Trial to Evaluate the Efficacy and Safety of a New Full Length Recombinant Human FVIII for Hemophilia A (Leopold I)

A Two Part Randomized Cross-Over Trial to Evaluate the Pharmacokinetics, Efficacy, and Safety Profile of Plasma Protein-Free Recombinant FVIII Formulated With Sucrose (BAY81-8973) in Previously Treated Subjects With Severe Hemophilia A Under Prophylaxis Therapy

The study will assess the pharmacokinetics (part A) safety, tolerability, and efficacy of prophylaxis treatment (2 to 3 times a week) (part B) with BAY81-8973 over a one year period (split into two six month treatment periods). The study will compare 2 different methods (assays) for measuring the amount of study drug, the chromogenic substrate assay per European Pharmacopeia (CS/EP) with the classical assay (Chromogenic Substrate Adjusted, CS/ADJ). During one six month period patients will receive the study drug where the dose has been measured using the" (CS/EP) and during the other six months period the dose will be measured based on the Chromogenic Substrate Adjusted assay CS/ADJ)

Study Overview

• Status: Completed
• Conditions: Hemophilia A; Blood Coagulation Disorders
• Intervention / Treatment: Biological: Recombinant Factor VIII (BAY81-8973); Biological: Recombinant Factor VIII (BAY81-8973); Biological: Recombinant Factor VIII (BAY81-8973); Biological: Recombinant Factor VIII (Kogenate FS, BAY14-2222)

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires
    • Bahia Blanca, Buenos Aires, Argentina, B8001HXM
  • Santa Fe
    • Rosario, Santa Fe, Argentina, S2000CKF
• Austria
  • Graz, Austria, 8036
  • Wien, Austria, 1090
• Croatia
  • Zagreb, Croatia, 10000
• Denmark
  • DK-Aarhus N, Denmark, 8200
• Germany
  • Hessen
    • Frankfurt, Hessen, Germany, 60596
  • Nordrhein-Westfalen
    • Bonn, Nordrhein-Westfalen, Germany, 53127
  • Rheinland-Pfalz
    • Mainz, Rheinland-Pfalz, Germany, 55131
  • Saarland
    • Homburg, Saarland, Germany, 66421
  • Sachsen-Anhalt
    • Magdeburg, Sachsen-Anhalt, Germany, 39112
• Hong Kong
  • Hongkong, Hong Kong
• India
  • Bangalore, India, 34
  • Mumbai, India, 400012
  • Pune, India, 411005
• Indonesia
  • Jakarta, Indonesia, 10430
• Israel
  • Ramat Gan, Israel, 5262000
• Italy
  • Calabria
    • Catanzaro, Calabria, Italy, 88100
  • Campania
    • Napoli, Campania, Italy, 80131
    • Napoli, Campania, Italy, 80144
  • Lazio
    • Roma, Lazio, Italy, 00168
  • Lombardia
    • Milano, Lombardia, Italy, 20122
  • Veneto
    • Vicenza, Veneto, Italy, 36100
• Norway
  • Oslo, Norway, 0027
• Pakistan
  • Karachi, Pakistan, 75300
• Poland
  • Krakow, Poland, 31-501
  • Warszawa, Poland, 02-776
• Serbia
  • Belgrade, Serbia, 11000
  • Beograd, Serbia, 11000
  • Nis, Serbia, 18000
  • Novi Sad, Serbia, 21000
• South Africa
  • Parktown, South Africa, 2132
  • Gauteng
    • Pretoria, Gauteng, South Africa, 0001
• Spain
  • A Coruña, Spain, 15006
  • Barcelona, Spain, 08035
  • Jaén, Spain, 23007
  • Valencia, Spain, 46026
  • Asturias
    • Oviedo, Asturias, Spain, 33006
  • Cantabria
    • Santander, Cantabria, Spain, 39008
• Sweden
  • Göteborg, Sweden, 413 45
  • Malmö, Sweden, 205 02
  • Stockholm, Sweden, 171 76
    • Karolinska Universitetssjukhuset i Solna
• Taiwan
  • Changhua, Taiwan, 500
  • Taipei, Taiwan, 11217
  • Taipei, Taiwan, 10016
• Thailand
  • Bangkok, Thailand, 10400
  • Bangkok, Thailand, 10330
• Turkey
  • Adana, Turkey, 01330
  • Antalya, Turkey, 07059
  • Izmir, Turkey, 35-100
• United Kingdom
  • London, United Kingdom, SE1 7EH
  • Dundee City
    • Dundee, Dundee City, United Kingdom, DD1 9SY
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OX3 7LJ
  • South Yorkshire
    • Sheffield, South Yorkshire, United Kingdom, S10 2JF
• United States
  • California
    • Orange, California, United States, 92868
    • Sacramento, California, United States, 95817
  • Florida
    • Tampa, Florida, United States, 33607
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
  • Michigan
    • East Lansing, Michigan, United States, 48823
  • Missouri
    • Kansas City, Missouri, United States, 64108-9898
  • Ohio
    • Cleveland, Ohio, United States, 44106-2602

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Male, aged 12 to 65 years
• Severe hemophilia A defined as < 1% FVIII:C
• >/= 150 days of previous treatment with FVIII in lifetime
• Currently receiving on-demand or any type of prophylaxis treatment regimen with any FVIII product
• No history of or current FVIII inhibitors

Exclusion Criteria:

• Presence of another bleeding disease that is different from hemophilia A (e.g., von Willebrand disease, hemophilia B)
• Low platelet count, abnormal kidney function, or liver disease
• Received treatment with immune suppressing drugs within the last 3 months prior or requires treatment during the study. (Some drugs for hepatitis C, Human immunodeficiency virus (HIV), and steroids are allowed)
• Receiving or has received other experimental drugs within 3 months prior to study entry
• Allergy to Factor VIII or hamsters or mouse protein

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: Recombinant Factor VIII (BAY81-8973) then Kogenate FS; Part A - Arm 1: Participants first received one single intravenous (IV) injection of BAY81-8973 50 IU/kg, then 1 single IV injection of Kogenate FS (BAY14-2222) 50 IU/kg with a wash-out period of at least 2-3 days in between	Biological: Recombinant Factor VIII (BAY81-8973); Single dose of BAY81-8973 crossed over to single dose of Kogenate FS; Biological: Recombinant Factor VIII (BAY81-8973); Participants received IV injections of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by Chromogenic Substrate Assay Potency Per European Pharmacopeia (CS/EP) for 6 months and by Chromogenic Substrate Assay/Adjusted to Label Potency (CS/ADJ) for 6 months, sequence according to randomization.; Biological: Recombinant Factor VIII (BAY81-8973); Participants received a loading dose of approximately 50 IU/kg of BAY 81-8973 before the first surgical incision followed by further treatment with BAY 81-8973 according to surgical requirements for up to 3 weeks
Experimental: Arm 2: Kogenate FS then Recombinant Factor VIII (BAY81-8973); Part A - Arm 2: Participants first received one single intravenous (IV) injection of Kogenate FS (BAY14-2222) 50 IU/kg, then 1 single IV injection of BAY81-8973 50 IU/kg with a wash-out period of at least 2-3 days in between	Biological: Recombinant Factor VIII (Kogenate FS, BAY14-2222); Single dose of Kogenate FS crossed over to Single dose of BAY81-8973
Experimental: Arm 3: Recombinant Factor VIII by CS/EP then by CS/ADJ; Part B - Arm 3: Participants received IV injection of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by Chromogenic Substrate Assay Potency Per European Pharmacopeia for 6 months and then crossed over to study drug measured by Chromogenic Substrate Assay/Adjusted to Label Potency for 6 months	Biological: Recombinant Factor VIII (BAY81-8973); Single dose of BAY81-8973 crossed over to single dose of Kogenate FS; Biological: Recombinant Factor VIII (BAY81-8973); Participants received IV injections of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by Chromogenic Substrate Assay Potency Per European Pharmacopeia (CS/EP) for 6 months and by Chromogenic Substrate Assay/Adjusted to Label Potency (CS/ADJ) for 6 months, sequence according to randomization.; Biological: Recombinant Factor VIII (BAY81-8973); Participants received a loading dose of approximately 50 IU/kg of BAY 81-8973 before the first surgical incision followed by further treatment with BAY 81-8973 according to surgical requirements for up to 3 weeks
Experimental: Arm 4: Recombinant Factor VIII by CS/ADJ then by CS/EP; Part B - Arm 4:. Participants received IV injection of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by Chromogenic Substrate Assay/Adjusted to Label Potency for 6 months and then crossed over to study drug measured by Chromogenic Substrate Assay Per European Pharmacopeia for 6 months	Biological: Recombinant Factor VIII (BAY81-8973); Single dose of BAY81-8973 crossed over to single dose of Kogenate FS; Biological: Recombinant Factor VIII (BAY81-8973); Participants received IV injections of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by Chromogenic Substrate Assay Potency Per European Pharmacopeia (CS/EP) for 6 months and by Chromogenic Substrate Assay/Adjusted to Label Potency (CS/ADJ) for 6 months, sequence according to randomization.; Biological: Recombinant Factor VIII (BAY81-8973); Participants received a loading dose of approximately 50 IU/kg of BAY 81-8973 before the first surgical incision followed by further treatment with BAY 81-8973 according to surgical requirements for up to 3 weeks
Experimental: Arm 5: Recombinant Factor VIII by CS/EP; Part C - Arm 5: Participants received a loading dose of approximately 50 IU/kg of BAY 81-8973 before the first surgical incision followed by further treatment with BAY 81-8973 according to surgical requirements for up to 3 weeks	Biological: Recombinant Factor VIII (BAY81-8973); Single dose of BAY81-8973 crossed over to single dose of Kogenate FS; Biological: Recombinant Factor VIII (BAY81-8973); Participants received IV injections of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by Chromogenic Substrate Assay Potency Per European Pharmacopeia (CS/EP) for 6 months and by Chromogenic Substrate Assay/Adjusted to Label Potency (CS/ADJ) for 6 months, sequence according to randomization.; Biological: Recombinant Factor VIII (BAY81-8973); Participants received a loading dose of approximately 50 IU/kg of BAY 81-8973 before the first surgical incision followed by further treatment with BAY 81-8973 according to surgical requirements for up to 3 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A - Area Under the Drug Concentration-time Curve (AUC)	To examine the Pharmacokinetic (PK) characteristics of BAY 81-8973 and ensure that the new drug is similar to Kogenate FS. All results are based on the chromogenic assay.	Samples taken at pre-injection, and at 0.25, 0.5, 1, 3, 6, 8, 24, 30 and 48 hours post injection. AUC calculated from time of injection to infinity.
Part A - Half-life (t 1/2)	To examine the PK characteristics of BAY81-8973 and ensure that the new drug is similar to Kogenate FS. All results are based on the chromogenic assay.	Samples taken at pre-injection, and at 0.25, 0.5, 1, 3, 6, 8, 24, 30 and 48 hours post injection.
Part B - Annualized Number of Total Bleeds	The annualized number of bleeds experienced by participants	12 months after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part B - The in Vivo Recovery Values of Human Factor VIII (FVIII)	The amount of Factor VIII found in blood samples taken after the injection of the study drug at the beginning of the CS/EP treatment period.	15-30 minutes after the injection
Part B - Annualized Number of Bleeds in Each 6-month Potency Assignment Period	The annualized number of bleeds experienced by participants in each of the two treatment periods	6 months on each potency
Part B - Control of Bleeding as Measured by the Number of Injections Required to Treat a Bleed	The number of injections needed by participants to stop a bleed	6 months on each potency
Part B - Changes From Baseline at 12 Months in Quality of Life (QoL) as Measured by Transformed Total Score of Haemo-QoL Questionnaire	A measure of how treatment with BAY81-8973 affected the daily life of participants. the scoring system has 100 points. 0 is the worst possible score. 100 is the best possible score. Positive changes from baseline indicate an improvement in quality of life and negative changes indicate a deterioration.	Baseline and 12 months
Part B - Changes From Baseline at 12 Months in Utility Index as Measured by EQ-5D Questionaire	A measure of how treatment with BAY81-8973 affected the daily life of participants. 1.0 = Best possible score, -0.594 = Worst possible score. Positive changes from baseline indicate an improvement and negative changes indicate a deterioration.	Baseline and 12 months
Part A - Number of Participants With Inhibitory Antibody Formation	A test to ensure that participants have not developed antibodies that will interfere with the action of BAY81-8973	Up to 6 weeks after first injection of study drug
Part B - Number of Participants With Incidence of Inhibitory Antibody Formation	A test to ensure that participants have not developed antibodies that will interfere with the action of BAY81-8973	Up to 12 months after drug administration
Part C - Number of Participants With Incidence of Inhibitory Antibody Formation	A test to ensure that participants have not developed antibodies that will interfere with the action of BAY81-8973	before and 3 weeks after surgery
Part A - Number of Participants With Incidence of Antibody Formation to Heat-shock Protein (HSP-70)	A test to analyze the formation of antibodies to HSP-70	Up to 6 weeks after drug administration
Part B - Number of Participants With Incidence of Antibody Formation to Heat-shock Protein (HSP-70)	A test to analyze the formation of antibodies to HSP-70	Up to 12 months after drug administration
Part C - Number of Participants With Incidence of Antibody Formation to Heat-shock Protein (HSP-70)	A test to analyze the formation of antibodies to HSP-70	before and 3 weeks after surgery
Part A - Number of Participants With Incidence of Antibody Formation to Host Cell Proteins (HCP)	A test to ensure that participants have not developed antibodies to HCP during the study	Up to 4 weeks after drug administration
Part B - Number of Participants With Incidence of Antibody Formation to Host Cell Proteins (HCP)	A test to ensure that participants have not developed antibodies to HCP during the study	Up to 12 months after drug administration
Part C - Number of Participants With Incidence of Antibody Formation to Host Cell Proteins (HCP)	A test to ensure that participants have not developed antibodies to HCP during the study	before and 3 weeks after surgery
Part B - Number of Participants With Assessment of the Hemostasis During Major Surgery	An assessment made by surgeons of how effective BAY81-8973 was in stopping bleeding during major operations	An average of 1 month after start of treatment
Part C - Number of Participants With Assessment of the Hemostasis During Major Surgery	An assessment made by surgeons of how effective BAY81-8973 was in stopping bleeding during major operations	at the time of surgery

Collaborators and Investigators

• Sponsor: Bayer

Publications and helpful links

General Publications

• Kitchen S, Katterle Y, Beckmann H, Maas Enriquez M. Chromogenic assay for BAY 81-8973 potency assignment has no impact on clinical outcome or monitoring in patient samples. J Thromb Haemost. 2016 Jun;14(6):1192-9. doi: 10.1111/jth.13322. Epub 2016 May 3.
• Oldenburg J, Windyga J, Hampton K, Lalezari S, Tseneklidou-Stoeter D, Beckmann H, Maas Enriquez M. Safety and efficacy of BAY 81-8973 for surgery in previously treated patients with haemophilia A: results of the LEOPOLD clinical trial programme. Haemophilia. 2016 May;22(3):349-53. doi: 10.1111/hae.12839. Epub 2016 Mar 1.
• Saxena K, Lalezari S, Oldenburg J, Tseneklidou-Stoeter D, Beckmann H, Yoon M, Maas Enriquez M. Efficacy and safety of BAY 81-8973, a full-length recombinant factor VIII: results from the LEOPOLD I trial. Haemophilia. 2016 Sep;22(5):706-12. doi: 10.1111/hae.12952. Epub 2016 Jun 24.

Helpful Links

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe

Study record dates

Study Major Dates

• Study Start: December 1, 2009
• Primary Completion (Actual): June 1, 2012
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: December 8, 2009
• First Submitted That Met QC Criteria: December 8, 2009
• First Posted (Estimate): December 9, 2009

Study Record Updates

• Last Update Posted (Estimate): November 28, 2016
• Last Update Submitted That Met QC Criteria: October 14, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: Prophylaxis; Factor VIII; Hemophilia A
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Hemostatic Disorders; Hemophilia A; Blood Coagulation Disorders; Coagulants; Factor VIII
• Other Study ID Numbers: 12954; 2009-012149-43 (EudraCT Number)