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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