Hemophilia A
Conditions
Keywords
Hemophilia A, factor VIII, prophylaxis
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.
Interventions
BIOLOGICALBAY94-9027
Intravenous infusion of BAY94-9027
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
12 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Bleeds According to Locations - Part A | Weeks 0 -36 | Bleed locations were categorised as joint, muscle, skin/mucosa, internal, others and missing. |
| Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram Per Infusion - Part A | On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A | For prophylaxis patients, the dose per infusion related to prophylaxis infusion. |
| 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 | — |
| Number of Surgeries According to Physician's Assessment of Adequacy of Hemostasis in Major Surgery - Part B | Day of surgery | 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. |
| Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram Per Infusion for Major Surgery - Part B | Up to 3 weeks post-surgery during 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). |
| Recombinant Human Factor VIII (rFVIII) Usage Expressed as Number of Infusions for Major Surgery - Part B | Up to 3 weeks post-surgery during 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. |
| Maximum Drug Plasma Concentration (Cmax) Following Single and Multiple Doses of BAY94-9027, Chromogenic Assay - Part A | Weeks 0 and 36: pre-infusion (0 hours), post-infusion 15, 30 minutes, 1, 3, 6, 8, 24, 48, 72, 96 hours | Cmax: Maximum observed drug concentration following an infusion of 60 IU/kg |
| 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 | Weeks 0 and 36: pre-infusion (0 hours), post-infusion 15, 30 minutes, 1, 3, 6, 8, 24, 48, 72, 96 hours | AUC: The total area under the plasma concentration versus time curve following an infusion of 60 IU/kg . |
| Terminal Elimination Half Life (t1/2) Following Single and Multiple Doses of BAY94-9027, Chromogenic Assay - Part A | Weeks 0 and 36: pre-infusion (0 hours), post-infusion 15, 30 minutes, 1, 3, 6, 8, 24, 48, 72, 96 hours | t1/2: Terminal half-life is the time the plasma concentration during terminal phase is halved following an infusion of 60 IU/kg . |
| Overall Human Coagulation Factor VIII (FVIII) Recovery Value by Chromogenic Assay - Part A | Weeks 0 to 36 during 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 |
| 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 | Week 0 (baseline) and Week 36 during 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). |
| 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 | On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during 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. |
| Annualized Number of Total Bleeds in On-demand Treatment Arm and in Each Prophylaxis Arm, Part A, Extension | at least 100 total exposure days acquired, median time 3.9 years up to 7 years maximum | Annualized number of total bleeds was defined as the annualized sum of spontaneous bleeds and trauma bleeds. |
| Number of Participants Developed Human Coagulation Factor VIII (FVIII) Inhibitor - Part A | Weeks 0 to 36 during 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. |
| Number of Bleeds Requiring 1, 2 or >= 3 Infusions to Control the Bleed - Part A | Weeks 0 to 36 | Number of bleeds requiring 1, 2 or \>= 3 infusions to control the bleeding |
| Number of Bleeds Over Time Since Previous Prophylaxis Infusion - Part A | Weeks 0 to 36 | — |
| Number of Bleeds According to Participant's Assessment of Response to Treatment - Part A | Weeks 0 to 36 during Part A | Response to treatment was assessed by participant as excellent, good, moderate, poor or missing during Part A of the study. |
| Recombinant Human Factor VIII (rFVIII) Usage Expressed as Total Dose Per Kilogram Per Year - Part A | On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A | For prophylaxis patients, the dose is related to all infusions. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Recombinant Human Factor VIII (rFVIII) Usage Expressed as Number of Infusions- Part A | On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A | For prophylaxis patients, the dose is related to all infusions. |
| Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram With Prophylaxis Treatment - Part A | Weeks 10 - 36 during Part A | For prophylaxis patients, the dose per kilogram is related to prophylaxis infusions. |
| Number of Minor Surgeries According to Physician's Assessment of Adequacy of Hemostasis - Part A | Weeks 0 to 36 during 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. |
| Number of Surgeries According to Physician's Assessment of Response to Hemostasis, Post-surgery - Part B Main Trial | Up to 3 weeks post-surgery during Part B | Response to treatment during surgery was assessed by investigator/surgeon as excellent, good, moderate, poor or missing during Part B of the study. |
| Number of Participants With Change/Drop in Hemoglobin/Hematocrit Laboratory Assessments - Part B | Up to 3 weeks post-surgery during Part B | Hematocrit is defined as the volume percentage (%) of red blood cells in blood. |
| Maximum Blood Loss During Major Surgery - Part B | day of surgery | 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. |
| Number of Participants Who Took Anti-fibrinolytic Medications During Major Surgery - Part B | Up to 3 weeks post-surgery during 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. |
| Volume of Blood Transfused in Major Surgery - Part B | Up to 3 weeks post-surgery during 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. |
| Change From Baseline in Overall Pain Severity and Interference Due to Pain at Week 36 - Part A | Week 0 (baseline) and Week 36 during 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. |
| Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire at Week 36 - Part A | Week 0 (baseline) and Week 36 during 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. |
Countries
Austria, Belgium, Canada, Colombia, Denmark, France, Germany, Israel, Italy, Japan, Netherlands, Norway, Poland, Romania, Singapore, South Korea, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
The study was conducted in 3 parts: Part A (main study \[36-week treatment period\] and an optional extension \[at least 100 total exposure days\]) and Part B for major surgeries (up to 3 weeks).
Pre-assignment details
Of 149 participants screened in Part A, 134 were treated, reasons for non-inclusion were screen failure, consent withdrawal, and non-adherence to protocol visit windows. Participants selected either on-demand or prophylaxis treatment at start of study according to their preference. Randomization to prophylaxis arms occurred after week 10.
Participants by arm
| Arm | Count |
|---|---|
| BAY94-9027 On-demand Treatment, Main Trial Participants received on-demand treatment with BAY94-9027 as an intravenous (IV)infusion at a dose as indicated based upon location and severity of bleeds (a maximum of 60 international units per kilogram \[IU/kg\]). | 20 |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Dropped, Main Trial 4 participants dropped out during week 0-10 | 4 |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. High bleeders (with 2 or more muscle or joint bleeds in the first 10 weeks) continued 2x/week infusion (2x/week 'failed') at a dose of 30 to 40 IU/kg. | 13 |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Forced, Main Trial All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants with \< 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen. Participants enrolled after randomization arms were filled continued 2x/week treatment at a dose of 30-40 IU/kg (2x/week 'forced'). | 11 |
| BAY94-9027 Prophylaxis Treatment, Every 5 Days, Main Trial All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants with \< 2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen, participants randomized to the every 5 days treatment arm were to begin treatment with 45 IU/kg every 5 days with the option to increase dose up to 60 IU/kg/infusion. | 43 |
| BAY94-9027 Prophylaxis Treatment, Every 7 Days, Main Trial All participants started BAY94-9027 IV infusion with 2x/week at a dose of 25 IU/kg for 10 weeks. Participants \<2 spontaneous joint and/or muscle bleeds were randomized 1:1 to either every 5 or every 7 days dosing regimen, participants randomized to the every 7 days treatment arm were to administer a dose of 60 IU/kg (maximum 6000 IU) every 7 days. | 43 |
| BAY94-9027 Treatment in Major Surgery, Part B Only Participants treated in Part B only were included. Participants treated in Part A and continued in Part B were excluded. Participants who underwent major surgery received study drug during their hospital stay and up until hospital discharge or 3 weeks post-surgery, whichever came first. Participants were treated according to the type of procedure, using tailored doses (a maximum of 60 IU/kg) expected to maintain acceptable therapeutic level of FVIII activity. | 11 |
| Total | 145 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Part A_Extension | Adverse Event | 0 | 2 | 0 |
| Part A_Extension | Completed Japan only | 0 | 5 | 0 |
| Part A_Extension | Lost to Follow-up | 0 | 1 | 0 |
| Part A_Extension | Other Reason | 0 | 1 | 0 |
| Part A_Extension | Withdrawal by Subject | 0 | 3 | 0 |
| Part A_Main Trial | Adverse Event | 0 | 2 | 0 |
| Part A_Main Trial | Non-adherence to the protocol | 1 | 0 | 0 |
| Part A_Main Trial | Withdrawal by Subject | 1 | 4 | 0 |
| Part B | Other reason | 0 | 0 | 1 |
| Part B | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | BAY94-9027 On-demand Treatment, Main Trial | BAY94-9027 Prophylaxis Treatment, 2x/Week Dropped, Main Trial | BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | BAY94-9027 Prophylaxis Treatment, 2x/Week Forced, Main Trial | BAY94-9027 Prophylaxis Treatment, Every 5 Days, Main Trial | BAY94-9027 Prophylaxis Treatment, Every 7 Days, Main Trial | BAY94-9027 Treatment in Major Surgery, Part B Only | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 44.8 years STANDARD_DEVIATION 13.5 | 27.3 years STANDARD_DEVIATION 14.2 | 31.4 years STANDARD_DEVIATION 11.6 | 33.1 years STANDARD_DEVIATION 11 | 33.7 years STANDARD_DEVIATION 13 | 37.0 years STANDARD_DEVIATION 13.5 | 37.9 years STANDARD_DEVIATION 13.7 | 36.1 years STANDARD_DEVIATION 13.5 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 20 Participants | 4 Participants | 13 Participants | 11 Participants | 43 Participants | 43 Participants | 11 Participants | 145 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 134 | 0 / 121 | 0 / 22 |
| other Total, other adverse events | 67 / 134 | 74 / 121 | 16 / 22 |
| serious Total, serious adverse events | 13 / 134 | 36 / 121 | 2 / 22 |
Outcome results
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).
Time frame: On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A
Population: Intent to treat (ITT) population part A week 10-36, 4 participants dropped out during week 0-10.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | 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 | 23.42 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | 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 | 4.11 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Forced, Main Trial | 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 | 1.93 bleeds |
| BAY94-9027 Prophylaxis Treatment, Every 5 Days, Main Trial | 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 | 1.93 bleeds |
| BAY94-9027 Prophylaxis Treatment, Every 7 Days, Main Trial | 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 | 3.85 bleeds |
| BAY94-9027 Prophylaxis Treatment Total, Main Trial | 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 | 2.09 bleeds |
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.
Time frame: On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A
Population: ITT population part A week 10-36, 4 participants dropped out during week 0-10.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | 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 | Joint Bleeds | 16.34 bleeds |
| BAY94-9027 On-demand Treatment, Main Trial | 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 | Spontaneous Bleeds | 14.29 bleeds |
| BAY94-9027 On-demand Treatment, Main Trial | 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 | Trauma Bleeds | 9.09 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | 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 | Trauma Bleeds | 1.98 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | 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 | Spontaneous Bleeds | 3.87 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | 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 | Joint Bleeds | 4.01 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Forced, Main Trial | 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 | Joint Bleeds | 1.93 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Forced, Main Trial | 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 | Trauma Bleeds | 0.00 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Forced, Main Trial | 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 | Spontaneous Bleeds | 0.00 bleeds |
| BAY94-9027 Prophylaxis Treatment, Every 5 Days, Main Trial | 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 | Joint Bleeds | 1.86 bleeds |
| BAY94-9027 Prophylaxis Treatment, Every 5 Days, Main Trial | 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 | Trauma Bleeds | 0.00 bleeds |
| BAY94-9027 Prophylaxis Treatment, Every 5 Days, Main Trial | 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 | Spontaneous Bleeds | 0.00 bleeds |
| BAY94-9027 Prophylaxis Treatment, Every 7 Days, Main Trial | 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 | Spontaneous Bleeds | 1.93 bleeds |
| BAY94-9027 Prophylaxis Treatment, Every 7 Days, Main Trial | 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 | Joint Bleeds | 1.92 bleeds |
| BAY94-9027 Prophylaxis Treatment, Every 7 Days, Main Trial | 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 | Trauma Bleeds | 0.00 bleeds |
| BAY94-9027 Prophylaxis Treatment Total, Main Trial | 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 | Trauma Bleeds | 0.00 bleeds |
| BAY94-9027 Prophylaxis Treatment Total, Main Trial | 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 | Spontaneous Bleeds | 0.00 bleeds |
| BAY94-9027 Prophylaxis Treatment Total, Main Trial | 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 | Joint Bleeds | 1.93 bleeds |
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.
Time frame: at least 100 total exposure days acquired, median time 3.9 years up to 7 years maximum
Population: ITT extension population. Participants in each regimen stayed on this regimen without switch. Participants who switched regimen were analyzed in the variable frequency arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Annualized Number of Total Bleeds in On-demand Treatment Arm and in Each Prophylaxis Arm, Part A, Extension | 34.09 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Annualized Number of Total Bleeds in On-demand Treatment Arm and in Each Prophylaxis Arm, Part A, Extension | 1.57 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Forced, Main Trial | Annualized Number of Total Bleeds in On-demand Treatment Arm and in Each Prophylaxis Arm, Part A, Extension | 1.17 bleeds |
| BAY94-9027 Prophylaxis Treatment, Every 5 Days, Main Trial | Annualized Number of Total Bleeds in On-demand Treatment Arm and in Each Prophylaxis Arm, Part A, Extension | 0.65 bleeds |
| BAY94-9027 Prophylaxis Treatment, Every 7 Days, Main Trial | Annualized Number of Total Bleeds in On-demand Treatment Arm and in Each Prophylaxis Arm, Part A, Extension | 3.10 bleeds |
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 .
Time frame: Weeks 0 and 36: pre-infusion (0 hours), post-infusion 15, 30 minutes, 1, 3, 6, 8, 24, 48, 72, 96 hours
Population: PKS with participants evaluable for this outcome
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | 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 | 3707.5 h*IU/dL | Geometric Coefficient of Variation 33.77 |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | 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 | 4130.8 h*IU/dL | Geometric Coefficient of Variation 28.8 |
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).
Time frame: Week 0 (baseline) and Week 36 during Part A
Population: Part A ITT population with participants evaluable for this outcome
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | 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 | -0.14 scores on a scale | Standard Deviation 9.7 |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | 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 | 2.59 scores on a scale | Standard Deviation 7.98 |
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
Time frame: Weeks 0 and 36: pre-infusion (0 hours), post-infusion 15, 30 minutes, 1, 3, 6, 8, 24, 48, 72, 96 hours
Population: Pharmacokinetic Analysis Set (PKS) with participants evaluable for this outcome, PKS included all participants with a valid profile of BAY94-9027 during Part A of the study.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Maximum Drug Plasma Concentration (Cmax) Following Single and Multiple Doses of BAY94-9027, Chromogenic Assay - Part A | 162.8 IU/dL | Geometric Coefficient of Variation 14.74 |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Maximum Drug Plasma Concentration (Cmax) Following Single and Multiple Doses of BAY94-9027, Chromogenic Assay - Part A | 177.1 IU/dL | Geometric Coefficient of Variation 20.98 |
Secondary
Number of Bleeds According to Locations - Part A
Bleed locations were categorised as joint, muscle, skin/mucosa, internal, others and missing.
Time frame: Weeks 0 -36
Population: Analysis population includes participants who presented \>=1 bleeding event.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Number of Bleeds According to Locations - Part A | Internal | 7 bleeds |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Bleeds According to Locations - Part A | Missing | 0 bleeds |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Bleeds According to Locations - Part A | Skin/Mucosa | 12 bleeds |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Bleeds According to Locations - Part A | Joint | 303 bleeds |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Bleeds According to Locations - Part A | Other | 26 bleeds |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Bleeds According to Locations - Part A | Muscle | 54 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Bleeds According to Locations - Part A | Other | 16 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Bleeds According to Locations - Part A | Skin/Mucosa | 12 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Bleeds According to Locations - Part A | Internal | 7 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Bleeds According to Locations - Part A | Muscle | 59 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Bleeds According to Locations - Part A | Missing | 0 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Bleeds According to Locations - Part A | Joint | 235 bleeds |
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.
Time frame: Weeks 0 to 36 during Part A
Population: Analysis population includes participants who presented \>=1 bleeding event.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Number of Bleeds According to Participant's Assessment of Response to Treatment - Part A | Good | 171 bleeds |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Bleeds According to Participant's Assessment of Response to Treatment - Part A | Poor | 16 bleeds |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Bleeds According to Participant's Assessment of Response to Treatment - Part A | Excellent or Good | 252 bleeds |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Bleeds According to Participant's Assessment of Response to Treatment - Part A | Excellent | 81 bleeds |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Bleeds According to Participant's Assessment of Response to Treatment - Part A | Missing | 3 bleeds |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Bleeds According to Participant's Assessment of Response to Treatment - Part A | Moderate | 115 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Bleeds According to Participant's Assessment of Response to Treatment - Part A | Missing | 6 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Bleeds According to Participant's Assessment of Response to Treatment - Part A | Excellent | 107 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Bleeds According to Participant's Assessment of Response to Treatment - Part A | Good | 149 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Bleeds According to Participant's Assessment of Response to Treatment - Part A | Moderate | 47 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Bleeds According to Participant's Assessment of Response to Treatment - Part A | Poor | 7 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Bleeds According to Participant's Assessment of Response to Treatment - Part A | Excellent or Good | 256 bleeds |
Secondary
Number of Bleeds Over Time Since Previous Prophylaxis Infusion - Part A
Time frame: Weeks 0 to 36
Population: Analysis population includes participants who presented \>=1 bleeding event.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Number of Bleeds Over Time Since Previous Prophylaxis Infusion - Part A | <1 day | 4 bleeds |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Bleeds Over Time Since Previous Prophylaxis Infusion - Part A | >=1 to <2 days | 19 bleeds |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Bleeds Over Time Since Previous Prophylaxis Infusion - Part A | >=2 to <3 days | 30 bleeds |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Bleeds Over Time Since Previous Prophylaxis Infusion - Part A | >=3 to <4 days | 30 bleeds |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Bleeds Over Time Since Previous Prophylaxis Infusion - Part A | >=4 to <5 days | 38 bleeds |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Bleeds Over Time Since Previous Prophylaxis Infusion - Part A | >=5 to <6 days | 42 bleeds |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Bleeds Over Time Since Previous Prophylaxis Infusion - Part A | >=6 to <7 days | 31 bleeds |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Bleeds Over Time Since Previous Prophylaxis Infusion - Part A | >=7 days | 192 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Bleeds Over Time Since Previous Prophylaxis Infusion - Part A | >=7 days | 3 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Bleeds Over Time Since Previous Prophylaxis Infusion - Part A | <1 day | 21 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Bleeds Over Time Since Previous Prophylaxis Infusion - Part A | >=4 to <5 days | 32 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Bleeds Over Time Since Previous Prophylaxis Infusion - Part A | >=1 to <2 days | 62 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Bleeds Over Time Since Previous Prophylaxis Infusion - Part A | >=6 to <7 days | 11 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Bleeds Over Time Since Previous Prophylaxis Infusion - Part A | >=2 to <3 days | 82 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Bleeds Over Time Since Previous Prophylaxis Infusion - Part A | >=5 to <6 days | 36 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Bleeds Over Time Since Previous Prophylaxis Infusion - Part A | >=3 to <4 days | 69 bleeds |
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
Time frame: Weeks 0 to 36
Population: Part A ITT population, analysis population includes participants who presented \>=1 bleeding event.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Number of Bleeds Requiring 1, 2 or >= 3 Infusions to Control the Bleed - Part A | 1 infusion | 307 bleeds |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Bleeds Requiring 1, 2 or >= 3 Infusions to Control the Bleed - Part A | 2 infusions | 45 bleeds |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Bleeds Requiring 1, 2 or >= 3 Infusions to Control the Bleed - Part A | Greater than or equal to (>=) 3 infusions | 34 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Bleeds Requiring 1, 2 or >= 3 Infusions to Control the Bleed - Part A | 1 infusion | 262 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Bleeds Requiring 1, 2 or >= 3 Infusions to Control the Bleed - Part A | 2 infusions | 22 bleeds |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Bleeds Requiring 1, 2 or >= 3 Infusions to Control the Bleed - Part A | Greater than or equal to (>=) 3 infusions | 32 bleeds |
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.
Time frame: Weeks 0 to 36 during Part A
Population: Part A safety population (N=134) included all participants who received at least 1 dose of study drug during Part A of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Number of Participants Developed Human Coagulation Factor VIII (FVIII) Inhibitor - Part A | 0 Participants |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Participants Developed Human Coagulation Factor VIII (FVIII) Inhibitor - Part A | 0 Participants |
Secondary
Number of Participants Requiring an Increase in Dose Frequency, or Dose Increase, During Weeks 10 to 36 - Part A
Time frame: Weeks 10 to 36 during Part A
Population: ITT population part A week 10-36, 4 participants dropped out during week 0-10.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Number of Participants Requiring an Increase in Dose Frequency, or Dose Increase, During Weeks 10 to 36 - Part A | Dose frequency increased | 0 Participants |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Participants Requiring an Increase in Dose Frequency, or Dose Increase, During Weeks 10 to 36 - Part A | Dose increased | 2 Participants |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Participants Requiring an Increase in Dose Frequency, or Dose Increase, During Weeks 10 to 36 - Part A | Dose frequency increased | 0 Participants |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Number of Participants Requiring an Increase in Dose Frequency, or Dose Increase, During Weeks 10 to 36 - Part A | Dose increased | 0 Participants |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Forced, Main Trial | Number of Participants Requiring an Increase in Dose Frequency, or Dose Increase, During Weeks 10 to 36 - Part A | Dose frequency increased | 0 Participants |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Forced, Main Trial | Number of Participants Requiring an Increase in Dose Frequency, or Dose Increase, During Weeks 10 to 36 - Part A | Dose increased | 7 Participants |
| BAY94-9027 Prophylaxis Treatment, Every 5 Days, Main Trial | Number of Participants Requiring an Increase in Dose Frequency, or Dose Increase, During Weeks 10 to 36 - Part A | Dose increased | 0 Participants |
| BAY94-9027 Prophylaxis Treatment, Every 5 Days, Main Trial | Number of Participants Requiring an Increase in Dose Frequency, or Dose Increase, During Weeks 10 to 36 - Part A | Dose frequency increased | 11 Participants |
| BAY94-9027 Prophylaxis Treatment, Every 7 Days, Main Trial | Number of Participants Requiring an Increase in Dose Frequency, or Dose Increase, During Weeks 10 to 36 - Part A | Dose frequency increased | 11 Participants |
| BAY94-9027 Prophylaxis Treatment, Every 7 Days, Main Trial | Number of Participants Requiring an Increase in Dose Frequency, or Dose Increase, During Weeks 10 to 36 - Part A | Dose increased | 9 Participants |
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.
Time frame: Day of surgery
Population: 17 participants were included in the Part B ITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Number of Surgeries According to Physician's Assessment of Adequacy of Hemostasis in Major Surgery - Part B | Moderate | 0 surgeries |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Surgeries According to Physician's Assessment of Adequacy of Hemostasis in Major Surgery - Part B | Poor | 0 surgeries |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Surgeries According to Physician's Assessment of Adequacy of Hemostasis in Major Surgery - Part B | Good | 13 surgeries |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Surgeries According to Physician's Assessment of Adequacy of Hemostasis in Major Surgery - Part B | Excellent | 7 surgeries |
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
Time frame: Weeks 0 to 36 during Part A
Population: Part A ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Overall Human Coagulation Factor VIII (FVIII) Recovery Value by Chromogenic Assay - Part A | 2.67 Kilogram per deciliter | Standard Deviation 0.54 |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Overall Human Coagulation Factor VIII (FVIII) Recovery Value by Chromogenic Assay - Part A | 2.68 Kilogram per deciliter | Standard Deviation 0.55 |
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).
Time frame: Up to 3 weeks post-surgery during Part B
Population: Part B ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram Per Infusion for Major Surgery - Part B | 33.7 IU/kg/infusion |
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.
Time frame: On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A
Population: ITT population part A week 10-36, 4 participants dropped out during week 0-10.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram Per Infusion - Part A | 32.8 IU/kg/infusion |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram Per Infusion - Part A | 39.2 IU/kg/infusion |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Forced, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram Per Infusion - Part A | 30.6 IU/kg/infusion |
| BAY94-9027 Prophylaxis Treatment, Every 5 Days, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram Per Infusion - Part A | 45.3 IU/kg/infusion |
| BAY94-9027 Prophylaxis Treatment, Every 7 Days, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram Per Infusion - Part A | 59.0 IU/kg/infusion |
| BAY94-9027 Prophylaxis Treatment Total, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram Per Infusion - Part A | 46.9 IU/kg/infusion |
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.
Time frame: Up to 3 weeks post-surgery during Part B
Population: Part B ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Number of Infusions for Major Surgery - Part B | 8.0 infusions |
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.
Time frame: On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A
Population: ITT population part A week 10-36, 4 participants dropped out during week 0-10.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Total Dose Per Kilogram Per Year - Part A | 1518.5 IU/kg/year |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Total Dose Per Kilogram Per Year - Part A | 4421.4 IU/kg/year |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Forced, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Total Dose Per Kilogram Per Year - Part A | 3314.4 IU/kg/year |
| BAY94-9027 Prophylaxis Treatment, Every 5 Days, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Total Dose Per Kilogram Per Year - Part A | 3482.9 IU/kg/year |
| BAY94-9027 Prophylaxis Treatment, Every 7 Days, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Total Dose Per Kilogram Per Year - Part A | 3338.7 IU/kg/year |
| BAY94-9027 Prophylaxis Treatment Total, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Total Dose Per Kilogram Per Year - Part A | 3421.0 IU/kg/year |
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 .
Time frame: Weeks 0 and 36: pre-infusion (0 hours), post-infusion 15, 30 minutes, 1, 3, 6, 8, 24, 48, 72, 96 hours
Population: PKS with participants evaluable for this outcome
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Terminal Elimination Half Life (t1/2) Following Single and Multiple Doses of BAY94-9027, Chromogenic Assay - Part A | 17.1 Hours | Geometric Coefficient of Variation 27.05 |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Terminal Elimination Half Life (t1/2) Following Single and Multiple Doses of BAY94-9027, Chromogenic Assay - Part A | 19.6 Hours | Geometric Coefficient of Variation 38.48 |
Other Pre-specified
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.
Time frame: Week 0 (baseline) and Week 36 during Part A
Population: Analysis population includes participants evaluable in each category for this outcome.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Change From Baseline in Overall Pain Severity and Interference Due to Pain at Week 36 - Part A | Pain severity subscale | -0.8 scores on a scale | Standard Deviation 1.8 |
| BAY94-9027 On-demand Treatment, Main Trial | Change From Baseline in Overall Pain Severity and Interference Due to Pain at Week 36 - Part A | Interference subscale | -0.99 scores on a scale | Standard Deviation 2.54 |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Change From Baseline in Overall Pain Severity and Interference Due to Pain at Week 36 - Part A | Pain severity subscale | 0.1 scores on a scale | Standard Deviation 1.39 |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Change From Baseline in Overall Pain Severity and Interference Due to Pain at Week 36 - Part A | Interference subscale | -0.06 scores on a scale | Standard Deviation 1.39 |
Other Pre-specified
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.
Time frame: Week 0 (baseline) and Week 36 during Part A
Population: Analysis population includes participants evaluable in each category for this outcome.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire at Week 36 - Part A | Activity impairment | 4.74 scores on a scale | Standard Deviation 24.12 |
| BAY94-9027 On-demand Treatment, Main Trial | Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire at Week 36 - Part A | Overall work impairment | 4.44 scores on a scale | Standard Deviation 21.94 |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire at Week 36 - Part A | Activity impairment | -7.13 scores on a scale | Standard Deviation 20 |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Change From Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire at Week 36 - Part A | Overall work impairment | -1.22 scores on a scale | Standard Deviation 21.94 |
Other Pre-specified
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.
Time frame: day of surgery
Population: Part B ITT population with participants treated for major surgery
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Maximum Blood Loss During Major Surgery - Part B | 1000 milliliter |
Other Pre-specified
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.
Time frame: Weeks 0 to 36 during Part A
Population: Part A ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Number of Minor Surgeries According to Physician's Assessment of Adequacy of Hemostasis - Part A | Excellent | 9 minor surgeries |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Minor Surgeries According to Physician's Assessment of Adequacy of Hemostasis - Part A | Good | 6 minor surgeries |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Minor Surgeries According to Physician's Assessment of Adequacy of Hemostasis - Part A | Missing | 2 minor surgeries |
Other Pre-specified
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.
Time frame: Up to 3 weeks post-surgery during Part B
Population: Part B ITT population with participants treated for major surgery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Number of Participants Who Took Anti-fibrinolytic Medications During Major Surgery - Part B | 8 Participants |
Other Pre-specified
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.
Time frame: Up to 3 weeks post-surgery during Part B
Population: Part B Safety population (N=17) included all participants who received at least 1 dose of study drug during Part B of the study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Number of Participants With Change/Drop in Hemoglobin/Hematocrit Laboratory Assessments - Part B | Hematocrit | 6 Participants |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Participants With Change/Drop in Hemoglobin/Hematocrit Laboratory Assessments - Part B | Hemoglobin | 2 Participants |
Other Pre-specified
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.
Time frame: Up to 3 weeks post-surgery during Part B
Population: Part B ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Number of Surgeries According to Physician's Assessment of Response to Hemostasis, Post-surgery - Part B Main Trial | Excellent | 8 surgeries |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Surgeries According to Physician's Assessment of Response to Hemostasis, Post-surgery - Part B Main Trial | Good | 5 surgeries |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Surgeries According to Physician's Assessment of Response to Hemostasis, Post-surgery - Part B Main Trial | Moderate | 3 surgeries |
| BAY94-9027 On-demand Treatment, Main Trial | Number of Surgeries According to Physician's Assessment of Response to Hemostasis, Post-surgery - Part B Main Trial | Missing | 1 surgeries |
Other Pre-specified
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.
Time frame: Weeks 10 - 36 during Part A
Population: ITT population part A week 10-36, 4 participants dropped out during week 0-10.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram With Prophylaxis Treatment - Part A | 1986.9 IU/kg |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram With Prophylaxis Treatment - Part A | 1669.1 IU/kg |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Forced, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram With Prophylaxis Treatment - Part A | 1704.3 IU/kg |
| BAY94-9027 Prophylaxis Treatment, Every 5 Days, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram With Prophylaxis Treatment - Part A | 1530.2 IU/kg |
| BAY94-9027 Prophylaxis Treatment, Every 7 Days, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Dose Per Kilogram With Prophylaxis Treatment - Part A | 1644.9 IU/kg |
Other Pre-specified
Recombinant Human Factor VIII (rFVIII) Usage Expressed as Number of Infusions- Part A
For prophylaxis patients, the dose is related to all infusions.
Time frame: On-demand: Weeks 0 -36 and Prophylaxis: Weeks 10 - 36 during Part A
Population: ITT population part A week 10-36, 4 participants dropped out during week 0-10.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Number of Infusions- Part A | 29 infusions |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Failed, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Number of Infusions- Part A | 56.0 infusions |
| BAY94-9027 Prophylaxis Treatment, 2x/Week Forced, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Number of Infusions- Part A | 55.0 infusions |
| BAY94-9027 Prophylaxis Treatment, Every 5 Days, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Number of Infusions- Part A | 38.0 infusions |
| BAY94-9027 Prophylaxis Treatment, Every 7 Days, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Number of Infusions- Part A | 27.0 infusions |
| BAY94-9027 Prophylaxis Treatment Total, Main Trial | Recombinant Human Factor VIII (rFVIII) Usage Expressed as Number of Infusions- Part A | 37.5 infusions |
Other Pre-specified
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.
Time frame: Up to 3 weeks post-surgery during Part B
Population: Part B ITT population who had blood transfusions during major surgery
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BAY94-9027 On-demand Treatment, Main Trial | Volume of Blood Transfused in Major Surgery - Part B | 865 milliliter |