%) had null F8 mutations and 12 (11.8%) had non-null mutations. Of 105 PUPs evaluable for inhibitor development, 28 (26.7%) developed inhibitors; 17 high titre (16.2%) and 11 low titre (10.5%). No PUPs with non-null F8 mutations developed inhibitors. Conclusion In the NuProtect study, the rate of inhibitor development in PUPs with severe haemophilia A treated with simoctocog alfa was lower than the rate reported for hamster-cell-derived recombinant factor VIII products in other recent clinical trials. No inhibitors were reported in PUPs with non-null F8 mutations.

scholarly journals Inhibitor Development with Simoctocog Alfa in Previously Untreated Patients with Severe Haemophilia a: Final Results of the Nuprotect Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 903-903 ◽  
Author(s):  
Ri Liesner ◽  
Ellis J. Neufeld
Keyword(s):  
Research Funding ◽  
High Titer ◽  
Human Cell Line ◽  
High Titre ◽  
Phase Iii ◽  
Protein Fusion ◽  
Surgical Prophylaxis ◽  
Open Label ◽  
Inhibitor Development ◽  
Breakthrough Bleeding

Introduction FVIII inhibitor development is the greatest challenge when treating previously untreated patients (PUPs) with hemophilia A (HA). The SIPPET study reported a cumulative inhibitor incidence of 44.5% (28.4% high-titre) in PUPs treated with recombinant FVIII (rFVIII) products produced in hamster cell lines and 26.8% (18.6% high-titre) with plasma-derived FVIII products containing von Willebrand factor (pdFVIII/VWF). Simoctocog alfa (Nuwiq®) is a 4th generation rFVIII produced in a human cell line without chemical modification or protein fusion. The NuProtect study assessed the immunogenicity, efficacy and safety of simoctocog alfa in PUPs with severe HA. A prespecified interim analysis was published with data up to 20 and 50 EDs (Haemophilia 2018; 24:211) and here we report the final results. Methods NuProtect was a prospective, multinational, open-label, non-controlled, phase III study. True PUPs (no prior FVIII treatment) with severe HA of any age and ethnicity were to be enrolled and treated for 100 exposure days (EDs) or a maximum of 5 years with simoctocog alfa for prophylaxis, on-demand treatment, treatment of breakthrough bleeding episodes (BEs) and surgical prophylaxis. Type of treatment and dose were determined by the investigator. Inhibitor screening (modified Bethesda assay) was performed at screening, every 3-4 EDs until ED20, then every 10-12 EDs or at least every 3 months, at completion, and if inhibitor development was suspected. Inhibitor levels of ≥0.6 to &lt;5 Bethesda units [BU]/mL were defined as low-titer and ≥5 BU/mL as high-titer. Cumulative inhibitor incidence (primary endpoint) and 95% confidence intervals (CIs) were calculated (Kaplan-Meier). Efficacy endpoints (inhibitor-free periods) included the annualized bleeding rate (ABR) during prophylaxis and efficacy in treating BEs/surgical prophylaxis (4-point objective scales: excellent, good [successful]; moderate or none). Adverse events (AEs) were monitored throughout the study. Results Of 108 subjects consented, 105 PUPs, median age of 12 months (range 0-146) at ED1 were evaluable for inhibitor development. They were treated for a median of 101 EDs (range 1-1164), with 96 patients treated for ≥100 EDs (or until inhibitor development, including 5 patients with 97-99 EDs). The majority of patients with available genetic data had null F8 gene mutations (90/102 [88.2%]) and 13 (12.0%) had a family history of inhibitors. Cumulative inhibitor incidence was 17.6% (95% CI: 10.0%, 25.3%) for high-titre inhibitors and 27.9% (95% CI: 19.1%, 36.7%) for all inhibitors (Figure 1). No PUPs with non-null F8 mutations developed inhibitors. In 50 PUPs on continuous prophylaxis for ≥6 months, the mean (SD) ABR was 0.54 (1.07) [median 0] for spontaneous BEs and 3.61 (3.82) [median 2.53] for all BEs. The treatment of BEs was successful in 92.9% (747/804) of rated BEs in 85 patients with treated BEs and 91.9% of BEs were controlled with 1 or 2 infusions. Surgical prophylaxis was successful for 94.7% (18/19) of rated procedures and moderate for 5.3% (1/19). Excluding inhibitors, only one (0.9%) patient had an AE classified as serious by the investigator (hospitalization due to a mild rash that resolved with anti-histamine treatment). Conclusions Simoctocog alfa had a similar inhibitor incidence in PUPs with severe HA as pdFVIII/VWF products in SIPPET. No inhibitors occurred in PUPs with non-null F8 mutations. Simoctocog alfa had a median spontaneous ABR of 0 during prophylaxis and was successful in the treatment of 92.9% of BEs and in 94.7% of surgical procedures. These results complement results in previously treated patients (PTPs) and support the use of simoctocog alfa in the prevention and treatment of BEs in PUPs and PTPs. References Liesner R, et al. Haemophilia 2018; 24: 211-20. Disclosures Liesner: Octapharma, Bayer, Takeda, Novo Nordisk, CSL Behring, Roche: Research Funding; Octapharma, SOBI, Novo Nordisk: Speakers Bureau; Octapharma, Bayer, Takeda: Consultancy. Neufeld:Octapharma, Shire Pharmaceuticals (Baxalta), Novo Nordisk, Celgene, NHLBI/NIH: Research Funding; Octapharma, Agios, Acceleron, Grifols, Pfizer, CSL Behring, Shire Pharmaceuticals (Baxalta), Novo Nordisk, ApoPharma, Genentech, Novartis, Bayer Healthcare: Consultancy; Octapharma: Other: study investigator, NuProtect study (Octapharma-sponsored).

Increased inhibitor incidence in severe haemophilia A since 1990 attributable to more low titre inhibitors

2016 ◽  
Vol 115 (04) ◽  
pp. 729-737 ◽  
Author(s):  
Kathelijn Fischer ◽  
Pia Petrini ◽  
Rolf Ljung ◽  
Anne Rafowicz ◽  
Manuel Carcao ◽  
...  
Keyword(s):  
Cox Regression ◽  
High Titre ◽  
P Value ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Birth Cohorts ◽  
Inhibitor Development ◽  
Hazard Ratios ◽  
Development Inhibitor ◽  
Unselected Cohort

SummaryMany studies have reported an increased incidence of inhibitors in previously untreated patients (PUPs) with severe haemophilia A after the introduction of recombinant products. It was the objective of this study to investigate whether the inhibitor incidence has increased between 1990 and 2009 in an unselected cohort of PUPs with severe haemophilia A (FVIII < 1 %). Patients were consecutively recruited from 31 haemophilia treatment centres in 16 countries and followed until 50 exposure days or until inhibitor development. Inhibitor development was studied in five-year birth cohorts comparing cumulative incidences. Furthermore the risk for inhibitor development per five-year birth cohort was studied using multivariable Cox regression, adjusting for potential genetic and treatment-related confounders. A total of 926 PUPs were included with a total cumulative inhibitor incidence of 27.5 %. The inhibitor incidence increased from 19.5 % in 1990-1994 (lowest) to 30.9 % in 2000-2004 (highest; p-value 0.011). Low titre inhibitor incidence increased from 3.1 % in 1990-1994 to 10.5 % in 2005-2009 (p-value 0.009). High titre inhibitor incidences remained stable over time. After 2000, risk of all inhibitor development was increased with adjusted hazard ratios 1.96 (95 % CI 1.06-2.83) in 2000-2004 and 2.34 (1.42-4.92) in 2005-2009. Screening for inhibitors was intensified over this 20-year study period from a median of 1.9 to 2.9 tests/year before 2000 to 2.7 to 4.3 tests/ year after 2000. In conclusion, the cumulative inhibitor incidence has significantly increased between 1990 and 2009. The high titre inhibitor incidence has remained stable.

Prospective surveillance study of haemophilia A patients switching from moroctocog alfa or other factor VIII products to moroctocog alfa albumin-free cell culture (AF-CC) in usual care settings

2015 ◽  
Vol 114 (10) ◽  
pp. 676-684 ◽  
Author(s):  
Laszlo Nemes ◽  
Victor Jimenez-Yuste ◽  
Luminita Rusen ◽  
Ana Cid ◽  
Robert Charnigo ◽  
...  
Keyword(s):  
Factor Viii ◽  
Clinical Manifestations ◽  
Surveillance Study ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Inhibitor Development ◽  
On Demand ◽  
Fviii Inhibitor ◽  
Increased Risk ◽  
Clinically Significant

SummaryThis prospective, open-label, postauthorisation safety surveillance study assessed clinically significant inhibitor development in patients with severe haemophilia A transitioning from moroctocog alfa or other factor VIII (FVIII) replacement products to reformulated moroctocog alfa (AF-CC). Males aged12 years with severe haemophilia A (FVIII:C) < 1 IU/dl), > 150 exposure days (EDs) to recombinant or plasma-derived FVIII products, and no detectable inhibitor at screening were enrolled. Primary end point was the incidence of clinically significant FVIII inhibitor development. Secondary end points included annualised bleeding rate (ABR), less-than-expected therapeutic effect (LETE), and FVIII recovery. Patients were assigned to one of two cohorts based on whether they were transitioning to moroctocog alfa (AF-CC) from moroctocog alfa (cohort 1; n=146) or from another recombinant or plasma-derived FVIII product (cohort 2; n=62). Mean number of EDs on study was 94 (range, 1–139). Six positive FVIII inhibitor results, as determined by local laboratories, were reported in four patients; none were confirmed by a central laboratory, no inhibitor-related clinical manifestations were reported, and all anti-FVIII antibody assays were negative. Median ABRs were 23.4 and 3.4 in patients categorised at baseline as following on-demand and prophylactic regimens, respectively; 86.5 % of bleeding episodes resolved after one infusion. LETE incidence was 0.06 % and 0.19 % in the on-demand and prophylaxis settings, respectively. FVIII recovery remained constant throughout the study. No new safety concerns were identified. This study found no increased risk of clinically significant FVIII inhibitor development in patients transitioning from moroctocog alfa or other FVIII replacement products to moroctocog alfa (AF-CC).

scholarly journals Practical Utilisation of Octapharma FVIII Concentrates in Previously Untreated and Minimally Treated Haemophilia a Patients Entering Routine Clinical Treatment with Nuwiq®, Octanate® or Wilate® — the Protect-NOW Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5034-5034
Author(s):  
Johannes Oldenburg ◽  
Anna Pavlova ◽  
Susan Halimeh ◽  
Robert Klamroth ◽  
Joris Versteden ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Research Funding ◽  
Treatment Effectiveness ◽  
Real Life ◽  
High Titre ◽  
Controlled Study ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Inhibitor Development ◽  
The Impact

Abstract Introduction/Objective: The development of FVIII inhibitors remains the greatest challenge to the treatment of previously untreated patients (PUPs) with haemophilia A. Uncontrolled studies in PUPs have suggested that immunogenicity of FVIII concentrates varies between different products. In the SIPPET study, the first and only large randomised controlled study to examine the impact of FVIII product type on immunogenicity, the cumulative incidence of high-titre inhibitors in PUPs and minimally treated patients (MTPs) treated with hamster cell-derived recombinant FVIII (rFVIII) products was 28.4%, compared with 18.6% for plasma-derived FVIII/von Willebrand factor (pdFVIII/VWF) products [1]. However, SIPPET did not include all currently available FVIII products, limiting the applicability of its conclusions to the current haemophilia treatment landscape. In previous clinical studies of true PUPs treated with the pdFVIII/VWF concentrates octanate® [2] and wilate®, the cumulative incidences of high-titre inhibitors were 8.0% and 11.3%, respectively. For the human-cell derived rFVIII Nuwiq®, the cumulative incidence of high-titre inhibitors was 12.8% (data from a preplanned interim analysis) [3]. These incidences suggest a favourable immunogenicity profile compared to products in the SIPPET study. However, there is a need for more real-life data on treatment effectiveness and safety in PUPs and MTPs. The ongoing, non-interventional, multi-centre Protect-NOW study is a prospective and retrospective study evaluating real-life treatment patterns, effectiveness and safety, including inhibitor development, in PUPs and MTPs with severe haemophilia A who are treated with Octapharma's pdFVIII or rFVIII products. Methods: One hundred and forty PUPs (no previous treatment) and MTPs (<5 previous EDs with other FVIII products) with severe haemophilia A of all ages and ethnicities will be studied for 100 EDs or up to 3 years. Treatment effectiveness will be evaluated for regular prophylaxis, treatment of bleeding episodes, and surgical prophylaxis. Optional sub-studies, including epitope mapping, detection of non-neutralising inhibitors, and gene mutation analysis, will assess factors potentially associated with inhibitor development and eradication in patients with severe haemophilia A. Optional sub-studies will be carried out at the central laboratory at the Institute of Experimental Haematology in Bonn. Protect-NOW is planned to include around 17 countries and 50 centres worldwide. In the US, the Protect-NOW will be performed as part of the ATHN-8 study. Results: Recruitment is ongoing, with seven patients recruited at two German centres to date. The study has been approved by central and/or local ethics committees in Germany, US, UK, Spain and Russia, and is under ethical review in Canada. Final data collection is expected in 2022. Conclusions: Protect-NOW will collect real-life clinical experience with Octapharma's FVIII products in PUPs and MTPs. This study will contribute real-world data to the current debate on the relevance of FVIII concentrate type in inhibitor induction. ReferencesPeyvandi F et al. N Engl J Med 2016; 374:2054-64.Klukowska A et al. Haemophilia 2018; 24:221-28.Liesner R et al. Haemophilia 2018; 24: 211-20. Disclosures Oldenburg: Novo Nordisk: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Swedish Orphan Biovitrum: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Biogen: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Shire: Honoraria, Research Funding; Grifols: Honoraria, Research Funding. Pavlova:Octapharma: Honoraria; Novo Nordisk: Honoraria. Halimeh:Bayer healthcare, Baxalta Innovations, Biotest, CSL Behring, Novartis, Novo Nordisk, Octapharma, LFB, Pfizer: Honoraria; Bayer Healthcare, Baxalta Innovations, Biotest, CSL Behring, Novo Nordisk, Octapharma, Pfizer: Research Funding. Klamroth:Baxalta (Shire), Bayer, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Shire, and SOBI: Research Funding; Baxalta (Shire), Bayer, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Shire, and SOBI: Consultancy. Versteden:Octapharma AG: Employment. Jansen:Octapharma: Employment. Belyanskaya:Octapharma AG: Employment.

Clinical evaluation of glycoPEGylated recombinant FVIII: Efficacy and safety in severe haemophilia A

2017 ◽  
Vol 117 (02) ◽  
pp. 252-261 ◽  
Author(s):  
Paul Giangrande ◽  
Tatiana Andreeva ◽  
Pratima Chowdary ◽  
Silke Ehrenforth ◽  
Hideji Hanabusa ◽  
...  
Keyword(s):  
Randomised Trial ◽  
Phase Iii ◽  
Haemophilia A ◽  
Activity Levels ◽  
Severe Haemophilia ◽  
Open Label ◽  
Favourable Safety Profile ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Recombinant Fviii

SummaryTuroctocog alfa pegol (N8-GP) is a novel glycoPEGylated extended half-life recombinant factor VIII (FVIII) product developed for prophylaxis and treatment of bleeds in patients with haemophilia A, to enable higher activity levels with less frequent injections compared with standard FVIII products. This phase III (NCT01480180), multinational, open-label, non-randomised trial evaluated the safety and clinical efficacy of N8-GP when administered for treatment of bleeds and for prophylaxis, in previously treated patients aged ≥12 years with severe haemophilia A. Patients were allocated to receive N8-GP for prophylaxis or on-demand treatment for up to 1.8 years. Patients on prophylaxis were administered one dose of 50 IU/kg of N8-GP every fourth day. Bleeds were treated with doses of 20–75 IU/kg. Total exposure to N8-GP in the trial was 14,114 exposure days (159 patient-years). For the prophylaxis arm (n=175), the median annualised bleeding rate (ABR) was 1.33 (interquartile range, 0.00–4.61), the mean ABR was 3.70 (95 % confidence interval 2.94–4.66) and 70 (40 %) patients had no bleeds during the trial. Across treatment arms, 83.6 % of bleeds resolved with one injection and 95.5 % with up to two injections. N8-GP had a favourable safety profile and was well tolerated. The frequency and types of adverse events reported were as expected in this population. One patient developed inhibitory antibodies against FVIII (≥0.6 Bethesda units [BU]) after 93 N8-GP exposure days. No clinically significant safety concerns were identified and N8-GP was effective for prophylaxis and treatment of bleeds in previously treated patients.

Inhibitor treatment by rituximabin congenital haemophilia A

2009 ◽  
Vol 29 (02) ◽  
pp. 151-154 ◽  
Author(s):  
Escuriola Ettingshausen ◽  
R. Linde ◽  
G. Kropshofer ◽  
L.-B. Zimmerhackl ◽  
W. Kreuz ◽  
...  
Keyword(s):  
B Cell ◽  
Immune Tolerance ◽  
High Titre ◽  
Clotting Factor ◽  
Severe Bleeding ◽  
High Morbidity ◽  
Haemophilia A ◽  
Concomitant Treatment ◽  
Bleeding Tendency ◽  
Severe Haemophilia

SummaryThe development of neutralizing alloanti-bodies (inhibitors) to factor VIII (FVIII) is one of the most serious complications in the treatment of haemophiliacs. Inhibitors occur in approximately 20 to 30% of previously untreated patients (PUPs), predominantly children, with severe haemophilia A within the first 50 exposure days (ED). Immune tolerance induction (ITI) leads to complete elimination of the inhibitor in up to 80% of the patients and offers the possibility to restore regular FVIII prophylaxis. However, patients with high titre inhibitors, in whom standard ITI fails, usually impose with high morbidity and mortality and therefore prompting physicians to alternate therapy regimens. Rituximab, an anti-CD 20 monoclonal antibody has been successfully used in children and adults for the management of B-cell mediated disorders. We report on the use of a new protocol including rituximab in two adolescents with severe haemophilia A and high titre inhibitors, severe bleeding tendency and high clotting factor consumption after failing standard ITI. Both patients received a concomitant treatment with FVIII according to the Bonn protocol, cyclosporine A and immunoglobulin. Treatment with rituximab resulted in a temporary B-cell depletion leading to the disappearance of the inhibitor. FVIII recovery and half-life turned towards normal ranges. In patient 1 the inhibitor reappeared 14 months after the last rituximab administration. In patient 2 complete immune tolerance could be achieved for 60 months. Bleeding frequency diminished significantly and clinical joint status improved in both patients. In patient 1 the treatment course was complicated by aspergillosis and hepatitis B infection. Conclusion: Rituximab may be favourable for patients with congenital haemophilia, high-titre inhibitors and a severe clinical course in whom standard ITI has failed. Prospective studies are required to determine safety, efficacy and predictors of success.

scholarly journals Dutch Breast Cancer Trialists' Group (BOOG)

2006 ◽  
Vol 9 (S1) ◽  
pp. 61-79
Author(s):  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Metastatic Breast Cancer ◽  
Endocrine Therapy ◽  
Metastatic Breast ◽  
Phase Iii ◽  
List Type ◽  
First Line ◽  
Open Label ◽  
Phase Iii Study

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by Dutch breast cancer trialists' group (BOOG). Clinical trials include:An open label randomized (inter)national multicenter comparative trial of 5 years adjuvant endocrine therapy with an LHRH agonist plus an aromatase inhibitor (goserelin + anastrozole) versus five courses FE90C chemotherapy followed by the same endocrine therapy in pre- or perimenopausal patients with hormone receptor-positive primary breast cancer (PRemenopausal Optimal Management IS Endocrine therapy). BOOG 2002-01/PROMISE. ISRCTN23561723Open label, comparative, randomized, multicenter, study of trastuzumab (Herceptin) given with docetaxel (Taxotere) versus sequential single agent therapy with trastuzumab followed by docetaxel as first-line treatment for metastatic breast cancer (MBC) patients with HER2neu overexpression. BOOG 2002-02/HERTAX ISRCTN13770586Micro-metastases and Isolated tumour cells: Robust and Relevant Or Rubbish? The MIRROR study in BREAST CANCER. BOOG 2003-03/ZonMW 3214Radiation dose intensity study in breast cancer in young women: a randomized phase III trial of additional dose to the tumor bed. BOOG 2004-01/Young Boost SRCTN45066831Microarray analysis in breast cancer to Tailor Adjuvant Drugs Or Regimens, a randomized phase III study. MATADOR, BOOG 2005-02, CKTO 2004-04 ISRCTN61893718A prospective randomised, open, multicentre, phase III study to assess different Durations of Anastrozole therapy after 2–3 years Tamoxifen as Adjuvant therapy in postmenopausal women with breast cancer. 2006-01/DATAA randomized, open-label phase III study of first line chemotherapy in elderly metastatic breast cancer patients, comparing intravenous pegylated liposomal doxorubicin with oral capecitabine; and the incorporation of a complete geriatric assessment. 2006-02/OMEGABOOG participation in International studies:. BOOG 2001-01/TEAM trial. BOOG 2001-02/AMAROS (EORTC 10981/22023). BOOG 2002-04/HERA (BIG 1-01/EORTC 10011/BO16348B). BOOG 2003-02 (BIG 1-02/IBCSG 27-02). BOOG 2003-04 (GBG 29). BOOG 2004-02/TBP (GBG 26, BIG 3-05). BOOG 2005-01/CASA (IBCSG 32-05/BIG 1-05). BOOG 2005-03/MINDACT (EORTC 10041, BIG 3-04). BOOG 2006-03/SUPREMO (BIG 2-04). BOOG 2006-04/Adjuvant lapatinib study (BIG 2-06/EGF106708)

Inhibitor development in haemophilia according to concentrate

2015 ◽  
Vol 113 (05) ◽  
pp. 968-975 ◽  
Author(s):  
Riita Lassila ◽  
Flora Peyvandi ◽  
Gabriele Calizzani ◽  
Alex Gatt ◽  
Thierry Lambert ◽  
...  
Keyword(s):  
Calculated Data ◽  
Incidence Rates ◽  
Clotting Factor ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Inhibitor Development ◽  
Haemophilia B ◽  
Number Of Patients ◽  
Recombinant Fviii ◽  
Set Up

SummaryInhibitor development represents the most serious side effect of haemophilia treatment. Any difference in risk of inhibitor formation depending on the product used might be of clinical relevance. It was this study’s objective to assess inhibitor development according to clotting factor concentrate in severe haemophilia A and B. The European Haemophilia Safety Surveillance (EUHASS) was set up as a study monitoring adverse events overall and according to concentrate. Since October 2008, inhibitors were reported at least quarterly. Number of treated patients was reported annually, specifying the number of patients completing 50 exposure days (Previously Untreated Patients, PUPs) without inhibitor development. Cumulative incidence, incidence rates and 95 % confidence intervals (CI) were calculated. Data from October 1, 2008 to December 31, 2012 were analysed for 68 centres that validated their data. Inhibitors developed in 108/417 (26 %; CI 22–30 %) PUPs with severe haemophilia A and 5/72 (7 %; CI 2–16%) PUPs with severe haemophilia B. For Previously Treated Patients (PTPs), 26 inhibitors developed in 17,667 treatment years [0.15/100 treatment years; CI 0.10–0.22) for severe haemophilia A and 1/2836 (0.04/100; (CI 0.00–0.20) for severe haemophilia B. Differences between plasma-derived and recombinant concentrates, or among the different recombinant FVIII concentrates were investigated. In conclusion, while confirming the expected rates of inhibitors in PUPs and PTPs, no class or brand related differences were observed.

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