A Post Approval Commitment Study to Gain More Information on How Safe and Effective KOVALTRY is in Chinese Children, Adolescents /Adults With Severe Hemophilia A

• ClinicalTrials.gov Identifier: NCT04565236
• Recruitment Status: Completed
• First Posted: September 25, 2020
• Last Update Posted: March 28, 2024
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

Tracking Information

• First Submitted Date: September 4, 2020
• First Posted Date: September 25, 2020
• Last Update Posted Date: March 28, 2024
• Actual Study Start Date: September 22, 2020
• Actual Primary Completion Date: March 15, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 5, 2021)

• Annualized bleeding rate of all bleeding episodes during prophylaxis treatment [ Time Frame: Part A: up to 6 months ]
  Annualized bleeding rate (ABR) of all bleeding episodes during prophylaxis treatment in previously treated patients (PTPs).
• Annualized bleeding rate within 48 hours of previous prophylaxis infusion [ Time Frame: Part B: up to 48 hours post-infusion for at least 50 exposure days ]
  Annualized bleeding rate (ABR) of bleeding episodes within 48 hours of previous prophylaxis infusion in previously untreated/minimally treated patients (PUPs/MTPs).

Original Primary Outcome Measures (submitted: September 21, 2020)

Annualized bleeding rate [ Time Frame: Up to 6 months ]

Annualized bleeding rate (ABR) of all bleeding episodes during prophylaxis treatment

Current Secondary Outcome Measures (submitted: February 5, 2021)

• Annualized bleeding rate of treated bleeding episodes [ Time Frame: Part A: up to 6 months; Part B: up to at least 50 exposure days ]
  Annualized bleeding rate (ABR) of bleeding episodes treated with BAY81-8973 during prophylaxis treatment.
• Annualized bleeding rate of target joint bleeding episodes [ Time Frame: Part A: up to 6 months; Part B: up to at least 50 exposure days ]
  Annualized bleeding rate (ABR) of target joint bleeding episodes during prophylaxis treatment.
• Annualized bleeding rate within 48 hours of previous prophylaxis infusion [ Time Frame: Part A: up to 48 hours post-infusion for 6 months ]
  Annualized bleeding rate (ABR) of bleeding episodes within 48 hours of previous prophylaxis infusion.
• Annualized bleeding rate of all bleeding episodes during prophylaxis treatment [ Time Frame: Part B: up to at least 50 exposure days ]
  Annualized bleeding rate (ABR) of all bleeding episodes during prophylaxis treatment in previously untreated/minimally treated patients (PUPs/MTPs).
• Assessment of response to treatment of bleeds [ Time Frame: Part A: up to 6 months; Part B: up to at least 50 exposure days ]
  Participants or caregivers assessment to Kovaltry treatment on ISTH 4 point response scale for response to treatment of bleed [excellent, good, moderate or poor].
• Number of surgeries based on physician's assessment of adequacy of hemostasis in minor surgery [ Time Frame: Part A: up to 6 months; Part B: up to at least 50 exposure days ]
  Physician's assessment of participant's hemostatic response to Kovaltry treatment on the ISTH 4 point response scale for adequacy of hemostasis for surgical procedures [excellent, good, moderate or poor].
• Number of participants without bleeding episodes [ Time Frame: Part A: up to 6 months; Part B: up to at least 50 exposure days ]
  Number of participants who report no bleeding event during prophylaxis.
• Number of infusions per bleeding episode [ Time Frame: Part A: up to 6 months; Part B: up to at least 50 exposure days ]
  Number of infusions of BAY81-8973 needed to achieve hemostasis for a bleeding episode.
• Factor VIII usage [ Time Frame: Part A: up to 6 months; Part B: up to at least 50 exposure days ]
  BAY81-8973 consumption during the study.
• Factor VIII inhibitor development by the Nijmegen Bethesda assay [ Time Frame: Part A: up to 6 months; Part B: up to at least 50 exposure days ]
  Number of participants with positive Factor VIII (FVIII) inhibitor test (≥0.6 Bethesda unit [BU]).
• In-vivo recovery [ Time Frame: Part A: baseline, Month 2 and Month 6; Part B: baseline and end of study ]
  In-vivo recovery (or incremental recovery) is defined as the increase in the circulating FVIII activity level for one unit (IU) of the FVIII product per kilogram body weight.
• Maximum concentration (Cmax) of Kovaltry in plasma [ Time Frame: Part A: pre-infusion and up to 30 minutes post-infusion ]
  Cmax: Maximum observed drug concentration following an infusion of 50 IU/kg.
• Area under the plasma concentration versus time curve (AUC) from zero to infinity after single (first) dose [ Time Frame: Part A: pre-infusion and up to 48 hours post-infusion ]
  AUC: The total area under the plasma concentration versus time curve following an infusion of 50 IU/kg.
• Half-life (t1/2) of Kovaltry in plasma [ Time Frame: Part A: pre-infusion and up to 48 hours post-infusion ]
  t1/2: Terminal half-life is the time the plasma concentration during terminal phase is halved following an infusion of 50 IU/kg.
• Treatment-emergent adverse events [ Time Frame: Part A: up to 6 months; Part B: up to at least 50 exposure days ]

Original Secondary Outcome Measures (submitted: September 21, 2020)

• Number of infusions per bleeding episode [ Time Frame: Up to 6 months ]
• ABR within 48 hours of previous prophylaxis infusion [ Time Frame: Up to 48 hours post-infusion ]
  Annualized bleeding rate (ABR) of bleeding episodes within 48 hours of previous prophylaxis infusion
• In-vivo recovery [ Time Frame: Baseline, Month 2 and Month 6 ]
  In-vivo recovery (or incremental recovery) is defined as the increase in the circulating FVIII activity level for one unit (IU) of the FVIII product per kilogram body weight
• Number of surgeries based on physician's assessment of adequacy of hemostasis in minor surgery [ Time Frame: Up to 6 months ]
  Physician's assessment of participant's hemostatic response to Kovaltry treatment on the ISTH 4 point response scale for adequacy of hemostasis for surgical procedures [Excellent, Good, Moderate or Poor]
• FVIII inhibitor development by the Nijmegen Bethesda assay [ Time Frame: Up to 6 months ]
  Number of participants with positive Factor VIII (FVIII) inhibitor test (≥0.6 Bethesda unit [BU])
• Treatment-emergent adverse events [ Time Frame: Up to 6 months ]
• Maximum concentration (Cmax) of Kovaltry in plasma [ Time Frame: Pre-infusion and up to 30 minutes post-infusion ]
  Cmax: Maximum observed drug concentration following an infusion of 50 IU/kg
• Area under the plasma concentration versus time curve (AUC) from zero to infinity after single (first) dose [ Time Frame: Pre-infusion and up to 48 hours post-infusion ]
  AUC: The total area under the plasma concentration versus time curve following an infusion of 50 IU/kg
• Half-life (t1/2) of Kovaltry in plasma [ Time Frame: Pre-infusion and up to 48 hours post-infusion ]
  t1/2: Terminal half-life is the time the plasma concentration during terminal phase is halved following an infusion of 50 IU/kg

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Post Approval Commitment Study to Gain More Information on How Safe and Effective KOVALTRY is in Chinese Children, Adolescents /Adults With Severe Hemophilia A
• Official Title: A Post Approval Commitment Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of KOVALTRY in Chinese Children, Adolescents /Adults With Severe Hemophilia A
• Brief Summary: The goal of this study is to gather more information on safety and efficacy of Kovaltry for the prevention and treatment of bleeds in Chinese children, adolescents/adults with severe hemophilia A. In addition, pharmacokinetic parameters of Kovaltry will be assessed in a subset of patients.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Hemophilia A

Intervention

• Biological: Recombinant Factor VIII (Kovaltry, BAY81-8973) Treatment Group 1

  25 to 50 IU of Kovaltry per kg body weight given via intravenous (IV) infusion twice weekly, three times weekly, or every other day according to individual requirements for 6 months.

  The dose decisions are at the discretion of the investigator.

• Biological: Recombinant Factor VIII (Kovaltry, BAY81-8973) Treatment Group 2

  12 year-old: 25 to 50 IU of Kovaltry per kg body weight given via intravenous (IV) infusion twice weekly, three times weekly, or every other day for 6 months.

  >12 year-old: 20 to 40 IU of Kovaltry per kg of body weight given via intravenous (IV) infusion two or three times per week for 6 months.

  The dose decisions are at the discretion of the investigator.

• Biological: Recombinant Factor VIII (Kovaltry, BAY81-8973) Treatment Group 3

  15 to 50 IU of Kovaltry per kg body weight (minimum dose: 250 IU) given via intravenous (IV) infusions at least once a week.

  The dose decisions are at the discretion of the investigator.

Study Arms

• Experimental: Part A: PTPs <12 years of age
  Previously treated severe hemophilia A patients (PTPs) <12 years of age
  Intervention: Biological: Recombinant Factor VIII (Kovaltry, BAY81-8973) Treatment Group 1
• Experimental: Part A: PTPs ≥12 to 65 years of age
  Previously treated severe hemophilia A patients (PTPs) ≥12 to 65 years of age
  Intervention: Biological: Recombinant Factor VIII (Kovaltry, BAY81-8973) Treatment Group 2
• Experimental: Part B: PUPs/MTPs <6 years of age
  Previously untreated/minimally treated severe hemophilia A patients (PUPs/MTPs) <6 years of age
  Intervention: Biological: Recombinant Factor VIII (Kovaltry, BAY81-8973) Treatment Group 3

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 27, 2024): 45
• Original Estimated Enrollment (submitted: September 21, 2020): 42
• Actual Study Completion Date: March 15, 2024
• Actual Primary Completion Date: March 15, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Part A (PTPs):

• Chinese participants with severe hemophilia A (defined as Factor VIII (FVIII): C < 1% with one- stage clotting assay documented at the time of screening)
• Currently receiving on-demand or any type of prophylaxis treatment regimen with any FVIII product
• For participants < 12 years of age, ≥ 50 exposure days (ED); for participants ≥ 12 to 65 years of age, ≥ 150 ED with any FVIII product
• No current evidence of inhibitor
• No history of FVIII inhibitor formation
• Signed informed consent

Part B (PUPs/MTPs):

• Participants must be <6 years of age at the time of their parent or legal representative's signature of informed consent on the participant's behalf
• Chinese participants with severe hemophilia A (defined as Factor VIII (FVIII): C < 1% with one- stage clotting assay documented at the time of screening)
• PUPs must have no previous exposure to any FVIII product. MTPs must have no more than 1 ED with any purified FVIII concentrate or 3 exposures with FFP or cryoprecipitate.
• MTPs must have no current evidence of inhibitor antibody as measured by the Nijmegen-modified Bethesda assay (<0.6 BU/mL) in 2 consecutive samples and must have absence of clinical signs or symptoms of decreased response to FVIII administration. Testing for the 2 negative samples must be performed by the central laboratory at least 1 week but not more than 2 weeks apart. Participants may not receive FVIII product within 72 hours prior to the collection of samples for inhibitor testing.
• PUPs and MTPs must observe a 6-month washout period if they have received subcutaneous factor substitution therapy (emicizumab).
• PUPs may be included if they will receive their first FVIII dose with KOVALTRY for treatment of first bleed and agree to start prophylaxis as part of their care. MTPs may be included if they agree to start prophylaxis as part of their care.

Exclusion Criteria:

Part A (PTPs):

• Any other bleeding disease that is different from hemophilia A (e.g. von Willebrand disease, hemophilia B)
• Platelet count < 100 000/mm^3
• Impaired renal function (serum creatinine > 2.0 mg/dL) or active liver disease (alanine aminotransferase/aspartate aminotransferase [ALT/AST] > 5x ULN)
• Human immunodeficiency virus (HIV) positive with an absolute CD4 lymphocyte cell count < 250 cells/μL
• Known hypersensitivity to the active substance, mouse or hamster protein
• Receiving chemotherapy, immune modulatory drugs other than anti-retroviral chemotherapy, or chronic use of oral or intravenous (IV) corticosteroids (> 14 days) within the last 3 months.
• Requiring any pre-medication to tolerate FVIII infusions (e.g. antihistamines)
• Currently participating in another investigational drug study, or having previously participated in a clinical study involving an investigational drug within 30 days of signing informed consent or participated in completed interventional clinical studies with BAY81-8973 (Kovaltry)
• Planned major surgery, defined as surgery with respiratory assistance and/or general anesthesia

Part B (PUPs/MTPs):

• Any other bleeding disease that is different from hemophilia A (e.g. von Willebrand disease, hemophilia B)
• Platelet count < 100 000/mm^3
• Impaired renal function (serum creatinine >2× upper limit of normal [ULN]) or active liver disease (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] >5× ULN) based on screening laboratory assessments
• MTPs with history of FVIII inhibitor formation
• Known hypersensitivity to the active substance, mouse or hamster protein
• First treatment with KOVALTRY for high risk bleeding situations (e.g., surgery, intracranial bleed) or requiring intensive or prolonged treatment
• Receiving chemotherapy, immune modulatory drugs other than anti-retroviral chemotherapy, or chronic use of oral or intravenous (IV) corticosteroids (> 14 days) within the last 3 months.
• Requiring any pre-medication to tolerate FVIII infusions (e.g. antihistamines)
• Currently participating in another investigational drug study, or having previously participated in a clinical study involving an investigational drug within 30 days of signing informed consent or participated in completed interventional clinical studies with BAY 81-8973 (Kovaltry)
• Planned major surgery, defined as surgery with respiratory assistance and/or general anesthesia
• Unable to tolerate volume of blood draws required for study participation

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 0 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: China

Administrative Information

• NCT Number: NCT04565236
• Other Study ID Numbers: 19855; 2021-003537-11 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

IPD Sharing Statement

• Plan to Share IPD: No

Plan Description

Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014.

Interested researchers can use www.vivli.org to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal.

• Current Responsible Party: Bayer
• Original Responsible Party: Same as current
• Current Study Sponsor: Bayer
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Bayer
• Verification Date: March 2024