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. 2021 Aug 18;8(8):CD014201.
doi: 10.1002/14651858.CD014201.

Clotting factor concentrates for preventing bleeding and bleeding-related complications in previously treated individuals with haemophilia A or B

Omotola O Olasupo  1 , Megan S Lowe  2 , Ashma Krishan  3 , Peter Collins  4 , Alfonso Iorio  1 , Davide Matino  5
Affiliations

Clotting factor concentrates for preventing bleeding and bleeding-related complications in previously treated individuals with haemophilia A or B

Omotola O Olasupo et al. Cochrane Database Syst Rev. .

Abstract

Background: The hallmark of severe hemophilia (A or B) is recurrent bleeding into joints and soft tissues with progressive joint damage, despite on-demand treatment. Prophylaxis has long been used, but not universally adopted, because of medical, psychosocial, and cost controversies.

Objectives: To determine the effectiveness of clotting factor concentrate prophylaxis in managing previously-treated individuals with hemophilia A or B.

Search methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. In addition, we searched MEDLINE and Embase and online trial registries. Most recent search of Group's Coagulopathies Trials Register: 24 February 2021.

Selection criteria: Randomised controlled trials (RCTs) and quasi-RCTs evaluating people with hemophilia A or hemophilia B, who were previously treated with clotting factor concentrates to manage their hemophilia.

Data collection and analysis: Two authors independently reviewed trials for eligibility, assessed risk of bias and extracted data. The authors used the GRADE criteria to assess the certainty of the evidence.

Main results: Ten trials (including 608 participants) were eligible for inclusion. Eight of the trials (477 participants) had arms comparing two or more prophylactic regimens to one another and four of the trials (n = 258) compared prophylaxis to on-demand treatment (two trials had multiple arms and were included in both comparisons). Comparison of two or more prophylactic regimens For trials comparing one prophylaxis regimen to another, given the heterogeneity of the data, none of the data were pooled for this comparison. Considering the individual trials, three trials reported the primary outcome of joint bleeding, and none showed a dfference between dosing regimens (low-certainty evidence). For the secondary outcome of total bleeding events, prophylaxis with a twice-weekly regimen of FIX likely results in reduced total bleeds compared to a once-a-week regimen of the same dose, mean difference (MD) 11.2 (5.81 to 16.59) (one trial, 10 participants, low-certainty evidence). Transient low-titer anti-FVIII inhibitors were reported in one of the trials. Blood-transmitted infections were not identified. Other adverse events reported include hypersensitivity, oedema, and weight gain. These were, however, rare and unrelated to study drugs (very low-certainty evidence). Comparison of prophylactic and on-demand regimens Four of the trials (258 participants) had arms that compared prophylaxis to on-demand treatment. Prophylaxis may result in a large decrease in the number of joint bleeds compared to on-demand treatment, MD -30.34 (95% CI -46.95 to -13.73) (two trials, 164 participants, low-certainty evidence). One of these trials (84 participants) also reported the long-term effects of prophylaxis versus on-demand therapy showing improved joint function, quality of life, and pain; but no differences between groups in joint structure when assessed by magnetic resonance imaging (MRI). In one trial (84 participants) validated measures for joint health and pain assessment showed that prophylaxis likely improves joint health compared to an on-demand regimen with an estimated change difference of 0.94 points (95% CI 0.23 to 1.65) and improves total pain scores, MD -17.20 (95% CI -27.48 to -6.92 (moderate-certainty evidence). Two trials (131 participants) reported that prophylaxis likely results in a slight increase in adverse events, risk ratio 1.71 (1.24 to 2.37) (moderate-certainty evidence). No inhibitor development and blood-transmitted infections were identified. Overall, the certainty of the body of evidence was judged to be low because of different types of bias that could have altered the effect. AUTHORS' CONCLUSIONS: There is evidence from RCTs that prophylaxis, as compared to on-demand treatment, may reduce bleeding frequency in previously-treated people with hemophilia. Prophylaxis may also improve joint function, pain and quality of life, even though this does not translate into a detectable improvement of articular damage when assessed by MRI. When comparing two different prophylaxis regimens, no significant differences in terms of protection from bleeding were found. Dose optimization could, however, result in improved efficacy. Given the heterogeneity of the data, pooled estimates were not obtained for most comparisons. Well-designed RCTs and prospective observational controlled studies with standardised definitions and measurements are needed to establish the optimal and most cost-effective treatment regimens.

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Conflict of interest statement

Omotola Olasupo: has no conflict of interest.

Megan Lowe: has no conflict of interest.

Peter Collins has acted as a paid consultant, received lecture fees and support to attend meetings from Novo Nordisk, Bayer, Baxter, CSL Behring. Grant support has been received from CSL Behring.

Ashma Krishan: none known.

Alfonso Iorio does not perceive any relevant conflict of interest, while his institution receives grants from pharmaceutical companies, he does not benefit from these, nor does he have control over the use of the funds.

Davide Matino reports research grants paid directly to the Institution from Bayer, Pfizer, Novo Nordisk, Sanofi, Spark, Octapharma; personal fees outside the submitted work from Sanofi, Sobi, Novo Nordisk, Bayer, Pfizer, Octapharma for participation in advisory boards, lectures and preparation of educational material.

Figures

1
1
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: Comparison between two prophylaxis regimens, Outcome 1: Joint bleeds per year
1.2
1.2. Analysis
Comparison 1: Comparison between two prophylaxis regimens, Outcome 2: Joint bleeds per year (2)
1.3
1.3. Analysis
Comparison 1: Comparison between two prophylaxis regimens, Outcome 3: Spontaneous joint bleeds
1.4
1.4. Analysis
Comparison 1: Comparison between two prophylaxis regimens, Outcome 4: Joint bleeds per year (3)
1.5
1.5. Analysis
Comparison 1: Comparison between two prophylaxis regimens, Outcome 5: Total bleeds per year
1.6
1.6. Analysis
Comparison 1: Comparison between two prophylaxis regimens, Outcome 6: Overall bleeding frequency (bleeds per 100 days)
1.7
1.7. Analysis
Comparison 1: Comparison between two prophylaxis regimens, Outcome 7: Annualised bleeding rates
1.8
1.8. Analysis
Comparison 1: Comparison between two prophylaxis regimens, Outcome 8: Total bleeding frequency (HB)
1.9
1.9. Analysis
Comparison 1: Comparison between two prophylaxis regimens, Outcome 9: Overall bleeding frequency
1.10
1.10. Analysis
Comparison 1: Comparison between two prophylaxis regimens, Outcome 10: Total bleeds per year (2)
1.11
1.11. Analysis
Comparison 1: Comparison between two prophylaxis regimens, Outcome 11: Total treatment emergent adverse event
1.12
1.12. Analysis
Comparison 1: Comparison between two prophylaxis regimens, Outcome 12: Rate of adverse events
2.1
2.1. Analysis
Comparison 2: Standard prophylaxis versus investigational drug, Outcome 1: Annualised joint bleeding rate
2.2
2.2. Analysis
Comparison 2: Standard prophylaxis versus investigational drug, Outcome 2: Annualised total bleeding rate
3.1
3.1. Analysis
Comparison 3: Prophylaxis versus on‐demand, Outcome 1: Mean total joint bleeds per year
3.2
3.2. Analysis
Comparison 3: Prophylaxis versus on‐demand, Outcome 2: Mean change in joint health scores (CAJAS)
3.3
3.3. Analysis
Comparison 3: Prophylaxis versus on‐demand, Outcome 3: Mean total bleeds per year
3.4
3.4. Analysis
Comparison 3: Prophylaxis versus on‐demand, Outcome 4: Pain scores
3.5
3.5. Analysis
Comparison 3: Prophylaxis versus on‐demand, Outcome 5: Radiologic measurements of joint damage (deterioration shown in eMRI)
3.6
3.6. Analysis
Comparison 3: Prophylaxis versus on‐demand, Outcome 6: Participants with adverse events
See this image and copyright information in PMC

References

References to studies included in this review

A‐LONG 2014 {published data only}
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Aronstam 1976 {published data only}
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Aronstam 1977 {published data only}
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LEOPOLD II 2015 {published data only}
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LipLong 2012 {published data only}
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    1. Lalezari S, Coppola A, Lin J, Enriquez MM, Tseneklidou-Stoeter D, Powell J, et al. Patient characteristics that influence efficacy of prophylaxis with rFVIII-FS three times per week: a subgroup analysis of the LIPLONG study. Haemophilia 2014;20(3):354-61. [CFGD REGISTER: HA104f] - PubMed
    1. Lalezari S, Coppola A, Lin J, Enriquez MM. Subgroup analyses of annualized number of bleeds with three-times-per-week prophylaxis with rFVIII-FS. Journal of thrombosis and haemostasis : JTH 2011;9 Suppl 2:373. [ABSTRACT NO: P-TU-204] [CFGD REGISTER: HA104g]
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    1. Martinowitz U, Windyga J, Powell J, Maas Enriquez M, Scharrer I. Pharmacokinetic results and correlations with intrinsic von Willebrand factor levels form a randomized, double-blind study of prophylaxis with once-weekly BAY 79-4980 vs. 3-times-weekly sucrose-formulated recombinant factor VIII. Haemophilia 2012;18 Suppl 3:25. [ABSTRACT NO: PO-WE-061] [CFGD REGISTER: HA104a]
Morfini 1976 {published data only}
    1. Morfini M, Mannucci PM, Mariani G, Panicucci F, Petrucci F, Baicchi U, et al. Evaluation of prophylactic replacement therapy in haemophilia B. Scandinavian Journal of Haematology 1976;16(1):41-7. [CENTRAL: CN-00013490] [CFGD REGISTER: HB8] [EMBASE: 1977017603] [PMID: ] - PubMed
PROPEL III 2020 {published data only}
    1. Collins P, Windyga J, Escobar M, Ibrahim HM, Lam JCM, Tangada SD, et al. Efficacy and target joint resolution with pharmacokinetic-guided rurioctocog alfa pegol prophylaxis targeting two factor VIII trough levels in patients with severe hemophilia A: post-hoc analysis of the phase 3 propel trial. Research and Practice in Thrombosis and Haemostasis 2020;4 Suppl 1:455. [CFGD REGISTER: HA137j]
    1. Escuriola-Ettingshausen C, Klamroth R, Escobar M, Mullins ES, Stasyshyn O, Tangada S, et al. Personalizing prophylaxis with rurioctocog alfa pegol in previously treated patients with severe hemophilia A: outcomes from the phase 3B continuation and phase 3 propel studies. Research and Practice in Thrombosis and Haemostasis 2020;4(Suppl 1):453-4. [CFGD REGISTER: HA137i]
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SPINART 2013 {published data only}
    1. EUCTR2008-000985-21-BG. Trial to evaluate the effect of two treatment regimens for adults with severe hemophilia A [Randomized, controlled, parallel, prospective trial to evaluate the effect of secondary prophylaxis with rFVIII therapy in severe hemophilia A adult and/or adolescent subjects, as applicable, compared to that of episodic treatment. (SPINART) - SPINART]. www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2008-000985-21-BG (date of registration 4 February 2008). [CENTRAL: CN-01847483] [CFGD REGISTER: HA105r]
    1. Funk S, Lundin B, Hong W. Spinart 3-year analyses: patient- and joint-level changes in colorado adult joint assessment scale and magnetic resonance imaging scores with Bayer's sucrose-formulated recombinant factor VIII in adolescents and adults. Journal of thrombosis and haemostasis : JTH 2015;13 Suppl 2:244. [ABSTRACT NO: OR388] [CFGD REGISTER: HA105j]
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Valentino 2012 {published data only}
    1. Chowdary P, Fischer K, Collins PW, Cotterill A, Konkle BA, Blanchette V, et al. Modeling to predict factor VIII levels associated with zero bleeds in patients with severe hemophilia a initiated on tertiary prophylaxis. Thrombosis and Haemostasis 2020;120(5):728-36. [CFGD REGISTER: HA107g] - PubMed
    1. NCT00243386. Prophylaxis study of recombinant factor VIII manufactured protein-free (rahf-pfm) in patients with hemophilia a. clinicaltrials.gov/show/NCT00243386 2005 (first posted 24 October 2005). [CFGD REGISTER: HA107f]
    1. Quon DV, Shapiro AD, Santagostino E, Valentino LA. Impact of rAHF-PFM prophylactic treatment on annual bleeding rate and health-related quality of life of adults with severe hemophilia A. Journal of thrombosis and haemostasis : JTH 2013;11 Suppl 2:1081. [ABSTRACT NO: PO 160] [CFGD REGISTER: HA107c]
    1. Shapiro AD, Santagostino E, Epstein JD, Schroth P, Wong WY. Significant improvement in health-related quality of life with prophylaxis in severe hemophilia A: results from the rAHF-PFM randomized, controlled prophylaxis study. Journal of thrombosis and haemostasis : JTH 2011;9 Suppl 2:827. [ABSTRACT NO: P-TH-184] [CFGD REGISTER: HA107d]
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Valentino 2014 {published data only}
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References to studies excluded from this review

Aledort 1994 {published data only}
    1. Aledort LM, Haschmeyer RH, Pettersson H, The orthopaedic outcome study group. A longitudinal study of orthopaedic outcomes for severe factor VIII deficient haemophiliacs. Journal of Internal Medicine 1994;236(4):391-9. - PubMed
Ali 2018 {published data only}
    1. Ali TM, Crea R, Wanek K, Cano V. Tolerability/safety of feiba reconstituted in regular or 50% reduced volume and faster infusion rates: rationale and study design in patients with hemophilia A or B with inhibitors. Haemophilia 2018;24 Suppl 1:119. [CENTRAL: CN-01467061] [CFGD REGISTER: HG107] [EMBASE: 621290942]
Andreeva 2015 {published data only}
    1. Andreeva T, Zorenko VY, Davydkin I, Konstantinova V, Zalepukhina O, Klimova N, et al. Safety and efficacy of new nonacog alfa drug (innonafactor) in prophylactic treatment in patients with severe and moderate hemophilia B. Blood 2015;126(23):3532. [CENTRAL: CN-01199405] [CFGD REGISTER: HB27a] [EMBASE: 72174222]
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Antunes 2013 {published data only}
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    1. Antunes SV, Tangada S, Phillips J, Stasyshyn O, Mamonov V, Guzman-Becerra N, et al. Comparison of historic on-demand versus prospective on-demand and prophylaxis bleeding episodes in hemophilia A and B patients with inhibitors treated with FEIBA NF. Haemophilia 2014;20:96. [CENTRAL: CN-01063882] [CFGD REGISTER: HG66g] [EMBASE: 71475655]
    1. Antunes SV, Tangada S, Stasyshyn O, Mamonov V, Phillips J, Guzman-Becerra N, et al. Randomized comparison of prophylaxis and on-demand regimens with FEIBA NF in the treatment of haemophilia A and B with inhibitors. Haemophilia 2014;20(1):65-72. [CFGD REGISTER: HG66a] - PMC - PubMed
    1. Stasyshyn O, Antunes S, Mamanov V, Ye X, Xiong Y, Tangada S. Health-related quality of life in hemophilia patients with inhibitors receiving prophylaxis with anti-inhibitor coagulant complex (AICC): results from the AICC prophylaxis study. Journal of thrombosis and haemostasis 2013;11 Suppl 2:719. [ABSTRACT NO: PB 2.58-5] [CFGD REGISTER: HG66d] - PubMed
    1. Stasyshyn O, Antunes S, Mamonov V, Ye X, Epstein J, Xiong Y, et al. Prophylaxis with anti-inhibitor coagulant complex improves health-related quality of life in haemophilia patients with inhibitors: results from FEIBA NF Prophylaxis Study. Haemophilia 2014;20(5):644-50. [CFGD REGISTER: HG66b] - PubMed
ASPIRE 2020 {published data only}
    1. Nolan B, Mahlangu J, Pabinger I, Young G, Konkle BA, Barnes C, et al. Recombinant factor VIII Fc fusion protein for the treatment of severe haemophilia A: final results from the ASPIRE extension study. Haemophilia 2020;26(3):494-502. - PMC - PubMed
    1. Nolan B, Mahlangu J, Perry D, Young G, Liesner R, Konkle B, et al. Long-term safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in subjects with haemophilia A. Haemophilia 2016;22(1):72-80. - PubMed
Astermark 1999 {published data only}
    1. Astermark J, Petrini P, Tengbrorn L, Schulman S, Ljung R, Berntorp E. Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized. British Journal of Haematology 1999;105(4):1109-13. - PubMed
Astermark 2019 {published data only}
    1. Astermark J, Angchaisuksiri P, Benson G, Castaman G, Chowdary P, Eichler H, et al. Subcutaneous prophylaxis with the anti-TFPI monoclonal antibody concizumab in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results. Research and Practice in Thrombosis and Haemostasis 2019;3(Suppl 2):1. [CFGD REGISTER: HG119c]
    1. EUCTR2016-000510-30-ES. A trial evaluating the efficacy and safety of prophylactic administration of concizumab in haemophilia a and b patients with inhibitors [A multi-Centre, randomised, open-label, controlled trial evaluating the efficacy and safety of prophylactic administration of concizumab in haemophilia a and b patients with inhibitors - explorer™4]. http://www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2016-000510-30-ES (date of registration 02 June 2017). [CFGD REGISTER: HG119b]
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    1. NCT03196284. A trial evaluating the efficacy and safety of prophylactic administration of concizumab in haemophilia a and b patients with inhibitors. clinicaltrials.gov/show/NCT03196284 (first posted 22 June 2017). [CFGD REGISTER: HG119a]
    1. Shapiro A, Castaman G, Cepo K, Hvitfeldt Poulsen L, Hollensen C, Matsushita T, et al. Efficacy and safety of subcutaneous prophylaxis with concizumab in patients with hemophilia A or B with inhibitors: results from explorer4, a phase 2, randomized, open-label, controlled trial. Blood 2019;134. [CFGD REGISTER: HG119e]
Bertolet 2020 {published data only}
    1. Bertolet M, Brooks MM, Ragni MV. The design of a Bayesian platform trial to prevent and eradicate inhibitors in patients with hemophilia. Blood Advances 2020;4(21):5433-41. [CFGD REGISTER: HA160b] - PMC - PubMed
    1. NCT04303559. The hemophilia inhibitor prevention trial. clinicaltrials.gov/show/NCT04303559 (first posted 11 March 2020). [CFGD REGISTER: HA160a]
Booth 2017 {published data only}
    1. Booth J, Ito D, Lee H-Y, Abbuehl B. Health-related quality of life in previously treated severe haemophilia a patients with extended half-life, pegylated, full-length, recombinant factor VIII (BAX855) prophylaxis. Haemophilia 2017;23:75.
Brackmann 1992 {published data only}
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Carlsson 1997 {published data only}
    1. Carlsson M, Berntorp E, Bjorkman S, Lethagen S, Lindvall K, Ljung R. Clinical experience of pharmacokinetic dosing of Factor VIII for prophylaxis. Haemophilia 1996;2 Suppl 1:16. [CENTRAL: CN-00462741] [CFGD REGISTER: HA11b]
    1. Carlsson M, Berntorp E, Bjorkman S, Lethagen S, Ljung R. Improved cost-effectiveness by pharmacokinetic dosing of factor VIII in prophylactic treatment of haemophilia A. Haemophilia 1997;3(2):96-101. [CENTRAL: CN-00198032] [CFGD REGISTER: HA11a] [EMBASE: 27187173] - PubMed
Chakraborty 2018 {published data only}
    1. Chakraborty J, Bhattacharyya M, Sankar Ray S. Effect of low dose prophylaxis versus episodic treatment on joint events in severe hemophilia a patients above 2 years: a randomized open label pilot study in Eastern India. Indian Journal of Hematology & Blood Transfusion 2018;34(1):68. [CFGD REGISTER: HA158]
Chowdary 2013 {published data only}
    1. Chowdary P, Friedrich U, Lethagen S, Angchaisuksiri P. A new treatment concept for haemophilia: Safety, pharmacokinetics and pharmacodynamics of single i.v. and s.c. Doses of a monoclonal anti-TFPI antibody in healthy males and haemophilia subjects. Journal of thrombosis and haemostasis 2013;11 Suppl 2:460. [CFGD REGISTER: HG86b]
    1. Chowdary P, Lethagen S, Friedrich U, Brand B, Hay C, Karim FA, et al. Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial. Journal of thrombosis and haemostasis : JTH 2015;13(5):743-54. [CFGD REGISTER: HG86a] - PubMed
Chowdary 2017 {published data only}
    1. Chowdary P, Georgiev P, Mant T, Creagh MD, Lissitchkov T, Bevan D, et al. Phase 1 and phase 1/2 extension study of fitusiran, an investigational rnai therapeutic targeting antithrombin for the treatment of hemophilia: updated results in patients without inhibitors. Haemophilia 2017;23 Suppl 2:118-9. [CENTRAL: CN-01333721] [CFGD REGISTER: HG103a] [EMBASE: 614511018]
    1. Pasi KJ, Georgiev P, Mant T, Creagh MD, Lissitchkov T, Bevan D, et al. Phase 1 and phase 1/2 extension study of fitusiran, an investigational rnai therapeutic targeting antithrombin for the treatment of hemophilia: updated results in patients with inhibitors. Haemophilia 2017;23 Suppl 2:88-9. [CFGD REGISTER: HG103b]
Chozie 2018 {published data only}
    1. Chozie N, Primacakti F, Tulaar A, Setiabudy R, Prasetyo M, Gatot D. Low-dose prophylaxis versus on-demand treatment in Indonesian children with severe hemophilia A: an interim report. Haemophilia 2018;24 Suppl 5:94. [CENTRAL: CN-01612434] [CFGD REGISTER: HA148a] [EMBASE: 622461495]
    1. Chozie NA, Primacakti F, Gatot D, Setiabudhy RD, Tulaar ABM, Prasetyo M. Comparison of the efficacy and safety of 12-month low-dose factor VIII tertiary prophylaxis vs on-demand treatment in severe haemophilia A children. Haemophilia 2019;25(4):633-9. [CENTRAL: CN-01937513] [CFGD REGISTER: HA148b] [EMBASE: 627554739] [PMID: ] - PubMed
Chuansumrit 1995 {published data only}
    1. Chuansumrit A, Hathirat I, Hathirat P. Prophylactic treatment for haemophilia A patients: a pilot study. Southeast Asian Journal of Tropical Medicine of Public Health 1995;26(2):243-6. - PubMed
Collins 2010 {published data only}
    1. Collins P, Faradji A, Morfini M, Enriquez MM, Schwarz L. Efficacy and safety of secondary prophylactic vs. on-demand sucrose-formulated recombinant factor VIII treatment in adults with severe hemophilia A: results from a 13-month crossover study. Journal of Thrombosis and Haemostasis 2010;8(1):83-9. - PubMed
Collins 2014 {published data only}
    1. Chowdary P, Kearney S, Meunier J, Hoxer CS, Yee DL. Improvement in health status and quality of life in patients with haemophilia B treated with nonacog beta pegol, an extended half-life glycopegylated recombinant FIX product. Haemophilia 2016;22 Suppl 4:119. [CENTRAL: CN-01409403] [CFGD REGISTER: HB25d] [EMBASE: 617734554] - PubMed
    1. Chowdary P, Kearney S, Regnault A, Hoxer CS, Yee DL. Improvement in health-related quality of life in patients with haemophilia B treated with nonacog beta pegol, a new extended half-life recombinant FIX product. Haemophilia 2016;22(4):e267-74. [CENTRAL: CN-01177257] [CFGD REGISTER: HB25e] [EMBASE: 611361168] [PMID: ] - PubMed
    1. Collins PW, Colberg T, Young G, Abdul Karim F, Angchaisuksiri P, Gursel T, et al. Safety, efficacy and pharmacokinetics of nonacog beta pegol (N9-GP) for prophylaxis and treatment of bleeding episodes in patients with haemophilia B. Journal of thrombosis and haemostasis : JTH 2013;11 Suppl:19. [ABSTRACT NO: AS 12.4] [CFGD REGISTER: HB25c]
    1. Collins PW, Young G, Knobe K, Karim FA, Angchaisuksiri P, Banner C, et al. Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial. Blood 2014;124(26):3880-6. [CFGD REGISTER: HB25a] - PMC - PubMed
    1. Escobar M, Young G, Oldenburg J, Mahlangu J, Carcao M, Santagostino E, et al. Prophylactic efficacy of nonacog beta pegol once weekly in adult and pediatric patients with hemophilia B: a pooled analysis. American Journal of Hematology 2016;91(9):E417. [CENTRAL: CN-01763712] [CFGD REGISTER: HB25j] [EMBASE: 611870302]
Courter 2001 {published data only}
    1. Courter SG, Bedrosian CL. Clinical evaluation of B-domain deleted recombinant factor VIII in previously untreated patients. Seminars in Hematology 2001;38(2 Suppl 4):52-9. [CENTRAL: CN-00385713] [CFGD REGISTER: HA62a] - PubMed
Curry 2019 {published data only}
    1. Carcao M, Clausen WH, Holme PA, Moss J, Tosetto A, Wheeler A, et al. Simple and fixed N8-GP dosing regimen associated with measurable trough levels and low annualised bleed rates in children and adolescents/adults treated with N8-GP prophylaxis. Haemophilia 2018;24 Suppl 5:92-3. [CENTRAL: CN-01612439] [CFGD REGISTER: HA151b] [EMBASE: 622461441]
    1. Chowdary P, Chitlur M, Clausen WH, Escobar M, Kearney S, Landorph A, et al. N8-GP treatment sustains low bleeding rates in patients with haemophilia A. Research and Practice in Thrombosis and Haemostasis 2019;3:266-7. [CENTRAL: CN-01980920] [CFGD REGISTER: HA151g] [EMBASE: 628813777]
    1. Chowdary P, Hvitfeldt PL, Escobar MA, Kearney S, Chitlur MB, Klamroth R, et al. Efficacy of an extended half-life glycoPEGylated rFVIII (N8-GP): pooled analysis of ABR (results from two clinical trials). Blood 2018;132 Suppl 1:1177. [CENTRAL: CN-01658795] [CFGD REGISTER: HA151a]
    1. Curry N, Albayrak C, Escobar M, Andre Holme P, Kearney S, Klamroth R, et al. Once-weekly prophylaxis with glycoPEGylated recombinant factor VIII (N8-GP) in severe haemophilia A: safety and efficacy results from Pathfinder 2 (randomized phase III trial). Haemophilia 2019;25(3):373-81. [CENTRAL: CN-01999995] [CFGD REGSTER: HA151e] [EMBASE: 626601436] [PMID: ] - PMC - PubMed
    1. Curry N, Albayrak C, Escobar M, Holme PA, Kearney S, Klamroth R, et al. Once-weekly prophylaxis with GlycoPEGylated recombinant factor VIII (N8-GP) in severe haemophilia A: safety and efficacy results from a randomised phase 3 trial (PathfinderTM2). Research and Practice in Thrombosis and Haemostasis 2017;1 Suppl 1:730. [CENTRAL: CN-01653696] [CFGD REGISTER: HA151c] [EMBASE: 624157645]
Davydkin 2015 {published data only}
    1. Andreeva T, Zorenko VY, Davydkin I, Konstantinova V, Zalepukhina O, Klimova N, et al. Safety and efficacy of new nonacog alfa drug (innonafactor) in prophylactic treatment in patients with severe and moderate hemophilia b. Blood 2015;126(23):3532. [CFGD REGISTER: HB27a]
    1. Davydkin I, Andreeva T, Zorenko VY, Konstantinova V, Zalepukhina O, Klimova N, et al. Safety and efficiency of new nonacog alfa drug in the treatment of bleeding episodes in patients with severe and moderate hemophilia b. Blood 2015;126(23):4690. [CFGD REGISTER: HB27b]
Dzinaj 1996 {published data only}
    1. Dzinaj T, Funk M, Schimdt H, Bottger S, Gngor T, Klarmann D, et al. Radiological score in paediatric haemophilic patients with early and late onset of factor VIII-prophylaxis. Thrombosis Haemostasis 1996;76(4):630-1. - PubMed
Eichler 2018 {published data only}
    1. Eichler H, Angchaisuksiri P, Kavakli K, Knoebl P, Windyga J, Jimenez-Yuste V, et al. A randomized trial of safety, pharmacokinetics and pharmacodynamics of concizumab in people with hemophilia A. Journal of thrombosis and Haemostasis 2018;16(11):2184-95. [CFGD REGISTER: HG120b] - PubMed
    1. Eichler H, Angchaisuksiri P, Kavakli K, Knoebl P, Windyga J, Jimenez-Yuste V, et al. Evaluation of safety and establishment of a PK/PD relationship of concizumab in hemophilia a patients. Research and Practice in Thrombosis and Haemostasis 2017;1(Suppl 2):1-2. [CFGD REGISTER: HG120c]
    1. NCT02490787. Trial investigating safety, pharmacokinetics and pharmacodynamics of concizumab administered subcutaneously to haemophilia a subjects [A multi-centre, randomised, placebo controlled, double blinded, multiple dose trial investigating safety, pharmacokinetics and pharmacodynamics of concizumab administered subcutaneously to haemophilia a subjects (Explorer™3)]. clinicaltrials.gov/show/NCT02490787 2015. [CFGD REGISTER: HG120a]
ENJOIH 2010 {published data only}
    1. EUCTR2009-010172-21-IT. An Investigator-sponsored study on rFVIIa prophylaxis in children with haemophilia A and inhibitors - ENJOIH 01. www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2009-010172-21-IT (date of registration 25 June 2009). [CENTRAL: CN-01815265] [CFGD REGISTER: HA100c]
    1. Santagostino E, Auerswald G, Jimenez-Yuste V, Ljung R, Morfini M, Rocino A, et al. European Initiative to prevent joint damage in haemophilia children with inhibitors (ENJOIH) - a prospective study. Haemophilia 2010;16(2):407. [CENTRAL: CN-01743918] [CFGD REGISTER: HA100d] [EMBASE: 70211995]
    1. Santagostino E, Auerswald G, Jimenez-Yuste V, Ljung R, Morfini M, Rocino A, et al. European initiative to prevent joint damage in haemophilia children with inhibitors (ENJOIH) - a prospective study. Haemophilia 2010;16 Suppl 4:78. [ABSTRACT NO: 17P63] [CFGD REGISTER: HA100a]
    1. Santagostino E. European initiative to prevent joint damage in haemophilia children with inhibitors (ENJOIH) - a prospective study. Haemophilia 2012;18 Suppl 1:4-5. [CFGD REGISTER: HA100b]
Escuriola 2019 {published data only}
    1. Escuriola Ettingshausen C, Hegemann I, Simpson ML, Cuker A, Kulkarni R, Pruthi RK, et al. Favorable pharmacokinetics in hemophilia B for nonacog beta pegol versus recombinant factor IX-Fc fusion protein: a randomized trial. Research and Practice in Thrombosis and Haemostasis 2019;3(2):268-76. [CENTRAL: CN-01916204] [CFGD REGISTER: HB29] [EMBASE: 626889048] [PMID: ] - PMC - PubMed
ESPRIT 2011 {published data only}
    1. Fusco F, Gringeri A, Riva S, Leissinger C, Mackensen S, Mannucci PM. Direct costs of children with haemophilia A undergoing prophylaxis or episodic treatment: results from the ESPRIT study. In: 16th Congress of the European Hematology Association; 2011 June 9-12; London, UK. 2011. [CENTRAL: CN-01017612] [CFGD REGISTER: HA63l]
    1. Gringeri A, Fusco F, Riva A, von M, Mantovani LG. Direct costs of children with haemophilia A undergoing prophylaxis or episodic treatment: results from the ESPRIT study. Journal of Thrombosis and Haemostasis 2011;9 Suppl 2:927. [ABSTRACT NO.: P-TH-510] [CENTRAL: CN-01015138] [CFGD REGISTER: HA63j]
    1. Gringeri A, Lundin B, Von Mackensen S, Mantovani L, Mannucci P. A randomized clinical trial on prophylaxis Vs. episodic treatment in children with haemophilia A: the ESPRIT study. Haemophilia 2010;16 Suppl 4:29. [ABSTRACT NO.: 07FP06] [CENTRAL: CN-00868063] [CFGD REGISTER: HA63g]
    1. Gringeri A, Lundin B, Mackensen S, Mantovani L, Mannucci PM, ESPRIT SG. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study). Journal of Thrombosis and Haemostasis 2011;9(4):700-10. [CENTRAL: CN-00785003] [CFGD REGISTER: HA63f] [PMID: ] - PubMed
    1. Gringeri A, Lundin B, Mackensen S, Mantovani LG, Mannucci PM, Bianchi Bonomi A. Primary and secondary prophylaxis in children with haemophilia A reduces bleeding frequency and arthropathy development compared to on-demand treatment: a 10-year, randomized, clinical trial. In: XXII Congress of the International Society on Thrombosis and Haemostasis (ISTH); 2009 Jul 11-16; Boston, MA, USA. 2009. [ABSTRACT NO.: OC-MO-034] [CENTRAL: CN-00759023] [CFGD REGISTER: HA63e]
Feldman 2006 {published data only}
    1. Feldman BM, Pai M, Rivard GE, Israels S, Poon MC, Demers C, et al. Tailored prophylaxis in severe hemophilia A: interim results from the first 5 years of the Canadian Hemophilia Primary Prophylaxis Study. Journal of Thrombosis and Haemostasis 2006;4(6):1228-36. - PubMed
Fernandez‐Bello 2017 {published data only}
    1. Fernandez-Bello I, Stenmo C, Butta N, Lind V, Ezban M, Jimenez-Yuste V. The pharmacokinetics and pharmacodynamics of single-dose and multiple-dose recombinant activated factor VII in patients with haemophilia A or B. Haemophilia 2017;23(6):868-76. [CENTRAL: CN-01432152] [CFGD REGISTER: HG101] [EMBASE: 619311897] [PMID: ] - PubMed
Fischer 2005 {published data only}
    1. Fischer K, Van Dijk K, Van Den Berg HM. Late prophylaxis for severe hemophilia: effects of prophylaxis started in adulthood. Journal of Thrombosis and Haemostasis 2005;3 Suppl 1:OR205.
HAVEN 1 2017 {published data only}
    1. Adamkewicz JI, Schmitt C, Asikanius E, Xu J, Levy G, Kim B, et al. Factor VIII (FVIII) inhibitor testing using a validated chromogenic bethesda assay (CBA) in HAVEN 1 (BH29884), a Phase 3 trial of emicizumab in persons with hemophilia a (PwHA) with inhibitors. Research and Practice in Thrombosis and Haemostasis 2017;1 Suppl 1:724-5. [CENTRAL: CN-01924804] [CFGD REGISTER: HA149l] [EMBASE: 624157307]
    1. Callaghan M, Negrier C, Young G, Khoo L, Mahlangu J, Windyga J, et al. Use of bypassing agents prior to and post bypassing agent dosing guidance during emicizumab prophylaxis: Analyses from the haven 1 study.. British Journal of Haematology 2018 Suppl 1;181:129. [CFGD REGISTER: HA149d]
    1. Callaghan MU, Kuebler PJ, Gao L, Ko RH, Devenport J, Liberman M. Characterization of the impact of prior iti on patient outcomes in haven1. American Journal of Hematology 2018;93(9):E10-1. [CENTRAL: CN-01654451] [CFGD REGISTER: HA149k] [EMBASE: 624570187]
    1. Callaghan MU, Negrier C, Young G, Khoo L, Mahlangu J, Windyga J, Oldenburg J, et al. Use of bypassing agents prior to and post bypassing agent dosing guidance during emicizumab prophylaxis: analyses from the HAVEN 1 study. Blood 2017;130 Suppl 1:3668. [CFGD REGISTER: HA149c]
    1. Kruse-Jarres R, Callaghan M, Croteau SE, JimenezYuste V, Khoo L, Liesner R, et al. Surgical experience in two multicentre, openlabel phase 3 studies of emicizumab in persons with haemophilia a with inhibitors (HAVEN 1 and HAVEN 2). British Journal of Haematology 2018;181 Suppl 1:128. [CFGD REGISTER: HA149f]
Hazendonk 2015 {published data only}
    1. Goedhart MHJ, Bukkems LH, Van Moort I, Spence CC, Gouw SC, Mathot RAA, et al. Does variation between label and actual potency of factor VIII concentrate vials affect results of pharmacokinetic (PK)-guided dosing of replacement therapy in hemophilia A. Research and Practice in Thrombosis and Haemostasis 2020;4 (Suppl 1):465. [CFGD REGISTER: HA133d]
    1. Hazendonk HC, Moort I, Fijnvandraat K, Kruip MJ, Laros-van Gorkom BA, Meer FJ, et al. The "OPTI-CLOT" trial. A randomised controlled trial on periOperative PharmacokineTIc-guided dosing of CLOTting factor concentrate in haemophilia A. Thrombosis and Haemostasis 2015;114(3):639-44. [CFGD REGISTER: HA133a] - PubMed
    1. Van Moort I, Bukkems LH, Heijdra JH, Schutgens R, Laros-Van Gorkom B, Nieuwenhuizen L, et al. Von Willebrand factor and its effect on FVIII clearance in perioperative hemophilia a patients. Haemophilia 2020;26:84-5. [CFGD REGISTER: HA133c] - PubMed
    1. Van Moort I, Preijers T, Bukkems L, Hazendonk H, Laros-van Gorkom B, Beckers E, et al. A randomized controlled trial: pharmacokinetic-guided dosing of factor VIII concentrate versus standard replacement therapy in perioperative hemophilia A patients (OPTI-CLOT Trial). Research and Practice in Thrombosis and Haemostasis 2020;4 Suppl 1:438. [CFGD REGISTER: HA133b]
INHIBIT 2014 {published data only}
    1. Ragni M, Kessler C, Fogarty P, Josephson N, Neff A, Raffini L. Phase III randomized, controlled trial of pre-emptive vs. standard prophylaxis to prevent inhibitor formation in children with severe hemophilia A: The inhibit study. Haemophilia 2011;17(3):563. [CENTRAL: CN-01003693] [CFGD REGISTER: HA138a] [EMBASE: 70566586]
    1. Ragni MV, Malec LM. Design of the INHIBITOR trial: preventing inhibitors by avoiding 'danger', prolonging half-life and promoting tolerance. Expert Review of Hematology 2014;7(6):747-55. [CENTRAL: CN-01426920] [CFGD REGISTER: HA138b] - PMC - PubMed
    1. Ragni MV. Feasibility of the Hemophilia INHIBIT trial. grantome.com/grant/NIH/U34-HL114674-02 (accessed 04 December 2017). [CENTRAL: CN-01426921] [CFGD REGISTER: HA138c]
Kavakli 1997 {published data only}
    1. Kavakli K, Nisli G, Aydinok Y, Oztop S, Cetingul N, Aydogdu S. Prophylactic therapy for hemophilia in a developing country, Turkey. Pediatric Hematology and Oncology 1997;14(2):151-9. - PubMed
Khayat 2016 {published data only}
    1. Auerswald G, Skotnicki A, Pompa MT, Lissitchkov T, Joch C, Seifert W, et al. Overview of the clinical development program swift for the VWF/FVIII concentrate voncento in haemophila a and von willebrand disease. Haemophilia 2017;23:68. [CENTRAL: CN-01333741] [CFGD REGISTER: HA121d] [EMBASE: 614510871]
    1. Khayat C, Iosava G, Romashevskaya I, Aleinikova O, Stasyshyn O, Vashchenko L, et al. Efficacy and safety results of a phase 3, open label, multicentre study with Voncento in paediatric haemophilia A subjects < 12 years of age (SWIFTLY-HA study). Hamostaseologie 2016;36:A54. [CENTRAL: CN-01364579] [CFGD REGISTER: HA121c] [EMBASE: 615222264]
    1. Klukowska A, Skotnicki A, Lissitchkov T, Mamonov V, Buevich E, Kuliczkowski K, et al. Efficacy, safety and pharmacokinetic results of a phase II/III, multicentre, double-blinded, randomized, cross-over study with a plasma-derived von Willebrand Factor (VWF)/factorVIII (FVIII) concentrate (Voncento®) in subjects with hemophilia A (the SWIFT-HA study). Haemophilia 2014;20 Suppl 3:16. [CFGD REGISTER: HA121a]
    1. Pompa MT, Iosava G, Khayat C, Romashevskaya I, Aleinikova O, Stasyshyn O, et al. A phase III, open-label, multicentre study to evaluate efficacy and safety of a plasma-derived von Willebrand factor/ factor VIII concentrate in pediatric subjects with hemophilia A (Swiftly-HA study). Journal of thrombosis and haemostasis : JTH 2015;13 Suppl 2:841. [ABSTRACT NO: PO249-WED] [CFGD REGISTER: HA121b]
Kids B‐LONG 2017 {published data only}
    1. Fischer K, Kulkarni R, Nolan B, Mahlangu J, Rangarajan S, Gambino G, et al. Recombinant factor IX Fc fusion protein in children with haemophilia B (Kids B-LONG): results from a multicentre non-randomised phase 3 study. Lancet Haematology 2017;4(2):e75-e82. - PubMed
Konkle 2016 {published data only}
    1. Booth J, Ito D, Lee H-Y, Abbuehl B. Health-related quality of life in previously treated severe haemophilia a patients with extended half-life, pegylated, full-length, recombinant factor VIII (BAX855) prophylaxis. Haemophilia 2017;23:75. [CFGD REGISTER: HA130h]
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    1. Konkle B, Stasyshn O, Wyn TT, Manco-Johnson MJ, Gruppo RA , Tran H, et al. Results of a pivotal clinical trial evaluating a full-length pegylated recombinant factor VIII (Peg-RFVIII) with extended half-life in haemophilia A. Haemophilia 2015;21 Suppl 2:30-31. [CFGD REGISTER: HA130c]
    1. Konkle BA, Stasyshn O, Wynn TT, Manco-Johnson MJ, Gruppo R , Chowdary P, et al. Bleeding patterns during prophylaxis with a full-length pegylated recombinant factor VIII (Bax 855) with extended half-life in hemophilia a. Haemophilia 2016;22 Suppl 2:99. [ABSTRACT NO.: P128] [CENTRAL: CN-01216066] [CFGD REGISTER: HA130e]
Kreuz 1998 {published data only}
    1. Kreuz W, Escuriola-Ettinghausen C, Funk M, Schmidt H, Kornhuber B. When should prophylactic treatment in patients with haemophilia A and B start?- the German experience. Haemophilia 1998;4(4):413-7. - PubMed
LEOPOLD I 2015 {published data only}
    1. Church N, Ayyagari R, Pocoski J, Sajeev G, Kelkar SS, Du EX, et al. Patterns of prior treatment and bleeds among patients with severe hemophilia a: impact on frequency of dosing with bay 81-8973 in the Leopold I trial. Blood 2015;126(23):1103. [CENTRAL: CN-01199448] [CFGD REGISTER: HA129h] [EMBASE: 72171649]
    1. Church N, Ayyagari R, Pocoski J, Sajeev G, Sneha K, Du EX, et al. Bleed occurrence after Bay 81-8973 injection and characteristics of patients who respond to prophylaxis: analyses from Leopold I and II. Haemophilia 2016;22 Suppl 2:78-9. [CENTRAL: CN-01612491] [CFGD REGISTER: HA129j] [EMBASE: 622470086]
    1. Garmann D, McLeay S, Shah A, Vis P, Maas Enriquez M, Ploeger BA. Population pharmacokinetic characterization of BAY 81-8973, a full-length recombinant factor VIII: lessons learned - importance of including samples with factor VIII levels below the quantitation limit. Haemophilia 2017;23(4):528-37. [CENTRAL: CN-01395099] [CFGD REGISTER: HA129q] [EMBASE: 614542165] - PubMed
    1. Humphries TJ, Church N, Lalezari S, Poulsen LH, Yoon M, Enriquez MM. Rationale for investigator-assigned prophylaxis dosing frequency in the leopold I study. Blood 2016;128(22):4984. [CENTRAL: CN-01334930] [CFGD REGISTER: HA129o] [EMBASE: 614266476]
    1. Kavakli K, Saxena K, Maas Enriquez M. Study design of 2 randomized, crossover, open-label trials to evaluate the pharmacokinetics, efficacy, and safety of plasma protein-free recombinant factor VIII formulated with sucrose (BAY 81-8973). Haemophilia 2012;18 Suppl 3:25. [ABSTRACT NO.: PO-WE-057] [CENTRAL: CN-00883170] [CFGD REGISTER: HA129a]
Liesner 1996 {published data only}
    1. Liesner RJ, Khair K, Hann IM. The impact of prophylactic treatment in children with severe haemophilia. British Journal of Haematology 1996;92(4):973-8. - PubMed
Lofqvist 1997 {published data only}
    1. Löfqvist T, Nilsson IM, Berntorp E, Pettersson H. Haemophilia prophylaxis in young patients - a long-term follow-up. Journal of Internal Medicine 1997;241(5):395-400. - PubMed
Ma 2015 {published data only}
    1. Ma AD, Klamroth R, Manco-Johnson MJ, Engl W, Dyck-Jones JA, Abbuehl BE. Characteristics of patients without bleeding in a pivotal trial of extended half-life, pegylated, full-length recombinant factor VIII (BAX 855) in the treatment of hemophilia a. Blood 2015;126(23):1105.
Manco‐Johnson 1994 {published data only}
    1. Manco-Johnson MJ, Nuss R, Geraghty S, Funk S, Kilcoyne R. Results of secondary prophylaxis in children with severe hemophilia. American Journal of Hematology 1994;47(2):113-7. - PubMed
Manco‐Johnson 2007 {published data only}
    1. Hacker MR, Page JH, Shapiro AD, Rich-Edwards JW, Manco-Johnson MJ. Central venous access device infections in children with hemophilia: a comparison of prophylaxis and episodic therapy. Journal of Pediatric Hematology/oncology 2007;29(7):458-64. [CENTRAL: CN-01714304] [CFGD REGISTER: HA65e] [EMBASE: 47026247] [PMID: ] - PubMed
    1. Manco-Johnson MJ, Abshire TC, Brown D, Buchanan GR, Cohen AR, DiMichele D, et al. Initial results of a randomized, prospective trial of prophylaxis to prevent joint disease in young children with factor VIII (FVIII) deficiency. Blood 2005;106 Suppl. [ABSTRACT NO: 3] [CFGD REGISTER: HA65c]
    1. Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. New England Journal of Medicine 2007;357(6):535-44. [CFGD REGISTER: HA65d] - PubMed
    1. Manco-Johnson MJ, Blanchette VS. North American prophylaxis studies for persons with severe haemophilia: background, rationale and design. Haemophilia 2003;9 Suppl 1:44-9. [CFGD REGISTER: HA65a] - PubMed
    1. Manco-Johnson MJ, Manco-Johnson ML, Blades TA, Funk S, Lane H, Dunn AL, et al. What is the cost of delaying prophylaxis until the school years? Results from the joint outcome study continuation project. Haemophilia 2014;20:99-100. [CFGD REGISTER: HA65i]
NCT03315455 {published data only}
    1. NCT03315455. Efficacy, safety, and pharmacokinetic study of prophylactic emicizumab versus no prophylaxis in hemophilia a participants [A randomized, multicenter, open-label, phase III clinical trial to evaluate the efficacy, safety, and pharmacokinetics of prophylactic emicizumab versus no prophylaxis in hemophilia a patients]. clinicaltrials.gov/show/NCT03315455 (first posted 20 October 2017). [CFGD REGISTER: HA159a]
    1. Wang S, Zhao X, Wang X, Sun J, Chuansumrit A, Zhou J, et al. A randomized, multicenter, open-label, phase III clinical trial to evaluate the efficacy, safety, and pharmacokinetics of prophylactic emicizumab versus no prophylaxis in persons with hemophilia A in the Asia-pacific region (HAVEN 5). Research and Practice in Thrombosis and Haemostasis 2020;4(Suppl 1):480. [CFGD REGISTER: HA159b]
NCT04303559 {published data only}
    1. NCT04303559. The hemophilia inhibitor prevention trial [Multicenter, randomized phase III inhibitor prevention trial, comparing eloctate vs. emicizumab to prevent inhibitor formation in severe hemophilia a]. clinicaltrials.gov/show/NCT04303559 (first posted 11 March 2020). [CFGD REGISTER: HA160a]
Nemes 2007 {published data only}
    1. Abbuehl B, Lissitchkov T, Dobaczewski G, Nemes L, Klukowska A, Komrska V, et al. Interum analysis of a phase 3, prospective, multicenter study to evaluate the pharmacokinetics, immunogenicity, safety, and efficacy of Immunate solvent detergent (Immunate S/D) in previously treated patients with severe or moderately severe hemophilia A. Haemophilia 2004;10 Suppl 3:02 PO 07. [CENTRAL: 593077] [CFGD REGISTER: HA86a]
    1. Nemes L, Lissitchkov T, Dobaczewski G, Klukowska A, Komrska V, Zimmermann R, et al. Pharmacokinetics, efficacy and safety of IMMUNATE solvent/detergent (IMMUNATE S/D) in previously treated patients with severe hemophilia A: results of a prospective, multicenter, open-label phase III study. Acta Haematologica 2008;119(2):89-97. [CENTRAL: 714803] [CFGD REGISTER: HA86c] - PubMed
    1. Nemes L, Lissitchkov T, Klukowska A, Dobaczewski G, Komrska V, Zimmermann R, et al. Evaluation of pharmacokinetics, efficacy and safety of Immunate solvent detergent in previously treated patients with severe haemophilia A. Haemophilia 2007;13(1):9-11. [CENTRAL: CN-00609089] [CFGD REGISTER: HA86b] [PMID: ] - PubMed
Nilsson 1970 {published data only}
    1. Nilsson IM, Blomback M, Ahlberg A. Our experience in Sweden with prophylaxis on haemophilia. Bibliotheca Hematologica 1970;34:111-24. - PubMed
Nilsson 1976 {published data only}
    1. Nilsson IM, Hedner U, Ahlberg A. Hemophilia prophylaxis in Sweden. Acta Paediatrica Scandinavica 1976;65(2):129-35. - PubMed
Nilsson 1992 {published data only}
    1. Nilsson IM, Berntorp E, Löfqvist T, Pettersson H. Twenty-five years experience of prophylactic treatment in severe haemophilia A and B. Journal of Internal Medicine 1992;232(1):25-32. - PubMed
PERSEPT 1 2017 {published data only}
    1. Wang M, Lawrence J, Quon D, Reding M, Ducore J, Simpson M, et al. The global, multi-center, phase III, randomized, efficacy, pharmacokinetic and safety cross-over study (PERSEPT 1) of two dose regimens of eptacog beta (rhFVIIa) in congenital hemophilia A and B patients with inhibitors to factor VIII or IX (HABI). Haemophilia 2016;22 Suppl 4:151-2. [CENTRAL: CN-01409384] [CFGD REGISTER: HG91a] [EMBASE: 617734708]
    1. Wang M, Lawrence JB, Quon DV, Ducore J, Simpson ML, Boggio LN, et al. PERSEPT 1: a phase 3 trial of activated eptacog beta for on-demand treatment of haemophilia inhibitor-related bleeding. Haemophilia 2017;23(6):832-43. [CENTRAL: CN-01614346] [CFGD REGISTER: HG91b] [EMBASE: 617649074] [PMID: ] - PubMed
Petrini 1991 {published data only}
    1. Petrini P, Lindvall N, Egberg N, Blomback M. Prophylaxis with factor concentrates in preventing hemophilic arthropathy. American Journal of Pediatric Hematology/Oncology 1991;13(3):280-7. - PubMed
Pettersson 1981 {published data only}
    1. Pettersson H, Nilsson IM, Hedner U, Norehn K, Ahlberg A. Radiologic evaluation of prophylaxis in severe haemophilia. Acta Paediatric of Scandinavia 1981;70(4):565-70. - PubMed
PRO‐FEIBA 2010 {published data only}
    1. Fusco F, Gringeri A, Leissinger C, Cortesi PA, Mantovani LG. Bleeding prophylaxis with an anti-inhibitor coagulant complex (AICC) in patients with hemophilia A and inhibitors can improve quality of life: results of the PRO-FEIBA Study. In: 16th Congress of the European Hematology Association; 2011 June 9-12; London, UK. 2011. [CFGD REGISTER: HA99k]
    1. Gringeri A, Leissinger C, Cortesi P, Matovani LG. Bleeding prophylaxis with an anti-inhibitor coagulant complex (AICC) in patients with hemophilia a and inhibitors can improve quality of life: results of the pro-FEIBA study. Journal of Thrombosis and Haemostasis 2011;9 Suppl 2:927. [ABSTRACT NO: P-TH-509] [CFGD REGISTER: HA99j]
    1. Gringeri A, Leissinger C, Cortesi PA, Jo H, Fusco F, Riva S, et al. Health-related quality of life in patients with haemophilia and inhibitors on prophylaxis with anti-inhibitor complex concentrate: results from the Pro-FEIBA study. Haemophilia 2013;19(5):736-43. [CFGD REGISTER: HA99i] - PubMed
    1. Gringeri A, Leissinger CA, Cortesi P, Jo H, Mantovani L. Cost-effectiveness of prophylaxis with anti-inhibitor complex concentrate in patients with hemophilia A and inhibitors: results from the Pro-FEIBA study. Blood 2011;118(21). [ABSTRACT NO: 4187] [HA99g]
    1. Gringeri A, Lessinger C, Santagostino E, Cortesi P, Mantovani L. Pharmacoeconomic evaluation with an activated prothrombin complex concentrate (APCC) in patients with hemophilia and inhibitors (PRO-FEIBA Study). Haemophilia 2012;18 Suppl 3:70. [ABSTRACT NO: PO-MO-052] [CFGD REGISTER: HA99e]
PROTECT VIII 2017 {published data only}
    1. Boggio LN, Hong W, Wang M, Eyster ME, Michaels LA. Bleeding protection using phenotype-guided bay 94-9027 prophylaxis: Protect VIII study subanalyses. Haemophilia 2015;21 Suppl 2:65. [CENTRAL: CN-01077522] [CFGD REGISTER: HA122b] [EMBASE: 71814491]
    1. Ducore J, Holme PA, Lalezari S, Mancuso M-E, Maas Enriquez M, Bayh I, et al. Consistent control of bleeds among patients with haemophilia A aged >40 years treated with prophylactic bay 94-9027 in the protect VIII study and its extension. Haemophilia 2020;26:101-2. [CFGD REGISTER: HA122cc]
    1. Ducore JM, Lalezari S, Santagostino E, Ahuja SP, Enriquez MM, Tueckmantel C, et al. Improvement in quality of life outcomes and bleeding rates among patients switching from on-demand FVIII to prophylactic bay 94-9027 in the protect VIII study. Blood 2019:134. [CFGD REGISTER: HA122bb]
    1. EUCTR2011-005210-11-AT. A clinical trial investigating safety and efficacy of a long-acting factor VIII in severe hemophila A [A Phase II/III, multicenter, partially randomized, open label trial investigating safety and efficacy of on-demand and prophylactic treatment with BAY 94-9027 in Severe Hemophilia A - PROTECT VIII]. www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2011-005210-11-AT (date of registration 28 March 2012). [CENTRAL: CN-01876552] [CFGD REGISTER: HA122t]
    1. EUCTR2011-005210-11-Outside-EU/EEA. A clinical trial investigating safety and efficacy of a long-acting factor VIII in severe hemophila A [A phase II/III, multicenter, partially randomized, open label trial investigating safety and efficacy of on-demand and prophylactic treatment with BAY94-9027 in severe hemophilia a]. www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2011-005210-11-Outside-... (date of registration 28 March 2012). [CFGD REGISTER: HA122jj]
Ragni 2017 {published data only}
    1. Ragni MV, Yabes JG, Fogarty PF, Josephson NC, Kessler CM, Neff AT, et al. Pilot randomized, non-inferiority, cross-over trial of once-weekly vs. three times-weekly recombinant factor VIII prophylaxis in adults with severe haemophilia A. Haemophilia 2017;23(1):e43-6. [CENTRAL: CN-01216068] [CFGD REGISTER: HA97b] [EMBASE: 613828270] [PMID: ] - PMC - PubMed
    1. Ragni MV. Rationale for a randomized controlled trial comparing two prophylaxis regimens in adults with severe hemophilia A: the Hemophilia Adult Prophylaxis Trial. Expert Review of Hematology 2011;4(5):495-507. [CFGD REGISTER: HA97a] - PMC - PubMed
Ramsay 1973 {published data only}
    1. Ramsay DM, Parker AC. A trial of prophylactic replacement therapy in haemophilia and Christmas disease. Journal of Clinical Pathology 1973;26(4):243-7. - PMC - PubMed
Royal 2002 {published data only}
    1. Royal S, Schramm W, Berntorp E, Giangrande P, Gringeri A, Ludlam C, et al. Quality-of-life differences between prophylactic and on-demand factor replacement therapy in European haemophilia patients. Haemophilia 2002;8(1):44-50. - PubMed
Santagostino 2016 {published data only}
    1. Santagostino E, Martinowitz U, Lissitchkov T, Pan-Petesch B, Hanabusa H, Oldenburg J, et al. Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood 2016;127(14):1761-9. - PMC - PubMed
Schimpf 1977 {published data only}
    1. Schimpf KI, Fisher B, Rothmann P. Hemophilia A prophylaxis with factor VIII concentrate in a home-treatment program: a controlled study. Scandinavian Journal of Haematology. Supplementum 1977;30:1979-80. - PubMed
Schobess 2008 {published data only}
    1. Schobess R, Kurnik K, Friedrichs F, Halimeh S, Krümpel A, Bildingmaier C. Effect of primary and secondary prophylaxis on the clinical expression of joint damage in children with severe haemophilia A. Thrombosis and Haemostasis 2008;99(1):71-6. - PubMed
Shah 2019 {published data only}
    1. NCT03364998. BAY94-9027 PK Study Comparing to Another Long Acting Product [Single dose, open label, randomized, crossover study in subjects with severe hemophilia a comparing pharmacokinetic parameters of BAY 94 9027 and Elocta]. clinicaltrials.gov/show/NCT03364998 2017 (first posted 07 December 2017). [CFGD REGISTER: HA154b]
    1. Shah A, Solms A, Wiegmann S, Ahsman M, Berntorp E, Tiede A, et al. Direct comparison of two extended-half-life recombinant FVIII products: a randomized, crossover pharmacokinetic study in patients with severe hemophilia A. Annals of Hematology 2019;98(9):2035-44. [CENTRAL: CN-01959432] [CFGD REGISTER: HA154a] [EMBASE: 628342728] [PMID: ] - PMC - PubMed
    1. Solms A, Shah A, Berntorp E, Delesen H, Lissitchkov T, Zhivkov T. Intra-individual across-study comparison of the pharmacokinetics of four recombinant factor VIII products in patients with severe haemophilia A. Haemophilia 2020;26 Suppl 2:74. [CFGD REGISTER: HA154c]
Shapiro 2018 {published data only}
    1. Astermark J, Angchaisuksiri P, Benson G, Castaman G, Chowdary P, Eichler H, et al. Subcutaneous prophylaxis with the anti-TFPI monoclonal antibody concizumab in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results. Research and practice in thrombosis and haemostasis 2019;3(Suppl 2):1. [CFGD REGISTER: HG119c]
    1. EUCTR2016-000510-30-ES. A trial evaluating the efficacy and safety of prophylactic administration of concizumab in haemophilia a and b patients with inhibitors [A multi-Centre, randomised, open-label, controlled trial evaluating the efficacy and safety of prophylactic administration of concizumab in aaemophilia a and b patients with inhibitors - explorer™4]. www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2016-000510-30-ES (date of registration 02 June 2017). [CFGD REGISTER: HG119b]
    1. Lee XY, Cepo K, Porstmann T. Concizumab subcutaneous prophylaxis improves health-related quality-of-life measures in patients with congenital hemophilia with inhibitors: phase 2 trial results. Blood 2019;134 Suppl 1:2419. [CFGD REGISTER: HG119f]
    1. NCT03196284. A trial evaluating the efficacy and safety of prophylactic administration of concizumab in haemophilia a and b patients with inhibitors (explorer™4) [A Multi-Centre, Randomised, Open-Label, Controlled Trial Evaluating the Efficacy and Safety of Prophylactic Administration of Concizumab in Haemophilia A and B Patients With Inhibitors]. clinicaltrials.gov/show/NCT03196284 (first posted 22 June 2017). [CFGD REGISTER: HG119a]
    1. Shapiro A, Castaman G, Cepo K, Hvitfeldt Poulsen L, Hollensen C, Matsushita T, et al. Efficacy and safety of subcutaneous prophylaxis with concizumab in patients with hemophilia A or B with inhibitors: results from explorer4, a phase 2, randomized, open-label, controlled trial. Blood 2019;134 Suppl 1:1139. [CFGD REGISTER: HG119e]
Smith 1996 {published data only}
    1. Smith PS, Teutsch SM, Shaffer PA, Rolka H, Evatt B. Episodic versus prophylactic infusions for hemophilia A: a cost-effectiveness analysis. Journal of Pediatrics 1996;129(3):424-31. - PubMed
Smith 2018 {published data only}
    1. Smith MP, Rupon J, Wali Y, Remawi H, Korth-Bradley J, Smith L, et al. Impact of treatment regimen with moroctocog alfa (AF-CC) on bleeding frequency in pediatric aged subjects with moderately severe to severe hemophilia a. Blood 2018;132 Suppl 1:1205. [CENTRAL: CN-01792868] [EMBASE: 626460727] [HA152a]
Solms 2020 {published data only}
    1. Solms A, Shah A, Berntorp E, Tiede A, Iorio A, Linardi C, et al. Direct comparison of two extended half-life PEGylated recombinant FVIII products: a randomized, crossover pharmacokinetic study in patients with severe hemophilia A. Annals of Hematology 2020;99(11):2689-98. [CFGD REGISTER: HA157] - PMC - PubMed
Song 2012 {published data only}
    1. Quon DV, Dolan G, Recht M, Guzman-Becerra N, Epstein JD, Song CK, et al. Access to prophylaxis benefits hemophilia a subjects in both low and high IU/capita countries: adult subset analysis of a multicenter, open-label, randomized, phase 4 clinical study of rAHF-PFM. American Journal of Hematology 2012;87 Suppl:S164. [CENTRAL: CN-01027885] [CFGD REGISTER: HA101b] [EMBASE: 71024379]
    1. Song CK, Quon DV, Dolan G, Recht M, Guzman-Becerra N, Epstein JD, et al. Access to prophylaxis benefits hemophilia A subjects in both low and high IU/capita countries: adult subset analysis of a multi-center, open-label, randomized, phase 4 clinical study of rAHF-PFM. Haemophilia 2012;18 Suppl 1:19-20. [ABSTRACT NO: 19] [CFGD REGISTER: HA101a]
Szucs 1996 {published data only}
    1. Szucs TD, Öffner A, Schramm W. Socioeconomic impact of haemophilia care: results of a pilot study. Haemophilia 1996;2(4):211-7. - PubMed
Tagliaferri 2008 {published data only}
    1. Tagliaferri A, Franchini M, Coppola A, Rivolta GF, Santoro C, Rossetti G, et al. Effect of secondary prophylaxis started in adult and haemophiliacs. Haemophilia 2008;14(5):945-51. - PubMed
Van den Berg 2001 {published data only}
    1. Van den Berg HM, Fisher K, Mauser-Bunschoten EP, Beek FJ, Roosendaal G, Bom JG, et al. Long-term outcome of individualized prophylactic treatment of children with severe haemophilia. British Journal of Haematology 2001;112(3):561-5. - PubMed
Verma 2016 {published data only}
    1. Verma SP, Dutta TK, Mahadevan S, Nalini P, Basu D, Biswal N, et al. A randomized study of very low-dose factor VIII prophylaxis in severe haemophilia - a success story from a resource limited country. Haemophilia 2016;22(3):342-8. [CENTRAL: CN-01158555] [CFGD REGISTER: HA120a] [EMBASE: 20160227673] [PMID: ] - PubMed
    1. Verma SP, Dutta TK, Mahadevan S, Nalini P, Basu D, Biswal N, et al. A randomized study of very low-dose factor VIII prophylaxis in severe haemophilia - A success story from a resource limited country. Haemophilia 2016;22(3):342-8. [CFGD REGISTER: HA120c] - PubMed
    1. Verma SP, Dutta TK, Mahavevan S, Nalini P, Biswal N, Basu D, et al. Low dose factor VIII prophylaxis in children with severe hemophilia. Indian Journal of Hematology & Blood Transfusion 2013;29(4):345. [ABSTRACT NO.: 200] [CENTRAL: CN-01024487] [CFGD REGISTER: HA120b] [EMBASE: 71223241]
Windyga 2014 {published data only}
    1. Solano Trujillo MH, Stasyshyn O, Rusen L, Serban M, Lamas JL, Perina FG, et al. Safe switching from a pdFIX (Immunine®) to a rFIX (Bax326). Haemophilia 2014;20(5):674-81. [CFGD REGISTER: HB23e] - PubMed
    1. Windyga J, Lin VW, Epstein JD, Ito D, Xiong Y, Abbuehl BE, et al. Improvement in health-related quality of life with recombinant factor IX prophylaxis in severe or moderately severe haemophilia B patients: results from the BAX326 Pivotal Study. Haemophilia 2014;20(3):362-8. [CFGD REGISTER: HB23c] - PubMed
    1. Windyga J, Lissitchkov T, Stasyshyn O, Mamonov V, Ghandehari H, Chapman M, et al. Efficacy and safety of a recombinant factor IX (Bax326) in previously treated patients with severe or moderately severe haemophilia B undergoing surgical or other invasive procedures: a prospective, open-label, uncontrolled, multicentre, phase III study. Haemophilia 2014;20(5):651-8. [CFGD REGISTER: HB23d] - PubMed
    1. Windyga J, Lissitchkov T, Stasyshyn O, Mamonov V, Rusen L, Lamas JL, et al. Pharmacokinetics, efficacy and safety of BAX326, a novel recombinant factor IX: a prospective, controlled, multicenter study in previously treated patients with severe (FIX level <1%) or moderately severe (FIX level ≤2%) hemophilia B. Blood 2012;120(21). [ABSTRACT NO: 2222] [CFGD REGISTER: HB23a] - PubMed
    1. Windyga J, Lissitchkov T, Stasyshyn O, Mamonov V, Rusen L, Lamas JL, et al. Pharmacokinetics, efficacy and safety of BAX326, a novel recombinant factor IX: a prospective, controlled, multicentre phase I/III study in previously treated patients with severe (FIX level &lt;1%) or moderately severe (FIX level ≤2%) haemophilia B. Haemophilia 2014;20(1):15-24. [CFGD REGISTER: HB23b] - PubMed
Wu 2011 {published data only}
    1. Wu R, Luke KH, Poon M, Wu X, Zhang N, Zhao L, et al. Low dose secondary prophylaxis reduces joint and severe bleeding in severe and moderate hemophilia children: A pilot study in China. Haemophilia 2011;17(1):70-4. - PubMed
Young 2015 {published data only}
    1. Young G, Mahlangu J, Kulkarni R, Nolan B, Liesner R, Pasi J, et al. Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A. Journal of Thrombosis and Haemostasis 2015;13(6):967-77. - PubMed
Young 2017 {published data only}
    1. Chowdary P, Kearney S, Yee D, Meunier J, Slothuus U, Hoxer CS. Improved health-related quality of life (QoL) of haemophilia B patients treated with a weekly 40 IU kg-1 dose of a new long-acting recombinant factor IX (FIX) product, nonacog beta pegol. Journal of Thrombosis and Haemostasis : JTH 2015;13 Suppl 2:229. [ABSTRACT NO: OR349] [CFGD REGISTER: HB26a]
    1. Chowdary P, Kearney S, Yee DL, Meunier J, Slothuus U, Hoxer CS. Improved health status of haemophilia b patients treated with nonacog beta pegol, a new glycopegylated recombinant fix product with prolonged half-life. Value in Health 2015;18(3):A300. [ABSTRACT NO: PSY49] [CFGD REGISTER: HB26b]
    1. Young G, Clausen WH, Negrier C, Santagostino E, Ronn BB, Oldenburg J. Comparison of the relationship between factor IX activity and bleeding risk during prophylaxis with nonacog beta pegol (N9-GP). Journal of Thrombosis and Haemostasis 2017;1 Suppl 1:793. [CENTRAL: CN-01653678] [CFGD REGISTER: HB26c] [EMBASE: 624158323]

Additional references

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