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Clinical Trial Results Synopsis
Study Design Description
Study Sponsor: Bayer HealthCare Pharmaceuticals Inc.
Study Number: 12954
NCT01029340
EudraCT Number: 2009-012149-43
Study Phase: I, II and III
Official Study Title: A two part, randomized, cross-over, open-label trial to evaluate the
pharmacokinetics, efficacy, and safety profile of plasma protein-free
recombinant FVIII formulated with sucrose (BAY 81-8973) in previously treated subjects with severe hemophilia A under prophylaxis therapy.
Therapeutic Area: Hematology
Test Product
Name of Test Product:
BAY81-8973
Name of Active Ingredient:
Recombinant, full-length, human coagulation factor VIII (rFVIII);
octocog alfa
Dose and Mode of Administration:
Part A (PK): Single injection of 50 IU/kg. The potency (dose) was
determined by the Chromogenic Substrate assay per European
Pharmacopoeia (CS/EP).
Part B and extension: 2-3 weekly doses of 20-50 IU/kg. Nominal dosage
had to be kept unchanged during Part B. The potency was determined by
CS/EP (CS/EP period) and for the CS/ADJ period the labeled potency was
adjusted by a predetermined factor, mimicking FVIII:C one-stage
coagulation assay for potency, resulting in a difference of approximately
20% in actual dosing between both periods. Manual i.v. injection over 1-15
minutes.
Part C: According to standard practice for the use of rFVIII in major surgeries.
Reference Therapy/Placebo
Reference Therapy: Kogenate FS (BAY 14-2222) (= Kogenate Bayer in Europe)
Dose and
Mode of Administration: Part A: Single injection of 50 IU/kg. The potency (dose) was determined by
the CS/EP.
Kogenate FS was not used during Part B or Part C.
Duration of Treatment: Part A: 1 day (single injection)
Part B: 1 year (2 periods [CS/EP and CS/ADJ] of 6 months) plus a 1-year extension
Part C: According to the subject’s individual need within the scope of
surgery (3 weeks maximum).
Studied period: Date of first subjects’ first visit: 21 DEC 2009
Date of last subjects’ last visit:
Part A: 01 JUN 2010
Part B/Extension: 14 MAR 2013
Premature Study Suspension / Termination:
Not applicable
Substantial Study Protocol There were 6 global amendments to the original study protocol, dated 22
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Amendments: JUN 2009.
Amendment 1, dated 20 NOV 2009, became effective before any subject
had started treatment. It clarified the surgery indication and the criteria to
analyze surgical outcomes. The times for PK measurements were revised. A
specification was added for the use of Kogenate FS only for the treatment
of any bleeds during Part A. Dosge and drug administration were clarified.
The objectives of Part B were changed to reflect the combined statistical analysis of the efficacy data with data from another study.
Amendment 5, dated 08 APR 2010, modified some in- and exclusion criteria
and the number of subjects in Part A was increased from 16 to 30.
Amendment 6, dated 11 MAY 2010, clarified “severe hemophilia A”
diagnosis, increased the number of surgeries needed and stipulated that
BAY81-8973 was not to be used in the surgical setting until at least 20 bleeding events (across two studies) had been assessed.
Amendment 7, dated 21 SEP 2010, added “known hypersensitivity against mouse protein” as an exclusion criterion.
Amendment 8, dated 13 JAN 2011, specified “addendum objectives”, to
include objectives for the pooled results of two studies. Importantly, no
Part B objectives were deleted or significantly revised. The highest dosage
was increased from 40 IU/kg to 50 IU/kg in Part B, to cater for some centers who use this dose as a standard prophylaxis dose.
Amendment 9, dated 01 APR 2011, specified additional study objectives and introduced a surgery only arm and an extension period.
All other amendments were local amendments.
Study Centre(s): The study was conducted at 26 study centers in 12 countries (number of
recruiting sites in parentheses): Denmark (1), Germany (1), Hong Kong (1
[Part A only]), Israel (1), Italy (4), Spain (4), Poland (2), Sweden (1),
South Africa (2), Turkey (3), United Kingdom (1) and United States of America (5).
Methodology: Part A (Phase I):
Pharmacokinetic non-inferiority of BAY 81-8973 as compared to Kogenate
FS was evaluated in 2 PK sessions with an at least 3-day wash-out period in
between. Blood samples were collected over 48 h. Mean in vivo recovery
after 15 min of BAY 81-8973 injection had to be >1.7 IU/kg for
continuation of the clinical development program. Subjects who completed
Part A could continue treatment in Part B and undergo a further PK session with BAY 81-8973 at the end of the CS/EP period in Part B.
Part B (Phase II-III):
The safety and efficacy were evaluated during the 1-year prophylaxis
treatment period with BAY 81-8973. An intra-individual cross-over from one
method of potency assignment to the other (CS/EP or CS/ADJ) was
performed after 6 months. All treatment data and bleeding episodes were
to be documented in an electronic patient diary (EPD). In vivo recovery was
to be assessed during each 6 month potency assignment period. Subjects
requiring any major or minor surgery during Part B of the study were to be
treated with BAY 81 8973. All subjects who completed the 1-year treatment in Part B were offered participation in the 1-year extension.
Part C (major surgeries):
The hemostatic outcome of treatment with BAY 81-8973 during major
surgeries was evaluated in subjects who did not participate in Part B. Major
surgery was defined as any surgical procedure that involved general
anesthesia and/or respiratory assistance in which a major body cavity was
penetrated and exposed, or a substantial impairment of physical or
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physiological functions was produced (eg, laparotomy, thoracotomy,
craniotomy, joint replacement, or limb amputation).
Indication/
Main Inclusion Criteria:
Severe hemophilia A (FVIII:C <1%)
Severe hemophilia A, defined as < 1% FVIII activity (FVIII:C) as determined by one-stage clotting assay at the time of screening.
Male, aged 12 to 65 years
At least 150 exposure days (ED) in total with any recombinant FVIII or
plasma-derived FVIII.
No current evidence of inhibitor antibody as measured by the Nijmegen
modified Bethesda assay.
No history of FVIII inhibitor formation, defined as inhibitor antibody < 0.6 BU/mL, by the Bethesda assay.
CD4 lymphocyte count ≥250 cells/µL.
Study Objectives:
Overall:
Part A (Phase I):
Primary objective:
To demonstrate the pharmacokinetic non-inferiority of BAY 81-8973 as
compared to Kogenate FS using bioequivalence criteria following single dose administration.
Secondary objective:
To evaluate the in vivo recovery of Human factor VIII (FVIII) plasma
levels 15 min post single injection of BAY 81-8973.
Part B (Phase II-III):
Primary objective:
To demonstrate the efficacy and safety of BAY 81-8973 for the treatment of bleeds and prophylaxis.
Secondary objectives:
To compare bleeding frequency of prophylactic treatment with BAY 81-
8973 (dose determined by Chromogenic substrate assay per European
Pharmacopoeia [CS/EP] versus dose determined by Chromogenic
substrate assay/adjusted to one-stage assay [CS/ADJ]) as measured by the bleeding rate.
To compare in vivo recovery at the 6 month periods based on potency
determinations (CS/EP versus CS/ADJ) during prophylactic treatment
with BAY 81-8973.
To evaluate the potential for inhibitory antibody formation during prophylactic treatment with BAY 81-8973.
To evaluate the potential for antibody formation to heat shock protein
70 (HSP-70) and/or hamster proteins during prophylactic treatment with BAY 81-8973.
To evaluate surgical outcomes in terms of hemostasis during treatment
with BAY 81 8973, including major surgeries of Part B and Part C.
To assess quality of life (QoL) and pharmaco-economic parameters during prophylactic treatment with BAY 81-8973.
To assess the safety and tolerability profile of BAY 81-8973 by
assessing clinical chemistry, hematological parameters, and adverse event (AE) presentation.
Evaluation Criteria: Efficacy (Primary):
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Primary efficacy variable was the annualized number of bleeds in each 6-month potency assignment period.
Efficacy (Secondary):
Annualized numbers of joint bleeds, spontaneous bleeds, trauma bleeds
and bleeds which occurred within 48 h after a prophy-laxis injection in each 6-month potency assignment period
Control of bleeding as measured by the number of injections required to
treat a bleed
In-vivo recovery of human FVIII
Hemostatic outcome of surgeries (both major and minor) including
blood loss, transfusion, and/or hemostasis-related surgical
complications
Change in QoL (as assessed by Hemophilia-Specific Quality of Life
[Haemo-QoL]–A questionnaire and European Quality of Life-5
Dimensions [EQ-5D] Health Questionnaire).
Part C efficacy variables:
Hemostatic outcome of surgeries as assessed by the surgeon.
Efficacy (Other)
Description of bleeds according to location
FVIII usage calculation in each 6-month period (CS/EP and CS/ADJ)
expressed as number of injections and dose (IU/kg per month, per year, per event)
Subject’s assessment of response to treatment of bleeds expressed as
“poor”, “moderate”, “good” or “excellent”.
Safety:
Incidences of adverse events (AEs) and serious adverse events (SAEs).
Immunogenicity as assessed by the development of inhibitory
antibodies to FVIII, antibody formation to HSP-70 and hamster proteins
(host cell protein [HCP]).
Changes in vital signs (pulse, blood pressure, and temperature) at pre injection and post- injection.
Changes in laboratory values (complete blood count [CBC] with
differential, clinical chemistry, coagulation panel, urinalysis).
Pharmacokinetics (Primary):
The primary pharmacokinetic analyses for BAY 81-8973 and Kogenate FS
were:
Area under the curve (AUC)
Half-life (t1/2)
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Statistical Methods: Efficacy (Primary):
Primary efficacy variable in Part B and Extension was the annualized
number of bleeds. This and all other efficacy variables related to bleeds
were analyzed by period (CS/EP and CS/ADJ) and for both periods
combined using summary statistics. The primary analysis was based on the data of the ITT population.
Efficacy (Secondary):
FVIII concentrations and recovery values (one-stage and chromo-genic
assays) were summarized and listed for each time point.
Safety:
All safety variables were analyzed using summary statistics.
Pharmacokinetics:
PK characteristics were analyzed using summary statistics (arith-metic
mean, standard deviation and coefficient of variation, geometric mean,
geometric standard deviation and coefficient of variation, minimum,
median, maximum value, and the number of measurements). The primary
PK characteristic AUC was analyzed using analysis of variance (ANOVA).
Based on this analysis, point estimates (least square mean [LSmeans]),
and exploratory 90% confidence intervals (CI) for the ratio ‘BAY 81 8973 /
Kogenate FS’ of AUC were calculated. These data were used to show the
non-inferiority of BAY 81-8973 as compared to Kogenate FS using bioequivalence criteria.
Number of Subjects:
Part A
Planned: N ≤ 30
Safety population: N = 28
PK analysis population (Part A): N = 26
PK analysis population for repeated PK (Parts A + B): N = 19
Part B
Planned: N = 60
Safety population: N = 62
ITT population: N = 62
PP population: N = 59
Part C Planned: N = 8-10 major surgeries in the 2 pivotal studies
Safety population: N = 7 major surgeries in 5 subjects in part C
Study Results
Results Summary — Subject Disposition and Baseline
Part A: 28 subjects aged between 12 and 61 years (median: 28.5 years) were randomized (14
per sequence group) and underwent PK sessions both with BAY 81-8973 and Kogenate FS.
Twenty-six subjects had valid PK data, which were used for the calculation of the PK parameters
for BAY 81-8973 and Kogenate FS. Twenty-two of the subjects in Part A continued in Part B, and 19 underwent a further valid PK session for the analysis of repeated PK.
Part B: The total number of randomized subjects (including those from Part A) was 63. One
subject withdrew his consent prior to treatment start with BAY 81-8973, resulting in 30 subjects
starting prophylaxis treatment with CS/EP potency assignment and 32 subjects starting with
CS/ADJ potency assignment. The total population had a mean age of 31.5 ± 12.7 years (median:
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30.0 years). The majority of subjects (80.6%) were being treated with prophylaxis prior to study
entry. The mean number of bleeds in the previous year was 11.5 ± 15.1 (median: 5.5). Target joints for bleeds were present in 44 subjects (71.0%).
All but 1 subject completed the 1-year prophylaxis treatment period of Part B and accumula-ted at
least 50 ED to BAY 81-8973. Overall, a total of 8,975 BAY 81-8973 injections (pro-phylaxis and
treatment of bleeds) were administered and the mean number of injections per subject was 144.8 ± 28.8 (median: 156.5).
Fifty-five of the 61 subjects, who had completed Part B participated in the extension study and 43 of these subjects completed it.
Overall, the 55 subjects received a total of 15,554 BAY 81-8973 injections (prophylaxis and
treatment of bleeds) during the 2-year treatment period, and the mean number of injections per
subject was 282.8 ± 61.0 (median: 309.0). The median number of exposure days in the extension period was 154 ED.
Part C: Twelve major surgeries had been performed with BAY 81-8973 treatment up to the end of
the study.
Results Summary — Efficacy
The efficacy of BAY 81-8973 was evaluated using the data of Part B (prophylaxis treatment with
BAY 81-8973) and Part C (BAY 81-8973 in major surgeries). Due to the fact that no clinically
relevant differences were observed between the results of the 2 periods of Part B (CS/EP and
CS/ADJ potency assignments), only the results for the 2 periods combined are presented in this
synopsis.
Primary efficacy variable was the annualized number of total bleeds.
An overview of the results for the primary efficacy variable and further efficacy variables related to the occurrence of bleeds is shown in the table below.
The mean individually annualized numbers of bleeds are shown below.
Summary of bleeds (ITT population)
Variable N Mean ± SD Median [Q1; Q3]
No. of total bleeds per year 62 3.79 ± 5.21 1.0 [0.00; 5.09]
No. of spontaneous bleeds per year 62 2.46 ± 3.50 1.0 [0.00; 3.94]
No. of trauma bleeds per year 62 1.27 ± 3.57 0.0 [0.00; 1.00]
No. of joint bleeds per year 62 3.03 ± 4.67 1.0 [0.00; 3.00]
ITT = Intent-to-treat; SD = Standard deviation
86% of bleeds responded to ≤ 2 BAY 81-8973 injections. A total of 484 BAY 81-8973 injections using a mean nominal dose of 31.3 ± 9.3 IU/kg were administered for the treatment of bleeds.
In accordance with the data for response to treatment, the subjects’ assessment of response was
“good” or “excellent” in 81% of all bleeds.
The hemostatic control during major and minor surgeries was good or excellent in all cases, and
the blood losses did not exceed expected amounts.
Prophylaxis treatment with BAY 81-8973 during the observation period of 1 year had no major
impact on QoL in the study subjects, >80% of whom were already on a regular prophylaxis regimen prior to entering the study.
Results Summary — Safety
The incidence of AEs was very different in Parts A, B and C of the study, ranging from 25% in Part
A to 80% in Part C. This was to be expected, considering the reasons for treatment (PK, prophylaxis, major surgery) and the duration of each part (from a few days up to a year).
Part A/B
In the majority of subjects with AEs, the maximum intensity of any AE was mild. The highest
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incidence was seen for infections and infestations (eg, in 48.4% of the subjects in Part B). Drug-
related AEs were infrequent and occurred in <10% of the subjects in total (including 3 drug-
related AEs which occurred in 2 subjects after Kogenate FS injection). AEs assessed as causally
related to treatment with BAY 81-8973 were: dysgeusia, flushing, headache, injection site pain,
myalgia, nasal congestion, nausea, and rhinorrhea. All of these AEs occurred in single subjects
only, and all but 2 (nasal congestion and rhinorrhea, both in the same subject) had resolved by the end of the Part B. There were no drug-related SAEs.
Extension
During the Extension, the incidence of treatment-emergent AEs was 67.3% and similar to the
incidence in Part B. In the majority of subjects with AEs, the maximum intensity of an AE was
mild, and in 5.5% of the subjects, drug-related AEs occurred. Nine subjects experienced a total of
14 SAEs during the extension period or in Part C. One subject experienced a myocardial infarction,
which was rated as drug-related. It occurred in a subject who had several risk factors for a
cardiovascular event. This was also the only AE which led to a subject’s discontinuation from the
study. All SAEs had improved or resolved by the end of the study and no subjects died.
The highest incidence of AEs (27.3%) was seen for infections and infestations. The 3 non-serious
AEs assessed as causally related to treatment with BAY 81-8973 were: mild seasonal allergy and 2
episodes of mild and moderate pruritus, which both occurred in the same subject. All of these AEs
had resolved by the end of the extension period.
Despite several treatment-emergent abnormalities in safety laboratory parameters, none was
rated as drug-related. Abnormal laboratory values were related to the underlying concomitant
diseases. Mean and median changes in the different laboratory values did not indicate any specific
trends during treatment. No influence of the BAY 81-8973 treatment on vital signs was seen.
The immunogenicity of BAY 81-8973 was evaluated with regard to antibody development against
FVIII (inhibitors), HSP-70 and hamster proteins (BHK/HCP). No subjects developed inhibitory
antibodies to FVIII or antibodies to BHK/HCP. There were 2 subjects with increases in anti-HSP-70
antibody levels to above the cut-off for positivity. These were not associated with any clinical signs or symptoms.
Results Summary — Pharmacokinetics
The primary objective of Part A (Phase I) was to demonstrate the non-inferiority of the PK
characteristics of a single-dose of 50 IU/kg BAY 81-8973 compared to its predecessor Kogenate FS
(potency determined via CS/EP for both products) in a randomized cross-over design. The data
from 26 of the 28 subjects in total were valid for PK analysis. For the calculation of the specific PK
parameters, individual FVIII levels were measured both with the one-stage assay and the
chromogenic assays. The results clearly demonstrated the non-inferior bioavailability of the new formulation and even hinted at a more favorable PK profile for BAY 81-8973.
Part A: Results of AUC and t1/2
BAY 81-8973 BAY 14-2222
No of participants 26 26
Geometric mean
Geometric coefficient of
variation
Geometric mean
Geometric coefficient of variation
Part A – Area under the drug concentration time curve (AUC) Units: Int. Units x
hours/deciliters (IU*h/dL)
1889.23 36.11 1583.91 39.89
Part A – Half-life (t ½) Units: Hours (h)
13.77 28.00 12.00 28.20
With both assays, the 90% CIs for the ratio of geometric LS means for AUC lay completely above
1, demonstrating non-inferiority. Repeated PK measurements after 6 or 12 months of prophylaxis
treatment with BAY 81-8973 in Part B did not indicate any relevant changes in PK characteristics
after long-term treatment. The in vivo recovery values of Human FVIII from Part B are shown
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below.
Part B: Results of in vivo recovery of Human FVIII
BAY 81-8973 by CS/EP
No of participants 59
Median Inter-quartile range Part B – In vivo recovery values of Human FVIII Units: Kg/dL
2.50 2.09 to 2.77
Conclusion(s)
Long-term treatment with BAY 81-8973 is efficacious and demonstrates an acceptable safety
profile. The efficacy of prophylaxis treatment as seen in the first study year was completely
maintained on continued treatment in the second year, with a trend towards a further reduction of
spontaneous bleeds during the second year without impairment of the safety and tolerability profile. The product has a favorable benefit/risk profile.
The PK profile of BAY 81-8973 is non-inferior to that of Kogenate FS. The PK characteristics of BAY
81-8973 overall remained unchanged after 6 or 12 months of treatment.
Publication(s): None
Date Created or
Date Last Updated: 19 FEB 2014 Date of Clinical Study Report:
17 DEC 2013
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Investigational Site List
Marketing Authorization Holder in Germany
Name Bayer Vital GmbH
Postal Address D-51368 Leverkusen
Germany
Sponsor in Germany (if applicable)
Legal Entity Name Bayer Pharma AG
Postal Address D-51368 Leverkusen Germany
List of Investigational Sites
No Investigator Name
Facility Name Street ZIP Code
City Country
1 Hr. Prof. Dr. J Oldenburg
Medizinische Einrichtungen der Universität Bonn
Institut für Experimentelle Hämatologie und Transfusionsmedizin Sigmund-Freud-Straβe 25
53127 Bonn Germany
2 Dr L Hvitfeldt Poulsen
Aarhus Universitetshospital, Skejby
Aarhus Universitetshospital, Skejby Center for Hæ mofili og Trombose Brendstrupgårdsvej 100, Indgang 3 DK-8200 Aarhus N
8200 DK-Aarhus N
Denmark
3 Dra. C Altisent Roca
Ciutat Sanitària i Universitaria de la Vall d'Hebron
Unitat d'Hemofília Passeig de la Vall d'Hebrón, 119-129
08035 Barcelona Spain
4 Dra. M López Fernández
Complejo Hospitalario Universitario A Coruña
Servicio de Hematología Edificio Teresa Herrera Avda. del Pasaje, s/n A Coruña
15006 A Coruña Spain
5 Dr. S Haya Hospital Universitari i Politècnic La Fe
Unidad de Coagulopatías congénitas Avda. Bulevar Sur, s/n Valencia
46026 Valencia Spain
6 Dra. M Fernández
Hospital Central de Asturias
Servicio de Hematología Celestino Villamil, s/n
33006 Oviedo Spain
7 Dr K Hampton Royal Hallamshire Hospital
Haematology Department H Floor Glossop Road
S10 2JF Sheffield United Kingdom
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8 Professor YLKwong
Queen Mary Hospital
Department of Medicine, Queen Mary Hospital 102 Pokulam Road
Hong Kong
Hong Kong
9 Prof. U Martinowitz
Chaim Sheba Medical Center
The Israeli National Hemophilia Center
52621 Tel Hashomer
Israel
10 Dr. E Santagostino
IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico
Centro Emofilia e Trombosi Angelo Bianchi Bonomi Dip. Medicina Interna 2 Via Pace, 9
20122 Milano Italy
11 Dr. R Santoro A.O. Pugliese-Ciaccio
Centro di Emofilia Emostasi e Trombosi Via Vinicio Cortese
88100 Catanzaro Italy
12 Dr. G Castaman
AULSS 06 Vicenza - Veneto
Ospedale S. Bortolo Ematologia e Trombosi Via Rodolfi, 37
36100 Vicenza Italy
13 Prof. G Di Minno
A.O.U. Federico II
CRR Emocoagulopatie Dip. Medicina Clinica e Sperimentale della Università Federico II Via S. Pansini, 5
80131 Napoli Italy
14 Prof J Windyga Instytut Hematologii i Transfuzjologii
Klinika Zaburzen Hemostazy i Chorob Wewn. oraz Poradnia Zaburzen Hemostazy ul. Indiry Gandhi 14
02-776 Warszawa Poland
15 Prof. A Skotnicki
Szpital Uniwersytecki w Krakowie
Oddzial Kliniczny Kliniki Hematologii ul. Kopernika 17
31-501 Krakow Poland
16 Prof. Dr. K Kavakli
Ege Universitesi Tip Fakultesi
Pediyatrik Hematoloji Bilim Dali Cocuk Hastanesi Bornova
35-100 Izmir Turkey
17 Assoc Prof Dr. I Sasmaz
Cukurova Universitesi Tip Fakultesi Hastanesi
Pediyatrik Hematoloji Bilim Dali Balcali Yuregir
01330 Adana Turkey
18 Assoc Prof Dr. A Kupesiz
Akdeniz Universitesi Tip Fakultesi Hastanesi
Pediyatrik Hematoloji Bilim Dali Arapsuyu Mevkii
07059 Antalya Turkey
19 Dr. D Obzut St. Joseph's Hospital
3001 West Dr. Martin Luther King, Jr. Blvd.
33607 Tampa United States
20 Dr. K Saxena Children's Hospital Boston
Division of Hematology Oncology Fegan-707 300 Longwood Avenue
02115 Boston United States
21 Dr. S Ahuja University Hospitals Case Medical Center
11100 Euclid Avenue 44106-2602
Cleveland United States
22 Dr. J S Powell University of California - Davis
Hemophilia Treatment Center 4625 2nd Avenue Room 010/CLB
95817 Sacramento
United States
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23 Dr. B Wicklund Children's Mercy Hospital
2401 Gillham Road 64108-9898
Kansas City
United States
24 Prof J Mahlangu
University of Witwatersrand
Haemophilia Comprehensive Care Centre Area 295, Yellow Block Charlotte Maxeke Johannesburg Hospital 7 York Rd
2132 Parktown South Africa
25 Prof R Pool Prinshof Campus
Pathology Building, Department of Haematology 5 Bophelo road Riviera
0001 Pretoria South Africa
26 Dr M Holmström
Karolinska Universitetssjukhuset i Solna
Koagulationsmottagningen, D1:02
171 76 Stockholm Sweden
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