Clinical trial NCT01580293: A Trial Investigating Safety and Efficacy of Treatment With BAY94-9027 in Severe Hemophilia A
Official title: A Phase II/III, Multicenter, Partially Randomized, Open Label Trial Investigating Safety and Efficacy of On-demand and Prophylactic Treatment With BAY94-9027 in Severe Hemophilia A
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Hemophilia A
Keywords: Hemophilia A, factor VIII, prophylaxis
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2012-04-19
Enrollment: 145
Sex: MALE
Minimum age (years): 12
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Haemophilia A is an inherited disorder in which one of the proteins, Factor VIII, needed to form blood clots is missing or not present in sufficient levels. In a person with haemophilia A, the clotting process is slowed and the person experiences bleeds that can result in serious problems and potential disability.

The current standard treatment for severe haemophilia A is regularly scheduled infusion of FVIII to keep levels high enough to prevent bleeding. Due to the short half-life of FVIII, prophylaxis may require treatment as often as every other day.

In this trial safety and efficacy of a long-acting recombinant factor VIII molecule is evaluated in subjects with severe Hemophilia A.

120-140 patients will receive open label treatment with long-acting rFVIII either on-demand to treat bleeds or prophylactically for 36 weeks in the main trial plus an optional extension to continue treatment for at least 100 total exposure days (ED). Patients on prophylactic treatment will receive study drug at dosing intervals between once and twice a week depending on their observed bleeding. Patients will attend the treatment centre for routine blood samples and be required to keep an electronic diary.

Male patients aged 12-65, with severe hemophilia A, previously treated with FVIII for at least 50 exposure days may be eligible for this study.

Detailed description: Subjects in prophylactic treatment arms will undergo clinical evaluation at 10 weeks. Those with adequate control of bleeding will undergo randomization to every 5 or 7 day infusion. Those with continued bleeding will remain in treatment arm and have an increase in dose.

Part B-major surgery - optional sub study included to collect information on efficacy of BAY94-9027 in major surgical setting. Due to rarity of surgery in this population, enrollment to this sub-study may be independent of participation in main study.

Eligibility criteria: Inclusion Criteria:

* Male; 12-65 years of age
* Subjects with severe hemophilia A
* Previously treated with factor VIII for a minimum of 150 exposure days

Exclusion Criteria:

* Inhibitors to FVIII (current evidence or history)
* Any other inherited or acquired bleeding disorder in addition to Hemophilia A
* Platelet count \< 100,000/mm3
* Creatinine \> 2x upper limit of normal or AST/ALT (aspartate aminotransferase/alanine aminotransferase) \> 5x upper limit of normal

Primary outcomes:
measure: Annualized Number of Total Bleeds in On-demand Treatment Arm (Weeks 0 -36) and in Each Prophylaxis Arm (Weeks 10 - 36, Excluding Rescue Bleeds) - Part A, Main Trial
timeFrame: On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A
Secondary outcomes:
measure: Annualized Number of Joint Bleeds, Trauma, Spontaneous Bleeds in On-demand Treatment Arm (Weeks 0 -36) and in Each Prophylaxis Arm (Weeks 10 - 36, Excluding Rescue Bleeds) - Part A
timeFrame: On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A
measure: Annualized Number of Total Bleeds in On-demand Treatment Arm and in Each Prophylaxis Arm, Part A, Extension
timeFrame: at least 100 total exposure days acquired, median time 3.9 years up to 7 years maximum
measure: Number of Participants Developed Human Coagulation Factor VIII (FVIII) Inhibitor - Part A
timeFrame: Weeks 0 to 36 during Part A
measure: Number of Bleeds Requiring 1, 2 or >= 3 Infusions to Control the Bleed - Part A
timeFrame: Weeks 0 to 36
measure: Number of Bleeds According to Locations - Part A
timeFrame: Weeks 0 -36
measure: Number of Bleeds Over Time Since Previous Prophylaxis Infusion - Part A
timeFrame: Weeks 0 to 36
measure: Number of Bleeds According to Participant's Assessment of Response to Treatment - Part A
timeFrame: Weeks 0 to 36 during Part A
measure: Recombinant Human Factor VIII (rFVIII) Usage Expressed as Total Dose Per Kilogram Per Year - Part A
timeFrame: On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A
measure: Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram Per Infusion - Part A
timeFrame: On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A
measure: Number of Participants Requiring an Increase in Dose Frequency, or Dose Increase, During Weeks 10 to 36 - Part A
timeFrame: Weeks 10 to 36 during Part A
measure: Number of Surgeries According to Physician's Assessment of Adequacy of Hemostasis in Major Surgery - Part B
timeFrame: Day of surgery
measure: Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram Per Infusion for Major Surgery - Part B
timeFrame: Up to 3 weeks post-surgery during Part B
measure: Recombinant Human Factor VIII (rFVIII) Usage Expressed as Number of Infusions for Major Surgery - Part B
timeFrame: Up to 3 weeks post-surgery during Part B
measure: Maximum Drug Plasma Concentration (Cmax) Following Single and Multiple Doses of BAY94-9027, Chromogenic Assay - Part A
timeFrame: Weeks 0 and 36: pre-infusion (0 hours), post-infusion 15, 30 minutes, 1, 3, 6, 8, 24, 48, 72, 96 hours
measure: Area Under the Plasma Concentration Versus Time Curve From Zero to Infinity (AUC) Following Single and Multiple Doses of BAY94-9027, Chromogenic Assay - Part A
timeFrame: Weeks 0 and 36: pre-infusion (0 hours), post-infusion 15, 30 minutes, 1, 3, 6, 8, 24, 48, 72, 96 hours
measure: Terminal Elimination Half Life (t1/2) Following Single and Multiple Doses of BAY94-9027, Chromogenic Assay - Part A
timeFrame: Weeks 0 and 36: pre-infusion (0 hours), post-infusion 15, 30 minutes, 1, 3, 6, 8, 24, 48, 72, 96 hours
measure: Overall Human Coagulation Factor VIII (FVIII) Recovery Value by Chromogenic Assay - Part A
timeFrame: Weeks 0 to 36 during Part A
measure: Change From Baseline in Quality of Life by Hemophilia Specific Quality of Life Instrument or Questionnaire for Adults (Haemo-QoL-A) Overall Score at Week 36 - Part A
timeFrame: Week 0 (baseline) and Week 36 during Part A
Other outcomes:
measure: Change From Baseline in Overall Pain Severity and Interference Due to Pain at Week 36 - Part A
timeFrame: Week 0 (baseline) and Week 36 during Part A
measure: Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire at Week 36 - Part A
timeFrame: Week 0 (baseline) and Week 36 during Part A
measure: Recombinant Human Factor VIII (rFVIII) Usage Expressed as Number of Infusions- Part A
timeFrame: On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A
measure: Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram With Prophylaxis Treatment - Part A
timeFrame: Weeks 10 - 36 during Part A
measure: Number of Minor Surgeries According to Physician's Assessment of Adequacy of Hemostasis - Part A
timeFrame: Weeks 0 to 36 during Part A
measure: Number of Surgeries According to Physician's Assessment of Response to Hemostasis, Post-surgery - Part B Main Trial
timeFrame: Up to 3 weeks post-surgery during Part B
measure: Number of Participants With Change/Drop in Hemoglobin/Hematocrit Laboratory Assessments - Part B
timeFrame: Up to 3 weeks post-surgery during Part B
measure: Maximum Blood Loss During Major Surgery - Part B
timeFrame: day of surgery
measure: Number of Participants Who Took Anti-fibrinolytic Medications During Major Surgery - Part B
timeFrame: Up to 3 weeks post-surgery during Part B
measure: Volume of Blood Transfused in Major Surgery - Part B
timeFrame: Up to 3 weeks post-surgery during Part B
Locations:
city: Tucson
country: United States
state: Arizona
city: Sacramento
country: United States
state: California
city: San Diego
country: United States
state: California
city: Jacksonville
country: United States
state: Florida
city: Miami
country: United States
state: Florida
city: Chicago
country: United States
state: Illinois
city: Detroit
country: United States
state: Michigan
city: Minneapolis
country: United States
state: Minnesota
city: Syracuse
country: United States
state: New York
city: Cincinnati
country: United States
state: Ohio
city: Cleveland
country: United States
state: Ohio
city: Columbus
country: United States
state: Ohio
city: Hershey
country: United States
state: Pennsylvania
city: Richmond
country: United States
state: Virginia
city: Wien
country: Austria
city: Brugge
country: Belgium
city: London
country: Canada
state: Ontario
city: Medellin
country: Colombia
state: Antioquia
city: Baranquilla
country: Colombia
state: Atlántico
city: Aarhus N
country: Denmark
city: BRON cedex
country: France
city: Marseille
country: France
city: Reims Cedex
country: France
city: Rennes Cedex
country: France
city: Heidelberg
country: Germany
state: Baden-Württemberg
city: Bonn
country: Germany
state: Nordrhein-Westfalen
city: Ramat Gan
country: Israel
city: Napoli
country: Italy
state: Campania
city: Roma
country: Italy
state: Lazio
city: Milano
country: Italy
state: Lombardia
city: Torino
country: Italy
state: Piemonte
city: Nagoya
country: Japan
state: Aichi
city: Nishinomiya
country: Japan
state: Hyogo
city: Kashihara
country: Japan
state: Nara
city: Shinjuku-ku
country: Japan
state: Tokyo
city: Suginami
country: Japan
state: Tokyo
city: Hiroshima
country: Japan
city: Busan
country: Korea, Republic of
state: Busan Gwang''yeogsi
city: Daejeon
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Amsterdam
country: Netherlands
city: Den Haag
country: Netherlands
city: Groningen
country: Netherlands
city: Maastricht
country: Netherlands
city: Oslo
country: Norway
city: Wroclaw
country: Poland
city: Timisoara
country: Romania
city: Singapore
country: Singapore
city: Singapore
country: Singapore
city: Singapore
country: Singapore
city: Changhua
country: Taiwan
city: Taipei
country: Taiwan
city: Taipei
country: Taiwan
city: Ankara
country: Turkey
city: Izmir
country: Turkey
city: Newcastle Upon Tyne
country: United Kingdom
state: Vale Of Glamorgan, The
city: London
country: United Kingdom
city: Sheffield
country: United Kingdom
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References:
citation: Baumann A, Piel I, Hucke F, Sandmann S, Hetzel T, Schwarz T. Pharmacokinetics, excretion, distribution, and metabolism of 60-kDa polyethylene glycol used in BAY 94-9027 in rats and its value for human prediction. Eur J Pharm Sci. 2019 Mar 15;130:11-20. doi: 10.1016/j.ejps.2019.01.015. Epub 2019 Jan 14.
citation: Lalezari S, Reding MT, Pabinger I, Holme PA, Negrier C, Chalasani P, Shin HJ, Wang M, Tseneklidou-Stoeter D, Maas Enriquez M. BAY 94-9027 prophylaxis is efficacious and well tolerated for up to >5 years with extended dosing intervals: PROTECT VIII extension interim results. Haemophilia. 2019 Nov;25(6):1011-1019. doi: 10.1111/hae.13853. Epub 2019 Oct 17.
citation: Reding MT, Ng HJ, Poulsen LH, Eyster ME, Pabinger I, Shin HJ, Walsch R, Lederman M, Wang M, Hardtke M, Michaels LA. Safety and efficacy of BAY 94-9027, a prolonged-half-life factor VIII. J Thromb Haemost. 2017 Mar;15(3):411-419. doi: 10.1111/jth.13597. Epub 2017 Feb 22.
citation: Reding MT, Pabinger I, Holme PA, Maas Enriquez M, Mancuso ME, Lalezari S, Miesbach W, Di Minno G, Klamroth R, Hermans C. Efficacy and safety of damoctocog alfa pegol prophylaxis in patients ⩾40 years with severe haemophilia A and comorbidities: post hoc analysis from the PROTECT VIII study. Ther Adv Hematol. 2023 Apr 22;14:20406207231166779. doi: 10.1177/20406207231166779. eCollection 2023.