e Official Journal of the 7
`rld Federation of He
`*
`
`VOLUME 16
`
`NUMBER 3
`
`MAY 2010
`
`
`
`:4
`PROPERTY OF THE
`//ll\\\\i§ NATIONAL
`%% LIBRARY OF
`.—I MEDICINE
`
`EDITED BY
`
`C.A.LEE
`
`C. M. KESSLER
`
`WILEY-
`BLACKWELL
`
`CSL 1137
`CSL 1137
`
`1/14
`
`

`

`HAEMOPHILIA
`
`The ()f/icinljom'lml oft/w World Federation ofliemop/Iilia and {be limo/wan Association for Hawnop/rilia and Allied Disorders
`
`
`Editors
`Christine A. Lee
`().\/}/I‘(/.
`I ”V
`profca1ee@1iotmail.com
`Associate Editors
`M. Makris .871tf]it'/((, UK ( Reviews)
`Translated Edition Editors
`_/{//7/lI/t‘.f(‘ wl/‘Iiml: Dr. A. Yoshioka
`Editorial Assistant
`Polly Sullivan (pollysullivan@gmail.com)
`
`Craig M. KCSSlLl'
`”Titling/nu NC,
`17.8141
`kesslerc@gunct.ge<)rgetownedu
`
`L. M. Aledort Nor Yurk, UH (Meeting reports)
`
`(Jr/mare ”Ii/ion: Dr. R. Yang
`
`\Vorld Federation of Hemophilia
`A. Street illr/IIm/i‘I/r,
`.‘l/IX/I'rI/ltl
`
`Journal Publishing Manager
`Judith Barback (jbarback@wi1ey.com)
`
`
`Editorial Board
`K. Becton Iltl//it’/I/, [IX
`11. lierntorp Mil/”m. A'Il'tY/i’ll
`M. van den Berg (Um-M. 77m 1\k‘//N’I'/(II/{/J'
`P. Bolton-Maggs .llmzr/mrm; 17K
`5. A. Brown link/2mm,
`.r'l/IIIHI/ltl
`A. Chuansumrit [iii/(glint;
`'l/m/Ymn/
`P. Collins (km/(fl. 17K
`1). DiMichele All”! HM, UH
`S. Dottfield (.7I1/f71‘//////’,
`(TY-1
`A. B. liederici Ali/rm. Ila/r
`K. Ghosh Alum/mi, [ml/u
`P. L. 1:. Giangrande (Iv/ml. UK
`N. Goddard Lam/mi. UK
`A. Coodevc .SZig/jir/tl,
`(/lx’
`C. R. M. llay illm/r/rm/rr. UK
`1..
`l leijnen [III/{rm 'I/ir AVIAN/mutt
`M. lleiln 'Ii'lxlr'fi'. linir/
`K.
`l loots Ila/trim],
`[KY-1
`I. lngel‘slev (,i;/ir///u(qri/. UNI/lurk:
`R. Kadir [mu/nu. I (K
`P. Kouides [tor/mm;
`R. Lassila I It‘lrinki,
`
`(/1821
`l’in/m/z/
`
`III/irm/i/ii/ia is an international journal dedicated to the
`Aims and scope.
`exchange of
`information regarding the comprehensive care of
`haemophilia, The journal contains review articles, original scientific
`papers and case reports related to haemophilia. All material
`is
`independently peer-reviewed. For submission instructions, subscription
`and all other information visit: www.b1ack\vc1lpublishing.com/1iac
`
`l/uwr/op/Ii/ia accepts articles for Open Access publication. Please see
`www.blackwe1|publishing.com/bae and select author guidelines for
`further information about ()nlineOpen.
`
`lustitu«
`Ilium/Malia is published in six issues per year.
`Subscriptions.
`tional subscription prices for 2010 are: Print & ()nline: US$1302 (US),
`US$1520 (Rest of World),
`€896
`(Europe),
`.6706 (UK). Prices are
`exclusive of tax. Asia-Pacific CST, Canadian CST and European VAT
`will be applied at the appropriate rates.
`lior more information on
`current tax rates, please go to \vww3.interscience.\vi1ey.com/aboutus/
`jonrnaLorderingiantLpayment.htmlliTax. The price includes online
`access to the current and all online back files to January 1st 1997,
`where available. For other pricing options, including access informa-
`tion and terlns and conditions, please visit www.interscieuce.wiley.
`com/journal-info. Prices include delivery of print
`journals to the
`recipient’s address. Delivery terms are Delivered Duty Unpaid (1)1)U):
`the recipient is responsible for paying any import duty or taxes. Legal
`title passes to the customer on despatch by our distributors. Single
`issues from current and recent volumes are available at the current
`single issue price from cs«journals®wiley.com. Earlier issues may be
`obtained from Periodicals Service Company, I 1 Main Street, German-
`town, NY 12526, USA. Tel: +1 518 537 4700,13ax: +1 518 537 5399,
`limailz psc(n7periodicals.com
`
`R. C. R. Ljung ALI/ma, .lii'n/m
`C. A. Ludlam [Eryn/”ugh, I /‘l\'
`J. Lusher H.811
`//u_/)‘
`P. M. Mannucci Ali/ml,
`U. Martinowitz ’li'l-l'lt/r/m/z/n: mm
`C. G. Negrier Lyn/I. I'M/Ire
`J. Oldenburg [in/III,
`(,i'N/III/{j'
`M. V. Ragni l’i/lr/zl/Igl/i. Ill-1
`11.. C. Rodriguez Merchan Aim/ml.
`1. Scharrer dbl/u; Orr/mun
`\V. Schramm Allin/4‘11, (,i'r/I/mgr
`S. Schulman [kiwi/Ion, Omar/t1
`A. Shapiro Im/z’mm/m/zir,
`[Mi-I
`L. Solimeno Ali/an.
`[In/)4
`M. Smith (.Yi/ir/r'lr/nr/i. NZ
`A. Srivastava 1'i’/Ill'(‘, [ml/a
`K. Steen Carlsson Ian/(l, Aim/m
`13. (i. l). Tuddenham [Jill/[Ill], UK
`P. Vincent Jenkins Duh/in,
`[Fr/tII/l/
`G. C. White ll'iltt‘u/lxiu.
`(IX-1
`I. T. \Vilde Howling/W”,
`I 1K
`
`.S'jmiu
`
`Copyright and photocopying. © 2010 Blackwell Publishing Ltd. All
`rights reserved. No part of this publication (apart from articles marked
`OnlineOpen) maybe reproduced, stored or transmitted in any form or by
`any means without the prior permission in writing from the copyright
`holder. Authorization to photocopy items for internal or personal use is
`granted by the copyright holder for libraries and other users registered
`with their
`local Reproduction Rights Organisation (RRO), e.g.
`Copyright Clearance Center (CCC), 222 Rosewood Drive, Danvers,
`MA 01913, USA (www.copyright.eom), provided the appropriate fee is
`paid directly to the RRO. This consent does not extend to other kinds of
`copying such as copying for general distribution for advertising or
`promotional purposes. or for creating new collective works for resale.
`Special requests should be addressed to PermissionsUK@wiley.com
`
`11) Statement A. 11A1iMOPlllL1A (ISSN: 1351-8216)
`Periodical
`is published bimonthly in January, March, May, July, September and
`November. US mailing agent: Mercury Airfreight International 1ne.,
`365 Blair Road, Aveuel, NJ 07001, USA. Periodical postage paid at
`Rahway, NJ. Postmaster: Send all address changes to HAliMOPl IILIA,
`Journal Customer Services, John Wiley & Sons 1nc., 350 Main St.,
`Malden, MA 02148-5020.
`
`llmwmp/ri/in is published by Blackwell Publishing l.td., 9600
`Publisher.
`Garsington Road, Oxford OX4 2DQ, UK. Tel: +44 1865776868,1iax:
`+44 1865 714591. Blackwell Publishing Ltd is now part ofJolm \‘Viley
`CV Sons.
`
`Wiley‘s Corporate Citizenship initiative statement. \Viley’s Corporate
`Citizenship initiative seeks
`to address the environmental,
`social,
`economic, and ethical challenges faced in our business and which are
`important to our diverse stakeholder groups.
`\Ve have made a long-
`term commitment to standardize and improve our efforts around the
`world to reduce our carbon footprint.
`Follow our progress at
`www.wi1ey.com/go/citizenship. Access to this journal is available free
`online within institutions in the developing world through the l'llNARl
`initiative with the W110. For information, visit www.healthinternet-
`Blackwell Publishing Ltd is now part of John Wiley t’\’ Somgs mate-rial wagsgglkjgag
`attire NLM and mast baa
`
`including orders
`Business correspondence. Business correspondence,
`for offprints and advertising space should be addressed to l/irir/uli/i/i/liu,
`Blackwell Publishing Ltd, 9600 (iarsington Road, Oxford, ()X4 2DQ,
`UK. (Tel. +44 ((1) 1365 776868; fax +44 (0) 1865 714591).
`2/14
`
`2/14
`
`

`

`HAEMOPHILIA Volume '16, Issue 3, May 2010
`
`Contents
`
`Review Articles
`The optimal mode of delivery for the haemophill
`,
`.
`/\.
`[4/11/13
`,
`t
`.
`-
`'
`,
`~
`' w ,,
`.4 ‘
`e
`Ihe optimal mode ofdelivery for the haemophilia c.1iriei e.\peeting an at ect d
`xl. / /. jaw/(1r and K. I loo/x
`
`:1 carrier expecting an affected infant is vaginal delivery
`
`infant is caesarean deliver i
`l
`
`Commmz taiy
`What is the optimal mode of delivery for the lmcmophilia carrier expecting an affected infant-vaginal
`delivery or caesarean delivery?
`if. Ala/X1711 and xl. AI. AYI'H/
`
`420
`
`4;[\J U1
`
`427
`
`Malignancy in patients with haemophilia: a reView of the lltCthUlL
`/ l. 1.. Uni/11
`
`447
`
`460
`
`46‘)
`
`Original Articles
`
`Clinical Imemop/a'lia
`with haemophilia, 1990—2007
`Mortality and causes of death in Italian persons
`7.
`11
`,.
`.
`.
`.
`i
`.-
`:i " ;,
`’
`11m
`Ill. {liar/[1a, A. Rod/m, Ill. C. dingy/[rm];
`A.
`lag/m/mv, C. 1’. Raw/m, /l. [OI/(J, Ii. Oil/Olatf‘llll, Ill. / ~
`.1 :{M i
`ll]. Mai/Milli, MI bi’lin/[o/flm Ila/[ml flavor/anal! (1/ l’ll’l/lfl/D/il/m J 11/05
`Patient resources in the therapeutic education of haemophilincs in lirance: their skills and roles as defined
`by consensus of a working group
`[Syn/[lard 1). ”1/0/0411. lim‘il/—1)(’I‘/ml, 1’. GNU/011, C I‘lzllz/ailatrlw,
`L. ”OH/z, /. .Sami/r, .S. xlymgmi; C. (WHOM/=1 -
`.
`t
`‘
`.
`.
`i
`»
`)
`'
`A
`I. Law/mi, A. Ala/mm; 1V. /I//mm//(f {ll/(ll /\. Gigi/{WP
`)philia in the state of Mississippi
`,
`.
`7'
`‘
`/,1_ [1'0’101/06 I}.
`[VIP/«171431011, (it C. Jigsaw/1 and R. [yer
`
`revalenee of obesity in haemt
`Alarminirlv hioh
`P
`b «
`b
`5'. Airy/Marla); /l. Alarm, C. Con/MI,/ C.
`l\(’I'///(I(/(’,
`
`Paediatrics
`
`l BenelilX® prophylaxis in children less than 6 years of age
`
`Safety and efficacy of investigatoitpi‘escril)ee
`with severe haemophilia B
`I). /1'. Alana/Jail, R. Liar/Mr,
`.S'. /. AIM/11W], 1
`
`11. 1.7. Rfl/Illll‘l’z,
`
`I).
`
`[\IP/[J' (ll/{l 1). /.i Roll)
`
`Inhibitors
`Polymorphisms in genes involved in autoimmune disease and the iislx of l \ lll inhibitm development in
`Italian patients with haemophilia /\
`Jud/m, l). l’imw/li, 1i .S'rrm,
`'l.‘
`'li‘of/a, (I. Yagar/Mo,
`I“. Pavia/1120' and
`l’f liq/hm”), R.
`.S}//11‘(a‘/‘I/z‘e, Ill. (JIM/a, C. l)/
`M, filmy/(Minna
`
`3/14
`
`,ttecunnuchccc L,
`This mate-rial wastnpian
`
`3/14
`
`

`

`
`
`Orthopaedics
`
`474
`
`Lon r-term evaluation of chromosomal breaka res after radioisoto e s 'noveetomv for treatment of target
`é:
`.,
`,
`]()1r1tS in patients with haemophilia
`K. Krer/(fi/j, O. Olga/II, .S'. Aj'dqgr/fl, ll. Ozléi/I'f, B. Dun/1:12., O. [Or/107,6, F.
`Y. A]
`
`(){k/‘m‘ry, C Bulk/m, D. szwilmrzmd
`
`479 Utility of the Haemophiliajoint Health Score in study of episodically treated boys with severe haemophilia
`A and B in Lithuania
`
`.S‘.
`
`.S‘. flaky/1km]. llgt’rI/(‘l‘ and L.
`
`[Cage/fella
`
`487 The value of early treatment in patients with haemophilia and inhibitors
`K Kayak/i, A.
`)”t‘Il-//./>(’/(’i,
`I}. Ail/211611,
`.S'. [lief/t, C: fizz/km], D. Yi/waz, l l\'//f)r§i:;f,
`j. Alerter/011
`
`I. fiery/(q, P. Linda/1'11 and
`
`495
`
`Physical activity for prevention of osteoporosis in patients with severe haemophilia on long-term
`prophylaxis
`V
`(W. K/mey‘i, ]. Artery/ark, K. Alanna/i and E. Herzl/m7)
`
`Hepatitis C
`
`502
`
`Efficacy and safety of pegylated interferon alpha—2a therapy for chronic hepatitis (L in HIV-infected
`patients with haemophilia
`R-F. Z/yzmg,
`[VA-5Q.
`.S‘zm, Q. Hull/(g, j.-R.
`
`”Va/(g, {\i—X. Z/mug, X—N. Li/I, Q. Ma (ll/(l H.-Z.
`
`[.11
`
`Labora tog; science
`
`Commentary
`
`508 The use of animal pharmacokinetic data to evaluate human dosing
`1W. L. Lee
`
`510 Thrombin generation and fibrinolysis in anti-factor IX treated blood and plasma spiked with factor VIII
`inhibitor bypassing activity or recombinant factor VIIa
`D.
`lid/{gm 17.
`.S'Z/am, R. ]. Ala/inn”), M. /l. [ma/1m“, _/. H. [any III/(l K. [1.
`
`'Ihmzkn
`
`518 Comparison of kaolin and tissue factor activated thromboelastography in haemophilia
`C. You/lg, R. Z/qug, R. [WU/er, D. Yam); (II/{l I). ]. [VI/gm!
`
`Genetics
`
`525
`
`Interlocus non-random association of multiallelic polymorphisms spanning the coagulation factor VIII
`gene on human chromosome distalmost Xc128
`E. [Medina-Atom
`
`538 Genetic analysis of haemophilia A in Taiwan
`YnCZ C/m},
`.SI-H. [‘III,
`.SI—ZV. C/ng and Ti-Y. CVJaa
`
`Letters to the Editors
`
`545 Maintenance of treatment logs by haemophilia patients
`.8: {11/7M], j. Rite and C. A. Lamb/grit
`
`548 Risk-sharing approach for managing factor VIIa reimbursement in haemophilia patients with inhibitors
`A. 111655077;
`.5‘. TH'p/M/l; 111. [II/Iomzti and M. AIM/int
`
`4/14
`This material was tnpied
`at the NLM and may be
`Su bjeet‘ UEkEcrpry'right‘ Laws
`
`4/14
`
`

`

`
`
`Ten novel factor VIII (178C) mutations in eighteen hacmophilia A families detected in Singapore
`A. /l/}d/!/-C/J(l {1", 1V. Egg/{1110121, L. C. I.1)”, Y. Z/mo, fl. [Nadia/“mid .S‘. L. 7}?”
`
`A novel point mutation in severe haemophilia A: a further proof of genotype—phenotype correlation
`z]. Barr/Jiv/lini, Ill. P. [Mort/ti, C xl‘g/qgi, xl. Va/pm/a, F. Vale/‘1', E. Brigg/(III), M. /lt‘(jl/i/{l and 1’. C.
`.Sk/J/m‘a
`
`Clinical use of l-Iaemate-l’ in inherited von \Villehrands disease: a patient with type 3 VWD and recurrent
`menometrorrhagia
`R. Do/m‘k/m/J, 1. x1. Kay/(1111', Z. 5211111111, X. Kai/i, j E. Zizm‘, /l. 1\7/',(2111gfar, /’l. lifla/Jan/ (II/[1.5: 1*]. CYIm'olLr/Ji
`
`Osteoid osteoma in a child with severe von \Villebrand disease
`
`D. Palm/0x, C. Ilia/tinny, ll. Peg/anion, ]. flildJ‘llIIfl/M/l/(If and I 1. P/zz/okamé/
`
`Management of patients with factor V deficiency: open issues from the challenging history of a woman
`with anaphylactic transfusion reactions
`A. (Mp/20M, C. 111. Alarm/Ii, C. Fro/u, xi. Cam/mm, F: QI/zqg/ia, 11/. Yb/I/in/ro/o, All. 1V. I). Di Ail-11110, /'l. 111. Orr/Jone,
`ill. tlIrI/gqg/ionc and P. Jllill1illt’///
`
`564
`
`Characterization of the genetic basis of FXl deficiency in two Turkish patients
`/ 1'.
`liar/2W, V. Rime/dz',
`.S'. Ur/Her, S. Alix/I. Y. Pt’lét‘fl/(‘IL .S'. 1‘]. Chg/{gym} am! 5'. Dug/1
`
`567
`
`t
`Corrigendum
`
`5/14
`Th is material was {Dplfid
`at; the NLM and may be
`Subject US {lupy‘rigm‘ Laws
`
`5/14
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`6/14
`
`

`

`and analogous data for haemophilia B are relatively
`limited. \X/ith recent reports suggesting the potential
`for a different severity of clinical phenotype for
`haemophilia B vs. haemophilia A, [7] it is important
`to evaluate prophylaxis directly in haemophilia B
`patients.
`This clinical trial with rFIX in severe haemophilia
`B patients was initiated with a design that allowed
`investigator choice of therapy,
`including prophy—
`laxis, in children <6 years old. Herein, we report the
`results of this international, multi-centre trial evalu-
`ating safety and efficacy of rFIX for usual haemo—
`philia B care in children, including use in the setting
`of routine prophylaxis.
`
`Patients and methods
`
`Study design
`
`The study protocol was approved by the institutional
`review board or ethics committee at each participat-
`ing site and was conducted in accordance with the
`ethical principles outlined in the Declaration of
`Helsinki. The study was initiated in October, 2002
`and was completed in November, 2007.
`This was an open-label study involving limited
`pharmacokinetic
`(PK)
`assessments
`(focusing on
`recovery determinations) and evaluations for safety
`and efficacy of
`rFIX in
`the
`setting of usual
`haemophilia B care. Subjects used rFIX, as pre-
`scribed by the investigator, for treatment of bleed-
`ing episodes and/or for prophylaxis (intermittent,
`routine, and/or surgery—related) over 6—12 months.
`Subjects who had accrued fewer than 30 exposure
`days
`(any calendar day on which rFIX was
`received) by month 6 continued treatment, for up
`to 12 months total. Clinical examinations, labora-
`tory testing, and recovery evaluations were con-
`ducted at '1—3 month intervals during the course of
`the study. For the recovery evaluations, subjects
`had one blood collection before and one collection
`025—05 11 after a 751U kg" dose of rFIX;
`the
`measured FIX activity results were to help inform
`rFIX dosing prescriptions (8|. At
`the initial and
`final recovery evaluations, blood samples were also
`collected at 4 and 24h postdose to estimate other
`PK parameters. Factor IX (F9) genotyping was also
`performed.
`
`Subjects
`
`Eligible participants were <6 years age, had severe
`haemophilia B (FIX activity 31%), and had no
`historical or current evidence of a FIX inhibitor.
`
`BENIiFlX PROPHYLAXIS IN CHILDREN 461
`
`functions,
`Subjects had normal hepatic and renal
`prothrombin times £1.25 times the upper limit of
`normal and platelet counts 2100 000 LIL—l. Written
`informed consent was obtained from the patient’s
`legal representative prior to study participation.
`
`Study test article
`
`Human recombinant FIX (rFIX), manufactured by
`Wyeth l9,10], was administered using nominal dos-
`age strengths of 250 and 500 IU per vial. At-home
`infusions were to be administered by the patient’s
`
`caregiver.
`
`Laboratory assessments
`
`IX activity, FIX inhibitor and anti-FIX
`Factor
`antibody assessments were performed by a central
`laboratory. Factor IX activity was measured by a
`one—stage, activated partial
`thromboplastin time-
`based assay. Factor IX inhibitor was measured by
`Bethesda inhibitor assay (BIA), with a positive
`inhibitor
`titre defined as 20.6 Bethesda Units
`(BU) mL‘l. Anti-FIX antibody was measured by
`enzyme-linked immunosorbent assay (ELISA). For
`these antibody determinations, serum titres against
`plasma-derived FIX (Mononine®; CSL Behring, King
`of Prussia, PA, USA) and rFIX were obtained in two
`independent ELISA tests
`each using a protein
`A-horseradish peroxidase conjugate and 2,2'-Azino-
`di(3-ethyl-benzthiazoline-6-sulphonate) as substrate
`for colorimetric readout.
`
`I’lmrmawkiuetic parameters
`
`Pharmacokinetic calculations were based on FIX
`activities at actual sampling times that were adjusted
`for corresponding pre-dose levels of FIX. The in viuo
`recovery was calculated as the ratio between the
`observed and theoretical maximum FIX activities
`(observed, activity at 025—05 h postinfusion; theo—
`retical, PK dose divided by subject plasma volume,
`estimated using measured haematocrit and assuming
`a 45 mL plasma volume per kg of body weight),
`Incremental recovery [K-value, (1U dL_')/(IU kg‘l)]
`was calculated as
`the observed maximum FIX
`activity divided by the PK dose. Pharmacokinctic
`parameters, determined using the WINNoNLIN ver-
`sion 4.1 software package (Pharsight Corporation,
`Mountain View, CA, USA), included peak activity
`(Cmax), area under the activity-vs.-timc curve from
`time zero to the last measurable activity (AUCt) and
`from time zero to infinity (AUCOO), terminal-phase
`elimination half life (tl/Z), and clearance (CL). For
`
`© 20l0 Blackwell Publishing Ltd
`
`7/14
`This material was copied
`at the NLM arid may be
`Subject US {iapyright‘ Laws
`
`”ammo/Julia (2010), 16, 460—468
`
`L)
`
`j“)
`
`7/14
`
`

`

`462 P. F MONAI'IAN et al.
`
`reasons of the sparse PK sampling included in this
`study, non-linear mixed effects modelling was used
`to estimate AUCoo and CL.
`
`each infusion administered for recovery evaluations.
`Some of these assessments were conducted more
`
`frequently for surgical procedures.
`
`Efficacy assessments
`
`Statistical methods
`
`The efficacy of rFIX for on-demand treatment was
`assessed by the number of infusions required to
`resolve each haemorrhage and by investigator/care-
`giver grading using a 4-point
`scale
`(Excellent:
`dramatic response with abrupt pain relief and clear
`reduction in joint or haemorrhage site size; Good:
`pain relief or
`reduction in haemorrhage site size
`which was delayed or required additional
`infusion
`for resolution; Moderate: probable or slight benefi-
`cial response requiring several additional
`infusions
`for resolution; or No Response: no improvement)
`based on the treatment response at approximately
`24 h following the time of the bleeding episode or
`just prior to an additional infusion when adminis-
`tered. The efficacy of rFIX prophylaxis was assessed
`by the frequency of breakthrough haemorrhages (any
`haemorrhage occurring during routine prophylaxis),
`including: the total number of breakthrough haem-
`orrhages, the number of breakthrough haemorrhages
`by aetiology (spontaneous or injury-related) and by
`location (joint or non-joint site) and the time of their
`occurrence relative to the prior
`rFIX infusion.
`Monthly (30-day) bleeding rates were calculated
`and then used to estimate annual bleeding rates.
`Investigators also rated the overall clinical response
`to rFIX therapy, with consideration of any adverse
`events and/or relevant clinical and laboratory find-
`ings, every 1—3 months using a 5-point scale (Very
`Useful, Useful, Slightly Useful, Useless, Ulzfauozzr—
`able). Investigators (and/or surgeons) also used this
`5-point scale to assess
`the efficacy of
`rFIX for
`surgical prophylaxis, providing ratings for the peri-
`operative periods when rFIX was used.
`
`Safety assessments
`
`Safety was assessed by routine clinical and labora-
`tory evaluations and by adverse event
`reporting.
`Haematology, serum chemistry and viral serologies
`(antibodies against HIV (types I and 2), hepatitis A,
`hepatitis B (surface and core antibodies, and surface
`antigen), hepatitis C] were determined at baseline
`and again at study completion. Factor IX inhibitor
`and anti-FIX antibody assessments were conducted
`at baseline and were repeated every 1—3 months
`thereafter. Thrombin activation markers [prothrom-
`bin fragment
`1 + 2, thrombin-antithrombin (TAT),
`and D—dimer] were measured prior to and at 4 h after
`
`Descriptive statistics were used for recovery, efficacy
`and safety data. The primary recovery and efficacy
`analyses were performed on per-protocol popula-
`tions. For analyses of recovery,
`this included all
`subjects who completed the PK evaluations after a
`24-day washout period; for efficacy analyses,
`this
`included all subjects who had accrued at
`least 30
`rFIX exposure days over 6—12 months. Subjects with
`any major protocol violation were excluded from
`these per-protocol analyses. Safety analyses included
`all subjects who received at
`least one infusion of
`study drug.
`
`Results
`
`Subjects
`
`A total of 25 subjects received at least one dose of
`rFIX. Baseline characteristics of
`the 25 treated
`subjects are summarized in Table 1. Twenty-three
`subjects completed the study and two did not: one
`was withdrawn because of a protocol violation
`(screening laboratory assessments not completed
`within the protocol—specified period) and one with—
`drew consent citing personal
`reasons. Of the 23
`subjects who completed the study, 22 accrued 230
`rFIX exposure days, including 10 subjects with >50
`exposure days, five subjects with 40 to <50 exposure
`days and seven subjects with 30 to <40 exposure
`days. The median duration of study participation
`
`Table 1. Demographic and baseline characteristics for subjects
`treated with rIiIX (r2 = 25).
`
`Age in years, median (range)
`Age category, 11 (%)
`<2 years
`2—6 years
`Race, 11 (”0)
`
`2.0 (0.6—4.0)
`
`7 (28)
`[8 (72)
`
`18 (72)
`7 (28)
`
`White
`Other
`Previous lifetime exposure
`(days) to FIX products, )1 (%)
`(4)
`|
`0
`6 (24)
`<20
`18 (72)
`220
`9 (36)
`Central venous access device: Yes
`8 (32)
`21 haemarthroses within
`——————_—w—_
`previous 12 months: Yes
`
`llaemo/IIIi/ia (2010), 16, 460—468
`
`8/14
`This material was {spied
`atthe NLM and may be
`Eu Eject: U$ Eepy‘right Laws
`
`© 20“) lilackwell Publishing Ltd
`
`8/14
`
`

`

`was 31.3 weeks (range, 7.9—65.3 weeks) for the 25
`treated subjects.
`
`I’Izarmacokinctics
`
`In total, 20 subjects were evaluable for PK parameter
`determinations at baseline and at the end of rFIX
`
`treatment. At baseline, the mean (:SD) incremental
`recovery (K-value) was 0.58 (10.09)
`(1U dL7')/
`(IU kg“'), and the mean in viz/o recovery was
`31.9% (15.3). Mean Cmax was 43.6 (:68) IU .11.",
`mean AUCt was 435 (1102) h 1U dIfl, mean in;
`was 10.9 (22.3) h, and model-predicted mean AUCoo
`and CL were 574 (=107) h 1U dli' and 13.6 (13.4)
`mL 11—1 kg‘1 respectively. I’barmacokinetic parame—
`ters,
`including
`recoveries,
`remained
`consistent
`throughout the study period: the mean incremental
`and in viz/o recoveries, measured at
`the end of
`treatment (6-12 months after baseline), were 0.61
`(=0.10)
`(IU (urn/(111 kg")
`and 33.1 (15.4)
`respectively.
`
`Efficacy
`
`In total, 22 subjects were evaluable for efficacy.
`Routine prophylaxis was prescribed for
`all 22
`subjects. Eighteen subjects were prescribed routine
`prophylaxis regimens exclusively, while four subjects
`were each initially prescribed on-demand regimens
`and later switched to routine prophylaxis. The
`reasons for switching included caregiver request (2
`subjects), recurrent bleeding episodes (1 subject) and
`risk of recurrent bleeding as a result of increasing
`physical activity level
`(1 subject). Investigator-pre-
`scribed prophylaxis included one infusion per week,
`with doses
`ranging from 42 to 105 IU kg"l
`(9
`subjects); a 1—2 infusion per week schedule, with a
`dose of 100 IU kg~l
`(1 subject); and two infusions
`per week, with doses ranging from 33 to 87 IU kg-l
`(12 subjects). There were no changes in the respective
`prescribed infusion schedules during prophylaxis
`treatment
`(mean
`of
`6.6 months;
`range,
`1.9—
`1 1.4 months).
`
`BIZNIiFIX I’ROI’HYI./\XIS IN CHILDREN 463
`
`15
`
`.3 O
`
`U!
`
`Numberofhaemorrhages
`
`
`
`
`
`-aorrhge
`
`Spontaneous
`lnju ry-related
`
`Fig, 1. Number of breakthrough haemorrhages, by aetiology
`(spontaneous or injury-related), during routine prophylaxis with
`rIiIX and the time of occurrence relative to the prior prophylaxis
`infusion.
`
`Including seven subjects (32%) with no bleeding
`episodes at all, 17 of 22 subjects (77%) had no
`spontaneous haemorrhages and 15 subjects (68%)
`had no haemarthroses during their course of pro-
`phylaxis. In total, 44 bleeding episodes occurred in
`15 subjects during prophylaxis. Most haemorrhages
`were caused by injury (84“.), 37 of 44; Fig.
`’1), most
`involved non-joint sites (73%, 32 of 44), and most
`occurred >48 11 after the prior rFIX infusion (61%,
`27 of 44; Fig. 1). Spontaneous bleeding episodes
`were uncommon within 48 h of
`rFIX infusion
`(Fig.
`’1). The single spontaneous haemorrhage that
`occurred in this time period was a knee haemorrhage
`in a 3-year-old subject with a history of prior serious
`haemarthroses (requiring hospitalization), including
`bleeding episodes in this specific target joint. This
`subject also accounted for 42% (5/12) of all break-
`through haemarthroses in this study, with three of
`his five episodes (60%) occurring in his target knee
`joint. Overall, 91% (20/22) of patients had S1 joint
`haemorrhage during their course of prophylaxis.
`Estimated annual bleeding rates (ABRS) during
`prophylaxis were 0.58, 1.0, and 3.7 for spontaneous,
`
`Table 2. Bleeding rate during rl-‘IX prophylaxis by infusion schedule (n = 22 subjects).
`
`Annual bleeding rate
`____’__’—-————-
`
`Patient age,
`Prophylaxis duration
`Infusion
`
`Total
`IIaemarthroses
`Spontaneous
`years (median, range)
`(mean 2 SI) months)
`)1
`schedule
`3.1
`1.4
`0.84
`2.5 (0.6—4.3)
`8.0 x 2.7
`9
`1 per week
`4.9
`0
`(I
`1.0 (NA)
`2.5 (NA)
`1
`1—2 per week
`4-3
`0-69
`0.34
`3.6 (1.2—4.8)
`5.9 2 1.1
`12
`2 per week
`3.7
`1.0
`0.58
`2.9 (0.6—4.8)
`22
`All schedules
`6.6 2 2.3
`__——____—____—__——’———
`
`NA, not applicable.
`
`to 2010 Blackwell Publishing Ltd
`
`9/14
`This mate rial was copied
`attihe NLM and may be
`Subjeet Uiafiiapyright Laws
`
`“mm/111m (2011)), 16, 460—468
`
`9/14
`
`

`

`464 P. E. MONAHAN at al.
`
`joint, and all haemorrhages respectively (Table 2).
`These rates were achieved with multiple, subject-
`specific, prophylaxis regimens. Marked decreases in
`bleeding rates were observed for three of the four
`children who were initially prescribed on-demand
`therapy, but were later switched to prophylaxis by
`the investigator
`(Fig. 2). Collectively, during the
`periods when prophylaxis was not practised (mean
`duration, 3.9 months), these four patients had esti-
`mated ABRs of 3.9, 3.1, and 15.6, for spontaneous,
`joint, and all haemorrhages, respectively.
`Although prophylaxis treatments were not ran-
`domly assigned in this study to support a direct
`comparison of prophylactic infusion schedules, sim-
`ilar outcomes were observed with the once or twice
`weekly regimens, which used similar dosing ranges.
`The reported bleeding episodes during the observa-
`tion period predict <1 spontaneous haemorrhage per
`year for subjects treated on both the once and twice
`weekly schedules (0.84 and 0.34 spontaneous haem-
`orrhages per year respectively). A trend for more
`frequent haemarthroses was observed with the once
`weekly infusion schedule (Table 2).
`Dosing during prophylaxis (prophylactic infusions
`and supplementary on—demand infusions to treat
`haemorrhages as needed) is summarized in Table 3.
`Most bleeding episodes occurring during prophylaxis
`were resolved with one or two infusions of rFIX
`
`(89%; 39 of 44), with comparable efficacy found for
`haemorrhages occurring in joints and those occurring
`at other sites: 8300 (10/12) and 90.6% (29/32) of
`bleeding episodes in joints and at other sites resolved
`with $2 infusions. Response to the first rFIX infusion
`used to initiate treatment of breakthrough bleeding
`was rated ‘Excellent’ or ‘Good’ for 89% (39/44) of
`
`Table 3. Summary of rFIX dosing during prophylaxis (11: 22
`subjects).______(_______———
`Infusion reason
`
`I’rophylaxis"‘
`803
`
`On-demaud
`
`treatment
`68
`
`57.6 (27.9—187.2)
`64.6 2 21.3
`
`58.2 (27.5—11.5.2)
`69.4 x 22.3
`
`Cumulative number
`of infusions
`
`Dose (1U kg")
`per infusion
`Median (range)
`Mean 2: SI)
`Number of infusions
`
`per patient
`2 (0—12)
`38.0 (9-52)
`Median (range)
`3.1 t 3.5
`36.5 = 13.1
`Mean 2 SD
`
`"'Includes 787 routine prophylaxis and I6 intermittent infusions.
`SI), standard deviation.
`
`haemorrhages, ‘Moderate’ for 11% (5/44) of bleed-
`ing episodes and no ratings of ‘No Response’ were
`reported (Fig. 3). Two children also received rFIX to
`support surgical haemostasis. Together,
`these two
`subjects received a cumulative total of 21 522 IU
`rFIX (24 total
`infusions; median dose and range:
`97.1, 59.3—130.5 IU kg”) for one procedure each
`(circumcision and port-a—catheter insertion). In both
`cases, each patient received rFIX for 6 days after the
`procedure for follow-up treatment, blood loss was
`minimal
`(S20 mL) and no transfusions were re—
`quired. Investigator 5-point global assessments of
`rI:IX for usual treatment of haemophilia B were rated
`Very Useful or Useful for 100% of reported assess-
`ments (86 total, including surgical assessments).
`
`Safety
`
`2 _
`
`l On-demand
`
`1 067 549 IU of rFIX, delivered by 1028
`In total,
`infusions over 1016 exposure days, were adminis-
`
`D Prophylaxis
`
`17,4, 10.1 weeks
`
`.
`13.3 1
`
`31.4. 8.0 weeks
`' 09 was“
`, ,
`
`
`100
`
`89%
`
`n = 44 haemorrhages
`
`’_l
`
`
`
`Haemorrhages(%)AmonOOO
`
`MO
`
`u\
`
`0
`
`Excellent or Good
`
`Moderate
`Response ratings
`
`.
`
`0%
`No Response
`
`Fig. 3. Response rating to the first rI’IX infusion used for treat-
`ment of haemorrhages during prophylaxis.
`
`Fig. 2. Monthly bleeding rate by treatment modality for each of
`the four subjects initially prescribed on-demand treatment and
`later switched to prophylaxis. Durations of each treatment period
`(in weeks) are indicated above each bar.
`
`I'laemop/zilia (2010), 16, 460-468
`
`10/14
`This material wast-timed
`atltLhE N LM and may be
`Subject US {lam-Tight; Laws
`
`(O 2010 Blackwell Publishing Ltd
`
`4.9, 48.9 weeks
`,~
`
`u)
`
`0E
`
`E 1.6J
`c”
`E
`8 1.2 1
`2.0
`>.
`C
`,5. 0.8 —
`
`
`
`0.4 1
`
`
`
`
`
`1 (2.5)
`2 (2)
`3 (0.6)
`4 (1)
`Subject number (age at study entry, years)
`
`10/14
`
`

`

`tered to a total of 25 subjects during this study for
`recovery assessments and open-label treatments. Ten
`(40%) patients accrued more than 50 exposure days
`to rFIX.
`
`Adverse events judged related to rFIX treatment
`were uncommon, occurring in only two of 25
`children (8%). For one subject,
`the related event
`was mild rash. The other subject, an African Amer-
`ican who was a previously untreated patient (PUI’) at
`study entry, experienced an allergic reaction which
`was later confirmed as associated with low—titre FIX
`
`initiated rFIX
`I’UI’
`inhibitor development. This
`therapy with his baseline recovery assessment fol-
`lowed by 8 days of surgical prophylaxis coverage
`with rFIX for an uncomplicated circumcision proce-
`dure. Subsequently, three spontaneous bleeding epi-
`sodes were each controlled with a single on—demand
`rFIX treatment of approximately 60 IU kg"1 with an
`‘Excellent’ response. Treatment of a 4th spontaneous
`haemorrhage, also with an ‘Excellent’
`response,
`occurring approximately 2 months
`following his
`surgery was associated with an allergic reaction
`manifested as a mild cough, moderate rash and
`urticaria. Inhibitor testing, performed 19 days after
`the reaction, showed the presence of low—titre FIX
`inhibitor
`(peak titre, 2.4 BU mL‘l). The subject
`
`Table 4. 1:9 genotype data for study subjects (n z 23)“‘.
`Amino acid
`Point mutation, nucleotide change/site affected
`
`C9G
`Promoter, C/lilil’
`binding site
`v- 171
`R29X
`G938
`(:95Y
`RII6X
`(11201)
`11221Y
`R248X
`R248Q
`(:305V
`mast
`P3681.
`1397T
`\v407x
`
`(;1 17/\
`CG460T“
`(:17692A
`(117699A
`Cl776|TI
`020.54%
`C30114T
`C30863Ti
`(130864A
`G31035T
`(:31223A
`C31224T
`T31311C
`(:3134 1 A
`Other mutations
`
`double point mutation
`resulting in li30V
`frameshift at codon 74
`
`splice defect disrupting
`acceptor site of intron C
`deletion, nucleotides
`31230—31235—_—_———————-
`
`a*Ccnotype data not available for two subjects.
`TReported for two subjects.
`*Reported for three subjects, including the one inhibitor patient.
`
`BliNIll‘lX I’ROI’HYLAXIS IN CHILDREN 465
`
`continued rFIX on-demand treatment at a higher
`dose (100 IU kg”) for bleeding episodes (mostly
`injury-related),
`all with
`‘Excellent’
`or
`‘Good’
`responses, using premedication (antihistamine and
`corticosteroid), with no allergic manifestations or
`anamnestic inhibitor response. The inhibitor titre
`spontaneously
`decreased
`to
`0.8 BU mL‘1
`over
`3 months, and was undetectable (0 BU mIf', with
`negative anti-FIX ELISA) on two subsequent assess—
`ments 2 and 3 months later, during which time the
`patient
`followed routine prophylaxis
`(prescribed
`regimen, 100 IU kg—l once weekly) with no reported
`bleeding episodes. Two subjects had haemophilia-
`related events (one case of mild skin haematoma
`each) and both cases were judged possibly related to
`rFIX treatment.
`for 23 subjects
`I19 ge