Clinical Trial Results:
An Open-Label, Single-Dose, Phase 1/2 Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Human Protein C (TAK-662) for the Treatment of Congenital Protein C Deficiency in Japanese Subjects Followed by an Extension Part
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Summary
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EudraCT number |
2022-003877-48 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
31 Oct 2024
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Results information
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Results version number |
v1(current) |
This version publication date |
08 May 2025
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First version publication date |
08 May 2025
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
TAK-662-1501
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04984889 | ||
WHO universal trial number (UTN) |
U1111-1267-4412 | ||
Other trial identifiers |
jRCT: jRCT2031210209 | ||
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Sponsors
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Sponsor organisation name |
Takeda
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Sponsor organisation address |
95 Hayden Avenue, Lexington, United States, MA 02421
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Public contact |
Study Director, Takeda, +1 877-825-3327, TrialDisclosures@takeda.com
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Scientific contact |
Study Director, Takeda, +1 877-825-3327, TrialDisclosures@takeda.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
10 Dec 2024
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Oct 2024
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To measure the pharmacokinetic (PK) parameters of TAK-662 in asymptomatic participants with homozygous or double heterozygous congenital protein C deficiency in Japanese participants.
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Protection of trial subjects |
This study was conducted in accordance with International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) of GCP, the principles of the Declaration of Helsinki, as well as other applicable national and local ethical and legal requirements.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
07 Sep 2021
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Japan: 5
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Worldwide total number of subjects |
5
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
2
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Adolescents (12-17 years) |
1
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Adults (18-64 years) |
2
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
This study was conducted at 4 centers in Japan from 7 September 2021 to 31 October 2024. A total of 5 Japanese participants were enrolled in this 2-part study to receive TAK-662 in Pharmacokinetic (PK) part (Part 1) followed by 3 treatment options in the Extension part (Part 2) (on-demand, short-term, or long-term prophylaxis). | |||||||||
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Pre-assignment
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Screening details |
As per planned analysis, the Extension Part data was collected, analyzed and reported as per On-demand and Short-term Prophylaxis treatments and per dose level wise data was not collected in this study. | |||||||||
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Period 1
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Period 1 title |
PK Part: Up to 7 Days
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | |||||||||
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Arms
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Arm title
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PK Part: TAK-662 | |||||||||
Arm description |
Participants received a single 80 IU/kg dose of TAK-662, intravenous infusion on Day 1 in PK part. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
TAK-662
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Investigational medicinal product code |
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Other name |
Protein C Concentrate
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
TAK-662 80 IU/kg administered as intravenous infusion.
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Period 2
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Period 2 title |
Extension Part: Up to 35 Months
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Is this the baseline period? |
No | |||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | |||||||||
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Arms
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Are arms mutually exclusive |
No
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Arm title
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Extension Part, On-demand Treatment (TAK-662) | |||||||||
Arm description |
Participants with purpura fulminans (PF), coumarin-induced skin necrosis/warfarin-induced skin necrosis (CISN/WISN), and/or other acute thromboembolic episode received a single dose of TAK-662 (100-120 IU/kg), followed by three subsequent infusions, every 6 hours at a dose of 60-80 IU/kg, and followed by subsequent infusions (45-60 IU/kg) continued every 6 or 12 hours until resolution of all non-necrotic lesions and/or stabilization of thrombi. Treatment could be terminated when an acute episode improved. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
TAK-662
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Investigational medicinal product code |
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Other name |
Protein C Concentrate
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
TAK-662 (100-120 IU/kg), followed by three subsequent infusions, every 6 hours at a dose of 60-80 IU/kg, and followed by subsequent infusions (45-60 IU/kg) continued every 6 or 12 hours until resolution of all non-necrotic lesions and/or stabilization of thrombi.
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Arm title
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Extension Part, Short-term Prophylaxis Treatment (TAK-662) | |||||||||
Arm description |
Participants who required short-term prophylaxis of acute thrombotic episodes during surgery received TAK-662 at a dose of 100-120 IU/kg, intravenous infusion once daily, until anticoagulation therapy was successfully switched to TAK-662 prior to surgery. Fifteen minutes prior to surgery, a dose of 60-80 IU/kg was administered and continued once every 6 hours for the first 24 hours after surgery began. The frequency of infusions was reduced to 3 times daily between 24 and 48 hours, and twice daily after 48 hours at the same dose (45-60 IU/kg). Treatment with TAK-662 continued twice daily until anticoagulation therapy was initiated (if applicable) and the investigator determined that adequate level of the anticoagulation was achieved. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
TAK-662
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Investigational medicinal product code |
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Other name |
Protein C Concentrate
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
TAK-662 at a dose of 100-120 IU/kg, intravenous infusion once daily, until anticoagulation therapy was successfully switched to TAK-662 prior to surgery. Fifteen minutes prior to surgery, a dose of 60-80 IU/kg was administered and continued once every 6 hours for the first 24 hours after surgery began. The frequency of infusions was reduced to 3 times daily between 24 and 48 hours, and twice daily after 48 hours at the same dose (45-60 IU/kg).
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Baseline characteristics reporting groups
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Reporting group title |
PK Part: TAK-662
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Reporting group description |
Participants received a single 80 IU/kg dose of TAK-662, intravenous infusion on Day 1 in PK part. | ||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
PK Part: TAK-662
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Reporting group description |
Participants received a single 80 IU/kg dose of TAK-662, intravenous infusion on Day 1 in PK part. | ||
Reporting group title |
Extension Part, On-demand Treatment (TAK-662)
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Reporting group description |
Participants with purpura fulminans (PF), coumarin-induced skin necrosis/warfarin-induced skin necrosis (CISN/WISN), and/or other acute thromboembolic episode received a single dose of TAK-662 (100-120 IU/kg), followed by three subsequent infusions, every 6 hours at a dose of 60-80 IU/kg, and followed by subsequent infusions (45-60 IU/kg) continued every 6 or 12 hours until resolution of all non-necrotic lesions and/or stabilization of thrombi. Treatment could be terminated when an acute episode improved. | ||
Reporting group title |
Extension Part, Short-term Prophylaxis Treatment (TAK-662)
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Reporting group description |
Participants who required short-term prophylaxis of acute thrombotic episodes during surgery received TAK-662 at a dose of 100-120 IU/kg, intravenous infusion once daily, until anticoagulation therapy was successfully switched to TAK-662 prior to surgery. Fifteen minutes prior to surgery, a dose of 60-80 IU/kg was administered and continued once every 6 hours for the first 24 hours after surgery began. The frequency of infusions was reduced to 3 times daily between 24 and 48 hours, and twice daily after 48 hours at the same dose (45-60 IU/kg). Treatment with TAK-662 continued twice daily until anticoagulation therapy was initiated (if applicable) and the investigator determined that adequate level of the anticoagulation was achieved. | ||
Subject analysis set title |
Extension Part, Long-term Prophylaxis Treatment (TAK-662)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Participants who required long-term prophylaxis were planned to receive TAK-662 at a dose of 45-60 IU/kg, intravenous infusion, twice daily. The dose was to be adjusted by referring to the latest protein C activity at the investigator’s discretion. No participants received TAK-662 for long-term prophylaxis during the study.
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End point title |
PK Part: Protein C Activity Level of TAK-662 [1] | ||||||||||||||||||||||||||
End point description |
Protein C is a vitamin K-dependent plasma protein and is an important component of the coagulation system. Protein C activity level was measured by chromogenic assays. Protein C activity level of TAK-662 was reported. The PK population included all study participants who took at least 1 dose of TAK-662 and had enough number of quantifiable blood levels for TAK-662 collected post-dose without important protocol deviations (PDs)/violations or events thought to substantially affect the PK.
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End point type |
Primary
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End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 12, 24, and 36 hours post-infusion
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||
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End point title |
PK Part: Incremental Recovery (IR) of TAK-662 [2] | ||||||||
End point description |
IR of TAK-662 was reported measured in terms of international unit per millilitre/ international unit per kilogram (IU/mL)/(IU/kg). The PK population included all study participants who took at least 1 dose of TAK-662 and had enough number of quantifiable blood levels for TAK-662 collected post-dose without important PDs/violations or events thought to substantially affect the PK.
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End point type |
Primary
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End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 12, 24, and 36 hours post-infusion
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
PK Part: Percentage of In-vivo Recovery (IVR) of TAK-662 [3] | ||||||||
End point description |
IVR corrected for plasma was determined using the formula: IVR (percentage [%])= (Maximum observed plasma concentration (Cmax) [IU/mL] – Concentration (C) pre-infusion [IU/mL]) * Plasma volume pre-infusion (PV) millilitre (mL)/ Dose (international unit [IU])*100 where Cmax was the observed Cmax value before baseline correction. IVR of TAK-662 measured in terms of percentage was reported. The PK population included all study participants who took at least 1 dose of TAK-662 and had enough number of quantifiable blood levels for TAK-662 collected post-dose without important PDs/violations or events thought to substantially affect the PK.
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End point type |
Primary
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End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 12, 24, and 36 hours post-infusion
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
PK Part: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of TAK-662 [4] | ||||||||
End point description |
AUClast of TAK-662 was reported measured in terms of international unit*hour per millilitre (IU*h/ml). The PK population included all study participants who took at least 1 dose of TAK-662 and had enough number of quantifiable blood levels for TAK-662 collected post-dose without important PDs/violations or events thought to substantially affect the PK.
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End point type |
Primary
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End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 12, 24, and 36 hours post-infusion
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| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
PK Part: Terminal Phase Elimination Half-life (t1/2) of TAK-662 [5] | ||||||||
End point description |
t1/2 of TAK-662 was reported. The PK population included all study participants who took at least 1 dose of TAK-662 and had enough number of quantifiable blood levels for TAK-662 collected post-dose without important PDs/violations or events thought to substantially affect the PK.
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End point type |
Primary
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End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 12, 24, and 36 hours post-infusion
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
PK Part: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-infinity) of TAK-662 [6] | ||||||||
End point description |
AUC0-infinity of TAK-662 was reported. The PK population included all study participants who took at least 1 dose of TAK-662 and had enough number of quantifiable blood levels for TAK-662 collected post-dose without important PDs/violations or events thought to substantially affect the PK.
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End point type |
Primary
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End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 12, 24, and 36 hours post-infusion
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| Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
PK Part: Maximum Observed Plasma Concentration (Cmax) of TAK-662 [7] | ||||||||
End point description |
Cmax of TAK-662 was reported. The PK population included all study participants who took at least 1 dose of TAK-662 and had enough number of quantifiable blood levels for TAK-662 collected post-dose without important PDs/violations or events thought to substantially affect the PK.
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End point type |
Primary
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End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 12, 24, and 36 hours post-infusion
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
PK Part: Time to Reach the Maximum Plasma Concentration (Tmax) of TAK-662 [8] | ||||||||
End point description |
Tmax of TAK-662 was reported. The PK population included all study participants who took at least 1 dose of TAK-662 and had enough number of quantifiable blood levels for TAK-662 collected post-dose without important PDs/violations or events thought to substantially affect the PK.
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End point type |
Primary
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End point timeframe |
Pre-infusion, 0.5, 1, 2, 4, 8, 12, 24, and 36 hours post-infusion
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| Notes [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
PK and Extension Parts: Number of Participants With Treatment-Related Adverse Experiences (AEs) | |||||||||||||||
End point description |
A treatment-related AE was defined as an adverse event that followed a reasonable temporal sequence from administration of a drug (including the course after withdrawal of the drug), or for which possible involvement of the drug was not able to be ruled out, although factors other than the drug, such as underlying diseases, complications, concomitant medications and concurrent treatments, might also be responsible. Number of participants with treatment-related AEs as assessed by the Investigator were reported. The safety population included all enrolled participants in the study who took at least 1 dose of TAK-662.
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End point type |
Secondary
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End point timeframe |
PK Part: From the start of study drug administration up to Day 7; Extension Part: From the first dose of study drug administration in the Extension Part up to 35 months
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| Notes [9] - No participants received TAK-662 for long-term prophylaxis treatment. |
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Extension Part: Number of Episode Rated as Effective, Effective With Complications, or Not Effective on Efficacy Rating Scale During On-Demand Treatment | ||||||||||||||
End point description |
The treatment of episodes of PF, CISN/ WISN, and/or other vascular thromboembolic events were rated as “effective”, “effective with complications”, or “not effective” according to the efficacy rating scale, as judged by investigators on the basis of following criteria, Effective: stabilization and regression of skin lesions/stabilization of thrombi; Effective with complications: treatment was effective but caused an adverse drug reaction that interfered with the regimen (resulted in change of dose or frequency of dosing) or forcing discontinuation of treatment or introducing pathogenic viral infection; Not effective: all other cases. Efficacy Analysis Set in On-Demand Treatment included all participants who took at least 1 dose of TAK-662 on-demand in the extension part.
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End point type |
Secondary
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End point timeframe |
Extension Part: From the first dose of TAK-662 on-demand treatment in the Extension Part up to 35 months
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Extension Part: Percentage of Surgical Episodes During Short-Term Prophylaxis That is Free of Presentations of PF or Thromboembolic Complications | ||||||||
End point description |
Percentage of surgical episodes for which TAK-662 was utilized as short-term prophylaxis that is free of presentations of PF or thromboembolic complications was reported. Efficacy Analysis Set in Short-term Prophylaxis included all participants who took at least 1 dose of TAK-662 during short-term prophylaxis in the extension part.
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End point type |
Secondary
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End point timeframe |
Extension Part: From the first dose of TAK-662 short-term prophylaxis treatment in the Extension Part up to 35 months
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| No statistical analyses for this end point | |||||||||
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End point title |
Extension Part: Number of Episodes of PF and/or Thrombotic Episodes During Long-Term Prophylaxis | ||||||||
End point description |
Number of Episodes of PF and/or Thrombotic Episodes During Long-Term Prophylaxis was planned to be reported. Efficacy Analysis Set in long-term prophylaxis included all study participants who took at least 1 dose of TAK-662 during long-term prophylaxis in the extension part. The “Number of Participants Analysed” is zero because no participants received TAK-662 for long-term prophylaxis; therefore, no data was collected and reported.
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End point type |
Secondary
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End point timeframe |
Extension Part: From the first dose of TAK-662 long-term prophylaxis treatment in the Extension Part up to 35 months
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| Notes [10] - No participants received TAK-662 for long-term prophylaxis treatment. |
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
PK Part: From start of study drug administration up to Day 7; Extension part: From first dose of study drug administration in Extension Part up to up to 35 months
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Adverse event reporting additional description |
No participant received TAK-662 for long-term prophylaxis and therefore, no safety data could be collected and reported for ‘Extension Part, Long-term Prophylaxis treatment (TAK-662) arm.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
25.0
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Reporting groups
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Reporting group title |
PK Part: TAK-662
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Reporting group description |
Participants received a single 80 international unit per kilogram (IU/kg) dose of TAK-662, intravenous infusion on Day 1 in PK part. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Extension Part, On-demand Treatment (TAK-662)
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Reporting group description |
Participants with purpura fulminans (PF), coumarin-induced skin necrosis/warfarin-induced skin necrosis (CISN/WISN), and/or other acute thromboembolic episode received a single dose of TAK-662 (100-120 IU/kg), followed by three subsequent infusions, every 6 hours at a dose of 60-80 IU/kg, and followed by subsequent infusions (45-60 IU/kg) continued every 6 or 12 hours until resolution of all non-necrotic lesions and/or stabilization of thrombi. Treatment could be terminated when an acute episode improved. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Extension Part, Short-term Prophylaxis Treatment (TAK-662)
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Reporting group description |
Participants who required short-term prophylaxis of acute thrombotic episodes during surgery received TAK-662 at a dose of 100-120 IU/kg, intravenous infusion once daily, until anticoagulation therapy was successfully switched to TAK-662 prior to surgery. Fifteen minutes prior to surgery, a dose of 60-80 IU/kg was administered and continued once every 6 hours for the first 24 hours after surgery began. The frequency of infusions was reduced to 3 times daily between 24 and 48 hours, and twice daily after 48 hours at the same dose (45-60 IU/kg). Treatment with TAK-662 continued twice daily until anticoagulation therapy was initiated (if applicable) and the investigator determined that adequate level of the anticoagulation was achieved. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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13 Apr 2021 |
Protocol Amendment 1.0: •Regarding inclusion criteria 1 and 2, actions to be taken when consent was not able to be obtained from the participant were added. •The collection of AEs was changed by the follow-up on Day 7. |
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02 Sep 2021 |
Protocol Amendment 2.0: •The rationale, study design, objectives and endpoints, dosage regimen and dose adjustment, inclusion/exclusion criteria, assessments, blood sampling volume, acceptable concomitant treatment, and handling of SAE for the extension part were added. Justification: based on investigator's careful evaluation on participant's medical condition, on-demand therapy, short-term prophylaxis and/or long-term prophylaxis were allowed to be conducted as the extension part in the participants who had completed PK part. •The injection rate was added. Justification: to align the injection time with the current US package insert to assure participant's safety. •The handling of the vials was changed. Justification: in order to align with the pharmacy manual. •The instruction of self-injection was added. Justification: self-injection was allowed in the extension part. •Description of planned interim analysis was added in Section 9.2. Justification: to clarify the timing of the primary analysis because the extension part was added. •Section 9.7 was simplified including deletion of Table 4. Justification: to describe the detail of PK analyses in the CPAP. •Correction of inconsistencies within the Protocol Amendment 1.0. |
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08 Sep 2022 |
Protocol Amendment 3.0: •The description of "Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee" of statistical analysis in Section 1.1 and Section 9.2 was changed to use the safety and efficacy data of the extension part for the first interim analysis. •The supporting description on the procedure of on-demand treatment at home after the first infusion for the second and subsequent acute episode was added in the footnote (f) of Table 3 in Section 1.3 and in Section 8.1.2.3.1. •Editorial correction of the Protocol Amendment 2.0. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
