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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)

Study of TAK-672 in Participants With Acquired Hemophilia A

5

Of the 5 subjects, 3 subjects were male, 2 subjects were female, and all of 5 subjects were Japanese. The median age was 77.0 years. The median weight was 51.70 kg and the median height was 159.0 cm. The median time since first diagnosis of AHA was 0.1 months. Three subjects had history of rFVIIa treatment and 1 subject had history of pd-FVIIa/FX treatment within 6 months prior to obtaining informed consent. The median hFVIII inhibitor at baseline was 52.0 BU/mL. Three subjects had a detectable pFVIII inhibitor titer at baseline. The median pFVIII inhibitor titer for 5 subjects was 0.90 BU/mL, while 2 of those subjects were with undetectable titers.

A total of 6 subjects signed the informed consent form and 5 subjects were eligible for entrance to the treatment period. Of the 5 subjects who entered the study treatment period, all subjects completed TAK-672 treatment for initial qualified bleeding episode. After initial treatment period, 1 subject discontinued the study participation because the subject was judged to be required to receive prophylactic treatment with emicizumab (genetical recombination). The remaining 4 subjects completed the study. No subject received the TAK-672 treatment for subsequent qualified bleeding episode.

- A total of 49 TEAEs were reported in 5 subjects. Treatment-emergent AEs by System Organ Class reported in >=3 subjects were skin and subcutaneous tissue disorders (4 subjects), and gastrointestinal disorders (3 subjects). Treatment-emergent AEs by Preferred Term reported in >=2 subjects were haemorrhage subcutaneous (3 subjects) and urinary tract infection (2 subjects). - Most of TEAEs were mild or moderate in intensity. Two severe TEAEs (urinary tract infection and haemorrhage subcutaneous) were reported in 1 subject. No severe TEAEs related to TAK-672 were reported. - There was no particular period of which a high incidence of TEAEs was observed. - No deaths or TEAEs leading to study drug discontinuation were reported through the AE collection period of this study. - Five SAEs were reported in 2 subjects. The 3 SAEs (haemorrhage subcutaneous, haemorrhagic diathesis, and urinary tract infection) occurred in 1 subject were considered by the investigator to be not related to TAK-672. The 2 SAEs (central hypothyroidism and cryoglobulinaemia) occurred in the other subject were considered by the investigator to be related to TAK-672 because a causal relationship cannot be completely denied. However, both events were considered by the sponsor to be unlikely related to TAK-672 because there was no compelling evidence to directly implicate the study medication with the events. Other AEs (serious or nonserious) were considered by the investigator to be not related to TAK-672. - No AEs of special interest were reported by investigators. Only 1 AE of erythema was classified by the sponsor as an AE of special interest (hypersensitivity reactions). There were no AEs classified as de novo inhibitor to pFVIII, anamnestic reaction with increase of inhibitor titer to pFVIII and/or hFVIII, or thromboembolic events. - No clinically significant changes in laboratory parameters or vital signs. Brief summary (continued): TAK-672 treatment was well tolerated and showed a positive response for the treatment of serious bleeding events in Japanese subjects with AHA in the study. Furthermore, individualized treatment courses with FVIII:C monitoring can be tailored to account for individual responses to TAK-672 for efficacy and safety considerations, which fulfills an unmet need in the treatment of bleeds in AHA patients.

- Primary efficacy endpoint in this study was the proportion of severe bleeding episodes with demonstrated response to TAK-672 therapy at 24 hours after the initiation of treatment. All of 5 subjects (100%, 95% CI: 47.818-100.000) were assessed by the investigators to have a positive response to TAK-672 at 24 hours after initiation of treatment. - Severe bleeding episodes of 5 subjects (100%, 95% CI: 47.818-100.000) were assessed by the investigators to be successfully controlled. - Response to TAK-672 was negative in 1 of 5 subjects at 30 minutes after the initial dose of TAK-672. At 8 hours, 16 hours, and 24 hours after the initial dose, follow-up visits except follow-up at 84 days, and the end of study visit, all of assessable 4 or 5 subjects showed positive responses to TAK-672. - Subjects who were assessed to have a positive response to TAK-672 treatment earlier than 24 hours after initiation of treatment achieved eventual control of severe bleeding episodes. - Total median dose per subject was 548.4 U/kg for initial treatment period. One subject received 1 infusion and 4 subjects received 3 infusions of TAK-672. Median duration of initial treatment period was 1.0 day. Median number of infusions per day was 1.5 infusions. Compliance for initial treatment period was 100% in all of 5 subjects. - There were no anamnestic reactions with an increase of inhibitor titers against pFVIII and/or hFVIII. Despite the fact that 3 subjects had a detectable pFVIII inhibitor prior to initial dose, all of 5 subjects were assessed to have a positive response to TAK-672 at 24 hours after initiation of treatment and achieved eventual control of the bleeding episode. Regarding the 2 subjects in whom pFVIII inhibitors were not detected prior to initial dose, there were no development of pFVIII inhibitors after initiation of treatment. - One subject had new qualified severe bleeding episodes, which have not been treated by TAK-672.

The results of this study have suggested that treatment with TAK-672 can be well tolerated and effective as a first-line therapy for Japanese patients with AHA who have serious bleeding events.

Nov. 20, 2023

No

De-identified individual participant data from this particular study will not be shared as there is a reasonable likelihood that individual patients could be re-identified (due to the limited number of study participants/study sites.

https://jrct.niph.go.jp/latest-detail/jRCT2051200066

Koumura Emiko

Takeda Pharmaceutical Company Limited

1-1, Doshomachi 4-chome, Chuo-ku, Osaka, Osaka

smb.Japanclinicalstudydisclosure@takeda.com

Clinical Trial Information Contact for

Takeda Pharmaceutical Company Limited

1-1, Doshomachi 4-chome, Chuo-ku, Osaka, Osaka

+81-6-6204-2111

smb.Japanclinicalstudydisclosure@takeda.com

Complete

April. 09, 2021

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1. Male or female Japanese participants of >=18 years of age.
2. 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.
3. 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 factor VIII activity ( FVIII:C).
- Positive FVIII inhibitor (>=0.6 BU) as measured either in the local or central laboratory
4. 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).
5. Participants who are taking anti-thrombotics, (including anti-platelet agents and anticoagulants)with confirmatory laboratory testing documenting specific FVIII inhibitor titer and with 3 half-lives of the agent have elapsed since the last dose.
6. Participants with expected life expectancies of at least 90 daysprior to the onset of the hemorrhagic episode.
7. Participants of reproductive age who have agreed to use acceptable methods of contraception during the study and if female who have agreed to undergo pregnancy testing as part of the screening process.
8. Participant who are able to and willing and able to comply with the requirements of the protocol.

1. Participants with an established reason for bleeding that is not correctable even with hemostatic therapy.
2. Participants presenting a bleeding episode that is assessed likely to resolve on its own, even if left untreated.
3. 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).
4. 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 (rFVIIa)" 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.
5. 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.
6. Participants who are currently pregnant or breastfeeding, or planning to become pregnant or father a child during the study
7. 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.
8. 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.
9. Participants who are unable to or unwilling to comply with the study design, protocol requirements, and/or the follow-up procedures.
10. Participants whose majority of age are under legal protection.
11. 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.
12. Participants who are judged by the investigator as being ineligible for any other reason.

Both

Acquired Hemophilia A

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 FVIII:C achieved after the most recent dose given, the target FVIII:C, and porcine FVIII(pFVIII) inhibitor titer (when available)

1. Percentage of Participants With Severe Bleeding Episodes Who Demonstrated Response to TAK-672 Therapy at 24 Hours after the Initiation of Treatment
Time Frame: 24 hours after the initial dose of TAK-672
Percentage of severe bleeding episodes with demonstrated response to TAK-672 therapy at 24 hours after the initiation of treatment was assessed by using a well-defined 4-point ordinal scale - A 'positive response' was 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' was 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 20%'.

1. Percentage of Participants With Severe Bleeding Episodes Successfully Controlled with TAK-672 Therapy, as Assessed by the Investigator
Time Frame: From first dose of study drug up to 90 days after the last dose of study drug or until discontinued (up to 19 months 21 days)
If the status assessed by the investigator at the end of study treatment of initial treatment period was "successfully controlled", the participant's initial severe bleeding episode was considered as successfully controlled.

2. Percentage of Participants With Bleeding Episodes Responsive to TAK-672 Therapy at Designated Assessment Time Points After the Initiation of Therapy, as Assessed by the Investigator
Timeframe; At 0.5, 8, 16, 24, 48, 60, 96, and 120 hours post dose and at 1, 14, 28, 42, 56, 70, and 90 day follow-up
A 'positive response' was 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' was 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 20%'.

3. Frequency of Infusions Per Participant of TAK-672 Required to Successfully Control Qualifying Bleeding Episodes
Time Frame: From first dose of study drug up to 90 days after the last dose of study drug or until discontinued (up to 19 months 21 days)
'Frequency of infusions' was calculated as the 'average number of infusions per day'. 'Qualifying bleeding episode' was defined as the 'initial, severe bleeding episode'

4. Total Dose of Infusions Per Participant of TAK-672 Required to Successfully Control Qualifying Bleeding Episodes.
Time Frame: From first dose of study drug up to 90 days after the last dose of study drug or until discontinued (up to 19 months 21 days)
'Qualifying bleeding episode' was defined as the 'initial, severe bleeding episode'. Total dose of infusions is sum of doses from start of treatment with TAK-672 for qualifying bleeding episodes until completion of the management of the bleeding.

5. Total Number of Infusions Per Participant of TAK-672 Required to Successfully Control Qualifying Bleeding Episodes.
Time Frame: From first dose of study drug up to 90 days after the last dose of study drug or until discontinued (up to 19 months 21 days)
'Qualifying bleeding episode' was defined as the 'initial, severe bleeding episode'. If the status assessed by the investigator at the end of study treatment of initial treatment period was "successfully controlled", the participant's initial severe bleeding episode was considered as successfully controlled.

6. Percentage of Participants With Response to TAK-672 Therapy at Specified Time Points and Eventual Control of Severe Bleeding Episodes
Timeframe; At 0.5, 8, 16, 24, 48, 60, 96,120, and 144 hours post dose and at 1, 14, 28, 42, 56, 70, and 90 day follow-up
Percentage of participants with response to TAK-672 therapy at specified time points and eventual control of severe bleeding episodes was assessed to determine the correlation between response to TAK-672 therapy and eventual control of severe bleeding episodes.

7. Correlation among the Pre-infusion Anti-TAK-672 Antibody Titers and the Eventual Control of the Bleeding Episode
Timeframe; From first dose of study drug up to 90 days after the last dose of study drug or until discontinued (up to 19 months 21 days)
The pre-infusion anti-TAK-672 antibody titers and the eventual control of the bleeding episode was assessed to determine the correlation among the pre-infusion pFVIII inhibitor titers and the eventual control of the bleeding episode.

8. Correlation among the Total Dose Per Participant of TAK-672 and the Eventual Control of the Bleeding Episode.
Timeframe; From first dose of study drug up to 90 days after the last dose of study drug or until discontinued (up to 19 months 21 days)
The total dose per participant of TAK-672 and the eventual control of the bleeding episode was assessed to determine the correlation among the total dose of TAK-672, and the eventual control of the bleeding episode.

9. Number of Participants With Response at 24 Hours and the Eventual Control of the Bleeding Episode
Timeframe; From first dose of study drug up to 90 days after the last dose of study drug or until discontinued (up to 19 months 21 days)
Number of participants with response at 24 hours and the eventual control of the bleeding episode was assessed to determine the correlation among the response at 24 hours, and the eventual control of the bleeding episode.

10. Anti-hFVIII Inhibitor Titers
Timeframe: Baseline, 72 hours postdose, and at 14, 28, 42, 56, 70, and 90 days follow-up (up to 19 months 21 days)

11. Anti-pFVIII Inhibitor Titer
Timeframe: Baseline, 72 hours postdose, and at 14, 28, 42, 56, 70, and 90 days follow-up (up to 19 months 21 days)

12. Terminal Half-life (t1/2) for TAK-672
Timeframe: Pre-dose and at multiple time points post-dose (up to 24 hours) after over 48 hours from the last treatment with TAK-672

13. Clearance (CL) for TAK-672
Timeframe: Pre-dose and at multiple time points post-dose (up to 24 hours) after over 48 hours from the last treatment with TAK-672

14. Volume of Distribution (Vd) for TAK-672
Timeframe: Pre-dose and at multiple time points post-dose (up to 24 hours) after over 48 hours from the last treatment with TAK-672

15. Area Under the Concentration-Time Curve (AUC) for TAK-672
Timeframe: Pre-dose and at multiple time points post-dose (up to 24 hours) after over 48 hours from the last treatment with TAK-672

16. Maximum Drug Concentration (Cmax) per Dose (Cmax/Dose) for TAK-672
Timeframe: Pre-dose and at multiple time points post-dose (up to 24 hours) after over 48 hours from the last treatment with TAK-672

17. Duration Period Per Participant from Initial Dose of TAK-672 until Completion of Hemostasis Control
Timeframe: From first dose of study drug up to 90 days after the last dose of study drug or until discontinued (up to 19 months 21 days)

18. Total Dose Per Participant from Initial Dose of TAK-672 until Completion of Hemostasis Control
Timeframe: From first dose of study drug up to 90 days after the last dose of study drug or until discontinued (up to 19 months 21 days)
Total dose is sum of doses from start of treatment with TAK-672 until completion of hemostasis control.

19. Number of Participants With New Qualified Severe Bleeding Episodes
Timeframe; From first dose of study drug up to 90 days after the last dose of study drug or until discontinued (up to 19 months 21 days)

+81-744-22-3051

Oct. 28, 2020

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