A Trial Investigating Safety and Efficacy of Treatment With BAY94-9027 in Severe Hemophilia A (PROTECT-VIII)

• ClinicalTrials.gov Identifier: NCT01580293
• Recruitment Status: Completed
• First Posted: April 19, 2012
• Results First Posted: December 6, 2018
• Last Update Posted: December 2, 2020
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

Tracking Information

• First Submitted Date: March 28, 2012
• First Posted Date: April 19, 2012
• Results First Submitted Date: September 26, 2018
• Results First Posted Date: December 6, 2018
• Last Update Posted Date: December 2, 2020
• Actual Study Start Date: April 23, 2012
• Actual Primary Completion Date: June 13, 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 13, 2018)

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 [ Time Frame: 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).

• Original Primary Outcome Measures (submitted: April 18, 2012): Annualized number of total bleeds [ Time Frame: In the period of 32 weeks after Baseline ]

Current Secondary Outcome Measures (submitted: November 12, 2020)

• 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Weeks 0 to 36 ]
  Number of bleeds requiring 1, 2 or >= 3 infusions to control the bleeding
• Number of Bleeds According to Locations - Part A [ Time Frame: Weeks 0 -36 ]
  Bleed locations were categorised as joint, muscle, skin/mucosa, internal, others and missing.
• Number of Bleeds Over Time Since Previous Prophylaxis Infusion - Part A [ Time Frame: Weeks 0 to 36 ]
• Number of Bleeds According to Participant's Assessment of Response to Treatment - Part A [ Time Frame: 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 [ Time Frame: 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 Per Infusion - Part A [ Time Frame: 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 [ Time Frame: Weeks 10 to 36 during Part A ]
• Number of Surgeries According to Physician's Assessment of Adequacy of Hemostasis in Major Surgery - Part B [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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).

Original Secondary Outcome Measures (submitted: April 18, 2012)

• Safety variables will be summarized using descriptive statistics based on adverse events collection [ Time Frame: Baseline visit up to 32 weeks ]
• Quantification of blood loss in major surgery [ Time Frame: Pre-surgery infusion up to 24 hours after surgery ]
• Pharmacokinetic parameters will be measured by Tmax, Cmax, t1/2, AUC, and incremental recovery [ Time Frame: Baseline, 32 weeks ]

Current Other Pre-specified Outcome Measures (submitted: November 13, 2018)

• Change From Baseline in Overall Pain Severity and Interference Due to Pain at Week 36 - Part A [ Time Frame: 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 [ Time Frame: 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.
• Recombinant Human Factor VIII (rFVIII) Usage Expressed as Number of Infusions- Part A [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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.

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Hemophilia A

Intervention

Biological: BAY94-9027

Intravenous infusion of BAY94-9027

Study Arms

• Experimental: Arm 1
  On-demand treatment of BAY94-9027 at individual dose and number of infusions based upon location and severity of bleeds
  Intervention: Biological: BAY94-9027
• Experimental: Arm 2
  Prophylaxis treatment of BAY94-9027; 2 infusions per week over 10 weeks followed by 2 infusions per week over 26 weeks in the main trial; and at least 1 day per week in the extension for at least 100 ED
  Intervention: Biological: BAY94-9027
• Experimental: Arm 3
  Prophylaxis treatment of BAY94-9027; 2 infusions per week over 10 weeks followed by infusion every 5 days over 26 weeks in the main trial; and at least 1 day per week in the extension for at least 100 ED
  Intervention: Biological: BAY94-9027
• Experimental: Arm 4
  Prophylaxis treatment of BAY94-9027; 2 infusions per week over 10 weeks followed by infusion every 7 days over 26 weeks in the main trial; and at least 1 day per week in the extension for at least 100 ED
  Intervention: Biological: BAY94-9027

Publications *

• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 13, 2018): 145
• Original Estimated Enrollment (submitted: April 18, 2012): 140
• Actual Study Completion Date: November 21, 2019
• Actual Primary Completion Date: June 13, 2014 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 12 Years to 65 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Belgium, Canada, Colombia, Denmark, France, Germany, Israel, Italy, Japan, Korea, Republic of, Netherlands, Norway, Poland, Romania, Singapore, Taiwan, Turkey, United Kingdom, United States
• Removed Location Countries: Argentina, Sweden

Administrative Information

• NCT Number: NCT01580293
• Other Study ID Numbers: 13024; 2011-005210-11 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Bayer
• Original Responsible Party: Therapeutic Area Head, Bayer Healthcare AG
• Current Study Sponsor: Bayer
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Bayer Study Director; Bayer

• PRS Account: Bayer
• Verification Date: November 2020