A Trial Investigating Safety and Efficacy of Treatment With BAY94-9027 in Severe Hemophilia A

Hemophilia A Clinical Trial

— PROTECT-VIII  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01580293
• Other study ID #: 13024
• Secondary ID: 2011-005210-11
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: April 23, 2012
• Est. completion date: November 21, 2019

Study information

• Verified date: November 2023
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 145
• Est. completion date: November 21, 2019
• Est. primary completion date: June 13, 2014
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 12 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Hemophilia A

Intervention

Biological:
• BAY94-9027
Intravenous infusion of BAY94-9027

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Bayer

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Canada,  Colombia,  Denmark,  France,  Germany,  Israel,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Norway,  Poland,  Romania,  Singapore,  Taiwan,  Turkey,  United Kingdom, 

References & Publications (4)

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. — View 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. — View 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. — View 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 a — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change From Baseline in Overall Pain Severity and Interference Due to Pain at Week 36 - Part A	Brief Pain Inventory (BPI) - Short Form (BPI-SF) was a 15-item, self-administered, validated tool developed to assess pain used in the study for patient reported outcomes. Scores ranged from 0 to 10 and a higher score indicates a higher level of pain/interference.	Week 0 (baseline) and Week 36 during Part A
Other	Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire at Week 36 - Part A	The WPAI is a validated instrument to assess the effect of hemophilia on ability to work, attend classes, and perform regular daily activities in participants aged 12 and above. The WPAI also contained classroom impairment questions (CIQ). The questionnaire was self-administered and comprised of nine questions that elicited information on work, classroom, and daily activity impairment during the previous seven days. WPAI outcomes that are overall work and activity impairment, transformed to impairment percentages (range from 0 to 100), with higher numbers indicating greater impairment and less productivity.	Week 0 (baseline) and Week 36 during Part A
Other	Recombinant Human Factor VIII (rFVIII) Usage Expressed as Number of Infusions- Part A	For prophylaxis patients, the dose is related to all infusions.	On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A
Other	Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram With Prophylaxis Treatment - Part A	For prophylaxis patients, the dose per kilogram is related to prophylaxis infusions.	Weeks 10 - 36 during Part A
Other	Number of Minor Surgeries According to Physician's Assessment of Adequacy of Hemostasis - Part A	Minor surgery was defined as any surgical procedure that did not meet the definition of major, and included simple dental extractions, incision and drainage of abscesses, or simple excisions.	Weeks 0 to 36 during Part A
Other	Number of Surgeries According to Physician's Assessment of Response to Hemostasis, Post-surgery - Part B Main Trial	Response to treatment during surgery was assessed by investigator/surgeon as excellent, good, moderate, poor or missing during Part B of the study.	Up to 3 weeks post-surgery during Part B
Other	Number of Participants With Change/Drop in Hemoglobin/Hematocrit Laboratory Assessments - Part B	Hematocrit is defined as the volume percentage (%) of red blood cells in blood.	Up to 3 weeks post-surgery during Part B
Other	Maximum Blood Loss During Major Surgery - Part B	Major surgery was defined as any surgical or invasive procedure (elective or emergent) in which the overall bleeding risk was excessive, required a general anesthetic in an individual without a bleeding disorder, penetrated or exposed a major body cavity, resulted in substantial impairment of physical or physiological functions, or required special anatomic knowledge or manipulative skill.	day of surgery
Other	Number of Participants Who Took Anti-fibrinolytic Medications During Major Surgery - Part B	Major surgery was defined as any surgical or invasive procedure (elective or emergent) in which the overall bleeding risk was excessive, required a general anesthetic in an individual without a bleeding disorder, penetrated or exposed a major body cavity, resulted in substantial impairment of physical or physiological functions, or required special anatomic knowledge or manipulative skill.	Up to 3 weeks post-surgery during Part B
Other	Volume of Blood Transfused in Major Surgery - Part B	Major surgery was defined as any surgical or invasive procedure (elective or emergent) in which the overall bleeding risk was excessive, required a general anesthetic in an individual without a bleeding disorder, penetrated or exposed a major body cavity, resulted in substantial impairment of physical or physiological functions, or required special anatomic knowledge or manipulative skill.	Up to 3 weeks post-surgery during Part B
Primary	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	Annualized number of total bleeds was defined as the annualized sum of spontaneous bleeds and trauma bleeds. A participant who had the one-time increase in dose frequency was regarded as rescued. A rescue bleed was a bleed that occured after the dose frequency was increased. Rescue bleeds and periods were not considered for the annualized bleeding rate (ABR).	On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A
Secondary	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	A participant who had the one-time increase in dose frequency was regarded as rescued. A rescue bleed was a bleed that occured after the dose frequency was increased. Rescue bleeds and periods were not considered for the ABR.	On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A
Secondary	Annualized Number of Total Bleeds in On-demand Treatment Arm and in Each Prophylaxis Arm, Part A, Extension	Annualized number of total bleeds was defined as the annualized sum of spontaneous bleeds and trauma bleeds.	at least 100 total exposure days acquired, median time 3.9 years up to 7 years maximum
Secondary	Number of Participants Developed Human Coagulation Factor VIII (FVIII) Inhibitor - Part A	FVIII inhibitor testing was done according to the Nijmegen modified Bethesda assay. A positive inhibitor test was defined with a threshold of =0.6 Bethesda unit (BU) at the central laboratory.	Weeks 0 to 36 during Part A
Secondary	Number of Bleeds Requiring 1, 2 or >= 3 Infusions to Control the Bleed - Part A	Number of bleeds requiring 1, 2 or >= 3 infusions to control the bleeding	Weeks 0 to 36
Secondary	Number of Bleeds According to Locations - Part A	Bleed locations were categorised as joint, muscle, skin/mucosa, internal, others and missing.	Weeks 0 -36
Secondary	Number of Bleeds Over Time Since Previous Prophylaxis Infusion - Part A		Weeks 0 to 36
Secondary	Number of Bleeds According to Participant's Assessment of Response to Treatment - Part A	Response to treatment was assessed by participant as excellent, good, moderate, poor or missing during Part A of the study.	Weeks 0 to 36 during Part A
Secondary	Recombinant Human Factor VIII (rFVIII) Usage Expressed as Total Dose Per Kilogram Per Year - Part A	For prophylaxis patients, the dose is related to all infusions.	On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A
Secondary	Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram Per Infusion - Part A	For prophylaxis patients, the dose per infusion related to prophylaxis infusion.	On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A
Secondary	Number of Participants Requiring an Increase in Dose Frequency, or Dose Increase, During Weeks 10 to 36 - Part A		Weeks 10 to 36 during Part A
Secondary	Number of Surgeries According to Physician's Assessment of Adequacy of Hemostasis in Major Surgery - Part B	Major surgery was defined as any surgical or invasive procedure (elective or emergent) in which the overall bleeding risk was excessive, required a general anesthetic in an individual without a bleeding disorder, penetrated or exposed a major body cavity, resulted in substantial impairment of physical or physiological functions, or required special anatomic knowledge or manipulative skill. Adequacy of hemostasis was assessed as excellent, good, moderate or poor, by the surgeon or interventionalist during Part B of the study.	Day of surgery
Secondary	Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram Per Infusion for Major Surgery - Part B	Major surgery was defined as any surgical or invasive procedure (elective or emergent) in which the overall bleeding risk was excessive, required a general anesthetic in an individual without a bleeding disorder, penetrated or exposed a major body cavity, resulted in substantial impairment of physical or physiological functions, or required special anatomic knowledge or manipulative skill. Total dose per kilogram per Infusion was expressed in international units per kilogram per infusion (IU/kg/infusion).	Up to 3 weeks post-surgery during Part B
Secondary	Recombinant Human Factor VIII (rFVIII) Usage Expressed as Number of Infusions for Major Surgery - Part B	Major surgery was defined as any surgical or invasive procedure (elective or emergent) in which the overall bleeding risk was excessive, required a general anesthetic in an individual without a bleeding disorder, penetrated or exposed a major body cavity, resulted in substantial impairment of physical or physiological functions, or required special anatomic knowledge or manipulative skill.rFVIII usage expressed as number of infusions and IU/kg per year, as well as IU/kg per event (surgery) was assessed by investigator.	Up to 3 weeks post-surgery during Part B
Secondary	Maximum Drug Plasma Concentration (Cmax) Following Single and Multiple Doses of BAY94-9027, Chromogenic Assay - Part A	Cmax: Maximum observed drug concentration following an infusion of 60 IU/kg	Weeks 0 and 36: pre-infusion (0 hours), post-infusion 15, 30 minutes, 1, 3, 6, 8, 24, 48, 72, 96 hours
Secondary	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	AUC: The total area under the plasma concentration versus time curve following an infusion of 60 IU/kg .	Weeks 0 and 36: pre-infusion (0 hours), post-infusion 15, 30 minutes, 1, 3, 6, 8, 24, 48, 72, 96 hours
Secondary	Terminal Elimination Half Life (t1/2) Following Single and Multiple Doses of BAY94-9027, Chromogenic Assay - Part A	t1/2: Terminal half-life is the time the plasma concentration during terminal phase is halved following an infusion of 60 IU/kg .	Weeks 0 and 36: pre-infusion (0 hours), post-infusion 15, 30 minutes, 1, 3, 6, 8, 24, 48, 72, 96 hours
Secondary	Overall Human Coagulation Factor VIII (FVIII) Recovery Value by Chromogenic Assay - Part A	Recovery was calculated by the following formula: Recovery = (post-infusion FVIII activity - pre-infusion FVIII activity ) * weight / dose (in IU). Recovery is the increase of FVIII activity after the injection normalized by dose: IU/dl per IU/kg = kg/dL	Weeks 0 to 36 during Part A
Secondary	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	Quality of life (QoL) was measured by the Haemo-QoL-A overall score, which ranged from 0 (the worst condition) to 100 (the best condition).	Week 0 (baseline) and Week 36 during Part A

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