Study of TAK-672 in Participants With Acquired Hemophilia A

Study Overview
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Brief Summary
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The main aims of the study are to learn if TAK-672 can control bleeds in participants with acquired hemophilia A and if the participants have side effects from TAK-672. Acquired hemophilia A is when people's immune system attacks specific proteins, known as clotting factors, in their bodies. This is different from hemophilia A, which is a condition people are born with. At the first visit, the study doctor will check who can take part. For those who can take part, participants will visit the clinic or hospital when they get their next bleed. They will receive TAK-672 slowly through a vein. This is called an infusion. They might need extra infusions of TAK-672 to control the bleed. After their bleed is controlled, participants will regularly visit the clinic for a check-up and to treat any further bleeds. This will happen until all participants have received their last dose of TAK-672 to control their 1st bleed. After this, all participants will visit the clinic 90 days later for a final check-up.

Official Title
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A Phase 2/3, Open-Label, Non-controlled Study to Evaluate the Efficacy and Safety of B-Domain Deleted Recombinant Porcine Factor VIII (rpFVIII, TAK-672), in the Treatment of Serious Bleeding Episode in Japanese Subjects With Acquired Hemophilia A (AHA)

Conditions
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Acquired Hemophilia A

Intervention / Treatment
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* Biological: TAK-672


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female Japanese participants of >=18 years of age. Participants who (or their legally authorized representatives) have provided his/her written informed consent form prior to any study-related procedures and study product administration. Participants with a diagnosis of AHA based on clinical evaluation and supportive local laboratory testing as shown below: Presentation with spontaneous bleeding without anatomical cause and without prior known bleeding disorder. Prolonged activated partial thromboplastin time (aPTT) without explanation. Abnormal aPTT cross mixing test consistent with FVIII inhibitors Confirmation of a low FVIII:C. Positive FVIII inhibitor (>=0.6 BU) as measured either in the local or central laboratory Participants with a severe bleeding episode which the investigator finds necessary to treat and whose severe bleeding episode meets at least 1 of the following criteria: Bleeds that pose a threat to a vital organ that could threaten life (e.g. intracranial bleed, or any site that could obstruct the airway). Bleeds that pose a threat to a vital organ where life is not threatened but the organ function could be impaired (e.g., intraspinal bleed threatening the spinal cord and/or nerve conduction; a continual bleed into the kidney or bladder that could result in an obstructive uropathy, testicular bleed, bleed in and around the eye). Bleeds requiring a blood transfusion to maintain the Hgb level at above-life or organ threatening levels (e.g. post-surgical, gastro-intestinal, retro-peritoneal, and thigh bleeds). Intramuscular bleeds where muscle viability and/or neurovascular integrity is significantly compromised or at risk of being compromised. Intra-articular bleeds impacting a major joint associated with severe pain, swelling and severe loss of joint mobility (reduced >70%) or where a bleed could result in joint destruction (e.g. in and around the femoral head). Participants who are taking anti-thrombotics (including anti-platelet agents and anticoagulantswith confirmatory laboratory testing documenting specific FVIII inhibitor titer and with 3 half-lives of the agent have elapsed since the last dose. Participants with expected life expectancies of at least 90 days prior to the onset of the hemorrhagic episode. Participants of reproductive age who have agreed to use acceptable methods of contraception and if female, undergo pregnancy testing as part of the screening process. Participant who are able to willing and able to comply with the requirements of the protocol. Exclusion Criteria: Participants with an established reason for bleeding that is not correctable even with hemostatic therapy. Participants presenting a bleeding episode that is assessed likely to resolve on its own, even if left untreated. Participants with a known major sensitivity (anaphylactoid reactions) to therapeutic products of porcine or hamster origin; examples include therapeutics of porcine origin (e.g. previously marketed porcine FVIII, Hyate: C) and recombinant therapeutics prepared from hamster cells (e.g. Humira, Advate, and Enbrel). Participants with the use of hemophilia medication: prior to the administration of TAK-672 under one of the following conditions: (1) use of recombinant activated factor VII (rFVI)Ia  within 3 hours prior to TAK-672 administration (2) use of  activated prothrombin complex concentrate (aPCC) within 6 hours prior to TAK-672 administration or (3) use of  plasma-derived FX/FVIIa complex concentrate (pd-FX/FVIIa)  within 8 hours prior to TAK-672 administration. Participants with an anticipated need for treatment or device during the study that may interfere with the evaluation of the safety or efficacy of TAK-672, or whose safety or efficacy may be affected by TAK-672. Participants who are currently pregnant or breastfeeding, or planning to become pregnant or father a child during the study Participants who have participated in another clinical study and has been exposed to an investigational product or device within 30 days prior to the study enrollment. Participants who are scheduled to participate in another non-observational (interventional) clinical study involving an investigational product or device during the course of the study. Participants who are unable to or unwilling to comply with the study design, protocol requirements, and/or the follow-up procedures. Participants whose majority of age are under legal protection. Participants who are an immediate family member, study site employee, or are in a dependent relationship with a study site employee who is involved in the conduct of this study (e.g. spouse, parent, child, sibling) or may consent under duress. Participants who are judged by the investigator as being ineligible for any other reason.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TAK-672<br>TAK-672 will be administered at an initial dose of 200 U/kg with intravenous infusion at a rate of 1-2 mL/min. Subsequent doses will be determined based on the post-infusion factor VIII activity (FVIII:C) achieved after the most recent dose given, the target FVIII:C, and pFVIII inhibitor titer (when available) | Biological: TAK-672<br>* B-Domain Deleted Recombinant Porcine Factor VIII<br>* Other names: rpFVIII, TAK-672, Obizur;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Severe Bleeding Episodes with Demonstrated Response to TAK-672 Therapy at 24 Hours after the Initiation of Treatment | Percentage of severe bleeding episodes with demonstrated response to TAK-672 therapy at 24 hours after the initiation of treatment will be assessed by using a well-defined 4-point ordinal scale - A 'positive response' is defined as 'effective' (bleeding stopped with clinical control and FVIII:C levels of 50% or higher ) or 'partially effective' (bleeding reduced with clinical stabilization and FVIII:C levels of 20% or higher) control of bleeding, as determined by the investigator using a 4-point rating scale (effective - partially effective - poorly effective - not effective). 'Poorly effective' is defined as 'bleeding slightly reduced or unchanged and FVIII:C levels of less than 50%'. 'Not effective' is defined as 'bleeding worsening and FVIII:C levels of less than 50%'. | 24 hours after the initiation of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Overall Percentage of Severe Bleeding Episodes Successfully Controlled with TAK-672 Therapy, as Assessed by the Investigator | Treatment success is defined as control of qualifying bleeding episode at the time of final treatment dosing. A severe bleeding episode is considered 'successfully controlled' if the investigator has checked 'completed TAK-672 therapy as treatment success' on the electronic case report form (eCRF). | Up to 1 year (90 days after final treatment dosing) | 
| The Percentage of Bleeding Episodes Responsive to TAK-672 Therapy at Designated Assessment Time Points after the Initiation of Therapy, as Assessed by the Investigator | A 'positive response' is defined as 'effective' (bleeding stopped with clinical control and FVIII:C levels of 50% or higher ) or 'partially effective' (bleeding reduced with clinical stabilization and FVIII:C levels of 20% or higher) control of bleeding, as determined by the investigator using a 4-point rating scale (effective - partially effective - poorly effective - not effective). 'Poorly effective' is defined as 'bleeding slightly reduced or unchanged and FVIII:C levels of less than 50%'. 'Not effective' is defined as 'bleeding worsening and FVIII:C levels of less than 50%'. | Up to 1 year (90 days after final treatment dosing) | 
| Frequency of Infusions of TAK-672 Required to Successfully Control Qualifying Bleeding Episodes | 'Frequency of infusions' will be calculated as the 'average number of infusions per day'. 'Qualifying bleeding episode' is defined as the 'initial, severe bleeding episode' | Time of successful control of qualifying bleeding episode (varied from participant to participant) | 
| Total Dose of Infusions of TAK-672 Required to Successfully Control Qualifying Bleeding Episodes. | 'Qualifying bleeding episode' is defined as the 'initial, severe bleeding episode'. | Time of successful control of qualifying bleeding episode (varied from participant to participant) | 
| Total Number of Infusions of TAK-672 Required to Successfully Control Qualifying Bleeding Episodes | 'Qualifying bleeding episode' is defined as the 'initial, severe bleeding episode'. A severe bleeding episode is considered 'successfully controlled' if the investigator had checked 'completed TAK-672 therapy as treatment success' on the eCRF. | Time of successful control of qualifying bleeding episode (varied from participant to participant) | 
| Correlation between Response to TAK-672 Therapy at Specified Time Points and Eventual Control of Severe Bleeding Episodes |  | Up to 1 year (90 days after final treatment dosing) | 
| Correlation among the Pre-infusion Anti-TAK-672 Antibody Titers and the Eventual Control of the Bleeding Episode |  | Up to 1 year (90 days after final treatment dosing) | 
| Correlation among the Total Dose of TAK-672 and the Eventual Control of the Bleeding Episode |  | Up to 1 year (90 days after final treatment dosing) | 
| Correlation between the Response at 24 Hours and the Eventual Control of the Bleeding Episode |  | Up to 1 year (90 days after final treatment dosing) | 
| Anti-hFVIII Inhibitor Level |  | Up to 1 year (90 days after final treatment dosing) | 
| Anti-pFVIII Inhibitor Level |  | Up to 1 year (90 days after final treatment dosing) | 
| Terminal Half-life (t1/2) for TAK-672 |  | Pre-dose and at multiple time points (up to 24 hours) post-dose | 
| Clearance (CL) for TAK-672 |  | Pre-dose and at multiple time points (up to 24 hours) post-dose | 
| Volume of Distribution (Vd) for TAK-672 |  | Pre-dose and at multiple time points (up to 24 hours) post-dose | 
| Area Under the Concentration-Time Curve (AUC) for TAK-672 |  | Pre-dose and at multiple time points (up to 24 hours) post-dose | 
| Maximum Drug Concentration (Cmax) per Dose (Cmax/Dose) for TAK-672 |  | Pre-dose and at multiple time points (up to 24 hours) post-dose | 
| Duration Period from Initial Dose of TAK-672 until Completion of Hemostasis Control |  | Time of completion of hemostasis control (varied from participant to participant) | 
| Total Dose from Initial Dose of TAK-672 until Completion of Hemostasis Control |  | Time of completion of hemostasis control (varied from participant to participant) | 
| Number of new qualified severe bleeding episodes |  | Up to 1 year (90 days after final treatment dosing) |