Title: Treatment preference for weekly DPP-4 inhibitors versus daily DPP-4 inhibitors in patients with type 2 diabetes mellitus < TRINITY > NCT Number: NCT03231709 Protocol Approve Date: 6-Jun-2017 Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from view with a black/blue bar) to protect either personally identifiable information or company confidential information. This may include, but is not limited to, redaction of the following: Named persons or organizations associated with the study. Patient identifiers within the text, tables, or figures or in by-patient data listings. Proprietary information, such as scales or coding systems, which are considered confidential information under prior agreements with license holder. Other information as needed to protect confidentiality of Takeda or partners, personal information, or to otherwise protect the integrity of the clinical study. If needed, certain appendices that contain a large volume of personally identifiable information or company confidential information may be removed in their entirety if it is considered that they do not add substantially to the interpretation of the data (eg, appendix of investigator’s curriculum vitae). Note; This document was translated into English as the language on original version was Japanese.
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Title: Treatment preference for weekly DPP-4 inhibitors versus daily DPP-4 inhibitors
in patients with type 2 diabetes mellitus < TRINITY >
NCT Number: NCT03231709
Protocol Approve Date: 6-Jun-2017
Certain information within this protocol has been redacted (ie, specific content is
masked irreversibly from view with a black/blue bar) to protect either personally
identifiable information or company confidential information.
This may include, but is not limited to, redaction of the following:
Named persons or organizations associated with the study.
Patient identifiers within the text, tables, or figures or in by-patient data listings.
Proprietary information, such as scales or coding systems, which are considered
confidential information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners,
personal information, or to otherwise protect the integrity of the clinical study.
If needed, certain appendices that contain a large volume of personally identifiable
information or company confidential information may be removed in their entirety if it
is considered that they do not add substantially to the interpretation of the data (eg,
appendix of investigator’s curriculum vitae).
Note; This document was translated into English as the language on original version
was Japanese.
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PROTOCOL
Treatment preference for weekly DPP-4 inhibitors versus daily DPP-4 inhibitors in patients
with type 2 diabetes mellitus
(TRINITY)
Sponsor Takeda Pharmaceutical Company Limited
12-10, Nihonbashi 2-chome, Chuo-ku, Tokyo
Protocol number Trelagliptin-4003
Version Number Version 1
Study drug: Trelagliptin and alogliptin
Creation date June 6, 2017
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CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the
agreement by the recipient that no information contained herein will be published or disclosed without
written authorization from Takeda except to the extent necessary to obtain informed consent from those
persons to whom the drug may be administered. Furthermore, the information is only meant for review
and compliance by the recipient, his or her staff, and applicable institutional review committee and
regulatory agencies to enable conduct of the study.
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1.0 STUDY ADMINISTRATIVE INFORMATION AND CLINICAL STUDY PRINCIPLES
1.1 Clinical Study Principles This study will be conducted with the highest respect for the individual participants in accordance
with the requirements of this protocol and also in accordance with the following:
• The ethical principles that have their origin in the Declaration of Helsinki.
• Ethical Guideline for Clinical Research (the Ministry of Education, Culture, Sports, Science and
Technology and the Ministry of Health, Labour and Welfare, December 22, 2014).
• International Conference on Harmonisation E6 Good Clinical Practice: Consolidated Guideline.
• All applicable laws and regulations, including, without limitation, data privacy laws and conflict
of interest guidelines.
1.2 Clinical Study Implementation This study will be conducted in accordance with the requirements of this protocol designed and
prepared by the sponsor and also in accordance with the following. Other study administrative
structures are shown in the annexes.
Sponsor:
Japan Medical Affairs,
Japan Pharma Business Unit,
Takeda Pharmaceutical Company Limited
The sponsor shall be responsible for matters related to planning/preparation,
implementation/operation, and results/reporting in this study. Methods of supervision of the
contractor entrusted with the services related to this study will be described in the procedure to be
prepared separately.
Expenses* required for the operation of this study will be paid by the sponsor.
*: Based on the “Consignment Service Contract,” expenses incurred for the services of Office of
Clinical Study, monitoring, registration/allocation center, and statistical processing shall be paid
to the contractor entrusted with services related to this study. Expenses agreed by the study site
shall be paid to the site based on the “Research Expense Standard.”
PPD
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PPD
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SIGNATURES The signature of MACS program head, Medical Director of Japan Medical Affairs and the responsible statistician can be found on the signature page.
PPD
PPD
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TABLE OF CONTENTS
1.0 STUDY ADMINISTRATIVE INFORMATION AND CLINICAL STUDY PRINCIPLES ............... 3
1.1 Clinical Study Principles ................................................................................................................ 3
1.2 Clinical Study Implementation ....................................................................................................... 3
2.0 STUDY SUMMARY .......................................................................................................................... 11
3.0 LIST OF ABBERVIATIONS ............................................................................................................. 15
LIST OF IN-TEXT FIGURES Table 8.a. Dose and regimen ................................................................................................................... 28
Start of study drugAdministration Switch of study drug
Questionnaire for patientpreference
Visit 1 2 3Week 0 8 16
T-A group
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To investigate subjects' background which affect the patient preference for treatment.
Subject Population:
Patients with type 2 diabetes mellitus
Number of Subjects:
60 patients as randomized subjects
(T-A group: 30 subjects, A-T group: 30 subjects)
Number of Sites:
2 medical institutions
Dosage Levels:
Trelagliptin, 100 mg, once weekly.
Alogliptin, 25 mg, once daily.
Route of Administration:
Oral
Duration of administration:
16 weeks
Period of Evaluation:
16 weeks
Criteria for Inclusion:
Subject eligibility is determined according to the following criteria prior to entry into the study.
1. Subjects who have been diagnosed with type 2 diabetes mellitus
2. Subjects who are being treated with any of the following DPP-4 inhibitors for at least 8 weeks
prior to the start of treatment period (Week 0).
Sitagliptin : 50 mg once daily
Alogliptin : 25 mg once daily
Linagliptin : 5 mg once daily
Teneligliptin : 20 mg once daily
Saxagliptin : 5 mg once daily
3. Subjects who were judged by the investigators possible to change the treatment from once-daily
dosing of DPP-4 inhibitor shown in Inclusion Criteria 2 to study drug trelagliptin 100 mg or
alogliptin 25 mg
4. Subjects whose HbA1c value measured within 8 weeks prior to the start of treatment period
(Week 0) is below 10.0%
5. Subjects who responded to DTSQ (Diabetes Treatment Satisfaction Questionnaire) at the start of
treatment period (Week 0)
6. Subjects who were judged by the investigators capable to understand the contents of this clinical
research and comply with them
7. Subjects who are able to sign and date the Informed Consent Form before any clinical research
procedure begins
8. Subjects who are at least 20 years old at the time of giving the consent
9. Subjects who are classified as outpatients
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Criteria for Exclusion:
Subjects who correspond to any of the following criteria will not be subjects of this clinical research.
1. Subjects who have a history of taking once-weekly dosing of DPP-4 inhibitor (trelagliptin or
omarigliptin)
2. Subjects who are being treated with drugs other than those for once-daily oral dosing for the
purpose of treatment of chronic complication (for example, “BENET® Tablets 75 mg”, a
therapeutic agent for osteoporosis which is administered once monthly)
3. Subjects who are being treated with twice-daily dosing of DPP-4 inhibitor (vildagliptin or
anagliptin)
4. Subjects who are being treated with anti-diabetic fixed-dose combination pill contained a DPP-4
inhibitor.
5. Subjects with moderate or severe renal impairment (for example, patients whose eGFR is below
60 mL/min/1.73m2)
6. Subjects for whom blood sugar control by insulin preparations is desired (for example, patients
with severe ketosis, diabetic coma or precoma, type 1 diabetes mellitus, severe infection, or
serious trauma before or after surgery)
7. Subjects who have a history of hypersensitivity or allergy to DPP-4 inhibitor
8. Subjects with serious heart disease, cerebrovascular disorder, or patients with serious disease in
the pancreas, blood, etc.
9. Subjects with unstable proliferative diabetic retinopathy
10. Subjects with malignant tumor
11. Subjects who are pregnant, breast-feeding, possibly pregnant, or planning to become pregnant. 12. Subjects participating in other clinical studies. 13. Subjects who have been determined as inappropriate subjects by the investigator.
Criteria for Evaluation and Analyses:
The primary endpoint for this study is patient preference for treatment interviewed from the subjects
using the standardized questions* at the end of treatment period (treatment selection rate)
*: Questions Regarding the drug therapy after the end of this research, which treatment do you select from the following choices from 1 to 4?
1. Either once-weekly DPP-4 inhibitor or daily DPP-4 inhibitor 2. Once-weekly DPP-4 inhibitor 3. Daily DPP-4 inhibitor 4. Neither once-weekly DPP-4 inhibitor nor daily DPP-4 inhibitor
The secondary endpoints:
• Preference for treatment (treatment selection rate) by drug (trelagliptin or alogliptin) selected by
subjects at the end of treatment period and by background factor
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Additional endpoints:
• Change in DTSQ treatment satisfaction* at each evaluation point
*: Evaluated with the total points of questions 1, 4, 5, 6, 7, and 8
• Efficacy endpoint: HbA1c
• Safety endpoint: Adverse events
Statistical Consideration:
<Primary endpoint>
Patient preference for treatment interviewed from the subjects using the standardized questions at the
end of treatment period (treatment selection rate)
Among the subjects who were randomized and treated with the study drugs, the treatment selection
rate will be calculated by merging the subjects from whom preference for treatment was interviewed
by treatment group with the treatment groups. Also, the treatment selection rates for once-weekly
DPP-4 inhibitor and daily DPP-4 inhibitor are compared by applying the Mainland-Gart test.
Sample Size Justification:
By referring to the results of the questionnaire for treatment selection rate after dosing of once-weekly
DPP-4 inhibitor, the treatment selection rate of once-weekly DPP-4 inhibitor is assumed to be 60%,
treatment selection rate of daily DPP-4 inhibitor 20%, and rate of subjects who do not show any
preference for treatment (either is fine/prefer neither) 20%, respectively.
In doing so, a total of 54 patients will be necessary in order to secure 90% power in the binomial test
with two-sided significance level at 5%. With the estimated rate of discontinuation at 10%, the
number of randomized subjects was set to be 30 subjects per group or 60 subjects in total.
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Start of study drugAdministration Switch of study drug
Questionnaire for patientpreference
Visit 1 2 3Week 0 8 16
T-A group
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Premature Termination of Study or Study Site 6.3
6.3.1 Criteria for Premature Termination of the Study
The sponsor should immediately discontinue the study when at least one of the following criteria is
applicable:
New information or other evaluation regarding the safety or efficacy of the study drug that
indicates a change in the known risk/benefit profile for the product, such that the risk/benefit is
no longer acceptable for subjects participating in the study.
Significant violation of Good Clinical Practice (GCP) that compromises subject safety.
6.3.2 Criteria for Premature Termination of Study Sites
A study site may be terminated prematurely if the site (including the principal investigator) is found
in significant violation of the Ethical Guideline for Clinical Research, protocol, or contractual
agreement, is unable to ensure adequate performance of the study or as otherwise permitted by the
contractual agreement.
6.3.3 Procedures for Premature Termination or Suspension of the Study or the Participation of Study Sites
In the event that the sponsor or a study site committee such as an independent ethics committee
(IEC) elects to terminate or suspend the study or the participation of a study site, a study-specific
procedure for early termination or suspension will be provided by the sponsor; the procedure will be
followed by applicable study sites during the course of termination or study suspension.
Procedures for Protocol Revision 6.4
If the protocol needs to be revised, the sponsor shall consider and decide whether to revise the
protocol.
The principal investigator of each study site shall be informed of the details of each protocol revision.
Investigators shall confirm the content of the revision of the protocol and submit an agreement form
to the sponsor as evidence of agreement with the protocol revision.
[Protocol revision is required in the following cases:]
1. Change or addition of objectives
2. Change in or addition of efficacy or safety evaluation methods
3. More frequent or additional laboratory tests for which subjects incur additional expenses or
changes in laboratory test methods
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4. Change in dose
5. Significant change in or addition of inclusion and/or exclusion criteria
6. Change in the planned number of subjects
7. Change in plans or in description of the protocol due to serious adverse events or other reasons
8. Change which is considered as a significant change, as a result of discussion between the
sponsor and the chair of the Steering Committee
Upon notification, the principal investigator at each study site shall submit the revised contents to the
relevant committees (such as an institutional ethics review committee), for review and approval as
necessary according to institutional regulations.
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7.0 SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
The investigators shall confirm all the inclusion/exclusion criteria prior to enrollment.
Inclusion Criteria 7.1
Subject eligibility is determined according to the following criteria prior to entry into the study.
1. Subjects who have been diagnosed with type 2 diabetes mellitus
2. Subjects who are being treated with any of the following DPP-4 inhibitors for at least 8 weeks
prior to the start of treatment period (Week 0).
Sitagliptin : 50 mg once daily
Alogliptin : 25 mg once daily
Linagliptin : 5 mg once daily
Teneligliptin : 20 mg once daily
Saxagliptin : 5 mg once daily
3. Subjects who were judged by the investigators possible to change the treatment from daily
dosing of DPP-4 inhibitor shown in Inclusion Criteria 2 to study drug trelagliptin 100 mg or
alogliptin 25 mg
4. Subjects whose HbA1c value measured within 8 weeks prior to the start of treatment period
(Week 0) is below 10.0%
5. Subjects who responded to DTSQ (Diabetes Treatment Satisfaction Questionnaire) at the start
of treatment period (Week 0)
6. Subjects who were judged by the investigators capable to understand the contents of this
clinical research and comply with them
7. Subjects who are able to sign and date the Informed Consent Form before any clinical research
procedure begins
8. Subjects who are at least 20 years old at the time of giving the consent
9. Subjects who are classified as outpatients
7.1.1 Justification for Inclusion Criteria
1, 4, and 5 These were set to evaluate the efficacy of the drugs in patients with type 2 diabetes
mellitus.
2 and 3 These were set to include the subjects who would not have a significant change in their
blood glucose control, which may affect the outcomes (treatment preference)
6 to 9 These were set as fundamental items for the study.
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Exclusion Criteria 7.2
Subjects who correspond to any of the following criteria will not be subjects of this clinical research.
1. Subjects who have a history of taking once-weekly dosing of DPP-4 inhibitor (trelagliptin or
omarigliptin).
2. Subjects who are being treated with drugs other than those for daily oral dosing for the purpose
of treatment of chronic complication (for example, “BENET® Tablets 75 mg”, a therapeutic
agent for osteoporosis which is administered once monthly).
3. Subjects who are being treated with twice-daily dosing of DPP-4 inhibitor (vildagliptin or
anagliptin).
4. Subjects who are being treated with anti-diabetic fixed-dose combination pill contained a
DPP-4 inhibitor.
5. Subjects with moderate or severe renal impairment (for example, subjects whose eGFR is
below 60 mL/min/1.73m2).
6. Subjects for whom blood sugar control by insulin preparations is desired (for example, subjects
with severe ketosis, diabetic coma or precoma, type 1 diabetes mellitus, severe infection, or
serious trauma before or after surgery).
7. Subjects who have a history of hypersensitivity or allergy to DPP-4 inhibitor
8. Subjects with serious heart disease, cerebrovascular disorder, or subjects with serious disease in
the pancreas, blood, etc.
9. Subjects with unstable proliferative diabetic retinopathy
10. Subjects with malignant tumor
11. Subjects who are pregnant, breast-feeding, possibly pregnant, or planning to become pregnant. 12. Subjects participating in other clinical studies. 13. Subjects who have been determined as inappropriate subjects by the investigator.
7.2.1 Justification for Exclusion Criteria
1 This was set to exclude possible effects of previous experience of taking weekly DPP-4
inhibitors on the treatment preference.
2 This was set to exclude possible effects of previous experience of taking non-daily
orally available drugs on the treatment preference.
3 This was set to limit the dose frequencies as explanation factor to once daily and once
weekly, since vildagliptin or anagliptin is a twice daily DPP-4 inhibitor.
4 This was set to rule out the possibility that the drug change from combination tablet to
DPP-4 inhibitor only affects the subjects' blood glucose levels or the possibility that
increase of the tablets affects their treatment preference.
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5 to 11 These were set in consideration of safety of the subjects.
12, 13 These were set as fundamental items for the study.
Excluded Medications 7.3
Addition of drugs or changes in dose/regimen of drugs for treatment of type 2 diabetes mellitus
or concurrent medical conditions such as hypertension are not allowed. However, the drugs to
treat adverse events are permitted to be used.
[Justification for excluded medications]
These were set because they would affect evaluation of primary endpoint.
Subject Management 7.4
The investigators shall instruct subjects to adhere to the following throughout the study period: 1. Adhere to the instructions or restrictions prescribed in the study period.
2. Take glucose or sucrose (sugar) if hypoglycemia symptom (hunger abnormal, feeling of
weakness, trembling of hands and fingers, cold sweat, palpitations, etc.) is observed, and if
symptoms continue, visit the study site promptly.
3. For research subjects of childbearing potential, give instructions to use adequate
contraception. If pregnancy is discovered, have the research subject report promptly, and
discontinue the research immediately.
4. Adhere to instructed prohibited concomitant drugs. When drugs are taken other than the
drugs prescribed by the investigators, have the research subject report its content.
5. Regarding subjective symptoms/objective findings, have the research subject report at visit the necessary items from its contents, onset date, degree, outcome and date of outcome.
Criteria for Discontinuation or Withdrawal of a Subject 7.5
The primary reason for discontinuation or withdrawal of the subject from the study or study drug
should be recorded in the case report form (CRF) using the following categories. For subjects who
withdraw from the study before administration, refer to Section 9.1.11.
1. Adverse event
The subject has experienced an adverse event (AE) that requires early termination because
continued participation imposes an unacceptable risk to the subject’s health or the subject is
unwilling to continue because of the AE.
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2. Significant protocol deviation
The discovery after the first dose of study drug that the subject failed to meet protocol entry
criteria or did not adhere to protocol requirements, and continued participation poses an
unacceptable risk to the subject’s health.
3. Lost to follow-up
The subject did not return to the clinic and attempts to contact the subject were unsuccessful.
Attempts to contact the subject must be documented in the subject’s source documents
4. Voluntary withdrawal
The subject (or subject’s legally acceptable representative) wishes to withdraw from the study.
The reason for withdrawal, if provided, should be recorded in the CRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and,
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an AE
should not be recorded in the “voluntary withdrawal” category).
5. Study termination
The sponsor, IEC or regulatory authority terminates the study. Refer to Section 6.3.1 for details.
6. Pregnancy
The subject is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The
procedure is described in Section 9.1.10.
7. Lack of efficacy
The investigator has determined that the subject is not benefiting from study treatment; and,
continued participation would pose an unacceptable risk to the subject.
8. Others
The investigator determined to terminate the study for other reasons.
Note: The specific reasons should be recorded on the CRF.
Procedures for Discontinuation or Withdrawal of a Subjects 7.6
The investigator may discontinue a subject’s study participation at any time during the study when
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may
discontinue his or her participation without giving a reason at any time during the study. Should a
subject’s participation be discontinued, the primary criterion for termination must be recorded by the
investigator. In addition, efforts should be made to perform all procedures scheduled for the Early
Termination Visit.
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8.0 STUDY TREATMENT
This section indicates the treatment regimen of this study. See the latest package insert for details
Physical examination Concurrent medical conditions
Concomitant medication (a) Prescription of study drug
HbA1c DTSQ *Informed consent shall be obtained prior to any other tests, observations and evaluations.
(a) Record all concomitant medications
9.3.2 Switch of Study drug(VISIT2: Week 8)
As described in Section 8.4, the preceding drug is switched with the following drug. The study
subjects then stats to be administered with the following drug.
Tests, observations and evaluations performed during the treatment period (Visit 2: Week 8) are
shown below.
Physical examination Concomitant medication (a)
HbA1c Prescription of study drug
Treatment compliance DTSQ
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9.3.3 End of Study (VISIT3: Week 16)
The study subjects choose either trelagliptin or alogliptin, or neither of them. If the subjects cannot
choose either of them, then the investigators choose the drug for consequent treatment upon
adequate explanation.
Tests, observations and evaluations performed at the start of the screening period (Visit 3: Week 16)
are shown below.
9.3.4 Discontinuation
Tests, observations and evaluations performed at the discontinuation are shown below.
Physical examination Concomitant medication (a)
HbA1c Treatment compliance
DTSQ Questionnaire for patient preference for
treatment
Physical examination Concomitant medication (a)
HbA1c Treatment compliance
DTSQ Questionnaire for patient preference for
treatment
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10.0 ADVERSE EVENTS
Definitions 10.1
10.1.1 AEs
An AE is defined as any untoward medical occurrence in a subject administered a pharmaceutical
product (including the study drug). It does not necessarily have to have a causal relationship with
this pharmaceutical product (including the study drug).
An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant abnormal
laboratory value), symptom, or disease temporally associated with the use of a pharmaceutical
product (including the study drug) whether or not it is considered related to the pharmaceutical
product (including the study drug).
10.1.2 Additional Points to Consider for AEs
An untoward finding generally may:
• Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent events for pre-existing conditions or underlying disease should not be considered AEs.).
• Necessitate therapeutic intervention.
• Require an invasive diagnostic procedure.
• Require discontinuation or a change in the dose of the study drug, or concomitant medication.
• Be considered unfavorable by the investigator for any reason.
Diagnosis vs signs and symptoms:
Each event should be recorded to represent a single diagnosis. Accompanying signs (including
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as additional
AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded appropriately as an AE(s).
Laboratory values and ECG findings:
Changes in laboratory values or ECG findings are only considered to be PTEs or AEs if they are
judged to be clinically significant (ie, if some action or intervention is required or if the investigator
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory or ECG
re-test and/or continued monitoring of an abnormal value or findings are not considered an
intervention. In addition, repeated or additional noninvasive testing for verification, evaluation or
monitoring of an abnormality is not considered an intervention.
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If abnormal laboratory values or ECG findings are the result of pathology for which there is an
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be reported
appropriately as an AE.
Pre-existing conditions (a disease or symptom that is present at the start of study drug
administration):
Pre-existing conditions are considered concurrent medical conditions and should NOT be recorded
as AEs. However, if the subject experiences a worsening or complication of such a concurrent
medical condition, the worsening or complication should be recorded appropriately as an AE
(worsening or complication occurs after start of study drug). Investigators should ensure that the
event term recorded captures the change in the condition (eg, “worsening of…”).
If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, epilepsy) any
occurrence of an episode should only be captured as an AE if the condition becomes more frequent,
serious or severe in nature. Investigators should ensure that the AE term recorded captures the
change in the condition from baseline (eg “worsening of…”).
Worsening of AEs:
If the subject experiences a worsening or complication of an AE after any change in study drug, the
worsening or complication should be recorded as a new AE. Investigators should ensure that the AE
term recorded captures the change in the condition (eg, "worsening of…”).
Changes in intensity of AEs:
If the subject experiences changes in intensity of an AE, the event should be captured once with the
maximum intensity recorded.
Preplanned procedures (surgery or interventions):
Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of informed
consent are not considered AEs. However, if a preplanned procedure is performed early (eg, as an
emergency) due to a worsening of the pre-existing condition, the worsening of the condition should
be recorded as an AE. Complications resulting from any planned surgery should be reported as AEs.
Elective surgeries or procedures:
Elective procedures performed where there is no change in the subject’s medical condition should
not be recorded as AEs, but should be documented in the subject’s source documents. Complications
resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy):
Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as an AE.
The investigator must make the distinction between exacerbation of pre-existing illness and lack of
therapeutic efficacy.
Overdose:
Cases of overdose with any medication without manifested side effects are NOT considered AEs,
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but instead will be documented on an Overdose page of the CRF. Any manifested side effects will be
considered AEs and will be recorded on the AE page of the CRF.
10.1.3 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
● Results in death,
● Is life threatening*,
● Requires inpatient hospitalization or prolongation of existing hospitalization,
● Results in persistent or significant disability/incapacity,
● Leads to a congenital anomaly/birth defect,
● Is an important medical event that may expose the subject to danger even though the event is not
immediately life-threatening or fatal does not result in hospitalization, or requires intervention to
prevent items 1 through 5 above. In addition, event or synonym described in the Takeda
Medically Significant Adverse Event List (Table 10.a) is included in this section.
* The term “life threatening” refers to an event in which the subject was at risk of death at the time
of the event; it does not refer to an event that hypothetically might have caused death if it were more
severe.
Table 10.a Takeda Medically Significant Adverse Event List
Hepatic necrosis Acute hepatic failure Anaphylactic shock Acute renal failure Pulmonary hypertension Pulmonary fibrosis (including interstitial pneumonia) Neuroleptic malignant syndrome/ malignant hyperpyrexia Spontaneous abortion/ stillbirth and fetal death Confirmed or suspected transmission of infection by a medicinal product
Confirmed or suspected endotoxin shock
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10.1.4 Intensity of AEs
The different categories of intensity (severity) are characterized as follows.
Mild The event is transient and easily tolerated
by the subject.
Moderate The event interrupts the subject’s usual
activities.
Severe The event causes considerable interference
with the subject’s usual activities.
10.1.5 Causality of AEs
The relationship of each AE to the study drug will be assessed using the following categories.
Related
An AE that follows a temporal sequence (including clinical course after discontinuation),
or an AE in which there is at least a reasonable probability that a causal relationship to
the study drug cannot be ruled out, although other factors such as underlying disease,
complications, or concomitant drugs/treatment are also suspected.
Not
related
An AE that does not follow a temporal sequence from administration of the study drug
or comparative drug. Very likely due to other factors such as underlying disease,
complications, or concomitant drugs/treatment.
10.1.6 Relationship to Study Procedures
The relationship should be assessed as Related if the investigator considers that there is reasonable
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed
as Not Related.
10.1.7 Study Date
The start date of AEs will be determined using the following criteria.
AE Start date
Signs, symptoms, diseases (diagnoses)
The date on which the first signs/symptoms were noted by the subject and/or the investigator.
Asymptomatic diseases
The date on which a diagnosis was confirmed through a test(s). The date on which a diagnosis was confirmed, even when the test results indicate an old sign(s) of the disease or an approximate time of its onset.
Exacerbation of comorbidities The date on which the first worsening of diseases/symptoms was noted by the subject and/or the investigator.
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Onset of a test abnormality after the start of study drug administration
The date on which a clinically significant laboratory abnormality was detected.
Worsening of a baseline test abnormality after the start of study drug administration
The date on which a clear increase/decrease in a laboratory parameter was clinically confirmed based on the time profile of the parameter.
10.1.8 Stop Date
The stop date of the AE is the date at which the subject recovered, the event resolved but with
sequelae or the subject died. The AE will be recorded as “ongoing” if the subject has not yet
recovered by the end of the study.
10.1.9 Action Concerning Study Drug
Action concerning study drug will be classified or defined as shown below.
Drug withdrawn
The study drug is discontinued because of an AE (including withdrawal by the subject at his/her discretion).
If the study drug is continued after the study termination, the action should be “Dose not changed”.
Dose not changed
The dose was not changed after the onset of the AE.
The study drug was discontinued, reduced, or increased because of another AE.
The study drug was discontinued or reduced for a reason other than the AE, e.g., inadvertence of the subject.
Unknown It has not been possible to determine what action has been taken because the subject is lost to follow-up.
Not Applicable The administration of the study drug had already been completed or discontinued before the onset of the AE.
Dose reduced The dose of the study drug was reduced because of the AE (including dose reduction by the subject at his/her discretion).
Dose Increased The dose was increased due to the particular AE (including dose reduction by the subject at his/her discretion).
Washout The study drug was suspended (i.e., interrupted) because of the AE (including suspension/interruption by the subject at his/her discretion), but resumed later.
10.1.10 Outcome
Outcome of AEs is classified as follows: Category Criteria
Recovered Disappearance or recovery of symptoms and findings
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Laboratory values returned to normal or baseline
Improved
The intensity is lowered by one or more stages Symptoms or findings mostly disappeared Laboratory values improved, but have not returned to normal or baseline The subject died from a cause other than the concerned AE while the condition was
resolving (recording of the date of death unnecessary)
Not recovered
No change in symptoms, findings, or laboratory data The symptoms, findings, or laboratory data on the final day of observable period were aggravated compared with the date of onset Irreversible congenital anomaly The subject died from another cause before resolution of the concerned AE
(recording of the date of death unnecessary)
Recovered with sequelae Disability that disturbs daily life
Death
Direct relationship between death and the concerned AE “Direct relationship” means that the concerned AE was the cause of death, or the concerned AE was clearly responsible for death.
Outcome of an AE which was not determined (judged, presumed) a direct cause of death observed in the same subject is not considered as death.
The date of death shall be recorded.
Unknown Follow-up specified in the protocol after the date of onset was not possible due to
change of hospitals or relocation, etc.
Procedures 10.2
10.2.1 Collection and Reporting of AEs
10.2.1.1 AE collection Period
Collection of AEs will commence from the time that the subject is first administered study drug
(VISIT 1). Routine collection of AEs will continue until VISIT 3.
10.2.1.2 AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A neutral
question, such as “How have you been feeling since your last visit?”. Subjects may report AEs
occurring at any other time during the study.
All subjects experiencing AEs, whether considered associated with the use of the study drug or not,
must be monitored until the symptoms subside and any clinically relevant changes in laboratory
values have returned to baseline or until there is a satisfactory explanation for the changes observed.
All AEs will be documented in the AE page of the CRF, whether or not the investigator concludes
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that the event is related to the drug treatment. The following information will be documented for
each event:
1. Event term.
2. Start and stop date.
3. Frequency.
4. Intensity.
5. Investigator's opinion of the causal relationship between the event and administration of the
study drug (related or not related),
6. Investigator's opinion of the causal relationship to study procedures, including the detail of the
suspected procedure.
7. Action concerning study drug.
8. Outcome of event.
9. Seriousness.
10.2.1.3 Reporting of adverse events of special interest (specific adverse events)
If AE of Special interest (AESI) occurring during the AE collection period is considered to be
clinically significant based on the criteria below, it should be reported to the sponsor (refer to the
attachment for contact information) within 1 business day of first onset, or subject’s notification of
the event by the investigators. AESI Form should be completed and signed (or signed and sealed) by
the principal investigator and reported to the sponsor within 10 business days.
The criteria for AESIs (hypoglycemia-related AEs, intestinal obstruction-related AEs, acute
pancreatitis-related AEs, and QT/QTc interval prolongation-related AEs) are as shown below. If any
other AEs potentially related to the study drug occur, it will be considered whether to include them
in the AESIs.
[Hypoglycemia-related AEs]
AEs related to hypoglycemia
[Intestinal obstruction-related AEs]
Intestinal obstruction, ileus, subileus, obstruction of the digestive tract, gastrointestinal motility
disorder, impaired gastric emptying, and AEs related to these conditions