***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BAY 81‐8973 , a full‐length , unmodified ,  recombinant factor VIII ( FVIII ) in development for treatment of haemophilia A , has the same primary amino acid sequence as Bayer 's sucrose‐formulated recombinant FVIII but is produced with more advanced manufacturing technologies Purpose Beroctocog alfa is a second generation recombinant factor VIII manufactured by removing the B-domain from factor VIII . This prospect i ve clinical trial was conducted to evaluate the efficacy , safety , and pharmacokinetics of beroctocog alfa in patients of ages ≥12 years previously treated for severe hemophilia A. Material s and Methods Seventy subjects received beroctocog alfa as an on-dem and treatment for acute hemorrhage . Results The final hemostatic effect was excellent in 35 subjects ( 50 % ) and good in 26 subjects ( 37.1 % ) . The drug showed an overall efficacy rate of 87.1 % . The majority of acute hemorrhages was treated by administering the study drug once ( 86.2 % ) or twice ( 10.0 % ) , and the mean dose administered per single infusion was 28.55±6.53 IU/kg . Ten subjects underwent 12 surgical procedures , and hemostatic efficacy was excellent in seven cases ( 58.3 % ) and good in five cases ( 41.7 % ) , showing a 100 % efficacy rate . A total of 52 of 88 subjects ( 59.0 % ) experienced 168 adverse events . There were 18 serious adverse events ( 10.7 % ) in 11 subjects , and two ( mild dyspnea and facial edema ) in one subject were related to the study drug . Only one subject formed a de novo factor VIII inhibitor , for an occurrence rate of 1.4 % ( one-sided 95 % upper confidence limit : 3.85 % ) . The final elimination half-life was 13.3 h and 12.6 h at baseline and 6 months after administration , respectively . Conclusion Our results suggest that beroctocog alfa is safe and efficacious as either an on-dem and treatment for acute hemorrhage or a surgical prophylaxis in patients with hemophilia The development of antibodies to factor VIII ( inhibitors ) in response to clotting-factor concentrates administration in hemophilia is common during the first few years of treatment but rare in multitransfused patients . We have investigated the possible association of a recently introduced factor VIII concentrate ( Factor VIII CPS-P ) in The Netherl and s with the occurrence of inhibitors . To this effect , we conducted two studies . First , we performed a national multicenter study in which clinical information and inhibitor test results were obtained for 447 hemophilia A patients over the period 1988 through 1991 . Secondly , for a baseline comparison we estimated the frequency of inhibitor development in a closely followed cohort of 144 patients , from 1984 through 1989 . Before the introduction of Factor VIII CPS-P , the incidence of new inhibitors was 4.4/1,000 patient-years in the national study from March 1988 through May 1990 , and 3.9/1,000 patient-years in the cohort followed from 1984 through 1989 . These figures are similar to the incidence of new inhibitors that was found in a large cohort of patients in the United States followed in the 1970s . In the period that the new concentrate Factor VIII CPS-P was on the market , from June 1990 through November 1991 , 11 clinical ly relevant inhibitors were detected , which yielded an incidence over this interval of 20.1/1,000 patient-years , a 4.5-fold increase compared with the previous interval ( C195 : 1.4 to 14.3 ) . Nine of these 11 patients had in their lifetime received over 250 infusions with factor VIII preparations . whereas all of the inhibitors detected in the previous time interval , and all of the 24 inhibitor patients described in the US study , had received less than 250 infusions in their lifetime . All patients who developed inhibitors after June 1990 had been exposed to Factor VIII CPS-P , whereas only 75 % of the patients who did not develop an inhibitor had been exposed to this product . In a prospect i ve extension of the study , with a second inhibitor measurement after 3 months , we found that one additional inhibitor had developed during 52.5 patient-years of Factor VIII CPS-P use . In conclusion , there has been a sudden increase in the frequency of inhibitor patients , for a large part among multitransfused patients . It seems more than likely that this increase is associated with the introduction of a new factor VIII concentrate in The Netherl and s. ( ABSTRACT TRUNCATED AT 400 WORDS BACKGROUND The benefits of routine prophylaxis vs. on-dem and treatment with factor VIII products have not been evaluated in controlled clinical trials in older patients with hemophilia A. OBJECTIVES To report results from a preplanned analysis of data from the first year of the 3-year SPINART study , which compares routine prophylaxis with on-dem and treatment with sucrose-formulated recombinant FVIII ( rFVIII-FS ) . PATIENTS / METHODS SPINART is an open-label , r and omized , controlled , parallel-group , multinational trial . Males aged 12 - 50 years with severe hemophilia A , ≥ 150 days of exposure to FVIII , no FVIII inhibitors , no prophylaxis for > 12 consecutive months in the past 5 years and 6 - 24 bleeding episodes in the preceding 6 months were r and omized 1 : 1 to rFVIII-FS prophylaxis ( 25 IU kg(-1 ) , three times weekly ) or on-dem and treatment . The primary efficacy endpoint , number of total bleeding episodes in the intent-to-treat population , was analyzed after the last patient had completed 1 year of follow-up . A negative binomial model was used for the primary endpoint analysis ; analysis of variance was used for confirmatory analysis of annualized bleeding rates . RESULTS Eighty-four patients were enrolled and analyzed ( n = 42 per group ; mean age , 30.6 years ; median treatment duration , 1.7 years )  . The median number of total bleeding episodes and total bleeding episodes per year were significantly lower with prophylaxis than with on-dem and treatment ( total , 0 vs. 54.5 ; total per year , 0 vs. 27.9 ; both P < 0.0001 ) . No treatment-related adverse events occurred , and no patients developed FVIII inhibitors . CONCLUSIONS Routine prophylaxis with rFVIII-FS leads to a significant reduction in bleeding as compared with on-dem and treatment . Adverse events were consistent with the established rFVIII-FS safety profile This prospect i ve , open-label , postauthorisation safety surveillance study assessed clinical ly 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 aged ≥ 12 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 clinical ly 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-dem and and prophylactic regimens , respectively ; 86.5 % of bleeding episodes resolved after one infusion . LETE incidence was 0.06 % and 0.19 % in the on-dem and and prophylaxis setting s , respectively . FVIII recovery remained constant throughout the study . No new safety concerns were identified . This study found no increased risk of clinical ly significant FVIII inhibitor development in patients transitioning from moroctocog alfa or other FVIII replacement products to moroctocog alfa ( AF-CC ) Background BAY 81 - 8973 is a new full-length human recombinant factor VIII product manufactured with technologies to improve consistency in glycosylation and expression to optimize clinical performance . Objectives To demonstrate superiority of prophylaxis vs. on-dem and therapy with BAY 81 - 8973 in patients with severe hemophilia A. Patients / Methods In this multinational , r and omized , open-label crossover study ( LEOPOLD II ; Clinical Trials.gov identifier : NCT01233258 ) , males aged 12–65 years with severe hemophilia A were r and omized to twice-weekly prophylaxis ( 20–30 IU kg−1 ) , 3-times-weekly prophylaxis ( 30–40 IU kg−1 ) , or on-dem and treatment with BAY 81 - 8973 . Potency labeling for BAY 81 - 8973 was based on the chromogenic substrate assay or adjusted to the one-stage assay . Primary efficacy endpoint was annualized number of all bleeds ( ABR ) . Adverse events ( AEs ) and immunogenicity were also assessed . Results Eighty patients ( on dem and , n = 21 ; twice-weekly prophylaxis , n = 28 ; 3-times-weekly prophylaxis , n = 31 ) were treated and analyzed . Mean ± SD ABR was significantly lower with prophylaxis ( twice-weekly , 5.7 ± 7.2 ; 3-times-weekly , 4.3 ± 6.5 ; combined , 4.9 ± 6.8 ) vs. on-dem and treatment ( 57.7 ± 24.6 ; P < 0.0001 , anova ) . Median ABR was reduced by 97 % with prophylaxis ( twice-weekly , 4.0 ; 3-times-weekly , 2.0 ; combined , 2.0 ) vs. on-dem and treatment ( 60.0 ) . Median ABR was higher with twice-weekly vs. 3-times-weekly prophylaxis during the first 6-month treatment period ( 4.1 vs. 2.0 ) but was comparable in the second 6-month period ( 1.1 vs. 2.0 ) . Few patients reported treatment-related AEs ( 4 % ) ; no treatment-related serious AEs or inhibitors were reported . Conclusions Twice-weekly or 3-times-weekly prophylaxis with BAY 81 - 8973 reduced median ABR by 97 % compared with on-dem and therapy , confirming the superiority of prophylaxis . Treatment with BAY 81 - 8973 was well tolerated OBJECTIVE : To test the feasibility of creating a valid and reliable checklist with the following features : appropriate for assessing both r and omised and non-r and omised studies ; provision of both an overall score for study quality and a profile of scores not only for the quality of reporting , internal validity ( bias and confounding ) and power , but also for external validity . DESIGN : A pilot version was first developed , based on epidemiological principles , review s , and existing checklists for r and omised studies . Face and content validity were assessed by three experienced review ers and reliability was determined using two raters assessing 10 r and omised and 10 non-r and omised studies . Using different raters , the checklist was revised and tested for internal consistency ( Kuder-Richardson 20 ) , test-retest and inter-rater reliability ( Spearman correlation coefficient and sign rank test ; kappa statistics ) , criterion validity , and respondent burden . MAIN RESULTS : The performance of the checklist improved considerably after revision of a pilot version . The Quality Index had high internal consistency ( KR-20 : 0.89 ) as did the subscales apart from external validity ( KR-20 : 0.54 ) . Test-retest ( r 0.88 ) and inter-rater ( r 0.75 ) reliability of the Quality Index were good . Reliability of the subscales varied from good ( bias ) to poor ( external validity ) . The Quality Index correlated highly with an existing , established instrument for assessing r and omised studies ( r 0.90 ) . There was little difference between its performance with non-r and omised and with r and omised studies . Raters took about 20 minutes to assess each paper ( range 10 to 45 minutes ) . CONCLUSIONS : This study has shown that it is feasible to develop a checklist that can be used to assess the method ological quality not only of r and omised controlled trials but also non-r and omised studies . It has also shown that it is possible to produce a checklist that provides a profile of the paper , alerting review ers to its particular method ological strengths and weaknesses . Further work is required to improve the checklist and the training of rat 
    Output:
    
Conclusion These results suggest that some products may be associated with increased immunogenicity .
However , the low incidence of inhibitors in PTPs and the differences in study design may cause significant variation in estimates of risk