Clinical trial NCT04984889
Conditions: Congenital Protein C Deficiency
Sponsor: Takeda
Start date: 2021-09-07; Completion date: 2024-10-31
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Pharmacokinetic Part:

This study is for Japanese participants with congenital protein C deficiency. The main aim of this study is to check how much TAK-662 stays in their blood over time. This will help the study sponsor (Takeda) to work out the best dose to give patients in the future.

Participants will receive 1 single infusion of TAK-662.

They will stay at the clinic until 3 days after the infusion. Then, participants will return to their clinic 7 days after the infusion to check side effects from the study treatment.

Extension Part:

Participants who will complete the PK part will be given an opportunity to continue TAK-662 administration as 3 different treatment options (on-demand therapy, short-term prophylaxis, and long-term prophylaxis) in the Extension part, until the commercial protein C concentrate is available at each study site or study termination.

Detailed description:

Arms: arm 1: TAK-662 80 international unit (IU)/kg, single intravenous infusion over 15 minutes on Day 1. In the extension part, dose of TAK-662 will be modified per participants. TAK-662 is Protein C Concentrate, which is a lyophilized, sterile concentrate of human protein C.
Interventions: intervention 1: TAK-662
Intervention descriptions: intervention 1: Lyophilized, sterile concentrate of human protein C

Protocol documents:
Prot_000.pdf: 
 
 
Title: 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 
 
NCT Number: NCT04984889 
Protocol Approve Date: 08-Sep-2022 
 
Certain information within this protocol has been redacted (ie, specific content is 
masked irreversibly from view with a black bar) to protect either personally identifiable 
information or company confidential information. 
 


TAKEDA PHARMACEUTICALS
PROTOCOL:
TAK-662-1501
Title:
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
Short Title:
A Phase 1/2 Single-Dose Study of TAK-662 in Japanese Patients with 
Congenital Protein C Deficiency Followed by an Extension Part
Study Phase:
Phase 1/2
Drug:
TAK-662
IND Number:
Non-IND
EUDRACT 
Number:
Non-EUDRACT
Sponsor:
Takeda Pharmaceutical Company Limited
1-1, Doshomachi 4-chome, Chuo-ku, Osaka Japan
Principal / 
Coordinating 
Investigator:
Not applicable
Protocol History:
Protocol Amendment 3.0, Version Date: 08 September 2022
Replaces:
Protocol Amendment 2.0, Version Date: 02 September 2021
Protocol Amendment 1.0, Version Date: 13 April 2021
Original Protocol, Version Date: 09 March 2021
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Clinical Study Protocol: TAK-662-1501
08 September 2022
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION
The primary purpose of this amendment is to add clinical data obtained from the Extension part 
into the interim analysis to support the Japanese New Drug Application (JNDA). The following 
is a summary of the changes made in the amendment:

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.
See 
for protocol history, including all amendments.
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Clinical Study Protocol: TAK-662-1501
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EMERGENCY CONTACT INFORMATION
When a serious adverse event (SAE) occurs through the adverse event (AE) collection period it 
should be reported according to the following procedure:
An SAE should be reported by the investigator to the sponsor/the Emergency Reception Center 
for Safety Information (see Protocol Annex) within 1 business day of the SAE occurrence, along 
with any relevant information. The investigator should submit the detailed SAE form to the 
sponsor/the Emergency Reception Center for Safety Information appropriate personnel (see 
Protocol Annex) within 10 calendar days. The information should be completed as fully as 
possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number

Investigator’s name

Name of the study drug(s)

Causality assessment
The investigator should submit the original copy of the SAE form to the sponsor.
Any SAE spontaneously reported to the investigator following the AE collection period should 
be reported to the sponsor if considered related to study participation.
Reporting of serious pretreatment events (PTEs) will follow the procedure described for SAEs.
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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product (IP) quality complaints or non-
medical complaints to Takeda within 24 hours. If requested, defective product(s) will be returned 
to the sponsor for inspection and analysis.
A product quality complaint includes any instances where there is an allegation or report relating 
to Takeda licensed or IPs, received in writing, electronically, or orally, which indicates an impact 
to a product’s strength, identity, safety, purity, or quality, or which suggests that the product did 
not meet the criteria defined in the regulatory applications, licenses, or marketing authorizations 
for the product. Examples of IP quality complaints include, but are not limited to, the following:
Unit issues

Capsule fill empty or overage

Bottle/vial fill shortage or overage

Capsule/tablet damaged/broken

Syringe/vial cracked/broken

Syringe leakage

Missing components

Product discoloration

Device malfunction
Labeling

Label missing

Leaflet or Instructions For Use
(IFU) missing

Label illegible

Incomplete, inaccurate, or
misleading labeling

Lot number or serial number
missing
Packaging

Damaged packaging (eg, 
secondary, primary, bag/pouch)

Tampered seals

Inadequate or faulty closure

Missing components within
package
Foreign 
material

Contaminated product

Particulate in bottle/vial

Particulate in packaging
Please report the product quality complaint using the “Clinical Trial Material Complaint Form” 
provided with the pharmacy manual via the email address:
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE............................................................................................. 2
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION.......................... 3
EMERGENCY CONTACT INFORMATION .......................................................................... 4
PRODUCT QUALITY COMPLAINTS..................................................................................... 5
TABLE OF CONTENTS ............................................................................................................. 6
1. PROTOCOL SUMMARY ..................................................................................................... 10
1.1 Synopsis.............................................................................................................................. 10
1.2 Schedule of Activities (Pharmacokinetic Part) .............................................................. 16
1.3 Schedule of Activities (Extension part: On-Demand Treatment) ................................ 18
1.4 Schedule of Activities (Extension part: Short-Term Prophylaxis)............................... 22
1.5 Schedule of Activities (Extension part: Long-Term Prophylaxis) ............................... 23
2. INTRODUCTION................................................................................................................... 24
2.1 Indication and Current Treatment Options................................................................... 24
2.2 Product Background and Clinical Information............................................................. 25
2.3 Study Rationale................................................................................................................. 29
2.4 Benefit/Risk Assessment................................................................................................... 30
2.5 Compliance Statement...................................................................................................... 31
3. OBJECTIVES AND ENDPOINTS ....................................................................................... 32
3.1 Study Objectives ............................................................................................................... 32
3.1.1 Primary Objective ..................................................................................................... 32
3.1.2 Secondary Objectives ................................................................................................ 32
3.1.3 
............................................................................................. 32
3.2 Study Endpoints................................................................................................................ 33
4. STUDY DESIGN..................................................................................................................... 34
4.1 Overall Design................................................................................................................... 34
4.2 Scientific Rationale for Study Design.............................................................................. 35
4.3 Justification for Dose........................................................................................................ 36
4.4 Duration of Subject Participation and Study Completion Definition.......................... 36
4.5 Sites and Regions .............................................................................................................. 36
5. STUDY POPULATION ......................................................................................................... 37
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5.1 Inclusion Criteria.............................................................................................................. 37
5.2 Exclusion Criteria............................................................................................................. 38
5.3 Restrictions........................................................................................................................ 39
5.4 Reproductive Potential..................................................................................................... 39
5.4.1 Female Contraception ............................................................................................... 39
5.4.2 Male Contraception................................................................................................... 40
6. STUDY INTERVENTION..................................................................................................... 41
6.1 Investigational Product .................................................................................................... 41
6.1.1 Identity of Investigational Product .......................................................................... 41
6.1.2 Blinding the Treatment Assignment ........................................................................ 41
6.2 Administration of Investigational Product..................................................................... 41
6.2.1 Allocation of Subjects to Treatment ........................................................................ 41
6.2.2 Dosing.......................................................................................................................... 41
6.2.3 Unblinding the Treatment Assignment ................................................................... 43
6.2.4 Dose Modification ...................................................................................................... 43
6.3 Labeling, Packaging, Storage, and Handling of Investigational Product.................... 43
6.3.1 Labeling ...................................................................................................................... 43
6.3.2 Packaging.................................................................................................................... 44
6.3.3 Storage ........................................................................................................................ 44
6.3.4 Special Handling........................................................................................................ 45
6.4 Drug Accountability ......................................................................................................... 45
6.5 Subject Compliance.......................................................................................................... 47
6.6 Prior and Concomitant Therapy..................................................................................... 47
6.6.1 Prior Treatment......................................................................................................... 47
6.6.2 Concomitant Treatment............................................................................................ 47
7. DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT EARLY
TERMINATION/WITHDRAWAL ...................................................................................... 48
7.1 Early Termination of Study Treatment.......................................................................... 48
7.2 Reasons for Early Termination ....................................................................................... 48
7.3 Withdrawal from the Study............................................................................................. 48
7.4 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit.................................. 49
8. STUDY ASSESSMENTS AND PROCEDURES................................................................. 50
8.1 Study Periods..................................................................................................................... 50
8.1.1 PK Part ....................................................................................................................... 50
8.1.1.1 Screening Period................................................................................................. 50
8.1.1.2 Treatment Period (Day 1, Day 2 and Day 3).................................................... 51
8.1.1.3 Follow-up Period (Day 7)................................................................................... 52
8.1.2 Extension Part............................................................................................................ 52
8.1.2.1 Pre-dose/Pre-surgery.......................................................................................... 52
8.1.2.2 Treatment Period................................................................................................ 54
8.1.2.3 End of Treatment (On-Demand Treatment and Short-Term Prophylaxis) . 55
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1. PROTOCOL SUMMARY
1.1 Synopsis
Protocol number: TAK-662-1501
Drug: TAK-662
Title of the study: 
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
Short title: 
A Phase 1/2 Single-Dose Study of TAK-662 in Japanese Patients with Congenital Protein C Deficiency Followed 
by an Extension Part
Study phase: Phase 1/2
Number of subjects (total and per treatment arm):
The study is planned to enroll more than 3 subjects in Japan.
Investigator(s): 
Multicenter study.
Site(s) and Region(s): 
The study will be conducted in approximately 5 study sites in Japan.
Study period (planned):
PK part: Aug 2021 to Dec 2021
Extension part (only for subjects who have completed PK part): 
until the commercial protein C concentrate is available at each 
study site or study termination in the extension part.
Clinical phase:
1/2
Objectives:
Primary:
To measure the pharmacokinetic (PK) parameters of TAK-662 in asymptomatic subjects with homozygous or 
double heterozygous congenital protein C deficiency in Japanese subjects.
Secondary:
To assess safety profile of TAK-662.
To assess efficacy of TAK-662 in following 1) for on-demand treatment such as purpura fulminans (PF), 
coumarin-induced skin necrosis (CISN)/ warfarin-induced skin necrosis (WISN), and other vascular 
thromboembolic events; 2) for short-term thromboembolic prophylaxis during surgical procedures; and 3) for 
long-term prophylactic treatment of acute thrombotic episodes (Extension part).
Rationale:
The PK part of this Japanese study design will be identical with the overseas PK study design (Study IMAG-098) 
as much as possible for the purpose of comparing with the results of Study IMAG-098. Since obtaining PK
parameters is the primary objective, an open-label design is chosen for this study. No control group is used in this 
study. An extension part (on-demand therapy, short-term prophylaxis, and long-term prophylaxis) will be 
conducted in the subjects who have completed PK part until the commercial protein C concentrate is available at 
each study site or study termination. Even under currently-available treatment options, high mortality and poor 
clinical course of protein C deficiency has been reported in Japan. The extension part will provide subjects with 
protein C deficiency opportunities to experience TAK-662 administration as a new treatment option.
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Investigational product, dose, and mode of administration:
The investigational product (IP) is TAK-662, which will be provided in vial form. TAK-662 is Protein C 
Concentrate, which is a lyophilized, sterile concentrate of human protein C. The protein C content is indicated in 
international unit (IU) on the label of each vial.
PK part:
All subjects will receive a single 80 IU/kg dose of TAK-662, infused over 15 minutes for the measurement of 
PK parameters, at Day 1. TAK-662 should be administered at a maximum injection rate of 2 mL/min except for 
children with a body weight of < 10 kg, where the injection rate should not exceed a rate of 0.2 mL/kg/min.
Extension part:
Dose will be decided according to an extension treatment that the subject will be enrolled at the time of treatment. 
TAK-662 should be administered at a maximum injection rate of 2 mL/min except for children with a body 
weight of < 10 kg, where the injection rate should not exceed a rate of 0.2 mL/kg/min.
Methodology:
This is a phase 1/2 open-label, non-randomized, non-controlled, single-dose, multicenter study to evaluate PK, 
safety, and tolerability of TAK-662 in Japanese subjects with congenital protein C deficiency followed by an 
extension part. 
PK part:
The subject who has the prophylactic treatment of anticoagulants is allowed to be enrolled. The last prophylactic 
treatment including protein C ingredient must occur by at least 36 hours before the administration of TAK-662 on 
Day 1. Other prophylactic treatment such as oral anticoagulants can be administered without any restrictions on 
period.
The subject will receive a single 80 IU/kg dose of TAK 662 intravenously on Day 1. Prior to the IP 
administration, the subject will be admitted to the study site on Day −1. The prophylactic treatment will be 
given according to the subject’s established treatment regimen and at the discretion of the investigator. For the 
subject with prophylactic treatment including protein C ingredient, the IP for PK will be administered at least
after 36 hours of the prophylactic treatment.
From Day 1 to Day 3, the subject will stay in the study site and be followed up for PK and safety before and after 
the IP administration. The blood sampling for PK will be done immediately prior to infusion and at 30 minutes, 
and 1, 2, 4, 8, 12, 24, and 36 hours postinfusion; a sampling for the 36 hours postinfusion is allowed to be 
customized by age, especially for feasibility in children. After 7 days from the IP administration (Day 7), the 
subject will have the follow-up visit for safety assessment. For the subject who has the prophylactic treatment 
including protein C ingredient before the administration of the IP for PK, the blood sampling will be additionally 
done immediately prior to the prophylactic treatment and at 1, 17, and 25 hours post-treatment.
The analysis will be performed for PK and safety after all subjects have completed the Day 7 visit. It is planned
to compare PK parameter of Japanese and non-Japanese subjects, by calculating PK parameter of each Japanese 
subject, then confirming whether it is within the range of (or not substantially different from) PK parameter of 
each non-Japanese subject in Study IMAG-098.
Extension part:
In the extension part of the current study, sponsor provides 3 different treatment options; on-demand treatment, 
short-term prophylaxis, and long-term prophylaxis. Based on investigator's careful evaluation on subject’s 
medical condition, subject who completed PK part can continue the administration of TAK-662 until the 
commercial protein C concentrate is available at each study site or study termination. The 3 different treatment 
options provide different ways of protein C supplementation. Subject can participate in each of 3 options and can 
transfer from one to another at the investigator's discretion.
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For on-demand treatment, subjects with PF, CISN/WISN, and/or other acute thromboembolic episode will be 
enrolled. For short-term prophylaxis, subjects requiring short-term prophylaxis with protein C concentrate/
TAK-662 for surgical procedures will be enrolled. For long-term prophylaxis, subjects requiring long-term 
prophylaxis with protein C concentrate/TAK-662 will be enrolled.
On-demand treatment and short-term prophylaxis may be carried out more than once depending on the subject’s 
situation. In this case, after the completion of follow-up period, the subject will be re-enrolled and re-start the 
procedures from pre-dose/pre-surgery period. In addition, subject may transfer to the other treatment (eg, If a 
subjects who enrolled in long-term prophylaxis requires a surgery, he/she transfers to short-term prophylaxis. 
Once anticoagulation is initiated and the investigator determines that adequate anticoagulation is achieved, he/she 
will transfer back to long-term prophylaxis.).
Inclusion and Exclusion Criteria:
Inclusion Criteria:
PK part:
The subject will not be considered eligible for PK part of the study without meeting all of the criteria below:
1.
An understanding, ability, and willingness to fully comply with study procedures and requirements. If the
subject is <20 years of age or informed consent cannot be obtained from the subject, a parent or legally
authorized representative should perform this role.
2.
Ability to voluntarily provide written, signed, and dated (personally, or via a parent or legally authorized
representative if the subject is <20 years of age or informed consent cannot be obtained from the subject)
informed consent, and assent as applicable (only when informed consent can be obtained from the subject),
to participate in the study.
3.
Male and female subjects with Japanese nationality.
4.
A diagnosis of congenital protein C deficiency (homozygous or compound heterozygous).
5.
Asymptomatic subject.
6.
Oral anticoagulants allowed to be received.
7.
Male, or non-pregnant or non-lactating female who is sexually active and who agrees to comply with the
applicable contraceptive requirements of this protocol, or females of non-childbearing potential. A negative
pregnancy test at the Screening has to be documented.
Extension part:
The subject will not be considered eligible for extension part of the study without meeting all of the criteria 
below.
1.
Subjects who participated in the PK part of this study (TAK-662-1501).
2.
An understanding, ability, and willingness to fully comply with study procedures and requirements. If the
subject is <20 years of age or informed consent cannot be obtained from the subject, a parent or legally
authorized representative should perform this role.
3.
Ability to voluntarily provide written, signed, and dated (personally, or via a parent or legally authorized
representative if the subject is <20 years of age or informed consent cannot be obtained from the subject)
informed consent, and assent as applicable (only when informed consent can be obtained from the subject),
to participate in the extension part of this study
4.
Subject who are;
a.Diagnosed with PF, CISN/WISN, and/or other acute thromboembolic episode for on-demand treatment
only.
b.Requiring treatment with TAK-662 for short-term prophylaxis for surgical procedures.
c.Requiring treatment with TAK-662 for long-term prophylaxis.
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Exclusion Criteria:
PK part:
The subject will be excluded from the PK part of the study if any of the following exclusion criteria are met:
1.
Current or recurrent disease that could affect the action, or disposition of the IP, or clinical or laboratory
assessments.
2.
A body weight less than 8 kg.
3.
Serious liver dysfunction, judged by the investigator.
4.
Any thrombosis within 2 weeks prior to administration of the IP.
5.
Other investigational product than TAK-662 received within 60 days prior to the administration of the IP.
6.
Current or relevant history of physical or psychiatric illness, or any medical disorder that may require
treatment or make the subject unlikely to fully complete the study, or any condition that presents undue risk
from the IP or procedures.
7.
Current use of any medication (including over-the-counter, herbal, or homeopathic preparations) that could
affect (improve or worsen) the condition being studied, or could affect the action or disposition of the IP, or
clinical or laboratory assessment.
8.
Known or suspected intolerance or hypersensitivity to the IP, closely-related compounds, or any of the
stated ingredients.
9.
Known history of alcohol or other substance abuse within the last year.
10.
Within 30 days prior to the first dose of IP, a subject has been enrolled in a clinical study (including vaccine
studies) that, in the investigator's opinion, may impact this sponsored study.
Extension part:
The subject who participated in the PK part will be excluded from the extension part of the study if any of the 
following exclusion criteria are met.
1.
New serious medical conditions which could affect patient’s safety or treatment were observed during
participation in the PK part of this study (TAK-662-1501).
2.
Planning to participate in clinical trials of other investigational drugs or medical devices.
3.
Females of childbearing potential who do not agree to use acceptable contraception.
Maximum duration of subject participation in the study:
PK part:
The study period is composed of Screening period, Treatment period, and Follow-up period.

Screening period: 2 weeks (Day −14 to Day −1)

Treatment period: 3 days (Day 1 to Day 3) 

Follow-up period: 4 days (Day 4 to Day 7)
Extension part:
In the extension part, sponsor provides 3 different treatment options; on-demand treatment, short-term 
prophylaxis, and long-term prophylaxis. The extension part will continue until the commercial protein C 
concentrate is available at each study site or study termination. The duration of subject participation is determined 
depending on which study part to be enrolled. On-demand treatment is composed of pre-dose period, treatment 
period, and follow-up period. Short-term prophylaxis is composed of pre-surgery period, treatment period, and 
follow-up period. Long-term prophylaxis is composed of pre-dose period, treatment period, and follow-up period.
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Statistical analysis:

Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
Interim analyses of study data will be undertaken as described below. No adaptive design or data monitoring 
committee (DMC) is planned for this study. One formal interim data analyses to support the Japanese New Drug 
Application (JNDA) submission will be completed. It will summarize PK, safety and efficacy of treatment with 
TAK-662 in Japanese subjects with homozygous or double heterozygous congenital protein C deficiency. The 
first interim analysis will be conducted after all enrolled subjects have reached last visit of the PK part and at 
least 3 treatments (any of either on-demand treatment, short-term prophylaxis or long-term prophylaxis) have 
been provided to any subjects in the Extension part. The target data is all data obtained at this point in the PK part
and Extension part. An interim clinical study report summarizing data of the first interim analysis will be 
prepared. The clinical data cut-off date will be stated in the Statistical Analysis Plan. As applicable, additional 
interim analysis will be conducted after the first interim analysis. 

Sample Size and Power Considerations
The number of patients with severe congenital protein C deficiency is very low. And the target number of patients 
is set to 3 or more in consideration of feasibility and inclusion/exclusion criteria in this study based on the 
opinions of specialists in Japan.

Statistical Analysis Set(s)
The safety population will include all enrolled subjects in the study who take at least 1 dose of TAK-662. 
A subject will be considered enrolled in the study once the informed consent/assent has been obtained and the 
subject meets all of the study inclusion criteria. The safety population will be used for safety analyses.
The pharmacokinetic population will include all study participants who take at least 1 dose of TAK-662 and have 
enough number of quantifiable blood levels for TAK-662 collected post-dose without important protocol 
deviations/violations or events thought to substantially affect the PK. The PK population will be used for PK 
analyses.
The efficacy population will include all study participants who take at least 1 dose of TAK-662 in the extension 
part. The efficacy population will be used for efficacy analyses.

Efficacy Analyses
1.On demand therapy
The treatment of episodes of PF/CISN/WISN and/or other vascular thromboembolic events will be rated as 
“effective”, “effective with complications”, or “not effective” according to the efficacy rating scale. The rating of 
treatment effect will be listed and summarized using descriptive statistics.
2.Short-term prophylaxis
Percentage of surgical episodes for which TAK-662 will be utilized as short-term prophylaxis, that is free of 
presentations of PF or thromboembolic complications will be calculated. PF or thromboembolic complications 
will be listed and summarized using descriptive statistics.
3.Long-term prophylaxis
Number of episodes of PF and/or thrombotic episodes while receiving long-term prophylaxis and rate of episodes 
of PF and/or thrombotic episodes per month will be calculated. Episodes of PF and/or thrombotic episodes will 
be listed and summarized using descriptive statistics.
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
Safety Analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. The number of events, 
incidence, and percentage of treatment emergent adverse events (TEAEs) will be calculated overall, by system 
organ class (SOC), by preferred term. Treatment emergent adverse events will be further summarized by severity 
and relationship to IP. Adverse events related to IP, AEs leading to withdrawal, serious adverse events (SAEs), 
and deaths will be similarly summarized/listed.
Clinical laboratory tests and vital signs will be summarized by visit. Potentially clinically important findings will 
also be summarized or listed.

Pharmacokinetic Analyses
Pharmacokinetic analyses will be performed using the observed Protein C activity in plasma of the 
pharmacokinetic population. Pharmacokinetic parameters including but not limited to terminal half-life (t1/2), 
incremental recovery (IR), in-vivo recovery (IVR), area under the curve (AUC), maximum concentration (Cmax), 
and minimum time to reach maximum concentration (tmax) will be computed using noncompartmental methods. 
Pharmacokinetic parameters will be listed and summarized using descriptive statistics. Data will be presented 
graphically if appropriate.
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1.2 Schedule of Activities (Pharmacokinetic Part)
Table 1. Schedule of Activities (Pharmacokinetic Part)
Screening 
period
Treatment period
Day 7 (±3 day) 
/ Follow-up a
Extension part
Procedure
Days –14 to –2
Day –1
Day 1
Day 2
Day 3
Informed consent b
X
On-demand treatment; 
refer to Table 2, Table 3
Short-term prophylaxis; 
refer to Table 4
Long-term prophylaxis; 
refer to Table 5
Inclusion/exclusion criteria
X
X
Demographics and medical history
X
Medication history
X
Physical exam 
X
Vital signs c
X
X
X
X
Height, weight, and BMI d
X
Concomitant medications 
X
X
X
X
X
X
12-lead ECG
X
Clinical laboratory evaluations 
X
X e
X
X
Serum pregnancy test (β-hCG) f
X
FSH f
X
Hospitalization
X g
X
X
X
Study drug dosing h
X
PK blood collection i
X
X
X
PTE/AE assessment 
X
X
X
X
X
X j
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Table 1. Schedule of Activities (Pharmacokinetic Part)
Screening 
period
Treatment period
Day 7 (±3 day) 
/ Follow-up a
Extension part
Procedure
Days –14 to –2
Day –1
Day 1
Day 2
Day 3
a If a subject is early terminated, regardless of the reason, the evaluations listed for the Day 7 visit will be performed as completely as possible.
b Prior to initiation of any study procedures, the informed consent (and assent where applicable) to participate in the study must be obtained from a subject or 
the subject’s parent or legally authorized representative if the subject is <20 years of age or informed consent cannot be obtained from the subject.
c Vital signs (pulse rate, respiration rate, blood pressure, and temperature) will be assessed prior to and 1 hour after administration of the prophylactic 
treatment including protein C ingredient (in subjects participating in the pre-pharmacokinetic wash-out segment), and prior to and 30 minutes, 2 hours, 
4 hours, and 24 hours after administration of the investigational product (IP) for pharmacokinetics (PK).
d Body mass index (BMI) will be calculated by the Sponsor.
e Blood sample for clinical laboratory evaluations at Day 1 will be drawn before administration of the IP.
f A serum β-hCG pregnancy test and FSH test will only be performed on females of child-bearing potential.
g A subject is allowed to stay in a hospital from one day before Day −1 (ie, Day −2), if applicable.
h All subjects will receive a single 80 IU/kg dose of TAK-662 at Day 1 for the measurement of PK parameters. All subjects will be closely monitored 
throughout the course of the study. Subjects on prophylactic treatment including protein C ingredient will receive an intravenous infusion by 36 hours prior 
to administration of the IP. Should a subject experience a thrombotic event during the 36-hour washout period, that subject will not participate in the study.
i PK samples will be collected at pre-dose and at 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours (Day 2), and 36 hours *(Day 3) after 
completing administration of the test dose of the IP (* the feasibility of PK collection at 36 hours after administration needs to be assessed). For the subject 
who has the prophylactic treatment including protein C ingredient before the administration of the IP for PK, the blood sampling will be additionally done 
immediately prior to the prophylactic treatment and at 1, 17, and 25 hours post-treatment.
j All AEs and serious AEs that are not resolved at the time of this contact will be followed to closure (
).
Abbreviations. AE=adverse event, β-hCG= beta human chorionic gonadotropin, BMI=body mass index, ECG=electrocardiogram, 
FSH=follicle-stimulating hormone, IP=investigational product, PK=pharmacokinetics, PTE=pretreatment event.
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1.3 Schedule of Activities (Extension part: On-Demand Treatment)
Table 2. Schedule of Activities (On-Demand Treatment): First Acute Episode
Pre-
dose
Treatment period
At the end 
of 
treatment a
Follow-up
(7 days 
after the 
last dose of 
IP)
Day E1
On and After
Day E2
0 hour 6 hours after the 
first dose of IP
12 hours after the 
first dose of IP
18 hours after the 
first dose of IP
Every 6 or 
12 hours
Eligibility check b
X
Diagnosis of acute episode (PF, 
CISN/WISN, and thrombotic event) c
X
Concomitant medications
Lesion assessment / Photography d
X / X
X / X*
X / X*
X / X*
X / X*
X / X
Hematology e
X 
X
Protein C Activity f
(X)
(X)
(X)
(X)
(X)
Vital signs
X
X
Study drug dosing g
X
(X)**
(X) **
(X) **
(X) **
AE assessment
a Treatment with TAK-662 will be ended when the investigator determines that the acute episode have recovered or tend to improve (eg, purpura area reduction 
or fading). 
b Pregnancy urine test will be performed at the site within 3 days of first dose.
c The investigators will diagnose purpura fulminans (PF), coumarin-induced skin necrosis (CISN)/ warfarin-induced skin necrosis (WISN), and thrombosis.
d Lesion assessment will be performed by the investigators at each point before administrating of investigational product (IP). Images of the lesion site will be 
taken before the first infusion on Day E1 and at the end of treatment when investigators determine that the acute episode have recovered or tend to improve. 
Image of the lesion site can be taken between the 2 points if applicable. 
*In principle, it is carried out in the hospital, but the subject can return home after infusion if the investigator allows it. In this case, subject may take a picture
of the lesion site at home and send it to the investigator (refer to the manual for data handling of imaging data). If a next infusion is required based on the
investigator's decision, the subject will have to visit the site.
e Hematological tests will be performed at a central laboratory. 
f Protein C activity measurement may be performed at the discretion of the investigator. If protein C activity will be measured, the time point of measurement is 
also at the discretion of the investigator.
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Table 2. Schedule of Activities (On-Demand Treatment): First Acute Episode
Pre-
dose
Treatment period
At the end 
of 
treatment a
Follow-up
(7 days 
after the 
last dose of 
IP)
Day E1
On and After
Day E2
0 hour 6 hours after the 
first dose of IP
12 hours after the 
first dose of IP
18 hours after the 
first dose of IP
Every 6 or 
12 hours
g Upon presentation with an acute event, the subject will be infused with a dose of 100-120 IU/kg. The subsequent 3 infusions will be administered every 6 hours 
at a dose of 60-80 IU/kg. Subsequent infusions (45-60 IU/kg) are also continued every 6 or 12 hours until resolution of all non-necrotic lesions and/or 
stabilization of thrombi (in the case of a thrombotic episode).
** When the acute episode is not recovered or improved after the first dose, further infusions are continued.
Abbreviations. AE=adverse event, CISN= coumarin-induced skin necrosis, IP=investigational product, PF= purpura fulminans, 
WISN=warfarin-induced skin necrosis.
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Table 3. Schedule of Activities (On-Demand Treatment): Second and Subsequent Acute Episodes (Home Infusion)
Pre-
dose
Treatment period
At the end
of 
treatment a
Follow-up
(7 days 
after the 
last dose of 
IP)
Day E1
On and After
Day E2
0 hour 6 hours after the 
first dose of IP
12 hours after the 
first dose of IP
18 hours after the 
first dose of IP
Every 6 or 
12 hours
Diagnosis of acute episode (PF, 
CISN/WISN, and thrombotic event) b
X
Concomitant medications
Lesion assessment / Photography c
X / X*
X / X*
X / X*
X / X*
X / X
Hematology d
X
Protein C Activity e
(X)
(X)
(X)
(X)
Vital signs
X
Study drug dosing f
X
(X)**
(X)**
(X)**
(X)**
Subject Diaries g
X
AE assessment
a Treatment with TAK-662 will be ended when the investigator determines that the acute episode have recovered or tend to improve (eg, purpura area reduction 
or fading). 
b The investigators will diagnose purpura fulminans (PF), coumarin-induced skin necrosis (CISN)/ warfarin-induced skin necrosis (WISN), and thrombosis. 
Subject will have to take a picture of the lesion site at home upon presentation with an acute event. It is allowed for the investigators to confirm it later.
c A picture of the lesion site will be taken at each point before administrating of investigational product (IP). Images of the lesion site will be taken before the first 
infusion at pre-dose by subject (at the time of diagnosis of acute episode) and at the end of treatment when investigators determine that the acute episode have 
recovered or tend to improve. Image of the lesion site can be taken between the 2 points if applicable. 
*After visiting the site and received a subsequent infusion at the site, the subject can return home if the investigator allows it. In this case, subject may take a
picture of the lesion site at home and send it to the investigator so that the investigator will perform lesion assessment (refer to the manual for data handling of
imaging data). If a next infusion is required based on the investigator's decision, the subject will have to visit the site.
d Hematological tests will be performed at a central laboratory. 
e Protein C activity measurement may be performed at the discretion of the investigator. If protein C activity will be measured, the time point of measurement is 
also at the discretion of the investigator.
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Table 3. Schedule of Activities (On-Demand Treatment): Second and Subsequent Acute Episodes (Home Infusion)
Pre-
dose
Treatment period
At the end
of 
treatment a
Follow-up
(7 days 
after the 
last dose of 
IP)
Day E1
On and After
Day E2
0 hour 6 hours after the 
first dose of IP
12 hours after the 
first dose of IP
18 hours after the 
first dose of IP
Every 6 or 
12 hours
f The dose regimen of IP is the same as that of treatment for the first acute episode. The first infusion of IP will be possible at home. If the first infusion is done at 
home, subject will have to visit the site (however, if the investigator determines the recovery or improvement of the acute episode by assessing the picture of 
the lesion site, which is taken by the subject at home after the first infusion and is sent to the investigator, the timing of this investigator's decision is considered 
as the end of treatment and the subject will not have to visit the site. If a next infusion is required based on the investigator's decision, the subject will have to 
visit the site). If the first infusion is done at the site, follow the procedures for first acute episode (Table 2)
** When the acute episode is not recovered or improved after the first dose, further infusions are continued.
g  The dosing information at home will be recorded on a subject diary. Subject will have to bring the subject diary to the site when he/she visits the site.
Note: the schedule of activities for on-demand treatment differs depending on episodes which a subject has, ie, first acute episode OR second and subsequent 
acute episodes. Refer to Section 8.1.2.1 for details.
Abbreviations. AE=adverse event, CISN= coumarin-induced skin necrosis, IP=investigational product, PF= purpura fulminans, 
WISN=warfarin-induced skin necrosis.
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1.4 Schedule of Activities (Extension part: Short-Term Prophylaxis)
Table 4. Schedule of Activities (Short-Term Prophylaxis)
Pre-surgery a
Treatment period
At the end of 
treatment b
Follow-up
(7 days after the last 
dose of IP)
Day E1
(day of surgery)
Day E2
On and After 
Day E3
Eligibility check c
X
Physical exam
X
X
Concomitant medications
Hematology d
X
X
Protein C Activity e
(X)
(X)
(X)
(X)
(X)
Vital signs
X
X
X
Study drug dosing
X
X f
X f
X f
AE assessment
a For subjects on anticoagulation therapy who required elective surgery (non-emergency), treatment with TAK-662 will be initiated at a dose of 100-120 IU/kg 
once daily until anticoagulation therapy is successfully switched to TAK-662 prior to surgery. For subjects on anticoagulation therapy who required emergency 
surgery, vitamin K dosage can reverse anti-coagulation due to warfarin, and TAK-622 treatment (100-120 IU/kg) should be started.
b Treatment with TAK-662 will be ended when the investigator determines that adequate anticoagulation is achieved.
c Pregnancy urine test will be performed at the site within 3 days of first dose.
d Hematological tests will be performed at a central laboratory. Baseline hematologic tests will be performed within 7 days prior to first dose. 
e Protein C activity measurement may be performed at the discretion of the investigator. If protein C activity will be measured, the time point of measurement is 
also at the discretion of the investigator.
f Fifteen minutes prior to surgery, a dose of 60-80 IU/kg will be administered. The same dose will be continued once every 6 hours for the first 24 hours after 
surgery began. The frequency of infusions is reduced to 3 times daily at a dose of 45-60 IU/kg between 24 and 48 hours, and twice daily after 48 hours at the 
same dose (45-60 IU/kg).
Abbreviations. AE=adverse event, IP=investigational product.
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1.5 Schedule of Activities (Extension part: Long-Term Prophylaxis)
Table 5. Schedule of Activities (Long-Term Prophylaxis)
Pre-dose
Treatment period
End of study a/
Follow-up
(7 days after the last 
dose of IP)
1st 3 prophy. infusions
Following of 1st
3 prophy. infusions
Every 1 M±2 wks
Eligibility check b
X
Concomitant medications
Hematology c
X
X
Protein C Activity d
X
X
Hospitalization e
Study drug dosing f
Subject Diaries g
AE assessment
a End of study is defined as the time TAK-662 becomes available at the site.
b Pregnancy urine test will be performed at the site within 3 days of first dose.
c Hematological tests will be performed at a central laboratory. Baseline hematologic tests will be performed within 7 days prior to first dose. Hematologic tests 
every 1 month (±2 weeks) will be performed at pre-infusion, and may be skipped at the discretion of the investigator.
d Protein C activity will be performed before infusion of IP. Protein C activity every 1 month (±2 weeks) may be skipped at the discretion of the investigator.
e Subject is allowed to discharge at the investigator's discretion after the measurement of protein C activity following of 1st 3 prophylaxis infusions.
f A dose of 45-60 IU/kg will be administered upon initiation of long-term prophylaxis twice daily. The first 3 doses will be administered at the site. The dose will 
be adjusted by referring to the latest Protein C activity at the investigator's discretion.
g Subject diary will be completed throughout home treatment times after discharge. Subject will have to bring the subject diary to the site when he/she visits the 
site.
Abbreviations. AE=adverse event, IP=investigational product, M=month, prophy.= prophylaxis, wks=weeks.
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2. INTRODUCTION
Protein C Concentrate (human) (TAK-662) is approved as Ceprotin® in European countries and
the United States. TAK-662 is a double virus-inactivated, lyophilized concentrate for intravenous
use, manufactured from pooled human plasma.
2.1 Indication and Current Treatment Options
Protein C, a vitamin K-dependent plasma protein, is an important component of the coagulation 
system. Protein C exerts anticoagulant effects via a chemical cascade in which protein C is 
activated to activated protein C, a serine protease, by binding to thrombomodulin-bound 
thrombin. The activated protein C inactivates Factor Va and Factor VIIIa, thereby resulting in the 
inhibition of tenase and prothrombinase activities and ultimately creating an anticoagulant effect.
The pathophysiological role of protein C came to be understood through descriptions of 
congenital deficiency with lesions characteristic of hereditary thromboembolic diseases such as 
extensive necrotic skin lesions (purpura fulminans [PF]), thrombotic events in the central 
nervous system and thrombosis of the retinal vessels.
One of the most common symptoms of protein C deficiency, PF, is a life-threatening 
complication that frequently appears during the first several days of life in infants congenitally 
deficient in protein C (Marlar et al., 1989). The clinical symptoms of PF consist of ecchymotic 
skin lesions which rapidly develop into hemorrhagic bullae with subsequent gangrenous necrosis 
sometimes extending to the fascia and leading to autoamputation. In addition, cerebral 
thrombotic complications can occur in utero or after birth and are responsible for hydrocephalus, 
mental retardation, delayed development and seizures. Retinal thrombosis can cause partial or 
complete blindness.
Severe protein C deficiency (homozygous or compound heterozygous forms) is extremely 
rare (1 in 500,000 to 1 in 750,000 births), but partial deficiencies (heterozygous forms) are 
much more frequent (1 in 200 to 1 in 500) (Goldenberg and Manco-Johnson, 2008, 
Kottke-Marchant and Comp, 2002). The low prevalence of patients with severe genetic 
protein C deficiency may be explained by fetal demise and prenatal deaths before diagnosis. 
The incidence of protein C deficiency in persons who present with clinical symptoms has been 
estimated at 1 in 20,000 (Dahlbäck, 1995). In Japan, the number of the patients of congenital
protein C deficiency is estimated to be less than 1,000 as in the latest patient survey 2017 by the 
category of "Other hereditary coagulation factor deficiency" (Ministry of Health Labour and 
Welfare [MHLW], 2017). A survey for patients with cardiovascular disorder from 1986 to 
1996 in Japan reported that 43 patients with protein C deficiency were screened from 
approximately 26,800 patients, and the observed prevalence of protein C deficiency was 1 per 
620 (Sakata et al., 1999). This prevalence is in agreement with that of foreign countries.
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In overseas countries, according to guideline in American College of Chest Physicians (ACCP), 
for acute symptoms in newborn with homozygous protein C deficiency, replacement therapy 
with fresh frozen plasma and/or protein C is recommended. For long-term prophylaxis treatment 
in those patients after stabilization of acute symptoms, protein C replacement and vitamin K 
antagonists, low molecular heparin and liver transplantation are recommended (ACCP 9th;
(Guyatt et al., 2012). In addition, according to guideline in American Society of Hematology 
(ASH), for PF in infants with homozygous protein C deficiency, anticoagulant therapy and 
protein C replacement are recommended (Schünemann et al., 2018). The ASH guideline panel 
also suggests using protein C replacement rather than anticoagulation, or using anticoagulation 
plus protein C replacement rather than anticoagulation alone, in pediatric patients with 
congenital PF due to homozygous protein C deficiency (Monagle et al., 2018).
In Japan, for thrombosis in children, anticoagulant therapy and/or thrombolytic therapy are 
recommended based on severity. For long-term prophylaxis treatment in those patients, 
anticoagulant therapy is recommended, and replacement therapy is used, if needed. Currently, in 
Japan, human activated protein C, freeze-dried concentrated (activated protein C) is available for 
treatment of deep venous thrombosis (DVT), acute pulmonary thromboembolism, and PF caused 
by congenital protein C deficiency.
2.2 Product Background and Clinical Information
TAK-662 is considered to be a safe, well-tolerated and efficacious product for the treatment of 
PF and coumarin-induced skin necrosis (CISN)/ warfarin-induced skin necrosis (WISN) in 
patients with severe protein C deficiency and for short-term prophylaxis in patients with severe 
congenital protein C deficiency (e.g. prior to and during surgery or invasive therapy, in the initial 
phase of oral anticoagulation therapy, or in case of failure of oral anticoagulation therapy). 
Treatment with TAK-662 then may be life-saving and play a substantial role in preventing major 
thrombotic complications and irreversible organ damage. In addition, in March 2007, Food and 
Drug Administration (FDA) approved Ceprotin® for “pediatric and adult patients with severe 
congenital protein C deficiency for the prevention and treatment of venous thrombosis and
purpura fulminans” (Food and Drug Administration [FDA], 2018). There were no adverse events
(AEs), no literature reports on thrombotic events, and no protein C inhibitor formation during the 
time of long-term prophylaxis.
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The information of Protein C Concentrate/TAK-662 from non-clinical and clinical studies is 
summarized below.
Non-clinical safety
The Protein C Concentrate did not produce adverse effects in a series of safety pharmacology 
studies. The doses in these studies are 200 to 500 international unit (IU)/kg, which is greater than 
the anticipated maximum clinical dose of 120 IU/kg.
The No Observed Adverse Effect Level (NOAEL) of single dose toxicity studies in mice and rats 
were 1,500 and 2,000 IU/kg, respectively, which was the highest dose tested. Both results 
indicated a sufficiently large safety margin between the anticipated maximum human dose 
(120 IU/kg) and NOAEL. No concerns were raised by the in vitro studies on mutagenicity. 
Investigation of local tolerance in rabbits indicated that the product was well tolerated after 
intravenous, intraarterial, and paravenous injection. In addition, as a result of an exploratory 
study on antigenicity in a rabbit, no changes-neither formation of neoantigens nor disappearance 
of antigens were detected.
Clinical pharmacology
Pharmacokinetic (PK) properties of Protein C Concentrate/TAK-662 were investigated in 
2 studies in asymptomatic subjects (Studies IMAG-098 and 400101) as well as in symptomatic 
subjects (retrospective data collection [RDC] of the use of Protein C Concentrate for treatment of 
protein C deficiency [Studies IMAG-039, IMAG-041, and compassionate use]). The list of 
the studies is shown below.
The analysis of the PK parameters showed considerable inter-subject variation. Half-life (t1/2) is 
shorter and clearance (CL) of protein C is higher in children than in older subjects. Therefore, 
neonates and very young children require higher doses than adults, especially when they are in 
the acute phase of the disease.
Considering these variations, no general recommendations for a dosage regimen can be made. 
Consequently, careful monitoring throughout the treatment is necessary in order to ensure that 
adequate protein C activity are maintained. The amount of Protein C Concentrate administered, 
the frequency of administration and the duration of treatment should be based on the patient’s 
protein C plasma activity and on the clinical condition of the patient.
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Clinical efficacy and safety
The efficacy and safety of Protein C Concentrate/TAK-662 in subjects with severe congenital 
protein C deficiency were investigated in the following clinical studies:

RDC: Clinical Studies IMAG-039 and IMAG-041 and Compassionate Use
Study IMAG-039: An Open-Label Study of the Efficacy and Safety of Protein C
Concentrate (Human) Vapor Heated in the Treatment of Severe Congenital Protein C
Deficiency With or Without Purpura Fulminans
Study IMAG-041: An Open-Label Study of the Efficacy and Safety of Protein C
Concentrate (Human) Vapor Heated in the Treatment of Warfarin (Coumarin)-
Induced Skin Necrosis

Study IMAG-098: A Clinical Study on the Pharmacokinetics of Protein C Concentrate
(Human) Vapor Heated in Asymptomatic Subjects with Homozygous or Double
Heterozygous Congenital Protein C Deficiency

Study 400101: A Phase 2/3 Clinical Study for the Determination of the Efficacy and Safety
of Protein C Concentrate in Subjects with Severe Congenital Protein C Deficiency

Study 400501: A Retrospective Study to Capture Dosing and Treatment Outcome Data in
Subjects With Severe Congenital Protein C Deficiency Who Were Treated With Protein C
Concentrate Under an Emergency Investigational New Drug (IND)
In addition, following registry study was conducted in the United States (US) and European 
Union (EU) after the above clinical studies.

Study 400701: A prospective, international, multi-center, open-label, noninterventional,
observational, post-authorization registry of subjects prescribed and treated with
CEPROTIN (Protein C Concentrate [Human])
Efficacy:
In RDC of Study IMAG-039, Study IMAG-041, and compassionate use study, a large 
increase in protein C value from baseline was observed after the first dose of TAK-662 
based on all the treatments in available data. The initial dose was 20 U/kg to 70 U/kg twice 
a day (BID). TAK-662 was effective in the treatment of protein C deficiency in patients 
with severe congenital protein C deficiency and in patients with simple heterozygous, 
acquired, other/unknown protein C deficiency.
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The results of a prospective study, Study 400101, showed that TAK-662 is effective in the acute 
phase of treatment of PF, CISN/WISN, and other vascular thromboembolic events in patients 
with severe congenital protein C deficiency. In patients with severe congenital protein C 
deficiency, TAK-662 has been shown to be effective in both short-term replenishment (during 
surgery and at the initiation of oral or parenteral anticoagulant therapy) and long-term 
replenishment for thromboprophylaxis. In a retrospective study 400501, TAK-662 was shown to 
be effective in the treatment of acute thrombotic episodes in patients with severe congenital 
protein C deficiency. In addition, it was suggested that short-term and long-term replenishment 
with TAK-662 is effective for thromboprophylaxis.
A post-marketing registry study in 25 patients with severe congenital or acquired protein C 
deficiency (Study 400701) provided efficacy and safety for surgical/invasive procedures or acute 
episodes in patients with severe congenital or acquired protein C deficiency. Furthermore, it also 
provided an evidence to support a favorable benefit-risk profile of TAK-662 in long-term 
replacement in 19 patients.
Safety:
The safety profile of TAK-662 is based on data in patients with severe congenital protein C 
deficiency in clinical trial(s) and in 79 patients from the compassionate use. The exposure period 
ranged from 1 day to 8 years. Hypersensitivity/allergic reaction (pruritus and rash) and mild 
headache were reported from 1 subject and were assessed by the investigator to be treatment-
related.
As of 31 December 2020, the most frequent SAEs from company sponsored trials assessed as at 
least possibly related to study drug were pyrexia, vascular device infection, musculoskeletal 
chest pain, and seizure. Serious adverse events were reported predominantly from 4 studies 
(Studies 400101, IMAG-098, IMAG-103, and IMAG-112). Of all AEs reported in clinical trials 
regardless of seriousness, the adverse drug reactions assessed as probably related to TAK-662
identified were hypersensitivity (pruritus and rash) and dizziness.
No inhibitory anti-protein C antibodies were observed in 14 pediatric patients from long term 
prophylaxis part of Study 400101 were tested for antibody to protein C. None of  patients were 
positive. Similarly, in Study IMAG-098, all 13 subjects were negative for inhibitory antibodies 
against protein C at baseline and the 12 subjects whose antibody titers were measured were 
negative at 3 months.
Adverse reactions observed post-marketing included hemothorax, hypotension, hyperhidrosis, 
pyrexia, and restlessness. The frequency of these adverse reactions was difficult to estimate 
because of spontaneous reports. No serious hypersensitivity reactions had been reported as of 
31 December 2020.
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2.3 Study Rationale
The PK part of Japanese clinical study design will be identical with the overseas PK study design 
(Study IMAG-098) as much as possible except that: 1) the target population is Japanese 
patients and 2) the planned sample size will be 3 or more. After the PK part, an extension part 
(on-demand therapy, short-term prophylaxis, and long-term prophylaxis) will be conducted in 
the subjects who have completed PK part.
In the PK part, study design of the Japanese clinical study is investigated for the purpose of 
comparing with the results of Study IMAG-098. The Sponsor has concluded that the design of 
the Japanese study will be appropriate based on PK similarity evaluation and consistency of 
demographic characteristics as follows.
Dose and administration, sampling points and PK parameters in the Japanese study are identical 
to that in Study IMAG-098, for the purpose of evaluation of PK in Japanese subjects and 
comparing with the results of Study IMAG-098. Considering that number of subjects is very 
limited in the Japanese study, the Sponsor plans to evaluate PK similarity between Japanese and 
non-Japanese, by confirming whether the PK of each Japanese subject is within the range of (or 
not significantly different from) non-Japanese subjects in Study IMAG-098. Of note, as a result 
of PK evaluation for non-Japanese subject with age ranging 1 to 39 years old in overseas clinical 
trials, t1/2 was tended to be shorter and CL was tended to be higher in younger subjects. The 
Sponsor considers it is possible to evaluate PK similarity considering the effect of age, because 
age of the current Japanese patients with severe congenital protein C deficiency in a range of 
3 years to twenties, which is within the range of non-Japanese subject in overseas clinical trials.
To ensure consistency of demographic characteristics between Study IMAG-098 and the 
Japanese study, the target patient is same for both studies. In addition, inclusion/exclusion 
criteria in the Japanese study design are identical with Study IMAG-098 as much as possible.
For the patients with homozygous or double heterozygous protein C deficiency, the level of
protein C activity is less than 1% (Goldenberg and Manco-Johnson, 2008, Ishimura M et al., 
2018), which is significantly lower than that of heterozygous protein C deficiency (30% to 50%). 
To reduce the effect of endogenous protein C in patients with heterozygous protein C deficiency 
on evaluation for PK similarity, the Sponsor concludes target patient should be limited to severe 
congenital protein C deficiency, which is identical to Study IMAG-098.
The endpoints in the Japanese study are set identical to those in Study IMAG-098 as 
much as possible except that inhibitory antibodies against protein C (anti-protein C antibody) 
is not investigated in the Japanese study. No anti-protein C antibody development has 
been reported in both clinical development program of Protein C Concentrate and 
Periodic Benefit-Risk Evaluation Report. Furthermore, there is no laboratory 
institution to evaluate anti-protein C antibody over the world at the moment. 
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Taken together, it seems that the risk of anti-protein C antibody development is minimal, thus the 
Sponsor considers that measurement of inhibitory antibodies against protein C is not required.
If a subject wishes continuous administration of TAK-662 after the completion of the PK part, 
the subject can participate in the extension part based on the investigator's judgement. The study 
design, and dose and administration of TAK-662 for the extension part are referred to that of 
Study 400101; however, these are not identical to Study 400101 because the study purpose is 
different each other.
2.4 Benefit/Risk Assessment
Currently, in Japan, human activated protein C, freeze-dried concentrated (activated protein C) 
is available for treatment of DVT, acute pulmonary thromboembolism, and PF caused by 
congenital protein C deficiency. The activated protein C is generally used under hospitalization. 
Furthermore, a supply of this drug needs some time, and hence it cannot be used for long-term 
prophylaxis treatment due to too short t1/2 (alpha phase: 8.8 min, beta phase: 71.5 min) of this 
drug (Goldenberg and Manco-Johnson, 2008, Yoshida M et al., 2018).
Overseas clinical studies and literature reports have confirmed the efficacy of TAK-662 in 
patients with congenital protein C deficiency of acute treatment for thrombotic diseases such as 
PF and CISN/WISN, perioperative management such as surgical operation, and short-term and 
long-term supplementation such as initiation of oral anticoagulants. TAK-662 is effective in the 
treatment of life-threatening serious thrombotic diseases in patients with congenital protein C 
deficiency. It is considered that TAK-662 contributes to the improvement of prognosis and 
quality-of-life (QoL) by preventing the progression to serious disease and its sequelae.
The safety of TAK-662 was demonstrated in both RDC ([Studies IMAG-039, IMAG-041, and 
compassionate use] and Study 400501), all 2 prospective clinical studies (Studies IMAG-098 and 
400101), and the registry study (Study 400701). It then can be concluded that TAK-662 is a safe 
and well-tolerated product.
Thus, the overall assessment on the benefits and risks of TAK-662 concludes that the benefit of a 
single 80 IU/kg dose of TAK-662 for Japanese patients with congenial protein C deficiency in 
this Japanese study will outweigh the risks.
The extension part will be conducted to evaluate the safety and efficacy of on-demand 
therapy, short-term prophylaxis, and long-term prophylaxis. The study design of 
extension part will be identical with the overseas study design (Study 400101) as much 
as possible. The results of Study 400101 demonstrate that TAK-662 is effective in the 
treatment of acute episodes of PF, CISN/WISN, and other vascular thromboembolic 
events in subjects with severe congenital protein C deficiency. 
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The data also indicate that both short-term (during surgical procedures and the initiation of oral 
or parenteral anticoagulation) and long-term thrombotic prophylaxis with TAK-662 is effective 
in subjects with severe congenital protein C. In addition, the safety results also contributed 
supportive evidence that TAK-662 has acceptable safety and tolerability. No new safety signals 
were identified. Furthermore, the dosage and administration of TAK-662 for this study are the 
same as those described in the US package insert.
Always refer to the latest version of the TAK-662 investigator’s brochure (IB) for the overall 
benefit/risk assessment and the most accurate and current information regarding drug 
metabolism, PK, efficacy, and safety of TAK-662.
2.5 Compliance Statement
This study will be conducted in accordance with this protocol, the International Council for 
Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, 1996; ICH E6 R2, 2016), 
Title 21 of the US Code of Federal Regulations (US CFR), the EU Directives (2001/20/EC; 
2005/28/EC), and applicable national and local regulatory requirements.
The responsibilities of the study sponsor and investigator(s) are described fully in
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3. OBJECTIVES AND ENDPOINTS
3.1 Study Objectives
3.1.1 Primary Objective
To measure the PK parameters of TAK-662 in asymptomatic subjects with homozygous or
double heterozygous congenital protein C deficiency in Japanese subjects.
3.1.2 Secondary Objectives

To assess safety profile of TAK-662.

To assess efficacy of TAK-662 in following 1) for on-demand treatment such as PF,
CISN/WISN, and other vascular thromboembolic events; 2) for short-term
thromboembolic prophylaxis during surgical procedures; and 3) for long-term
prophylactic treatment of acute thrombotic episodes (Extension part).
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3.2 Study Endpoints
Table 6. Objectives and Endpoints
Objective
Endpoint(s)
Primary
•
To measure the pharmacokinetic (PK)
parameters of TAK-662 in
asymptomatic subjects with
homozygous or double heterozygous
congenital protein C deficiency in
Japanese subjects.
•
Protein C activity
•
PK parameters including but not limited to terminal half-life
(t1/2), incremental recovery (IR), in-vivo recovery (IVR), area
under the curve (AUC), maximum concentration (Cmax), and
minimum time to reach maximum concentration (tmax)
Secondary
•
To assess safety profile of TAK-662.
•
The primary variable for safety assessment is the number of
subjects with treatment-related adverse experiences.
Other Safety Endpoint
•
Body temperature, blood pressure, and pulse rate are monitored
before and after the investigational product administration, and
the last prophylactic treatment (if applicable) prior to the test
dose.
•
To assess efficacy of
TAK-662 (Extension
part)
On-demand 
treatment
•
The treatment of episodes of PF/CISN/WISN and/or other
vascular thromboembolic events are rated as effective, effective
with complications, or not effective when it is determined that
the next infusion is unnecessary according to the efficacy rating
scale.
Short-term 
prophylaxis
•
Percentage of surgical episodes during short-term prophylaxis,
for which TAK-662 is utilized as short-term prophylaxis, that is
free of presentations of PF or thromboembolic complications.
Long-term 
prophylaxis
•
Number and rate of episodes of PF and/or thrombotic episodes
during long-term prophylaxis.
•
•
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4. STUDY DESIGN
4.1 Overall Design
This is a phase 1/2 open-label, non-randomized, non-controlled, single-dose, multicenter study to
evaluate PK, safety, and tolerability of TAK-662 in Japanese subjects with congenital protein C
deficiency followed by an extension part.
PK part:
The study is planned to enroll more than 3 subjects in Japan. The subject who has the 
prophylactic treatment of anticoagulants is allowed to be enrolled. The last prophylactic 
treatment including protein C ingredient must occur by at least 36 hours before the 
administration of TAK-662 on Day 1. Other prophylactic treatment such as oral anticoagulants 
can be administered without any restrictions on period.
Once all screening assessments following informed consent (and assent where applicable) are 
completed and eligibility is confirmed, the subject will receive a single 80 IU/kg dose of 
TAK-662 intravenously on Day 1. Prior to the IP administration, the subject will be admitted to 
the study site on Day −1 (One day earlier hospitalization [Day −2] is allowed if applicable). The 
prophylactic treatment will be given according to the subject’s established treatment regimen 
and at the discretion of the investigator. For the subject with prophylactic treatment including 
protein C ingredient, the IP for PK will be administered at least after 36 hours of the prophylactic 
treatment.
From Day 1 to Day 3, the subject will stay in the study site and be followed up for PK and safety 
before and after the IP administration. The blood sampling for PK will be done immediately 
prior to infusion and at 30 minutes, and 1, 2, 4, 8, 12, 24, and 36 hours postinfusion; a sampling 
for the 36 hours postinfusion is allowed to be customized by age, especially for feasibility in 
children. After 7 days from the IP administration (Day 7), the subject will have the follow-up 
visit for safety assessment. For the subject who has the prophylactic treatment including 
protein C ingredient before the administration of the IP for PK, the blood sampling will be 
additionally done immediately prior to the prophylactic treatment and at 1, 17, and 25 hours 
post-treatment.
The analysis will be performed for PK and safety after all subjects have completed the 
Day 7 visit. It is planned to compare PK parameter of Japanese and non-Japanese subjects, 
by calculating PK parameter of each Japanese subject, then confirming whether it is within the 
range of (or not substantially different from) PK parameter of each non-Japanese subject in 
Study IMAG-098. PK similarity will be made comprehensively considering all the PK 
parameters together.
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Extension part:
In the extension part of the current study, sponsor provides 3 different treatment options; on-
demand treatment, short-term prophylaxis, and long-term prophylaxis. Based on investigator's 
careful evaluation on subject’s medical condition, subject who completed PK part can continue 
the administration of TAK-662 until the commercial protein C concentrate is available at each 
study site or study termination. The 3 different treatment options provide different ways of 
protein C supplementation. Refer to Section 8.1.2 for the assessments and procedures. Subject 
can participate in each of 3 options and can transfer from one to another at the investigator's 
discretion. Refer to Section 6.2.2 for the dosage regimen of each treatments.
For on-demand treatment, subjects with PF, CISN/WISN, and/or other acute thromboembolic 
episode will be enrolled. For short-term prophylaxis, subjects requiring short-term prophylaxis 
with protein C concentrate/TAK-662 for surgical procedures will be enrolled. For long-term 
prophylaxis, subjects requiring long-term prophylaxis with protein C concentrate/TAK-662 will 
be enrolled.
On-demand treatment and short-term prophylaxis may be carried out more than once depending 
on the subject’s situation. In this case, after the completion of follow-up period, the subject will 
be re-enrolled and re-start the procedures from pre-dose/pre-surgery period. In addition, subject 
may transfer to the other treatment. (eg, If a subject who enrolled in long-term prophylaxis
requires a surgery, he/she transfers to short-term prophylaxis. Once anticoagulation is initiated 
and the investigator determines that adequate anticoagulation is achieved, he/she will transfer 
back to long-term prophylaxis.)
4.2 Scientific Rationale for Study Design
PK part:
Since obtaining PK parameters is the primary objective, an open-label design is chosen for this
study. No control group is used in this study.
Extension part:
Even under currently-available treatment options, high mortality and poor clinical course of 
protein C deficiency has been reported in Japan (Ohga et al., 2013). The extension part will 
provide subjects with protein C deficiency opportunities to experience TAK-662 administration 
as a new treatment option until the commercial protein C concentrate is available at each study 
site or study termination.
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4.3 Justification for Dose
PK part:
The IP dose for PK measurements will be 80 IU/kg. The test dose was determined based on the 
dose used in clinical study IMAG-098 conducted in overseas countries.
In Study IMAG-098, this dose was used for evaluation of PK of protein C, and to compare the 
PK profile in Study IMAG-098, the same dose is chosen for this study.
The prophylactic treatment will be given according to the subject’s established treatment 
regimen and at the discretion of the investigator.
Extension part:
In the extension part, dose of TAK-662 will be decided by the treatment part that the subject will 
be enrolled at the time of treatment. The IP dose of on-demand treatment, short-term 
prophylaxis, and long-term prophylaxis were determined based on the dose used in clinical study 
(Study 400101) and clinical dose in overseas countries.
Japanese PK data derived from precedent PK part will be provided by sponsor to the 
investigator, which might help their judgement on the dosing.
4.4 Duration of Subject Participation and Study Completion Definition
PK part:
The subject’s maximum duration of participation is expected to be approximately 8 days 
including the Day −1 stay. The study will be completed in approximately 5 months.
The Study Completion Date is defined as the date on which the last subject in the study 
completes the final protocol-defined assessment(s). This includes the follow-up visit or contact, 
whichever is later (refer to Section 8.1.1.3 for the defined follow-up period for this protocol).
Extension part:
The extension part will continue until the commercial protein C concentrate is available at each 
study site or study termination. The duration of subject participation and study completion date 
are determined depending on which study part to be enrolled (refer to Section 6.2.2 for the IP 
dose for this protocol).
4.5 Sites and Regions
The study will be conducted in approximately 5 study sites in Japan.
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5. STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed
consent/assent before any procedures specified in the protocol are performed.
5.1 Inclusion Criteria
PK part:
The subject will not be considered eligible for PK part of the study without meeting all of the 
criteria below. 
1.
An understanding, ability, and willingness to fully comply with study procedures and
requirements. If the subject is <20 years of age or informed consent cannot be obtained
from the subject, a parent or legally authorized representative should perform this role.
2.
Ability to voluntarily provide written, signed, and dated (personally, or via a parent or
legally authorized representative if the subject is <20 years of age or informed consent
cannot be obtained from the subject) informed consent, and assent as applicable (only
when informed consent can be obtained from the subject), to participate in the study.
3.
Male and female subjects with Japanese nationality.
4.
A diagnosis of congenital protein C deficiency (homozygous or compound heterozygous).
5.
Asymptomatic subject.
6.
Oral anticoagulants allowed to be received.
7.
Male, or non-pregnant or non-lactating female who is sexually active and who agrees to
comply with the applicable contraceptive requirements of this protocol, or females of non-
childbearing potential. A negative pregnancy test at the Screening visit has to be
documented. Definitions of the childbearing potential female and the applicable
contraceptive requirements are defined in Section 5.4.
Extension part:
The subject will not be considered eligible for extension part of the study without meeting all of 
the criteria below.
1.
Subjects who participated in the PK part of this study (TAK-662-1501).
2.
An understanding, ability, and willingness to fully comply with study procedures and
requirements. If the subject is <20 years of age or informed consent cannot be obtained
from the subject, a parent or legally authorized representative should perform this role.
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3.
Ability to voluntarily provide written, signed, and dated (personally, or via a parent or
legally authorized representative if the subject is <20 years of age or informed consent
cannot be obtained from the subject) informed consent, and assent as applicable (only
when informed consent can be obtained from the subject), to participate in the extension
part of this study.
4.
Subject who are;
a. Diagnosed with PF, CISN/WISN, and/or other acute thromboembolic episode for
on-demand treatment only.
b. Requiring treatment with TAK-662 for short-term prophylaxis for surgical procedures.
c. Requiring treatment with TAK-662 for long-term prophylaxis.
5.2 Exclusion Criteria
PK part:
The subject will be excluded from the PK part of the study if any of the following exclusion 
criteria are met.
1.
Current or recurrent disease that could affect the action, or disposition of the IP, or clinical
or laboratory assessments.
2.
A body weight less than 8 kg.
3.
Serious liver dysfunction, judged by the investigator.
4.
Any thrombosis within 2 weeks prior to administration of the IP.
5.
Other investigational product than TAK-662 received within 60 days prior to the
administration of the IP.
6.
Current or relevant history of physical or psychiatric illness, or any medical disorder that
may require treatment or make the subject unlikely to fully complete the study, or any
condition that presents undue risk from the IP or procedures.
7.
Current use of any medication (including over-the-counter, herbal, or homeopathic
preparations) that could affect (improve or worsen) the condition being studied, or could
affect the action or disposition of the IP, or clinical or laboratory assessment. See
Section 6.6 (Prior and Concomitant Treatment) for a list of prohibited and restricted
medications.
8.
Known or suspected intolerance or hypersensitivity to the IP, closely-related compounds,
or any of the stated ingredients.
9.
Known history of alcohol or other substance abuse within the last year.
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10. Within 30 days prior to the first dose of IP, a subject has been enrolled in a clinical study
(including vaccine studies) that, in the investigator’s opinion, may impact this sponsored
study.
Extension part:
The subject who participated in the PK part will be excluded from the extension part of the study 
if any of the following exclusion criteria are met.
1.
New serious medical conditions which could affect patient’s safety or treatment were
observed during participation in the PK part of this study (TAK-662-1501).
2.
Planning to participate in clinical trials of other investigational drugs or medical devices.
3.
Females of childbearing potential who do not agree to use acceptable contraception.
5.3 Restrictions 
PK part:
Subjects on prophylactic treatment who experienced a thrombotic complication during the last 
prophylactic treatment or the subsequent washout period were not to be entered into the study.
Extension part:
There are no restrictions for the extension part.
5.4 Reproductive Potential
5.4.1 Female Contraception
Sexually active females of childbearing potential should use an acceptable form of contraception. 
Females of childbearing potential must be advised to use acceptable contraceptives throughout 
the study period and for 30 days following the last dose of IP. If used, hormonal contraceptives 
should be administered according to the package insert. Any female of childbearing potential 
who is not currently sexually active must agree to use acceptable contraception, as defined 
below, if she becomes sexually active during the study and for 30 days following the last dose 
of IP.
Female children and adolescent subjects should be either:

Premenarchal and either Tanner stage 1 or less than age 9 years, or

Females of childbearing potential with a negative serum beta-human chorionic
gonadotropin (β-hCG) pregnancy test at the Screening visit. Females of childbearing
potential must agree to abstain from sexual activity that could result in pregnancy or
agree to use acceptable methods of contraception.
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Female adult subjects should be either:

Postmenopausal (12 consecutive months of spontaneous amenorrhea and age ≥51 years)

Surgically sterile (having undergone one of the following surgical acts: hysterectomy,
bilateral tubal ligation, bilateral oophorectomy or bilateral salpingectomy) and at least
6 weeks post-sterilization, or

Of childbearing potential with a negative serum β-hCG pregnancy test at the Screening
visit. Females of childbearing potential must agree to abstain from sexual activity that
could result in pregnancy or agree to use acceptable methods of contraception.
Acceptable methods of contraception include the following:

Intrauterine device

Bilateral tubal interruption / tubal ligation

A male partner who is the only partner of the subject and was postvasectomy and have
confirmed that they have obtained documentation of the absence of sperm in the ejaculate

Progestin/estrogen mixed preparation for inhibition of ovulation
5.4.2 Male Contraception
A male subject who is non-sterilized and sexually active with a female partner of childbearing 
potential must use male condom with or without spermicide.
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6. STUDY INTERVENTION
6.1 Investigational Product
6.1.1 Identity of Investigational Product
The investigational product is TAK-662, which will be provided in vial form.
TAK-662 is Protein C Concentrate, which is a lyophilized, sterile concentrate of human 
protein C. The protein C content is indicated in IU on the label of each vial. Two vial sizes are 
available: 500 IU for reconstitution in 5 mL Sterile Water for Injection or 1,000 IU for 
reconstitution in 10 mL Sterile Water for Injection. The pH of the reconstituted product is 
6.7 to 7.3. The composition is described below:
Composition of TAK-662 After Reconstitution
Vial Size
Component
500 IU
1,000 IU
Human protein C activitya
500 IU
1,000 IU
Human albumin
40 mg
80 mg
Sodium chloride
44 mg
88 mg
Trisodium citrate.2H2O
22 mg
44 mg
a Protein C amidolytic activity is determined in comparison with a reference preparation calibrated against the 
1st International Standard for Protein C in Plasma, code 86/622.
Additional information is provided in the current TAK-662 IB.
6.1.2 Blinding the Treatment Assignment
Not applicable.
6.2 Administration of Investigational Product
6.2.1 Allocation of Subjects to Treatment 
Not applicable.
6.2.2 Dosing
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely), the subject number is assigned to subjects according to the sequence of 
presentation for study participation. 
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PK part:
All subjects will receive a single 80 IU/kg dose of TAK-662, infused over 15 minutes for 
the measurement of PK parameters, at Day 1. TAK-662 should be administered at a 
maximum injection rate of 2 mL/min except for children with a body weight of < 10 kg, 
where the injection rate should not exceed a rate of 0.2 mL/kg/min. For administration 
by infusion, a disposable infusion set with adequate filter must be used. All subjects will be 
closely monitored throughout the course of the study including, the 36-hour washout period, IP 
dose administration and PK and the follow-up period.
Extension part:
Dose will be decided according to an extension treatment that the subject will be enrolled at the 
time of treatment. The on-demand treatment, short-term prophylaxis, and long-term prophylaxis
will be given at the discretion of the investigator with reference to below. TAK-662 should be 
administered at a maximum injection rate of 2 mL/min except for children with a body weight of 
< 10 kg, where the injection rate should not exceed a rate of 0.2 mL/kg/min.
1)
On-demand treatment
Upon presentation with an acute event, the subject will be infused with a dose of 100-120 IU/kg. 
The subsequent 3 infusions will be administered every 6 hours at a dose of 60-80 IU/kg. 
Subsequent infusions (45-60 IU/kg) are also continued every 6 or 12 hours until resolution of 
all non-necrotic lesions and/or stabilization of thrombi (in the case of a thrombotic episode). 
The treatment can terminate when an acute episode tends to improve.
If the subject, a parent or legally authorized representative wants to have the first infusion of 
TAK-662 at home for the second and subsequent acute episodes, the subject or caregiver should 
be trained to reconstitute and administer the study doses correctly. The subject or caregiver will 
be observed in performing these tasks by the investigator or trained study staff to verify adequate 
training. Then, the infusions of IP will be possible at home (refer to the training manual for self-
injection). The dosing information at home will be recorded on a subject diary.
2)
Short-term prophylaxis
Specific treatment regimens will apply for short-term prophylaxis of acute thrombotic 
episodes during surgery. For subjects on anticoagulation therapy who required elective 
surgery (non-emergency), treatment with TAK-662 will be initiated at a dose of 100-120 IU/kg 
once daily until anticoagulation therapy is successfully switched to TAK-662 prior to surgery. 
For subjects on anticoagulation therapy who required emergency surgery, vitamin K dosage can 
reverse anti-coagulation due to warfarin, and TAK-622 treatment (100-120 IU/kg) should be 
started. Fifteen minutes prior to surgery, a dose of 60-80 IU/kg will be administered. 
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The same dose will be continued once every 6 hours for the first 24 hours after surgery began. 
The frequency of infusions is 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 continues twice daily 
until anticoagulation therapy is initiated (if applicable) and the investigator determines that 
adequate level of the anticoagulation is achieved.
3)
Long-term prophylaxis
A dose of 45-60 IU/kg will be administered upon initiation of long-term prophylaxis twice daily. 
The first 3 doses will be administered at the site. The dose will be adjusted by referring to the 
latest protein C activity at the investigator's discretion.
If the subject, a parent or legally authorized representative wants to have infusion of TAK-662 at 
home, the subject or caregiver should be trained to reconstitute and administer the study doses 
correctly. The subject or caregiver will be observed in performing these tasks by the investigator 
or trained study staff to verify adequate training. Then, the infusions of IP will be possible at 
home (refer to the training manual for self-injection). Each dosing information at home will be 
recorded on a subject diary.
The prophylactic treatment will be given according to the subject’s established treatment 
regimen and at the discretion of the investigator in both of PK part and extension part.
6.2.3 Unblinding the Treatment Assignment
Not applicable.
6.2.4 Dose Modification
Not applicable in PK part. In the extension part, dose of TAK-662 will be modified per subjects.
6.3 Labeling, Packaging, Storage, and Handling of Investigational Product
6.3.1 Labeling
Labels containing study information and pack identification, compliant with local laws and 
regulations, are applied to the IP container. 
Refer to the pharmacy manual for detail. Additional labels may not be added without the 
sponsor’s prior full agreement.
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6.3.2 Packaging
TAK-662 will be supplied lyophilized in vials containing target values of 500 IU or 1,000 IU 
protein C. Each vial will be accompanied by a suitable volume of Sterile Water for Injection.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3 Storage
TAK-662 is stable up to 3 years when stored at 2°C - 8°C. Do not use after the date of expiration 
provided by the sponsor. The vials must not be reused once subject information is filled out on 
their labels.
The investigator has overall responsibility for ensuring that IP is stored in a secure, limited-
access location. Limited responsibility may be delegated to the pharmacy or member of the study 
team, but this delegation must be documented. 
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the IP is maintained 
within an established temperature range. The investigator is responsible for ensuring that 
the temperature is monitored throughout the duration of the study and that records are 
maintained; the temperature should be monitored continuously by using either an in-house 
system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time 
period can be recorded and retrieved as required. Such a device (ie, certified min/max 
thermometer) would require manual resetting upon each recording. The sponsor must be 
notified immediately upon discovery of any excursion from the established range. 
Temperature excursions will require site investigation as to cause and remediation. The sponsor 
will determine the ultimate impact of excursions on the IP and will provide supportive 
documentation as necessary. Under no circumstances should the product be dispensed to subjects 
until the impact has been determined and the product is deemed appropriate for use by the 
sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the IP
that could affect the integrity of the product(s), eg, fumigation of a storage room.
If subject will have infusion of TAK-662 at home, refer to the manual for self-injection.
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6.3.4 Special Handling
TAK-662 is stored lyophilized and must be reconstituted immediately prior to application as 
follows:
1.
Warm the unopened bottle containing the solvent to room temperature (maximum 37°C).
2.
Remove the protective caps from the concentrate and solvent bottles and disinfect the
rubber stoppers of both bottles.
3.
The enclosed double-ended transfer needle is protected by two plastic caps sealed by a
weld mark. Break the seal by twisting the cap. Remove one cap and insert the exposed
needle into the rubber stopper of the solvent bottle. Remove the other cap from the double
ended transfer needle taking care not to touch the exposed end.
4.
Invert the solvent bottle over the concentrate bottle and insert the free end of the double-
ended needle into the rubber stopper of the concentrate bottle to half its length. The solvent
will be drawn into the concentrate bottle which is under a vacuum.
5.
Disconnect the two bottles by removing the needle from the concentrate bottle. Agitate or
rotate the concentrate bottle to accelerate dissolution.
6.
Remove and discard the filter needle, attach a suitable needle and administer intravenously.
The reconstituted solution should be used within 3 hours.
For handling of test kits such as blood collection tubes and needles, refer to the pharmacy 
manual.
If subject will have infusion of TAK-662 at home, refer to the manual for self-injection.
6.4 Drug Accountability
Investigators will be provided with sufficient amounts of the IP to carry out this protocol for 
the agreed number of subjects. The investigator or designee will acknowledge receipt of the 
IP, documenting shipment content and condition. Accurate records of all IP dispensed, 
used, returned, and/or destroyed must be maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing IP. Where permissible, 
tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately trained in the 
protocol and who works under the direct supervision of the investigator. This delegation must be 
documented in the applicable study delegation of authority form.
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The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer the IP only to subjects included in this study 
following the procedures set out in the study protocol. Each subject will be given only the IP
carrying his/her treatment assignment. All administered medication will be documented in the 
subject’s source and/or other IP record.
No IP stock or returned inventory from a sponsored study may be removed from the site where 
originally shipped without prior knowledge and consent by the sponsor. If such transfer is 
authorized by the sponsor, all applicable local, and national laws must be adhered to for the 
transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stocks are to be sent to a 
nominated contractor on behalf of the sponsor. Investigational product being returned to the 
sponsor’s designated contractors must be counted and verified by clinical site personnel and the 
sponsor (or designated contracted research organization [CRO]). For unused supplies where the 
original supplied tamper-evident feature is verified as intact, the tamper-evident feature must not 
be broken and the labeled amount is to be documented in lieu of counting. Shipment return 
forms, when used, must be signed prior to shipment from the site. Returned IP must be packed in 
a tamper-evident manner to ensure product integrity. Contact the sponsor for authorization to 
return any IP prior to shipment. Shipment of all returned IP must comply with local, and national 
laws.
At the end of the study all empty/used IP packaging may be destroyed at the site or a local 
facility. Destruction of IP must be in accordance with local, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile IPs 
delivered with those used and returned. All IPs must be accounted for and all discrepancies 
investigated and documented to the sponsor’s satisfaction.
The on-site pharmacist (site designee) will receive the pharmacy manual created by the Sponsor, 
according to which the site designee will appropriately manage the Sponsor-supplied drug.
The Investigator will also receive those procedures from the Sponsor. The procedures include 
those for ensuring appropriate receipt, handling, storage, management and dispensation of the 
Sponsor-supplied drug as well as return of them to the Sponsor or destruction of them. The 
on-site pharmacist (site designee) will immediately return unused IP to the Sponsor after the 
study is closed at the study site.
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If subject will have infusion of TAK-662 at home, refer to the manual for self-injection.
6.5 Subject Compliance
Drug accountability must be assessed at the container/packaging level for unused IP or at the 
individual count level for opened containers/packaging. The pharmacist/nominated person will 
record details on the drug accountability form.
6.6 Prior and Concomitant Therapy
All non-study treatment including but not limited to herbal treatments and vitamins received 
within 30 days prior to the Screening visit and through the follow-up period must be recorded in 
the subject’s source document.
6.6.1 Prior Treatment
Prior treatment includes all treatment (but not limited to herbal treatments and vitamins) received 
within 30 days prior to the Screening visit. Prior treatment information must be recorded in the 
subject’s source document.
6.6.2 Concomitant Treatment 
Concomitant treatment refers to all treatments taken between the dates of the first dose of IP and 
the end of the follow-up period, inclusive. Concomitant treatment information must be recorded 
in the subject’s source document.
PK part:
The last prophylactic treatment including protein C ingredient must occur by at least 36 hours 
before the administration of TAK-662 on Day 1. The IP administration should be discontinued if 
the prophylactic treatment including protein C ingredient is administered in 36 hours prior to the 
IP administration. Other prophylactic treatment such as oral anticoagulants can be administered 
without any restrictions on period.
Extension part:
For 3 different treatments options, any type of anticoagulant therapy is allowed to continue 
during treatment with TAK-662. For short-term prophylaxis, the anticoagulant therapy should be 
terminated before the surgery.
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7. DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT EARLY
TERMINATION/WITHDRAWAL
7.1 Early Termination of Study Treatment
PK part:
If a subject is early terminated, regardless of the reason, the evaluations listed for the Day 7 visit
will be performed as completely as possible. Comments (spontaneous or elicited) or complaints 
made by the subject must be recorded in the source documents. The reason for early termination,
date of early termination of the IP must be recorded in the source documents.
Extension part:
If a subject is terminated during each schedule of on-demand treatment, short-term prophylaxis, 
and long-term prophylaxis, the assessment of end of treatment/study will be performed.
7.2 Reasons for Early Termination
The reason for early termination must be determined by the investigator and recorded in the 
subject’s source document. If a subject is early terminated for more than 1 reason, each reason 
should be documented in the source and the most clinically relevant reason should be indicated.
Reasons for early termination include, but are not limited to:

Adverse event

Protocol deviation

Withdrawal by subject

Lost to follow-up

Lack of efficacy

Other
No predetermined reasons for early termination specifically defined to the study are established.
7.3 Withdrawal from the Study
A subject may withdraw from the study at any time and for any reason without prejudice to 
his/her future medical care by the physician or at the institution, or may be withdrawn at any 
time at the discretion of the investigator or sponsor (eg, in the interest of subject safety). The 
investigator is encouraged to discuss withdrawal of a subject with the medical monitor when 
possible.
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7.4 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject who is lost to 
follow-up at any time point prior to the last scheduled contact (office visit or telephone contact). 
At least 1 of these documented attempts must include a written communication sent to the 
subject’s last known address via courier or mail (with an acknowledgement of receipt request) 
asking that the subject return to the site for final safety evaluations.
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8. STUDY ASSESSMENTS AND PROCEDURES
8.1 Study Periods
Refer to Table 1, Table 2, Table 3, Table 4, and Table 5 for the schedule of treatment activities.
Study assessments are detailed in Section 8.2.
8.1.1 PK Part
8.1.1.1 Screening Period 
Prior to initiation of any study procedures, the informed consent (and assent where applicable) to 
participate in the study must be obtained from a subject, or the subject’s parent or legally 
authorized representative if the subject is <20 years of age or informed consent cannot be 
obtained from the subject. The nature and purpose of the study will be explained and the known 
adverse experiences with TAK-662 will be described to the subject or to the subject’s parent or 
legally authorized representative. If the subject agrees to participate, or the subject’s parent(s) or 
legally authorized representative agrees to permit participation in the study, they will be required 
to sign and date the consent form (and assent where applicable).
8.1.1.1.1 Screening Visit (Day −14 to Day −2)
At the Screening visit, the information/data of the subject in Table 1 will be collected by 
interview and appropriate tests, including but not limited to below:

Subject history
date protein C deficiency diagnosed and protein C activity at diagnosis
underlying diagnosis
current regimen for prophylactic treatment with Protein C Concentrate or including
protein C ingredient (if applicable)
medical history including surgeries
thrombotic events and skin necroses
previous treatment with blood products

Physical examination
A general physical examination is carried out including age and sex, weight (kg), height (cm), 
pulse rate, blood pressure, respiration rate and body temperature.
Any subject who met all eligibility criteria will be assigned a unique identification number
after receiving a signed informed consent. The study site is responsible for maintaining a 
current log of subject number assignments in order to avoid assignment errors. 
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The unique identification number must be entered on all study documentation (ie. Case report 
forms [CRFs], sample containers, etc.).
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been administered IP. Subjects who fail 
to meet eligibility criteria may be re-screened.
8.1.1.1.2 Baseline Visit (Day −1)
Subjects will be admitted to the study site at one day before the administration of the IP (Day −1) 
and will have the necessary study assessment (Table 1). If applicable, subjects are allowed to 
stay in a hospital from one day before Day −1 (ie, Day −2).
8.1.1.2 Treatment Period (Day 1, Day 2 and Day 3)
Subjects will have the necessary study assessment (Table 1). Blood sample for clinical laboratory 
evaluations at Day 1 will be drawn before administration of the IP.
All subjects will receive a single 80 IU/kg dose of TAK-662, infused over 15 minutes for the 
measurement of PK parameters, at Day 1. TAK-662 should be administered at a maximum 
injection rate of 2 mL/min except for children with a body weight of < 10 kg, where the injection 
rate should not exceed a rate of 0.2 mL/kg/min. All subjects will be closely monitored 
throughout the course of the study including the 36-hour washout period, IP dose administration, 
PK blood sampling, and the follow-up period.
Subjects on prophylactic treatment including protein C ingredient will receive an intravenous 
infusion by 36 hours prior to administration of the IP. Should a subject experience a thrombotic 
event during the 36-hour washout period, that subject will not participate in the study.
8.1.1.2.1 Subjects on prophylactic treatment
The last prophylactic treatment including protein C ingredient must occur by at least 36 hours 
before the administration of the IP on Day 1. Other prophylactic treatment such as oral 
anticoagulants can be administered without any restrictions on period. In subjects weighing more 
than 15 kg, additional 4 blood samples (7.2 mL, Table 7) will be drawn at the following intervals 
before and after administration:

Immediately prior to prophylactic treatment including protein C ingredient, 1, 17, and
25 hours post-treatment.
At least 36 hours after the administration of prophylactic treatment including protein C 
ingredient, the IP for PK will be administered. Samples (Table 7) will be drawn at the 
following intervals before and after administration of the IP:
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
Immediately prior to infusion, 30 minutes, and 1, 2, 4, 8, 12, 24, and 36 hours postinfusion;
a sampling for the 36 hours postinfusion is allowed to be customized by age, especially for
feasibility in children.
In order not to induce potential thrombotic events, those subjects who currently receive daily 
protein C replacement will not have blood drawn at the 36-hour time point.
After completing the PK blood collection, the subjects will be returned to their previously 
established prophylactic regimen.
8.1.1.2.2 Subjects on study treatment
The IP dose for PK will be administered and samples will be drawn at the following intervals 
before and after administration of the IP (Table 7):

Immediately prior to infusion, 30 minutes, and 1, 2, 4, 8, 12, 24, and 36 hours postinfusion;
a sampling for the 36 hours postinfusion is allowed to be customized by age, especially for
feasibility in children.
8.1.1.3 Follow-up Period (Day 7)
The follow-up from IP administration in this protocol is for 7 days. If a subject is early 
terminated, regardless of the reason, the evaluations listed for the Day 7 visit will be performed 
as completely as possible.
At the end of this period there will be a follow-up visit to query for SAEs, AEs, concomitant 
treatments and clinical laboratory evaluations. AEs that are considered a causal relationship with 
IP and not resolved at the time of this contact will be followed to closure (see
).
8.1.2 Extension Part
8.1.2.1 Pre-dose/Pre-surgery
Based on investigator's careful evaluation on subject's medical condition, subject who completed 
PK part can continue the administration of TAK-662 until the commercial protein C concentrate 
is available at each study site or study termination. Prior to initiation of any study procedures, the 
informed consent (and assent where applicable) to participate in the extension part of the study 
must be obtained from a subject, or the subject’s parent or legally authorized representative if the 
subject is <20 years of age or informed consent cannot be obtained from the subject. The nature 
and purpose of the study will be explained and the known adverse experiences with TAK-662 
will be described to the subject or to the subject’s parent or legally authorized representative. If 
the subject agrees to participate, or the subject’s parent(s) or legally authorized representative 
agrees to permit participation in the study, they will be required to sign and date the consent form 
(and assent where applicable).
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In the case a subject transfers from one treatment option to the other after entering the extension 
part (eg, If a subject who enrolled in long-term prophylaxis requires a surgery, he/she transfers to 
short-term prophylaxis. Once anticoagulation is initiated and the investigator determines that 
adequate anticoagulation is achieved, he/she will transfer back to long-term prophylaxis.), an 
additional informed consent (and assent where applicable) is unnecessary to be obtained.
At the pre-dose/pre-surgery visit, the information/data of the subject shown in Table 2, Table 3,
Table 4, or Table 5 will be collected by interview and appropriate tests, including but not limited 
to below:

Eligibility check (except for the second and subsequent acute episode of on-demand
treatment)

Physical exam (for short-term prophylaxis only)

Diagnosis of acute episode (PF, CISN/WISN, and thrombotic event) (for on-demand
treatment only)

Concomitant medications

Hematology (except for the second and subsequent acute episode of on-demand treatment)

Protein C activity (for the first acute episode of on-demand treatment and short-term
prophylaxis only. It is allowed to skip protein C activity at the discretion of the
investigator.)

Vital signs (for the first acute episode of on-demand treatment and short-term prophylaxis
only)
On-demand treatment includes 2 patterns of procedures. One is procedures at the occurrence of 
the first acute episode. The assessment/procedure are shown in Table 2. The other is procedures
at the occurrence of the second and subsequent acute episode which occurred after the end of 
treatment for the first episode. In the case of the second and subsequent acute episode, if a
subject, a parent or legally authorized representative wants to have the first infusion of TAK-662 
at home and is well trained, procedures and assessments shown in Table 3 will be performed. 
However, if the subject will have the first infusion at a site for the second and subsequent acute 
episode, procedures and assessments shown in Table 2 will be performed.
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8.1.2.2 Treatment Period
8.1.2.2.1 On-Demand Treatment (Day E1, On and After Day E2)
Upon presentation with an acute event, the subject will be initially infused with TAK-662 at 
Day E1. The infusions will be continued until resolution of all non-necrotic lesions and/or 
stabilization of thrombi. Refer to Section 6.2.2 for dose and administration of TAK-662.
At the treatment period, the information/data of the subject shown in Table 2 (the first acute 
episode) and Table 3 (the second and subsequent acute episodes) will be collected by interview 
and appropriate tests, including but not limited to below:

Concomitant medications

Lesion Assessment / Photography*

Protein C activity (6 and 12 hours after the first dose of IP at Day E1, every 6 or 12 hours
on and after Day E2, and at the end of treatment. It is allowed to skip protein C activity at
the discretion of the investigator.)

Subject Diaries (if applicable)

AE assessment
*: Lesion assessment will be performed by the investigators at each point before administrating of IP. 
Images of the lesion site will be taken before the first infusion on Day E1 (at the occurrence of the first 
acute episodes)/pre-dose (at the occurrence of the second and subsequent acute episodes) and at the 
end of treatment when investigators determine that the acute episode have recovered or tend to 
improve. Image of the lesion site can be taken between the 2 points if applicable. In principle, it is 
carried out in the hospital, but the subject can return home after infusion if the investigator allows it. In 
this case, subject may take a picture of the lesion site at home and send it to the investigator so that the 
investigator will perform lesion assessment (refer to the manual for data handling of imaging data). If 
a next infusion is required based on the investigator's decision, the subject will have to visit the site.
8.1.2.2.2 Short-Term Prophylaxis (Day E1, Day E2, On and After Day E3)
Specific treatment regimens will apply for short-term prophylaxis of acute thrombotic episodes 
during surgery. Subjects with elective surgery (non-emergency) and emergency surgery will be 
initially infused with TAK-662 at pre-surgery. The infusions will be continued until 
anticoagulation is initiated (if applicable) and the investigator determines that adequate level of 
anticoagulation is achieved. The items, contents, frequency of anticoagulation assessments will 
be determined by investigators. Refer to Section 6.2.2 for dose and administration of TAK-662.
At the treatment period, the information/data of the subject shown in Table 4 will be collected by 
interview and appropriate tests, including but not limited to below:

Concomitant medications
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
Protein C Activity (It is allowed to skip protein C activity at the discretion of the
investigator.)

Vital signs (Day E2 only)

AE assessment
8.1.2.2.3 Long-Term Prophylaxis (First 3 Prophylaxis Infusions, Following of First 
3 Prophylaxis Infusions, Every 1 Month)
Subjects with long-term prophylaxis will be infused according to the schedule (Table 5) and the 
infusions will be continued until TAK-662 became available at the site. Refer to Section 6.2.2 for 
dose and administration of TAK-662.
At the treatment period, the information/data of the subject shown in Table 5 will be collected by 
interview and appropriate tests, including but not limited to below:

Concomitant medications

Hematology (every 1 month only. It is allowed to skip this measurement at the discretion
of the investigator)

Protein C Activity (following of the first 3 prophylaxis infusions and every 1 month only.
It is allowed to skip protein C activity every 1 month at the discretion of the investigator)

Subject Diaries (during home treatment times)

AE assessment
8.1.2.3 End of Treatment (On-Demand Treatment and Short-Term Prophylaxis)
8.1.2.3.1 On-Demand Treatment
The treatment can be ended when the investigators determine that the acute episode have 
recovered or tend to improve (e.g. purpura area reduction or fading).
At the end of treatment visit, the information/data of the subject shown in Table 2 (the first 
episode) and Table 3 (the second and subsequent acute episodes) will be collected by interview 
and appropriate tests, including but not limited to below. However, if the investigator determines 
the recovery or improvement of the acute episode by assessing the picture of the lesion site, 
which is taken by the subject at home after the first infusion for the second and subsequent acute 
episode and is sent to the investigator, the timing of this investigator's decision is considered as 
the end of treatment. In this case, the subject will not have to visit the site, and obtainable 
information/data below will be collected.
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
Concomitant medications

Lesion Assessment/Photography*

Protein C activity (It is allowed to skip protein C activity at the discretion of the
investigator.)

AE assessment
*: It is allowed for him/her to take a picture of lesion site.
8.1.2.3.2 Short-Term Prophylaxis
Treatment will can be ended when anticoagulation is initiated (if applicable) and the investigator 
determines that adequate level of anticoagulation is achieved.
At the end of treatment visit, the information/data of the subject shown in Table 4 will be 
collected by interview and appropriate tests, including but not limited to below:

Physical exam

Concomitant medications

Hematology

Protein C activity (It is allowed to skip protein C activity at the discretion of the
investigator.)

Vital signs

AE assessment
8.1.2.4 End of Study/Follow-up (Long-Term prophylaxis)
Long-term prophylaxis will be ended when TAK-662 becomes available at the site. The subjects 
with long-term prophylaxis will be followed up for 7 days after the last dose of TAK-662.
At the end of study/follow-up visit, the information/data of the subject shown in Table 5 will be 
collected by interview and appropriate tests, including but not limited to below:

Concomitant medications

AE assessment (AEs that are considered a causal relationship with IP and not resolved at
the time of this contact will be followed to closure. Refer to 
)
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8.1.2.5 Follow-up (On-Demand Treatment and Short-Term Prophylaxis)
8.1.2.5.1 On-Demand Treatment
The subjects with on-demand treatment will be followed up for 7 days after the last dose of
TAK-662.
At the follow-up visit, the information/data of the subject shown in Table 2 (the first acute 
episode) and Table 3 (the second and subsequent acute episodes) will be collected by interview 
and appropriate tests, including but not limited to below:

Concomitant medications

Hematology

Vital signs

AE assessment (AEs that are considered a causal relationship with IP and not resolved at
the time of this contact will be followed to closure. Refer to 
)
8.1.2.5.2 Short-Term Prophylaxis
The subjects with short-term prophylaxis will be followed up for 7 days after last dose of 
TAK-662.
At the follow-up visit, the information/data of the subject shown in Table 4 will be collected by 
interview and appropriate tests, including but not limited to below:

Concomitant medications

AE assessment (AEs that are considered a causal relationship with IP and not resolved at
the time of this contact will be followed to closure. Refer to 
)
8.2 Study Assessments
The following sections describe the study procedures and data to be collected. For each 
procedure, subjects are to be assessed by the same Investigator or site personnel whenever 
possible. The schedule of study procedures is located in Table 1, Table 2, Table 3, Table 4, and
Table 5. All procedures must be performed by qualified and trained staff.
8.2.1 Demographic and Other Baseline Characteristics
Subject demographic information including gender, age, and race will be collected prior to the 
subject receiving the first dose of IP. 
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8.2.1.1 Height and Weight
Height and weight will be measured and recorded in the subject’s source documents. Body mass 
index (BMI) will be calculated by the Sponsor.
8.2.1.2 Medical and Medication History
Medical and medication history will be collected and recorded in the subject’s source documents.
8.2.1.3 Diagnosis of Acute Episode (PF, CISN/WISN, and Thrombotic Event) (On-Demand 
Treatment only)
Diagnosis of acute episode (PF, CISN/WISN, and thrombotic event) will be collected and 
recorded in the subject’s source documents.
8.2.2 Efficacy
In the PK part, no efficacy of TAK-662 will be evaluated.
In the extension part, the efficacy assessments will be performed. For on-demand therapy, the 
treatment of episodes of PF/CISN/WISN and/or other vascular thromboembolic events will be 
rated as effective, effective with complications, or not effective when it is determinate that the 
next infusion is unnecessary according to the efficacy rating scale. The procedures for lesion 
assessment / photography of on-demand treatment differs depending on the first acute episodes 
or the second and subsequent acute episodes. Refer to Section 8.1.2.2.1 for details.
For short-term prophylaxis, PF and/or thromboembolic complications during short-term 
prophylaxis, for which TAK-662 is utilized as short-term prophylaxis, will be recorded.
For long-term prophylaxis, the number of episodes of PF and/or thrombotic episodes while 
receiving long-term prophylaxis will be recorded.
8.2.3 Safety
8.2.3.1 Physical Examination
A physical examination will be performed by the investigator. A complete physical examination 
will include, at a minimum, assessments of the cardiovascular, respiratory, gastrointestinal, and 
neurological systems.
Abnormalities identified at the Screening visit and at subsequent study visits will be recorded in 
the subject’s source documents.
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8.2.3.2 Adverse Events
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events are collected from the time informed consent is signed. Refer to 
for 
AE definitions, assessment, collection time frame, and reporting procedures. 
8.2.3.3 Vital Signs
PK part:
Vital signs (pulse rate, respiration rate, blood pressure, and temperature) will be assessed prior to 
and 1 hour after administration of the prophylactic treatment including protein C ingredient (in 
subjects participating in the pre-pharmacokinetic wash-out segment) and prior to and 30 minutes, 
2 hours, 4 hours, and 24 hours after administration of the IP for PK. Measurement of vital signs 
is always performed prior to drawing the blood samples for PK.
The investigator will assess whether a change from baseline (Day −1) in vital signs may be
deemed clinically significant and whether the change should be considered and recorded as an 
AE.
Extension part:
For on-demand treatment, vital signs will be measured at pre-dose (the first acute episode only)
and follow-up. For short-term prophylaxis, vital signs will be measured at pre-surgery, Day E2, 
and the end of treatment. 
8.2.3.4 Clinical Laboratory Tests
All clinical laboratory tests will be performed by a central laboratory at the time points, including 
baseline, specified in Table 1, Table 2, Table 3, Table 4, and Table 5. Reference ranges will be 
supplied by the central laboratory and used to assess the results for clinical significance and out-
of-range changes which may be associated with, or constitute, an AE. The investigator should 
assess out-of-range clinical laboratory values for clinical significance, indicating if the value(s) 
is/are not clinically significant or clinically significant. Abnormal clinical laboratory values, 
which are unexpected or not explained by the subject’s clinical condition, may, at the discretion 
of the investigator or sponsor, be repeated as soon as possible until confirmed, explained, or 
resolved.
A complete list of the clinical laboratory tests to be performed is provided in
Volume of blood samples for clinical laboratory tests is shown in Table 7 to Table 11.
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8.2.3.5 Pregnancy Test
A serum β-hCG pregnancy test and follicle-stimulating hormone (FSH) test will be performed on 
all females of child-bearing potential at the Screening visit of PK part. A urine pregnancy test 
will be performed at pre-dose/pre-surgery of extension part.
8.2.3.6 Electrocardiogram
A 12-lead electrocardiogram (ECG) will be evaluated at the Screening visit to assess the 
eligibility of the subject by the investigator (PK part only).
8.2.4 Other
8.2.4.1 Pharmacokinetics
8.2.4.1.1 Collection of Samples 
Blood samples for the determination of the TAK-662 will be collected as detailed under schedule 
of assessments (Table 1 and Section 8.1.1.2).
Venous blood samples of approximately 1.8 mL will be collected for measurement of Protein C 
activity at times as specified in Table 1. Instructions for the collection and handling of biological 
samples will be provided by the Sponsor or designee. Blood samples will be taken either by 
direct venipuncture or an indwelling cannula inserted in a forearm vein. Blood sample will be 
collected at each PK time point. The actual date and time (24-hour clock time) of each sample 
and the time and date of IP infusion start and stop, as well as start/stop of any infusion 
interruptions and restart of infusion will be recorded. Samples will be collected, labeled, stored, 
and shipped as detailed in the laboratory manual.
8.2.4.1.2 Determination of Drug Concentration 
•
Samples for the determination of protein C activity will be analyzed on behalf of the
Sponsor using appropriate validated bioanalytical methods. Full details of the bioanalytical
methods will be described in a separate Bioanalytical Report.
•
All samples still within the known stability of the analyte of interest at the time of receipt
by the bioanalytical laboratory will be analyzed.
•
Samples collected for analyses of protein C activity may also be used to evaluate safety
aspects related to concerns arising during or after the study.
8.2.4.2 Pharmacodynamics
Not applicable.
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8.2.4.3 Genetics
Not applicable.
8.2.4.4 Health-related Quality of Life (QoL)
Not applicable.
8.2.4.5 Healthcare Resource Utilization 
Not applicable.
8.2.5 Volume of Blood to Be Drawn from Each Subject
PK part:
During the PK part of this study, it is expected that approximately 31 mL of blood will be drawn 
from all subjects (Table 7).
Table 7. Approximate Blood Volume (PK part)
Sample Type
Sample 
Volume (mL)
Number of Samples
Total 
Volume (mL)
Screening
Day 1 a
Day 2 a
Day 3 a
Day 7
Clinical laboratory tests
2 mL
1 (8 mL) b
1
1
0
1
14
PK blood collection
1.8 mL
0 c
9 d
0
16.2
Total Approximate Blood Sampling Volume
30.2
a Depending on the start time of administration on Day 1, it is allowed to draw 36-hour blood sample on Day 3.
b Sample volume at screening is 8 mL including samples for pregnancy test and alanine aminotransferase 
measurement.
c Subjects receiving prophylaxis treatment including protein C ingredient should take an additional 4 blood draws 
(7.2 mL) at the final pre-trial administration: immediately prior to the prophylactic treatment, 1, 17, and 25 hours 
post-treatment. After completing the pharmacokinetic blood collection, the subjects will be returned to their 
previously established prophylactic regimen.
d PK samples will be collected at pre-dose and at 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours 
(Day 2), and 36 hours (Day 3 a) after finishing administration of the test dose of the investigational product; a 
sampling for the 36 hours postinfusion is allowed to be customized by age, especially for feasibility in children.
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment; however, the total volume drawn over the course of the study 
should be approximately 31 mL.
Extension part:
During the extension part of this study, total volume will be determined depending on which 
study part to be enrolled. The number of samples will be drawn at each time point in Table 8, 
Table 9, Table 10, and Table 11.
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Table 8. Approximate Blood Volume (Extension Part: On-Demand Treatment):
First Acute Episode
Sample Type
Sample 
Volume 
(mL)
Number of Samples
Total 
Volume 
(mL)
Pre-dose
On and After
Day E1
At the end of 
treatment
Follow-up
(7 days after the 
termination of IP dose)
Hematology
2 mL
1
0
0
1
4
Protein C activity
1.8 mL
Protein C activity measurement may be performed 
at the discretion of the investigator. If protein C 
activity will be measured, the time point of 
measurement is also at the discretion of the 
investigator.
0
-
Table 9. Approximate Blood Volume (Extension Part: On-Demand Treatment); 
Second and Subsequent Acute Episodes
Sample Type
Sample 
Volume 
(mL)
Number of Samples
Total 
Volume 
(mL)
Pre-
dose
On and After
Day E1
At the end of 
treatment
Follow-up
(7 days after the 
termination of IP dose)
Hematology
2 mL
0
0
0
1
2
Protein C 
activity
1.8 mL
0
Protein C activity measurement may 
be performed at the discretion of the 
investigator. If protein C activity will 
be measured, the time point of 
measurement is also at the discretion 
of the investigator.
0
-
Table 10. Approximate Blood Volume (Extension Part: Short-Term Prophylaxis)
Sample Type
Sample
Volume 
(mL)
Number of Samples
Total 
Volume 
(mL)
Pre-surgery
On and After Day E1
At the end of treatment
Hematology 
2 mL
1 a
0
1
4
Protein C 
activity
1.8 mL
Protein C activity measurement may be performed at the 
discretion of the investigator. If protein C activity will be 
measured, the time point of measurement is also at the discretion 
of the investigator.
-
a Baseline hematologic test will have to be performed within 7 days prior to first dose. 
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Table 11. Approximate Blood Volume (Extension Part: Long-Term Prophylaxis)
Sample Type
Sample 
Volume 
(mL)
Number of Samples
Pre-dose 
1st 3 prophy. 
infusions
Following of 1st 
3 prophy. infusions
Every 1 M
±2 wks
Hematology
2 mL
1 a
0
1b
Protein C activity
1.8 mL
0
0
1
1 b
a Hematologic tests will have to be performed within 7 days prior to first dose.
b Hematologic test and protein C activity every 1 month (±2 weeks) will be performed at pre-infusion, and may be 
skipped at the discretion of the investigator.
Note: Total volume will be determined depending on the time of termination.
Abbreviations. M=month, prophy.= prophylaxis, wks=weeks.
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9. STATISTICAL CONSIDERATIONS
9.1 Statistical Analysis Process
The study will be analyzed by the sponsor or its agent.
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, IP exposure, and prior and concomitant medications. The SAP will also include a 
description of how missing, unused and spurious data will be addressed. Computational details 
and methodology for the calculation of PK parameters for TAK-662 and other details will be 
described in the Clinical Pharmacology Analysis Plan (CPAP).
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock.
All statistical analyses will be performed using SAS® (North Carolina, US) Version 9.4 or 
higher.
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
Interim analyses of study data will be undertaken as described below. No adaptive design or data 
monitoring committee (DMC) is planned for this study. One formal interim data analyses to 
support the Japanese New Drug Application (JNDA) submission will be completed. It will 
summarize PK, safety and efficacy of treatment with TAK-662 in Japanese subjects with 
homozygous or double heterozygous congenital protein C deficiency. The first interim analysis 
will be conducted after all enrolled subjects have reached last visit of the PK part and at least
3 treatments (any of either on-demand treatment, short-term prophylaxis or long-term 
prophylaxis) have been provided to any subjects in the Extension part. The target data is all data 
obtained at this point in the PK part and Extension part. An interim clinical study report 
summarizing data of the first interim analysis will be prepared. The clinical data cut-off date will 
be stated in the SAP. As applicable, additional interim analysis will be conducted after the first 
interim analysis.
9.3 Sample Size and Power Considerations
The number of patients with severe congenital protein C deficiency is very low. And the target 
number of patients is set to 3 or more in consideration of feasibility and inclusion/exclusion 
criteria in this study based on the opinions of specialists in Japan.
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9.4 Statistical Analysis Sets
The safety population will include all enrolled subjects in the study who take at least 1 dose of 
TAK-662. A subject will be considered enrolled in the study once the informed consent/assent 
has been obtained and the subject meets all of the study inclusion criteria. The safety population 
will be used for safety analyses.
The pharmacokinetic population will include all study participants who take at least 1 dose of 
TAK-662 and have enough number of quantifiable blood levels for TAK-662 collected post-dose 
without important protocol deviations/violations or events thought to substantially affect the PK. 
The PK population will be used for PK analyses.
The efficacy population will include all study participants who take at least 1 dose of TAK-662 
in the extension part. The efficacy population will be used for efficacy analyses.
9.5 Efficacy Analyses

On demand therapy
The treatment of episodes of PF/CISN/WISN and/or other vascular thromboembolic events will 
be rated as “effective”, “effective with complications”, or “not effective” according to the efficacy 
rating scale. The rating of treatment effect will be listed and summarized using descriptive 
statistics.

Short-term prophylaxis
Percentage of surgical episodes for which TAK-662 will be utilized as short-term prophylaxis, 
that is free of presentations of PF or thromboembolic complications will be calculated. PF or 
thromboembolic complications will be listed and summarized using descriptive statistics.

Long-term prophylaxis
Number of episodes of PF and/or thrombotic episodes while receiving long-term prophylaxis and 
rate of episodes of PF and/or thrombotic episodes per month will be calculated. Episodes of PF 
and/or thrombotic episodes will be listed and summarized using descriptive statistics.
9.6 Safety Analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. The 
number of events, incidence, and percentage of treatment-emergent adverse events (TEAEs) will 
be calculated overall, by system organ class (SOC), by preferred term. Treatment-emergent 
adverse events will be further summarized by severity and relationship to IP. Adverse events 
related to IP, AEs leading to withdrawal, SAEs, and deaths will be similarly summarized/listed.
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Clinical laboratory tests and vital signs will be summarized by visit. Potentially clinically 
important findings will also be summarized or listed.
9.7 Pharmacokinetic Analyses
Pharmacokinetic parameters will be derived using noncompartmental methods with Phoenix®
WinNonlin® Version 8.3 or higher (Certara, L.P. Princeton, New Jersey, US) and/or SAS®
Version 9.4 or higher (SAS Institute, Inc., Cary, North Carolina, US). Computational details and 
methodology for the calculation of PK parameters for TAK-662 and other details will be 
described in the CPAP.
Pharmacokinetic parameters will be listed and summarized using descriptive statistics. Data will 
be presented graphically if appropriate.
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10. REFERENCES
Dahlbäck, B. 1995. The protein C anticoagulant system: Inherited defects as basis for venous
thrombosis. Thromb Res, 77, 1-43.
Food and Drug Administration [FDA]. 2018. CEPROTIN [Online]. Available: 
https://www.fda.gov/vaccines-blood-biologics/approved-blood-products/ceprotin 
[Accessed Mar 2021].
Goldenberg, N. A. & Manco-Johnson, M. J. 2008. Protein C deficiency. Haemophilia, 14, 1214-
1221.
Guyatt, G. H., Eikelboom, J. W., Gould, M. K., Garcia, D. A., Crowther, M., Murad, M. H., 
Kahn, S. R., Falck-Ytter, Y., Francis, C. W., Lansberg, M. G., Akl, E. A. & Hirsh, J. 
2012. Approach to outcome measurement in the prevention of thrombosis in surgical and 
medical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: 
American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 
Chest, 141, e185S-e194S.
Ishimura M, Ichiyama M, Ochiai M, Hotta T, Koh T & Ohga S. 2018. A diagnosis and treatment 
of the childhood hereditary thrombosis in our country. [in Japanese]. 55(5):371–375. 
Available: https://www.jstage.jst.go.jp/article/jspho/55/5/55_371/_pdf/-char/ja.
Kottke-Marchant, K. & Comp, P. 2002. Laboratory Issues in Diagnosing Abnormalities of 
Protein C, Thrombomodulin, and Endothelial Cell Protein C Receptor. Archives of 
Pathology & Laboratory Medicine, 126, 1337-1348.
Marlar, R. A., Montgomery, R. R., Broekmans, A. W. & the Working Party 1989. Diagnosis and 
treatment of homozygous protein C deficiency. Report of the Working Party on 
homozygous protein C deficiency of the subcommittee on protein C and protein S, 
International Committee on Thrombosis and Haemostasis. The Journal of Pediatrics,
114, 528-534.
Ministry of Health  Labour and Welfare [MHLW]. 2017. Patient Survey [Online]. Available: 
https://www.mhlw.go.jp/toukei/saikin/hw/kanja/17/index.html [Accessed Mar 2019].
Monagle, P., Cuello, C. A., Augustine, C., Bonduel, M., Brandão, L. R., Capman, T., Chan, A. 
K. C., Hanson, S., Male, C., Meerpohl, J., Newall, F., O’Brien, S. H., Raffini, L., van
Ommen, H., Wiernikowski, J., Williams, S., Bhatt, M., Riva, J. J., Roldan, Y., Schwab,
N., Mustafa, R. A. & Vesely, S. K. 2018. American Society of Hematology 2018
Guidelines for management of venous thromboembolism: treatment of pediatric venous
thromboembolism. Blood advances, 2, 3292-3316.
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Ohga, S., Kang, D., Kinjo, T., Ochiai, M., Doi, T., Ishimura, M., Kayamori, Y., Urata, M., 
Yamamoto, J., Suenobu, S. I., Kanegane, H., Ikenoue, T., Shirahata, A. & Hara, T. 2013. 
Paediatric presentation and outcome of congenital protein C deficiency in Japan. 
Haemophilia, 19, 378-384.
Sakata, T., Katayama, Y., Matsuyama, T., Kato, H. & Miyata, T. 1999. Prevalence of Protein C 
Deficiency in Patients with Cardiovascular Problems in Japan. Thrombosis and 
Haemostasis, 81, 466-467.
Schünemann, H. J., Cushman, M., Burnett, A. E., Kahn, S. R., Beyer-Westendorf, J., Spencer, F. 
A., Rezende, S. M., Zakai, N. A., Bauer, K. A., Dentali, F., Lansing, J., Balduzzi, S., 
Darzi, A., Morgano, G. P., Neumann, I., Nieuwlaat, R., Yepes-Nuñez, J. J., Zhang, Y. & 
Wiercioch, W. 2018. American Society of Hematology 2018 guidelines for management 
of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical 
patients. Blood advances, 2, 3198-3225.
Yoshida M, Koh K, Watanabe K, Kawakami R, Yanagi M, Itabashi T, Sasaki K, Isobe K, Mori 
M, Arakawa Y & Hanada R. 2018. Usefulness of PPSB®-HT for severe congenital 
protein C deficiency. [in Japanese]. Japanese J Pediatr Hemat/Onco [Online], 
2018;55(2):204–207. Available: 
https://www.jstage.jst.go.jp/article/jspho/55/2/55_204/_pdf/-char/en.
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SAP_001.pdf: 
Title: 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 
NCT Number: NCT04984889 
Statistical analysis plan Approve Date: 28-Oct-2022 
Certain information within this statistical analysis plan has been redacted (ie, specific 
content is masked irreversibly from view with a black bar) to protect either personally 
identifiable information or company confidential information. 


STATISTICAL ANALYSIS PLAN
Study Number: TAK-662-1501
Study Title: An Open-Label, Single-Dose, Phase 1/2 Study to Evaluate the Pharmacokinetic, 
Safety, and Tolerability of Human Protein C (TAK-662) for the Treatment of Congenital Protein 
C Deficiency in Japanese Subjects
Phase: Phase 1/2
Version: 4.0
Date: 28 Oct 2022
Prepared by: 
Based on:
Protocol Version: Amendment 02
Protocol Date: 13 April 2021
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REVISION HISTORY
Version 
Approval Date
Primary Rationale for Revision
4.0
28 Oct2022
Updates for the analyses of the extension part.
•
Section 6.1: Corrected the definitions of duration for each
treatment types in the extension part.
•
Section 6.4: Described the definition of calculation for each
items.
•
Section 9.2.4: Specified the type of missing to be handled
3.0
15Sep2022
Updates for the analyses of the extension part.
•
Section 1.1.2: Added secondary objectives.
•
Section 1.2.3: Added new section for efficacy endpoints.
•
Section 5.4 and 5.5: Added new section for the safety analysis
set in the extension part and the efficacy analysis set.
•
Section 6.1: Described the analyses for the PK part and the
extension part.
•
Section 6.2, 6.2.1, 6.2.2, 6.2.4 and 6.3.2: Described the
analyses for the extension part.
•
Section 6.4: Described the efficacy analyses.
•
Section 6.5, 6.5.1, 6.6, 6.7 and 6.9: Described the analyses for
the extension part.
•
Section 6.11.2: Added new section for the extension part.
•
Section 6.12: Described the interim analysis for the extension
part and the final analysis.
•
Section 9.2.2: Added the definition of baseline in the
extension part.
•
Section 9.2.3: Added the tables of analysis visits in the
extension part.
Correction of errors.
Section 9.3: WinNonlin version
2.0
11Apr2022
Updates necessary for the interim analysis were made in 
accordance with the contents of Protocol amendment 2. (but does 
not include updates for efficacy analysis.)
•
Updated the ABBREVIATIONS list.
•
Section 2.0: Study design details updated as per Protocol
Amendment 2.
•
Section 5.1: “Screened Population” was changed to “Screened
Set”.
•
Section 5.3: Updated with Protocol Amendment 2.
•
Section 6.2.1: Added new section for the analysis of protocol
deviations.
•
Section 6.2.4: Added the handling of an incomplete date in the
calculation of “Duration of protein C deficiency” and the
method of identifying “Previous treatment with blood
products”
•
Section 6.3.1 : Deleted an erratum in display item (“dosing
frequency”).
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Version 
Approval Date
Primary Rationale for Revision
•
Section 6.3.1 and Section 6.3.2: Modified definitions of
“prior” and “concomitant” medications.
•
Section 6.4: Updated for interim analysis.
•
Section 6.6: Deleted unnecessary description (“End of
Treatment” and “potential clinically significant data”).
•
Section 6.7: Corrected the examples of analysis items. Deleted
unnecessary description (“End of Treatment” and “potential
clinically significant data”).
•
Section 6.10.2: Moved the description to Clinical
Pharmacology Analysis Plan.
•
Section 6.12: Added the description to perform Interim
Analysis.
•
Section 9.2.3: Added tables of analysis visit.
•
Section 9.2.4: Added new section for the handling of missing
severity and relationship for AEs.
1.0
30Apr2021
[Not Applicable]
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TABLE OF CONTENTS
REVISION HISTORY.....................................................................................................................2
TABLE OF CONTENTS.................................................................................................................4
LIST OF IN-TEXT TABLES ..........................................................................................................6
ABBREVIATIONS .........................................................................................................................7
1.0 OBJECTIVES, ENDPOINTS AND ESTIMANDS.................................................................8
1.1
Objectives...................................................................................................................8
1.1.1
Primary Objective....................................................................................................8
1.1.2
Secondary Objective(s)............................................................................................8
1.1.3
Additional Objective(s)............................................................................................8
1.2
Endpoints....................................................................................................................8
1.2.1
Primary Endpoint(s).................................................................................................8
1.2.2
Safety Endpoint(s) ...................................................................................................8
1.2.3
Efficacy Endpoint(s)................................................................................................8
1.2.4
Exploratory Endpoint(s)...........................................................................................9
1.3
Estimand(s).................................................................................................................9
2.0 STUDY DESIGN ...................................................................................................................10
3.0 STATISTICAL HYPOTHESES AND DECISION RULES .................................................12
3.1
Statistical Hypotheses ..............................................................................................12
3.2
Statistical Decision Rules.........................................................................................12
3.3
Multiplicity Adjustment ...........................................................................................12
4.0 SAMPLE-SIZE DETERMINATION.....................................................................................13
5.0 ANALYSIS SETS ..................................................................................................................14
5.1
Screened Set .............................................................................................................14
5.2
Safety Analysis Set...................................................................................................14
5.3
Pharmacokinetic Analysis Set..................................................................................14
5.4
Safety Analysis Set in the Extension part ................................................................14
5.5
Efficacy Analysis Set ...............................................................................................14
6.0 STATISTICAL ANALYSIS ..................................................................................................15
6.1
General Considerations ............................................................................................15
6.1.1
Analysis Approach for Continuous Variables .......................................................15
6.1.2
Analysis Approach for Categorical Variables .......................................................15
6.2
Disposition of Subjects.............................................................................................15
6.2.1
Protocol Deviations................................................................................................16
6.2.2
Demographics ........................................................................................................16
6.2.3
Medical History and Concurrent Medical Conditions...........................................17
6.2.4
Baseline Characteristics.........................................................................................17
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6.3
Medication History and Concomitant Medications .................................................18
6.3.1
Prior Medications...................................................................................................18
6.3.2
Concomitant Medications......................................................................................18
6.4
Efficacy Analysis .....................................................................................................18
6.5
Safety Analysis.........................................................................................................20
6.5.1
Adverse Events ......................................................................................................20
6.6
Clinical Laboratory Data..........................................................................................21
6.7
Vital Signs, Body Weight and BMI .........................................................................22
6.8
Electrocardiogram ....................................................................................................22
6.9
Extent of Exposure and Compliance........................................................................22
6.10
Pharmacokinetic Analyses .......................................................................................23
6.10.1 Pharmacokinetic Parameters..................................................................................23
6.10.2 Statistical Analysis of Pharmacokinetic Data........................................................23
6.11
Other Analyses .........................................................................................................23
6.11.1 Physical Examination.............................................................................................23
6.11.2 Protein C activity ...................................................................................................23
6.12
Interim Analyses ......................................................................................................23
7.0 REFERENCES .......................................................................................................................24
8.0 CHANGES TO PROTOCOL PLANNED ANALYSES .......................................................24
9.0 APPENDIX.............................................................................................................................25
9.1
Changes from the Previous Version of the SAP ......................................................25
9.2
Data Handling Conventions .....................................................................................25
9.2.1
General Data Reporting Conventions....................................................................25
9.2.2
Definition of Baseline............................................................................................25
9.2.3
Definition of Visit Windows..................................................................................26
9.2.4
Handling of Missing Severity Assessment and Relatedness .................................28
9.3
Analysis Software ....................................................................................................28
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LIST OF IN-TEXT TABLES
Table 1
List of Laboratory Tests ................................................................................21
Table 2
Analysis Visit of Vital Signs in the PK part..................................................26
Table 3
Analysis Visit of Vital Signs in the Extension part (On-Demand 
Treatment) .....................................................................................................26
Table 4
Analysis Visit of Vital Signs in the Extension part (Short-Term 
Prophylaxis)...................................................................................................27
Table 5
Analysis Visit of Clinical Laboratory Evaluations  -Hematology- in the 
PK part...........................................................................................................27
Table 6
Analysis Visit of Clinical Laboratory Evaluations -Hematology- in the 
Extension part (On-Demand Treatment).......................................................27
Table 7
Analysis Visit of Clinical Laboratory Evaluations -Hematology- in the 
Extension part (Short-Term Prophylaxis) .....................................................28
Table 8
Analysis Visit of Clinical Laboratory Evaluations -Hematology- in the 
Extension part (Long-Term Prophylaxis)......................................................28
Table 9
Analysis Visit of Clinical Laboratory Evaluations - Chemistry- in the 
PK part...........................................................................................................28
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ABBREVIATIONS
AE
adverse event
AUC
area under the curve
β-hCG
beta human chorionic gonadotropin
BMI
body mass index
CI
confidence interval
CISN
coumarin-induced skin necrosis
Cmax
maximum concentration
CPAP
Clinical Pharmacology Analysis Plan
CV
coefficient of variation
ECG
Electrocardiogram
eCRF
electronic case report form
ET
early termination
FSH
follicle-stimulating hormone
ICF
Informed Consent Form
IR
incremental recovery
IU
international unit
IVR
in-vivo recovery
MedDRA
Medical Dictionary for Regulatory Activities
NCA
non-compartmental analysis
PF
purpura fulminans
PK
Pharmacokinetic
PT
Preferred Term (MedDRA)
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SI
standard international
SOC
System Organ Class (MedDRA)
TEAE 
treatment-emergent adverse event
t1/2
half-life
tmax
time to maximum concentration
US
United States
WHO-DD
World Health Organization Drug Dictionary
WISN
warfarin-induced skin necrosis
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1.0
OBJECTIVES, ENDPOINTS AND ESTIMANDS
1.1
Objectives
1.1.1
Primary Objective
To measure the pharmacokinetic (PK) parameters of TAK-662 in asymptomatic subjects with 
homozygous or double heterozygous congenital protein C deficiency in Japanese subjects.
1.1.2
Secondary Objective(s)
To assess safety profile of TAK-662.
To assess efficacy of TAK-662 in following 1) for on-demand treatment such as purpura 
fulminans (PF), coumarin-induced skin necrosis (CISN)/ warfarin-induced skin necrosis
(WISN), and other vascular thromboembolic events; 2) for short-term thromboembolic 
prophylaxis during surgical procedures; and 3) for long-term prophylactic treatment of acute 
thrombotic episodes (Extension part).
1.1.3
Additional Objective(s)
Not applicable.
1.2
Endpoints
1.2.1
Primary Endpoint(s)
•
Protein C activity
•
PK parameters including but not limited to terminal half-life (t1/2), incremental recovery (IR),
in-vivo recovery (IVR) , area under the curve (AUC), maximum concentration (Cmax), and
minimum time to reach maximum concentration (tmax)
1.2.2
Safety Endpoint(s) 
•
The primary Safety Endpoint
The occurrence of treatment-related adverse experiences.
•
Other Safety Endpoint
Body temperature, blood pressure, and pulse rate monitored before and after the investigational 
product administration, and the last prophylactic treatment (if applicable) prior to the test dose.
1.2.3
Efficacy Endpoint(s)
On-demand treatment
•
The treatment of episodes of PF/CISN/WISN and/or other vascular thromboembolic events
are rated as effective, effective with complications, or not effective when it is determined that
the next infusion is unnecessary according to the efficacy rating scale.
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Short-term prophylaxis
•
Percentage of surgical episodes during short-term prophylaxis, for which TAK-662 is utilized
as short-term prophylaxis, that is free of presentations of PF or thromboembolic
complications.
Long-term prophylaxis
Number and rate of episodes of PF and/or thrombotic episodes during long-term prophylaxis.
1.2.4
Exploratory Endpoint(s)
Not applicable.
1.3
Estimand(s)
Not applicable.
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2.0
STUDY DESIGN
This is a phase 1/2 open-label, non-randomized, non-controlled, single-dose, multicenter study to 
evaluate PK, safety, and tolerability of TAK-662 in Japanese subjects with congenital protein C 
deficiency followed by an extension part.
PK part:
The study is planned to enroll 3 or more subjects in Japan. The subject who has the prophylactic 
treatment of anticoagulants is allowed to be enrolled. The last prophylactic treatment including 
protein C ingredient must occur by at least 36 hours before the administration of TAK-662 on 
Day 1. Other prophylactic treatment such as oral anticoagulants can be administered without any 
restrictions on period.
Once all screening assessments following informed consent (and assent where applicable) are 
completed and eligibility is confirmed, the subject will receive a single 80 IU/kg dose of 
TAK-662 intravenously on Day 1. Prior to the Investigational Product (IP) administration, the 
subject will be admitted to the study site on Day −1 (One day earlier hospitalization [Day −2] is 
allowed if applicable). The prophylactic treatment will be given according to the subject’s 
established treatment regimen and at the discretion of the investigator. For the subject with 
prophylactic treatment including protein C ingredient, the IP for PK will be administered at least 
after 36 hours of the prophylactic treatment.
From Day 1 to Day 3, the subject will stay in the study site and be followed up for PK and safety 
before and after the IP administration. The blood sampling for PK will be done immediately 
prior to infusion and at 30 minutes, and 1, 2, 4, 8, 12, 24, and 36 hours postinfusion; a sampling 
for the 36 hours postinfusion is allowed to be customized by age, especially for feasibility in 
children. After 7 days from the IP administration (Day 7), the subject will have the follow-up 
visit for safety assessment. For the subject who has the prophylactic treatment including 
protein C ingredient before the administration of the IP for PK, the blood sampling will be 
additionally done immediately prior to the prophylactic treatment and at 1, 17, and 25 hours 
post-treatment.
The analysis will be performed for PK and safety after all subjects have completed the Day 7 
visit.
Extension part:
In the extension part of the current study, sponsor provides 3 different treatment options; on-
demand treatment, short-term prophylaxis, and long-term prophylaxis. Based on investigator's 
careful evaluation on subject’s medical condition, subject who completed PK part can continue 
the administration of TAK-662 until the commercial protein C concentrate is available at each 
study site or study termination. The 3 different treatment options provide different ways of 
protein C supplementation.
For on-demand treatment, subjects with PF, CISN/WISN, and/or other acute thromboembolic 
episode will be enrolled. For short-term prophylaxis, subjects requiring short-term prophylaxis 
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with protein C concentrate/TAK-662 for surgical procedures will be enrolled. For long-term 
prophylaxis, subjects requiring long-term prophylaxis with protein C concentrate/TAK-662 will 
be enrolled.
On-demand treatment and short-term prophylaxis may be carried out more than once depending 
on the subject’s situation. In this case, after the completion of follow-up period, the subject will 
be re-enrolled and re-start the procedures from pre-dose/pre-surgery period. In addition, subject 
may transfer to the other treatment. (eg, If a subject who enrolled in long-term prophylaxis 
requires a surgery, he/she transfers to short-term prophylaxis. Once anticoagulation is initiated 
and the investigator determines that adequate anticoagulation is achieved, he/she will transfer 
back to long-term prophylaxis.)
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3.0
STATISTICAL HYPOTHESES AND DECISION RULES
3.1
Statistical Hypotheses
Not Applicable.
3.2
Statistical Decision Rules
Not Applicable.
3.3
Multiplicity Adjustment
Not Applicable.
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4.0
SAMPLE-SIZE DETERMINATION
The number of patients with congenital protein C deficiency is very few. And the target number 
of patients is set to 3 or more in consideration of feasibility and inclusion/exclusion criteria in 
this study based on the opinions of specialist in Japan.
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5.0
ANALYSIS SETS
5.1
Screened Set
All subjects who provided a signed Informed Consent Form (ICF) will be included in the
Screened Set.
5.2
Safety Analysis Set
The Safety Analysis Set will include all enrolled subjects in the study who take at least 1 dose of 
TAK-662. A subject will be considered enrolled in the study once the informed consent/assent 
has been obtained and the subject meets all of the study inclusion criteria.
5.3
Pharmacokinetic Analysis Set 
The Pharmacokinetic Analysis Set will include all study participants who take at least 1 dose of 
TAK-662 and have enough number of quantifiable blood level for TAK-662 collected post-dose 
without important protocol deviations/violations or events thought to significantly affect the PK.
5.4
Safety Analysis Set in the Extension part
The Safety Analysis Set in the Extension part will include all study participants who take at least 
1 dose of TAK-662 in the extension part.
5.5
Efficacy Analysis Set 
The Efficacy Analysis Set will include all study participants who take at least 1 dose of 
TAK-662 in the extension part.
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6.0
STATISTICAL ANALYSIS
6.1
General Considerations
The PK part analysis and extension part analysis will be performed separately.
The start date in the extension part is the later date of (1) the date of informed consent for the 
extension part or (2) the day after the end of study date of PK part.
In addition, the analysis will be performed on subjects who received each treatment type.
There are three treatment types in the extension part.
•
On-Demand Treatment
•
Short-Term Prophylaxis
•
Long-Term Prophylaxis
The duration for each treatment type is from the start date of the first dose of each treatment type 
to the last assessment day of that treatment.
6.1.1
Analysis Approach for Continuous Variables
Continuous variables will be summarized using the following descriptive statistics: the number 
of subjects, mean, median, standard deviation, minimum, maximum. 95% confidence interval 
(CI) of mean value will also be provided where needed.
6.1.2
Analysis Approach for Categorical Variables
Categorical variables will be summarized by the number and percentage of subjects in each 
category (with a category for missing data as needed). exact 2-sided Clopper-Pearson 95% CI of 
percentage value will also be provided where needed. Unless otherwise stated, the denominator 
for percentages is N (the number of subjects in the analysis set).
6.2
Disposition of Subjects
For the PK part: 
The number and percent of subjects in each study analysis set (i.e., Screened, Safety and PK) 
will be presented for the Screened Set. 
For the Safety Analysis Set, the number and percentage of subjects who completed or 
prematurely discontinued the treatment period will be presented. Reasons for premature 
discontinuation from the treatment period as recorded on the end of treatment page of the 
electronic case report form (eCRF) will be summarized (number and percentage). A subject data 
listing will present subject disposition for the Screened Set.
Inclusion and exclusion criteria violations, if any, will be presented in a listing for the Screened 
Set.
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For the Extension part: 
For the Safety Analysis Set, the number and percentage of subjects who signed the informed 
consent form of the extension part, subjects who received TAK-662 infusion in the extension 
part and subjects who completed or prematurely discontinued study in the extension part will be 
presented. Reasons for premature discontinuation from study in the extension part as recorded on 
the end of study page of the eCRF will be summarized (number and percentage). A subject data 
listing will present subject disposition for all subjects who signed the informed consent form of 
the extension part.
For all subjects who signed the informed consent form of the extension part, the number and 
percentage of the Safety Analysis Set in the Extension part and the Efficacy Analysis Set will be 
presented. For the Safety Analysis Set in the Extension part and the Efficacy Analysis Set, the
number and percentage of subjects by treatment type (on-demand treatment, short-term 
prophylaxis, or long-term prophylaxis) will also be presented.
Also, the listing of inclusion and exclusion criteria violations in the extension part will be output
for all subjects who signed the informed consent form of the extension part.
6.2.1
Protocol Deviations
For the PK part: 
The number and percent of subjects in each protocol deviation category by severity (critical, 
major and minor) will be presented for the Screened Set. A listing for protocol deviation will 
also be provided.
For the Extension part: 
The number and percentage of subjects in each protocol deviation category by severity (critical, 
major and minor) will be presented for the Safety Analysis Set in the Extension part.
Also, the listing for protocol deviation in the extension part will be output for the Safety Analysis 
Set in the Extension part.
6.2.2
Demographics
For the PK part: 
The baseline and demographic characteristics will be summarized for the Safety Analysis Set
and PK Analysis Set with descriptive statistics. A listing for demographic characteristics data 
will also be provided. Demographic and baseline characteristics to be presented include:
•
Age (at informed consent date) in years as a continuous parameter
•
Sex
•
Race
•
Ethnicity
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•
Height (cm) at the Screening visit
•
Weight (kg) at the Screening visit
•
BMI (kg/m2) at the Screening visit
BMI is calculated as weight (kg)/ [height (m)]2.
For the Extension part: 
The same analysis in the PK part will be performed for the Safety Analysis Set in the Extension 
part. The values used for analysis are also those of the PK part.
6.2.3
Medical History and Concurrent Medical Conditions
Medical and surgical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). Investigator verbatim as well as preferred terms (PT) and system organ 
class (SOC) will be included in the listings. The medical history will be summarized by SOC and 
PT within SOC for the Safety Analysis Set, with SOC sorted alphabetically and PT within SOC 
by descending incidence.
6.2.4
Baseline Characteristics
For the PK part: 
The following subject history collected at the Screening visit will be summarized with the 
descriptive statistics for the Safety Analysis Set and PK Analysis Set:
•
Duration of protein C deficiency diagnosed and protein C level at diagnosis
•
Current regimen for prophylactic treatment with protein C concentrate or including
protein C ingredient (if applicable)
•
Thrombotic events and skin necroses
•
Previous treatment with blood products
Duration of protein C deficiency will be calculated as (Date of ICF Signed – Date of Diagnosis 
of protein C deficiency +1)/365.25. If a date of diagnosis of protein C deficiency is incomplete
for calculation, the missing day and/or month will be imputed with “01”. If the year is missing, 
no imputation and calculation is performed.
The identification of previous treatment with blood products will be done by reviewing the actual 
medication data collected in eCRF.
A listing for subject history data will also be provided.
For the Extension part:
The same analysis in the PK part will be performed for the Safety Analysis Set in the Extension 
part. The values used for analysis are also those of the PK part.
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6.3
Medication History and Concomitant Medications
A listing of all medications, both prior and concomitant, will be presented. The listing will be 
sorted by subject identifier and will include preferred name, reported name, dose, route of 
administration, start date, end date, indication, and type of medication (prior only, concomitant
only, prior and concomitant).
6.3.1
Prior Medications
Prior medications will be coded using the WHO-DD (World Health Organization Drug 
Dictionary).
Prior medications are defined as medications with stop date prior to the date of ICF signed. 
Prior medication use will be summarized by preferred name using the number and percentage of 
subjects for the Safety Analysis Set. Medications will be sorted by descending incidence by 
preferred name. Subjects with multiple occurrences of a medication in preferred name will only 
be counted once within each preferred name.
6.3.2
Concomitant Medications
Concomitant medications will also be coded using the WHO-DD.
For the PK part:
Concomitant medications are defined as medications with onset dates on or after the date of ICF
signed, medications with onset dates prior to the date of ICF signed without a stop date, or 
medications with a stop date after the date of ICF signed.
Concomitant medications will be summarized in the same way as prior medications (refer to 
Section 6.3.1).
For the Extension part:
For concomitant medications after the start date of the extension part, the same analysis in the 
PK part will be performed for the Safety Analysis Set in the Extension part.
Also, the listing of concomitant medications in the extension part will be output for the Safety 
Analysis Set in the Extension part.
6.4
Efficacy Analysis
For the Extension part:
Efficacy analyses will be performed for the Efficacy Analysis Set by treatment type.
•
Efficacy Analysis Set in On-Demand Treatment
•
Efficacy Analysis Set in Short-Term Prophylaxis
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•
Efficacy Analysis Set in Long-Term Prophylaxis
The efficacy analyses by treatment type are as follows.
•
On-Demand Treatment
The treatment of episodes of PF/CISN/WISN and/or other vascular thromboembolic events 
will be rated as “effective”, “effective with complications”, or “not effective” according to 
the efficacy rating scale. The rating of treatment effect in Efficacy Analysis Set in 
On-Demand Treatment will be summarized by number of treatments (overall, first, second 
and subsequent) using descriptive statistics.
•
Short-Term Prophylaxis
Percentage of surgical episodes for which TAK-662 will be utilized as short-term 
prophylaxis, that is free of presentations of PF or thromboembolic complications will be 
calculated. PF or thromboembolic complications in Efficacy Analysis Set in Short-Term 
Prophylaxis will be summarized using descriptive statistics.
•
Long-Term Prophylaxis
Number of episodes of PF and/or thrombotic episodes while receiving long-term 
prophylaxis and rate of episodes of PF and/or thrombotic episodes per month (defined as 
30.4375 days) will be calculated. Episodes of PF and/or thrombotic episodes in Efficacy 
Analysis Set in Long-Term Prophylaxis will be summarized using descriptive statistics.
Time to resolution and total dose received until resolution of episodes of PF/CISN/WISN and/or 
other vascular thromboembolic events will be summarized using descriptive statistics for the 
Efficacy Analysis Set in On-Demand Treatment.
•
Time to Resolution of Episode (number of days): (date of last assessment - date of first
dose + 1 ) for each On-Demand Treatment period
•
Total Dose Received until Resolution of Episode (IU/mL) : Total amount of actual dose
(IU/ml) for each On-Demand Treatment period
Duration of treatment periods will be summarized using descriptive statistics for the Efficacy 
Analysis Set in Short-Term Prophylaxis and Efficacy Analysis Set in Long-Term Prophylaxis.
•
Duration of treatment periods of Short-Term Prophylaxis (number of days) : (date of
last dose – date of first dose + 1 ) for each Short-Term Prophylaxis period
•
Duration of treatment periods of Long-Term Prophylaxis (number of days) : (date of last
dose – date of first dose + 1 ) for each Long-Term Prophylaxis period
A listing for efficacy analysis data will also be provided for the Efficacy Analysis Set.
In addition, a listing for skin lesions of acute episodes of PF/CISN/WISN will be provided for 
the Efficacy Analysis Set.
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6.5
Safety Analysis
The safety analysis will be performed using the Safety Analysis Set. Safety variables include 
AEs, clinical laboratory variables, vital signs, ECG variables and physical examination. For each 
safety variable, the last value collected before the first dose of the investigational product will be 
used as the baseline for all analyses of that safety variable.
For the extension part, safety analyses will be performed for the following.
•
Safety Analysis Set in the Extension part
•
Safety Analysis Set in the Extension part in On-Demand Treatment
•
Safety Analysis Set in the Extension part in Short-Term Prophylaxis
•
Safety Analysis Set in the Extension part in Long-Term Prophylaxis
6.5.1
Adverse Events
AEs will be coded using MedDRA. Investigator verbatim as well as PT and SOC will be 
included in the listings. 
For the PK part:
Treatment emergent AEs (TEAEs) are defined as AEs whose onset occurs, severity worsens, or 
intensity increases after receiving the study medication. AEs with an unknown date of onset and 
a stop date after the start of the study treatment or unknown stop date will be included as TEAEs. 
Any AE with a start date equal to the date of first dose, where the time of the AE cannot
definitively place the start of the AE prior to the first dose, will be considered treatment 
emergent. AEs which are not treatment emergent will be flagged in listings.
AEs will be summarized overall using descriptive statistics (e.g., number and percent of 
subjects). The number of events will also be presented. Categories summarized will include any 
TEAEs, severity of TEAEs, relationship of TEAEs to study treatment, treatment emergent 
serious AEs (TESAEs), severity of TESAEs, relationship of TESAEs to study treatment and 
TEAEs leading to death.
TEAEs will be summarized using number and percentage of subjects. Subject incidence for AEs 
within each SOC and PT will be presented, unless otherwise specified. The number of events 
will also be presented. Categories summarized are as follows:
TEAEs, 
•
Severity of TEAEs,
•
Relationship of TEAEs to study treatment,
•
TESAEs.
Presentation by SOC and PT will present SOC sorted alphabetically and PT within SOC by 
descending incidence. Listings will be provided for serious adverse events (SAEs) and AEs 
leading to death. The listings will be sorted by subject identifier and will include SOC, PT, 
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reported term, start date/time, end date/time, frequency, severity, relationship, action taken, and 
outcome.
For the Extension part:
The same analysis in the PK part will be performed for the Safety Analysis Set in the Extension 
part, Safety Analysis Set in the Extension part in On-Demand Treatment, Safety Analysis Set in 
the Extension part in Short-Term Prophylaxis and Safety Analysis Set in the Extension part in 
Long-Term Prophylaxis.
Also, the listing of the extension part, which is the same as the PK part, will be output for the 
Safety Analysis Set in the Extension part.
6.6
Clinical Laboratory Data
For the PK part: 
Clinical laboratory tests are to be performed at site visits with results processed by a central 
laboratory. Laboratory tests include the following (Table 1):
Table 1
List of Laboratory Tests
Hematology:

Hematocrit

Hemoglobin

Platelet count

Red blood cell count

White blood cell count

White blood cell count with
differential
Biochemistry:

Alanine aminotransferase
Pregnancy tests (females of childbearing potential):

Urine β-HCG

FSH
Laboratory parameters will be presented in standard international (SI) units. The summaries will 
be based on central lab results only.
Quantitative results will be summarized for hematology and serum chemistry at each scheduled 
visit. Both actual values and change from baseline will be summarized. Laboratory results data 
will be presented in a listing for each lab panel (chemistry and hematology ) by subject, visit, and 
parameter. Laboratory values outside of the normal range will be flagged. Urine pregnancy 
results will be presented in a listing only.
For the Extension part:
The same analysis in the PK part will be performed. For the Safety Analysis Set in the Extension 
part in On-Demand Treatment, Safety Analysis Set in the Extension part in Short-Term 
Prophylaxis and Safety Analysis Set in the Extension part in Long-Term Prophylaxis, 
quantitative results will be summarized for hematology and serum chemistry at each scheduled 
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visit. However, only actual values will be summarized in On-Demand Treatment (change from 
baseline will not be included).
Also, the listing of the extension part, which is the same as the PK part, will be output for the 
Safety Analysis Set in the Extension part.
6.7
Vital Signs, Body Weight and BMI
For the PK part: 
Descriptive statistics will be used to summarize the vital signs (i.e., systolic blood pressure, 
diastolic blood pressure, pulse rate, respiratory rate, and body temperature) by scheduled visit for 
the Safety Analysis Set. Both actual values and changes from baseline will be summarized.
A listing for vital signs data will also be provided.
For the Extension part: 
The same analysis in the PK part will be performed. For the Safety Analysis Set in the Extension 
part in On-Demand Treatment, Safety Analysis Set in the Extension part in Short-Term 
Prophylaxis and Safety Analysis Set in the Extension part in Long-Term Prophylaxis, descriptive 
statistics will be used to summarize the vital signs by scheduled visit. However, only actual 
values will be summarized in On-Demand Treatment (change from baseline will not be 
included).
Also, the listing of the extension part, which is the same as the PK part, will be output for the 
Safety Analysis Set in the Extension part.
6.8
Electrocardiogram
The number and percentage of subjects with each type of ECG finding (Normal/Abnormal, Not 
Clinically Significant/Abnormal, Clinically Significant) will be presented for the Safety Analysis 
Set. All ECG data will be listed. 
6.9
Extent of Exposure and Compliance
For the PK part: 
All exposure data will be listed.
For the Extension part: 
The listing of the extension part, which is the same as the PK part, will be output for the Safety 
Analysis Set in the Extension part.
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6.10
Pharmacokinetic Analyses
6.10.1
Pharmacokinetic Parameters
The PK parameters will be derived and estimated based on measured Protein C activity in 
plasma using non-compartmental analysis (NCA) in accordance with the Clinical Pharmacology 
Analysis Plan (CPAP) generated separately.
6.10.2
Statistical Analysis of Pharmacokinetic Data
Details will be provided in the CPAP.
6.11
Other Analyses
6.11.1
Physical Examination
The physical examination data will be listed for all subjects in the Safety Analysis Set.
6.11.2
Protein C activity
For the Extension part: 
The protein C activity data will be listed for all subjects in the Safety Analysis Set in the 
Extension part.
6.12
Interim Analyses
For the PK part: 
Interim analyses of study data will be undertaken as described below. No adaptive design or data 
monitoring committee is planned for this study. One formal interim data analyses to support the 
Japanese New Drug Application submission will be completed. It will summarize safety and PK 
of treatment with TAK-662 in Japanese subjects with homozygous or double heterozygous 
congenital protein C deficiency. The first interim analysis will be conducted when all enrolled 
subjects have reached last visit of PK part. The target data is all data obtained at this point in PK 
part. An interim clinical study report summarizing data will be prepared.
For the Extension part: 
An interim analysis for the Extension part will be performed using the cut-off data of 
September 30, 2022. The required analyses are all tables and listings for the Safety Analysis Set 
in the Extension part or the Efficacy Analysis Set. (These are indicated in "For the Extension 
part:" of Section 6.2, Section 6.2.1, Section 6.2.2, Section 6.2.4, Section 6.3.2, Section 6.4, 
Section 6.5.1, Section 6.6, Section 6.7, and Section 6.9.) Analysis by treatment type will be 
performed only for the treatment type that occurred.
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7.0
REFERENCES
No references used in this SAP.
8.0
CHANGES TO PROTOCOL PLANNED ANALYSES
There is no change of analysis from protocol.
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Statistical Analysis Plan Final 
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9.0
APPENDIX 
9.1
Changes from the Previous Version of the SAP
Not Applicable.
9.2
Data Handling Conventions 
9.2.1
General Data Reporting Conventions 
The small sample size resulting from the small study population requires the use of descriptive 
statistics with a goal of summarizing the sample and thus discourages the use of inferential 
statistics.
Descriptive statistics will be presented as follows:
The following rules will be followed for decimal places and rounding:
•
Unless otherwise specified, means (arithmetic and geometric) and medians will be
rounded and presented to 1 decimal place more than the raw data and standard deviations
to 2 decimal places more than the raw data. Minimum and maximum values will be
presented to the same number of decimal places as the raw data.
•
Unless otherwise specified, percentages should be presented to one decimal place. Less
than signs (i.e., ‘<’) should be presented as appropriate (e.g., 0.04% should be presented
as < 0.1%, not 0.0%). This rule also applies to CV (%).
•
BMI and duration of protein C deficiency diagnosed should be rounded to 1 decimal place
for reporting.
Study day will be calculated as follows;
•
If the evaluation date is on or after the date of first day of study medication:
Study day = date of evaluation – first day of study medication + 1
•
If the evaluation date is before the date of first day of study medication:
Study day = date of evaluation – first day of study medication
9.2.2
Definition of Baseline 
For the PK part: 
For summary purposes, the baseline value will be defined as the last available pre-dose value.
For the Extension part: 
The baseline value in Short-Term Prophylaxis will be defined as the last available pre-surgery 
value in the extension part before the first dose of TAK-662 in the extension part.
The baseline value in Long-Term Prophylaxis will be defined as the last available predose value 
in the extension part before the first dose of TAK-662 in the extension part.
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