Post-marketing Database Survey: A Cohort Study of Comparison the Risk of Haemorrhage (Serious Intracranial Haemorrhage Such as Cerebral Haemorrhage and Subarachnoid Haemorrhage) Between Vortioxetine Tablets and SSRIs In Patients With Depression Using JMDC Claims Database
Conditions: Major Depressive Disorder
Sponsor: Takeda

Clinical Study Protocol 
NCT Number: NCT05932407 
Title: A Cohort Study to Compare the Risk of Hemorrhage (Serious Intracranial 
Hemorrhage Such as Cerebral Hemorrhage and Subarachnoid Hemorrhage) Between 
Trintellix Tablets and SSRIs in Patients With Depression Using JMDC Claims 
Database 
Study Number: Vortioxetine-4005 
Document Version and Date: Version 1.3 / 06-Sep-2024 
Certain information within this document has been redacted (ie, specific content is 
masked irreversibly from view) to protect either personally identifiable information or 
company confidential information. 
Note; This document was translated into English as the language on original version 
was Japanese. 

Post-Marketing Database Study Protocol 
< Trintellix Tablets 10 mg and 20 mg> 
A Cohort Study to Compare the Risk of Hemorrhage 
(Serious Intracranial Hemorrhage Such as Cerebral 
Hemorrhage and Subarachnoid Hemorrhage) Between 
Trintellix Tablets and SSRIs in Patients With 
Depression Using JMDC Claims Database
Sponsor 
Takeda Pharmaceutical Company 
Limited 
Protocol No.
Vortioxetine-4005 
Version No.
Ver. 1.3 
Date of preparation
6 September 2024
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1 
TABLE OF CONTENTS 
Study Protocol Update History ....................................................................................................... 2 
Outline of the Product ..................................................................................................................... 3 
Items to be Discussed in the Study.................................................................................................. 4 
Outline of the Study Protocol .......................................................................................................... 6 
Definition of Terms ......................................................................................................................... 8 
Definition of Abbreviations ............................................................................................................. 9 
Study Process ................................................................................................................................ 10 
7.1. 
Study Process Chart ............................................................................................................. 10 
7.2. 
Scheduled Milestones to Evaluate the Study Progress and Obtained Results, or Make a 
Report to the Pharmaceuticals and Medical Devices Agency, and Their Rationale ............. 10 
7.3. 
Additional Measures That May Be Taken Based on the Results of the Study and the 
Decision Criteria for Its Initiation ........................................................................................ 10 
7.4. 
Publication of Results .......................................................................................................... 10 
Organizational Structure for Conducting the Study ...................................................................... 11 
8.1. 
Organizational Chart for the Study ...................................................................................... 11 
8.2. 
Medical Expert ..................................................................................................................... 11 
8.3. 
Name and Address of the Contractor and the Scope of the Outsourced Operations ............ 12 
Study Objective (Research Question) ........................................................................................... 13 
Background of the Study ............................................................................................................... 14 
Summary of the Medical Information Database Used for the Study ............................................ 15 
Items to Be Investigated ................................................................................................................ 16 
Method of Study ............................................................................................................................ 17 
13.1. Study Period (Data Period) .................................................................................................. 17 
13.2. Study Design ........................................................................................................................ 17 
13.3. Scope of Study Participants.................................................................................................. 17 
13.4. Definition of Exposure and Control and Matters Used for Them ........................................ 19 
13.5. Flow Chart ............................................................................................................................ 20 
13.6. Outcome Definitions and Matters Used for Them ............................................................... 21 
13.7. Covariates and Matters Used for Them ................................................................................ 23 
13.8. Validation ............................................................................................................................. 25 
13.9. Items to be Analyzed and Methods ...................................................................................... 26 
Number of Study Participants and the Rationale .......................................................................... 27 
Limitations of the Study ................................................................................................................ 28 
Retention of Records ..................................................................................................................... 29 
References ..................................................................................................................................... 30 
Appendices .................................................................................................................................... 31 
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4 
 Items to be Discussed in the Study 
The risk management plan for Trintellix Tablets (hereinafter referred to as “Trintellix”) has selected 
“hemorrhage” as an important potential risk. Of the hemorrhage events, this study targeted serious 
intracranial hemorrhages, such as cerebral and subarachnoid hemorrhages. Hereafter, serious 
intracranial hemorrhages, such as cerebral and subarachnoid hemorrhages, are referred to as 
“intracranial hemorrhage.” 
(Excerpted from the Trintellix risk management plan) 
Important potential risks (only hemorrhage extracted) 
Hemorrhage 
 
Reason why it is identified as an important potential risk: 
Serotonin is involved in platelet aggregation. Trintellix not only acts on multiple 5-
hydroxytryptamine (5-HT) receptors, but also inhibits serotonin transporter (SERT). 
Therefore, Trintellix inhibits reuptake of serotonin, presumably inhibiting platelet 
aggregation and causing bleeding. 
A combined summary of the phase 2/3 global study, including Japan (Study CCT-002), and 
Japanese phase 3 controlled studies (Studies CCT-003 and CCT-004) in patients with 
major depressive disorder revealed that the incidence of hemorrhage-related adverse 
events* was 1.1% (5/436 patients) in the placebo group, 0.9% (4/435 patients) in the 
Trintellix 10 mg group, and 1.0% (3/313 patients) in the Trintellix 20 mg group. In Study 
OCT-001, a long-term study, the incidence was 3.6% (10/280 participants). Among these 
events, the outcome of death was reported in the 20 mg group in one patient with 
subarachnoid hemorrhage, which was not related to Trintellix, and one patient with 
cerebral hemorrhage related to Trintellix. 
Hemorrhage-related adverse events* (including serious cases) have been reported in the 
post-marketing setting in foreign countries. However, there is no evidence strongly 
suggesting a relationship between Trintellix administration and serious intracranial 
hemorrhages including cerebral and subarachnoid hemorrhages. 
As described above, the results of clinical studies and overseas post-marketing reports have 
demonstrated no clear relationship between Trintellix and hemorrhage-related adverse 
events. However, the possibility of hemorrhage occurring in patients receiving Trintellix 
cannot be ruled out. Therefore, hemorrhage is listed as an important potential risk of this 
drug. 
 
*: Events (Preferred Terms) included in narrow scope of “haemorrhage terms (excl 
laboratory terms)” in standardized MedDRA queries (SMQ) 
Contents of pharmacovigilance activities and reasons for selecting them: 
[Contents] 
• Routine pharmacovigilance activities 
•  As an additional pharmacovigilance activity, a post-marketing database study 
(hemorrhage) will be conducted. 
[Reason for selection] 
Hemorrhage is an adverse reaction reported with some drugs that inhibit serotonin-reuptake. 
However, there is no evidence strongly suggesting the relationship between Trintellix 
administration and serious intracranial hemorrhages including cerebral and subarachnoid 
hemorrhages. Therefore, a post-marketing database study with a control group will be 
conducted to evaluate the relative risks of Trintellix therapy to SSRI treatment with respect 
to serious intracranial hemorrhage requiring hospitalization. 
Contents of risk minimization activities and reasons for selecting them: 
[Contents] 
Describe hemorrhage in the package insert sections, “9.1 Patients with Complication or 
History of Diseases,” “10.2 Precautions for Co-administration,” and “11.2 Other Adverse 
Reactions,” and in the patient medication guide as routine risk minimization activities for 
calling attention. 
[Reason for selection] 
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To provide information on the event to healthcare professionals to promote their 
understanding of proper use of Trintellix, considering the importance of the event, although 
the relationship between Trintellix and hemorrhage is unclear. 
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7 
drug administration, NSAID administration, and 
hypertension 
 
Using the outcome Definition 3*, the incidence rate of serious 
hemorrhage (intracranial or gastrointestinal hemorrhage) (per 
10,000 person-years) with each SSRI* will be estimated in the 
control group. 
If there is a large difference in the incidence rate of outcomes 
between SSRIs, an additional analysis with an appropriate control 
group will be performed to appropriately interpret the relative risks 
of Trintellix to SSRIs for serious hemorrhage (intracranial or 
gastrointestinal hemorrhage). 
* Classify by the name of the ingredient administered at the index 
date 
Sensitivity analysis: 
 
The robustness of the primary analysis will be confirmed by 
observing how much the results of the primary analysis is changed 
by each of the following changes: change of the look-back period 
(changed to a period of 1 year [360 days] prior to the day before 
the index date), change of the prescription continuation period (the 
gap period and the grace period are changed to 90 days), and 
change of the definition of outcome (changed to Definition 1*; for 
Definition 2*, “within the same hospitalization” is defined as “the 
same claim ID or the hospitalization claim ID in the following 
month after the start of hospitalization,” the drug is changed to 
injection only, and the suspect flag is changed to “not considered”). 
 
In addition to [COV1] and [COV2], to adjust approximately 20 
covariates (covariance 3 [COV3]) that are suggested to possibly 
affect the outcome in the preceding research and the Trintellix 
package insert, the covariates of COV1 to COV3 will be combined 
in one propensity score, which will be added to the models 
(adjustment). Then, the adjusted hazard ratio of Trintellix relative 
to the control group will be calculated. 
*See “13.6. Outcome Definitions and Matters Used for Them.” 
 
 
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10 
 Study Process 
 
7.1. 
Study Process Chart 
 
Milestones 
Scheduled time 
Finalization of the study protocol 
April 2023 
Data collection completed 
November 2023 
Analysis data set lock 
July 2024 
Analysis completed (study completed) 
July 2024 
Evaluation of analysis results and finalization of study 
results report 
January 2025 
End of re-examination period 
September 2029 
 
7.2. 
Scheduled Milestones to Evaluate the Study Progress and Obtained Results, or Make a 
Report to the Pharmaceuticals and Medical Devices Agency, and Their Rationale  
Time to prepare the report: A report will be prepared at the end of the study period. 
 
7.3. 
Additional Measures That May Be Taken Based on the Results of the Study and the 
Decision Criteria for Its Initiation  
Review the risk management plan, including the following information, at the scheduled 
milestones. 
 The necessity of changing the contents of the study plan, including the addition of new 
safety specifications, will be examined.  
 The necessity of developing a risk-minimization plan for new safety specifications will be 
examined. 
 
7.4. 
Publication of Results 
The results of this study will be published in a research paper. 
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13 
 Study Objective (Research Question)  
To evaluate the relative risks of Trintellix therapy to SSRI treatment with respect to serious 
intracranial hemorrhage requiring hospitalization in patients with depression for approximately 3 
years after the launch of Trintellix (November 2019 to November 2022). 
 
 
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14 
 Background of the Study 
Trintellix is indicated for “depression and depressive state,” and as with other approved 
antidepressants, this drug can be a new treatment option for depression. 
Trintellix-related hemorrhage has been identified as an important potential risk factor for the risk 
management plan (RMP). Serotonin is involved in platelet aggregation. Trintellix not only acts on 
multiple 5-HT receptors, but also inhibits SERT. Therefore, Trintellix inhibits the reuptake of 
serotonin, thereby presumably inhibiting platelet aggregation and causing bleeding. A combined 
summary of the phase 2/3 global study including Japan (Study CCT-002) and Japanese phase 3 
controlled studies (Studies CCT-003 and CCT-004) in patients with major depressive disorder 
revealed that the incidence rate of hemorrhage-related adverse events* was 1.1% (5/436 patients) in 
the placebo group, 0.9% (4/435 patients) in the Trintellix 10 mg group, and 1.0% (3/313 patients) in 
the Trintellix 20 mg group. In Study OCT-001, a long-term study, the incidence rate was 3.6% (10/280 
patients). Among these events, death was reported in one patient with cerebral hemorrhage, which was 
related to Trintellix, and one patient with subarachnoid hemorrhage, which unrelated to Trintellix. 
Hemorrhage-related adverse events* (including serious cases) have been reported in the post-
marketing setting in foreign countries. However, there is no evidence strongly suggesting a 
relationship between Trintellix administration and serious intracranial hemorrhages, such as cerebral 
and subarachnoid hemorrhages. Therefore, we decided to investigate the onset of hemorrhage in 
patients with depression who use Trintellix in a post-marketing setting. 
 
*: Events (Preferred Terms) included in narrow scope of “haemorrhage terms (excl laboratory terms)” 
in SMQ 
 
 
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 Summary of the Medical Information Database Used for the Study 
In this study, the JMDC Claims Database (hereinafter referred to as the DB) provided by JMDC Inc. 
(hereinafter referred to as JMDC) will be used. The DB promotes health services in health insurance 
societies. JMDC Inc. has accumulated data as anonymized personal information after obtaining 
permission for third-party use of the medical care provided in January 2005. The number of health 
insurance societies contracted with JMDC is annually increasing, and the cumulative number of 
participants in the DB is approximately 14 million as of February 2022. 
The DB consists of members (insured persons and their dependents) of health insurance societies and 
includes member information (such as age, sex, and insurance coverage period) and health insurance 
claims information (such as name of injury/disease, prescribed drugs, and medical treatment). The 
names of injuries/diseases are coded using the International Statistical Classification of Diseases and 
Related Health Problems (ICD)-10, and prescribed drugs are coded using the Anatomical Therapeutic 
Chemical (ATC) classification. It is possible to track the behavior of visiting hospitals, even if the 
medical institution or dispensing pharmacy changes or multiple visits are made unless a member 
withdraws from the health insurance society after the health insurance society starts a contract with 
JMDC. However, as the DB is derived from health insurance societies, it does not include information 
on older adults aged 75 years or older, or information from the National Health Insurance, Mutual Aid 
Association, and other insurers not contracted by JMDC. Additionally, the DB includes a few older 
adults aged 65 years or older and has no test values other than the results of medical checkups. 
For the reliability of the DB, the procedures are audited in accordance with the “DB Study 
Management Tool” released by the Pharmaceuticals and Medical Devices Agency (PMDA). 
 
In a feasibility study conducted prior to the study, the number of patients with depression requiring 
drug therapy from November 2019 (launch date) to January 2022 was approximately 172,000. The 
number of patients in the Trintellix and control groups satisfying the inclusion/exclusion criteria was 
approximately 11,000 and 76,000, respectively. 
 
The study period (data period) was from November 2018 to November 2023. 
The start of the data period was decided as November 2018, the month obtained by going back 1 year 
(360 days) from the date of launch as the look-back period, and the end of the data period was decided 
as November 2023. 
 
 
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 Items to Be Investigated 
Attached in Appendix 1. 
 
 
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 Method of Study 
 
13.1. Study Period (Data Period) 
Data period: November 2018 to November 2023 
Enrollment period: November 2019 (launch date) to November 2022 
 
13.2. Study Design 
The study employed a cohort design. 
A cohort design was used to estimate the incidence rate of hemorrhage in the exposure and control 
groups. The risk of intracranial hemorrhage will be assessed, including the effects of Trintellix 
exposure duration. The exposure and control groups will include new users of Trintellix or other 
antidepressant SSRIs (hereinafter referred to as SSRIs). 
 
13.3. Scope of Study Participants 
Based on the inclusion and exclusion criteria and observation period, the study participants are 
defined below. The disease and drug codes are presented in Appendix 2. 
 
 Inclusion Criteria 
1) 
Patients diagnosed with depression and prescribed Trintellix or an SSRI during the 
enrollment period (index date: date of first prescription during the enrollment period). 
2) 
Patients who can be observed for 6 months (180 days) prior to the day before the index 
date (look-back period). 
3) 
No prescription of Trintellix or an SSRI during the look-back period. 
 
Rationale: 
1) 
This criterion is specified to enroll patients with depression requiring Trintellix or an 
SSRI. 
2) 
If there are multiple prescriptions within this period, the earliest prescription will be 
adopted as the first. 
3) 
This criterion is specified as the period for obtaining the covariates. The look-back period 
is specified as a period of 6 months (180 days) prior to the day before the index date 
based on the following: the prescription period of SSRIs for one prescription is assumed 
to be up to 3 months, and such patients could have visited the hospital twice during this 
period. 
4) 
This criterion is specified to include patients who have not been prescribed Trintellix or 
SSRIs during the look-back period as new users. 
 
 Exclusion Criteria 
1) 
A diagnosis of intracranial hemorrhage during the look-back period. 
For the diagnosis of intracranial hemorrhage, see “13.6. Outcome Definitions and Matters 
Used for Them.” 
2) 
Concomitant use of Trintellix and SSRIs on the index date. 
 
Rationale: 
1) and 2) These criteria are specified to understand the relationship of the onset of new events 
after prescription of Trintellix or an SSRI. 
The inclusion of patients with recurrent intracranial hemorrhage in the primary analysis cannot 
be ruled out. Therefore, a sensitivity analysis will be performed with a look-back period set as 
1 year (360 days) prior to the day before the index date, to confirm whether new events are 
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13.4. Definition of Exposure and Control and Matters Used for Them 
Exposure is defined as the prescription of Trintellix and SSRIs for the controls. Drug codes are 
provided in Appendix 2. 
The prescription continuation period is defined as the period from the day after the index date to 
30 days after the last prescription end date (grace period). If the interval (gap period) between 
consecutive prescription periods is within 30 days, the prescription will be considered to be 
continued. If the interval (gap period) between consecutive prescription periods is 31 days or 
longer, the prescription will be considered to be discontinued. 
 
Rationale: 
1) 
SSRIs, serotonin and norepinephrine reuptake inhibitors (SNRIs), or noradrenergic and 
specific serotonergic antidepressants (NaSSAs) are often used as first-line antidepressants 
for moderate depression, and all antidepressants can be candidates as first-line drugs for 
severe depression.1) Moreover, because Trintellix has an inhibitory effect on SERT, the 
drug may cause bleeding owing to mechanism of action. Similarly, SSRIs have been 
reported to inhibit platelet aggregation via SERT inhibitory action, potentially resulting in 
bleeding. SSRIs were selected as controls. 
2) 
The Japanese medical fee system advises careful consideration for prescriptions 
exceeding 30 days. Depression treatment appropriately provided by monitoring the 
clinical course, including the dosing regimen and treatment period of the drug,1) is also 
desirable. The standard prescription period is considered to be 30 days, and the gap and 
grace periods are set to 30 days, considering the possibility of delayed visits and missed 
doses. 
 
 
Fig. 2: Prescription Continuation Period 
 
In this study, for the prescription continuation period, a sensitivity analysis will be performed with 
the gap and grace periods of 90 days as the case for the longest prescription days to capture 
outcomes more broadly. 
 
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13.6. Outcome Definitions and Matters Used for Them 
An outcome is defined as serious intracranial hemorrhage, such as cerebral hemorrhage and 
subarachnoid hemorrhage, that requires inpatient treatment and meets all of the conditions for 
each definition as follows: 
Definition 1: 
1) ICD-10 codes: There are records of ICD-10 codes from any of the following: I60 
subarachnoid hemorrhage, I61 intracerebral hemorrhage, I62 other nontraumatic 
intracranial hemorrhage.4) 5) (excluding cases with suspect flags) 
2) There are records of hospitalization (“hospitalization or diagnosis procedure combination 
[DPC]” in “claim type”) in the same month as the diagnosis of intracranial hemorrhage, 
such as cerebral hemorrhage and subarachnoid hemorrhage in 1) above. 
3) There are records of any of the following tests within the same hospitalization (same 
“claim identification [ID]”) due to intracranial hemorrhage, such as cerebral hemorrhage 
and subarachnoid hemorrhage in 2) above: computed tomography (CT), magnetic 
resonance imaging (MRI), or magnetic resonance angiography (MRA) (category code: 
E200 computed tomography [CT] [per set], E202 magnetic resonance imaging [MRI] [per 
set], and E203 computed tomography diagnosis).4) (Date of onset of outcome) 
Definition 2: 
1) In addition to Definition 1, any of the following (1) to (6) is recorded within the same 
hospitalization (same “claim ID”) due to intracranial hemorrhage, such as cerebral 
hemorrhage and subarachnoid hemorrhage in 2) of Definition 1. 
(1) Anti-edema agents: drug code K01F1 (for osmotherapy)6) 
(2) Nitrite and nitrate: drug code C01E6) 
(3) Calcium antagonist: drug code C086) 
(4) Hemostatic drug: name of ingredient (tranexamic acid [B02A1])6) 
(5) Cerebrovascular spasm prophylactic drugs: name of ingredient (ozagrel 
sodium [B01C9], fasudil hydrochloride hydrate [C04A1], clazosentan sodium 
[C04A1])6) 
(6) Intracranial hemorrhage treatment: (category codes: K145 trepanning 
ventricular drainage, K147 trepanation, K149 decompressive craniectomy, 
K164 intracranial hematoma evacuation [performed with craniotomy], K176 
cerebral aneurysm inflow vessel clipping [performed with craniotomy], and 
K178 cerebrovascular surgery)5) 6) 
Definition 3: 
1) ICD-10 codes: There are records of ICD-10 codes from any of the following (excluding 
cases with suspect flags): intracranial hemorrhage (I60 subarachnoid hemorrhage, I61 
intracerebral hemorrhage, I62 other nontraumatic intracranial hemorrhage); or 
gastrointestinal hemorrhage7) (I850 esophageal varices with bleeding, K226 gastro-
esophageal laceration-hemorrhage syndrome, K250 gastric ulcer/acute with hemorrhage, 
K251 gastric ulcer/acute with perforation, K252 gastric ulcer/acute with both hemorrhage 
and perforation, K253 gastric ulcer/acute without hemorrhage or perforation, K254 gastric 
ulcer/chronic or unspecified with hemorrhage, K255 gastric ulcer/chronic or unspecified 
with perforation, K256 gastric ulcer/chronic or unspecified with both hemorrhage and 
perforation, K260 duodenal ulcer/acute with hemorrhage, K261 duodenal ulcer/acute with 
perforation, K262 duodenal ulcer/acute with both hemorrhage and perforation, K263 
duodenal ulcer/acute without hemorrhage or perforation, K264 duodenal ulcer/chronic or 
unspecified with hemorrhage, K265 duodenal ulcer/chronic or unspecified with perforation, 
K266 duodenal ulcer/chronic or unspecified with both hemorrhage and perforation, K270 
peptic ulcer, site unspecified/acute with hemorrhage, K284 gastrojejunal ulcer/chronic or 
unspecified with hemorrhage, K285 gastrojejunal ulcer/chronic or unspecified with 
perforation, K290 acute hemorrhagic gastritis, K920 hematemesis, K921 melena, K922 
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gastrointestinal hemorrhage, unspecified) 
2) There are records of hospitalization (“hospitalization or DPC” in “claim type”) in the same 
month as the diagnosis of intracranial hemorrhage, such as cerebral hemorrhage and 
subarachnoid hemorrhage or gastrointestinal hemorrhage in 1) above. 
 
Rationale: 
When serious intracranial hemorrhage occurs, patients are expected to be hospitalized in 
principle, given an injury/disease name related to the intracranial hemorrhage, undergo tests 
(CT, MRI, or MRA), and receive a prescription or treatment specific to the intracranial 
hemorrhage. 
Definition 1 is a broad definition consisting of a combination of injury/disease names and the 
conduct of tests (expected to have the highest sensitivity). The date of onset of outcome is 
defined as the date of the earliest test among CT, MRI, and MRA within the same 
hospitalization (same “claim ID”) owing to intracranial hemorrhage, such as cerebral and 
subarachnoid hemorrhages. 
Definition 2 is a narrow definition consisting of a combination of injury/disease names and the 
conduct of tests and procedures or prescriptions (expected to have the highest positive 
predictability and specificity). The date of onset of outcome is defined as the date of the earliest 
test among CT, MRI, and MRA within the same hospitalization (same “claim ID”) owing to 
intracranial hemorrhage, such as cerebral and subarachnoid hemorrhages. 
For Definition 3, serious hemorrhage requiring hospitalization (intracranial or gastrointestinal 
hemorrhage) is defined by injury/disease name from the viewpoint of multilaterally evaluating 
“hemorrhage,” an important potential risk of Trintellix. The date of onset of outcome is defined 
as the 15th day of the month of hospitalization for intracranial or gastrointestinal hemorrhage. 
This definition will be used for secondary analyses only. 
 
In this study, no outcome validation was conducted. However, based on the results of a 
previous study5), it is assumed that Definition 1 is more sensitive, but has lower positive 
predictability and specificity than Definition 2. However, Definition 2 has higher positive 
predictability and specificity, and it is assumed that adding drug conditions to the treatment 
conditions in the preceding study using “OR” conditions will further increase the sensitivity 
compared to that of the preceding study (0.889 [0.673–0.889]). 
If it is unlikely that the sensitivity of outcomes substantially differ between the two groups, the 
use of an outcome definition with a higher positive predictability is a prerequisite for obtaining 
correct results.8) In addition, if the outcome definition is strictly set to achieve high positive 
predictability, false-negative results may increase, resulting in a decrease in sensitivity.8) 
However, because not only treatment, but also prescription conditions are added in Definition 
2, such concerns are considered to be minor, and Definition 2 will be used for the primary 
analysis. Sensitivity analyses will be performed in the following cases: Definition 1 is used; for 
Definition 2, the definition of “within the same hospitalization” is defined as “the same claim 
ID or the hospitalization claim ID in the following month after the start of hospitalization,” the 
drug is limited to injection only, and the suspect flag is not taken into consideration. 
 
 
 
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13.7. Covariates and Matters Used for Them 
The following covariates will be used to adjust the patient characteristics of the exposure and 
control groups (COV1 and COV2 will be used for multivariate analysis, and COV1 to COV3 will 
be used for propensity score analysis). 
COV1: 
 
Age (continuous variable) 
 
Sex (male, female) 
COV2: 
 
Antithrombotic drug administration† (Yes, No) 
 
NSAID administration† (Yes, No) 
 
Hypertension (Yes, No) 
COV3: 
 
Administration of atypical antipsychotics† (Yes, No) 
 
Administration of phenothiazine antipsychotics† (Yes, No) 
 
Administration of tricyclic antidepressants† (Yes, No) 
 
Diabetes mellitus (Yes, No) 
 
Ischemic heart disease (Yes, No) 
 
Ischemic cerebral infarction (Yes, No) 
 
Cerebral amyloid angiopathy (Yes, No) 
 
Cerebral aneurysm (Yes, No) 
 
Brain tumor (Yes, No) 
 
Epilepsy (Yes, No) 
 
Liver disease (Yes, No) 
 
Renal failure (Yes, No) 
 
Alcohol dependence (Yes, No) 
 
Epistaxis (Yes, No) 
 
Dyslipidemia (Yes, No) 
 
Obesity (Yes, No) 
 
Metabolic syndrome (Yes, No) 
 
Sleep apnea syndrome (Yes, No) 
 
Peripheral arterial disease (Yes, No) 
 
Drinking history (Yes, No)* 
 
Smoking history (Yes, No)* 
† Drug administration during Days -30 to -1 
* For missing values, a category of “Unknown” is created. 
 
Rationale: 
The covariates selected included age and sex, as well as comorbidities and drug administration, 
which are considered risk factors for intracranial hemorrhage in the preceding studies6) 9), the 
electronic package insert of Trintellix, or other data. 
The number of patients with outcomes in this study is expected to be approximately 50 to 10010), 
COV1 and COV2, which are relatively important potential confounding factors, are used, 
assuming that the explanatory variable of the multivariate analysis, primary analysis, is 
approximately 5 to 10. For COV2, antithrombotic drugs and NSAIDs, for which previous studies 
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24 
have reported that concomitant use with SSRIs increased the risk of intracranial hemorrhage3) 11), 
and hypertension, which is the largest risk factor for cerebral hemorrhage6) and has the highest 
prevalence in the feasibility study, are selected. 
For COV1, data from the index date will be obtained. For complications of COV2 and COV3, 
data during the look-back period will be obtained considering the treatment intervals. For drug 
administration in COV2 and COV3, data on days -30 to -1 from the index date will be obtained, 
assuming that concomitant drugs are used on or after the index date. 
 
 
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13.8. Validation 
Scope of validation in “Development of basic principles in conducting a validation study of 
outcome definitions used for post-marketing database studies (July 31, 2020) (PMDA/CRS 
Notification No. 0731002/PMDA/CPE Notification No. 0731002) (Director of Center for 
Regulatory Science/Director of Center for Product Evaluation, Pharmaceuticals and Medical 
Devices Agency)”: It is judged that the study does not align an investigation conducted to serve as 
the main grounds for specific safety measures, and therefore validation is not performed in this 
study. 
 
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13.9. Items to be Analyzed and Methods 
The dataset to be used in this study will be obtained by the following process: JMDC Inc. 
performs its own data cleaning and data check from the viewpoint of quality assurance; the data 
between November 2018 and November 2023 are extracted; and then the dataset that meets the 
inclusion/exclusion criteria is created. 
A summary of the analysis is presented below. The details are specified in a separately prepared 
statistical analysis plan, and the figures and tables concerning the main results, which are 
described in the study report, are provided in Appendix 3. 
Primary analysis  
 
Using Definition 2, the incidence rate of intracranial hemorrhage (per 10,000 person-
years) in the Trintellix and control groups will be estimated, and the hazard ratio of 
Trintellix relative to the control will be calculated (crude and adjusted). 
Covariates: [COV1] age and sex, and [COV2] antithrombotic drug administration, 
NSAID administration, and hypertension 
Secondary analysis 
 
The survival function will be graphically presented using the Kaplan–Meier method, and 
the time to onset of intracranial hemorrhage will be evaluated. 
 
Using Definition 2, the incidence rate of intracranial hemorrhage (per 10,000 person-
years) for each SSRI* will be estimated in the control group. 
If there is a large difference in the incidence rate of outcomes between SSRIs, additional 
analysis with an appropriate control group will be performed to appropriately interpret the 
relative risks of Trintellix to SSRIs for intracranial hemorrhage. 
 
Using Definition 3, the incidence rate of serious hemorrhage requiring hospitalization 
(intracranial or gastrointestinal hemorrhage; per 10,000 person-years) in the Trintellix and 
control groups will be estimated, and the hazard ratio of Trintellix relative to the control 
will be calculated (crude and adjusted). 
Covariates: [COV1] age and sex, and [COV2] antithrombotic drug administration, 
NSAID administration, and hypertension 
 
Using Definition 3, the incidence rate of serious hemorrhage (intracranial or 
gastrointestinal hemorrhage; per 10,000 person-years) with each SSRI* will be estimated 
for the control group. 
If there is a large difference in the incidence rate of outcomes between SSRIs, additional 
analysis with an appropriate control group will be performed to appropriately interpret the 
relative risks of Trintellix to SSRIs for serious hemorrhage (intracranial or gastrointestinal 
hemorrhage). 
* Classified by the name of the ingredient administered on the index date. 
Sensitivity analysis  
 
The robustness of the primary analysis will be confirmed by observing how much the 
results of the primary analysis is changed by each of the following changes: change of the 
look-back period (changed to a period of 1 year [360 days] prior to the day before the 
index date), change of the prescription continuation period (the gap period and the grace 
period are changed to 90 days), and change of the definition of outcome (changed to 
Definition 1; for Definition 2, “within the same hospitalization” is defined as “the same 
claim ID or the hospitalization claim ID in the following month after the start of 
hospitalization,” the drug is changed to injection only, and the suspect flag is changed to 
“not considered”). 
 
In addition to [COV1] and [COV2], to adjust approximately 20 covariates [COV3] that 
are suggested to possibly affect the outcome in the preceding research and Trintellix 
package insert, the covariates of COV1 to COV3 will be combined in one propensity 
score, which will be added to the models (adjustment). The adjusted hazard ratio of the 
Trintellix group relative to the control group will be calculated. 
 
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 Number of Study Participants and the Rationale 
A feasibility study*1 using the DB was conducted before the main study. The results demonstrated 
that the number of patients with depression required drug therapy between November 2019 
(launch date) and January 2022 was approximately 172,000. The number of patients in the 
exposure and control groups that satisfied the inclusion and exclusion criteria was approximately 
11,000 and 76,000, respectively. Considering that the enrollment period in this study was up to 
November 2022, it is estimated that approximately 14,000 and 101,000 patients will be enrolled 
in the Trintellix and control groups, respectively. 
Renoux et al. reported the following findings: Using the Clinical Practice Research Datalink in 
the United Kingdom, 1.36 million or more adults who had started taking SSRIs or tricyclic 
antidepressants for the first time between 1 January 1995 and 30 June 2014 were followed up for 
a mean period of 5.8 years. The results showed that 3,036 patients were diagnosed with 
intracranial hemorrhage (3.8 cases per 10,000 patients per year; that is, the incidence rate per year 
was 0.038%), and risk of intracranial hemorrhage with SSRIs increased by 17% compared with 
that of tricyclic antidepressants.3) In addition, the incidence of cerebral hemorrhage is considered 
to be 2.4 times higher in Asians than that in non-Asians.12) Therefore, the estimated incidence rate 
of intracranial hemorrhage with SSRIs per year in this study was assumed to be 0.09%. 
In contrast, using the sample size calculation formula (Formula 6.9), which is proposed for 
comparative research in the post-marketing surveillance in a technical book “Sample Sizes for 
Clinical, Laboratory and Epidemiology Studies,13)” the sample sizes required to detect a two-fold 
increase in the incidence rate of intracranial hemorrhage (i.e., an additional 0.09% increase in the 
incidence rate per year of intracranial hemorrhage) for Trintellix compared to that with SSRIs are 
calculated to be 13,242 patients for the exposure group (Trintellix group) and 92,694 patients for 
the non-exposure group (control group), assuming the allocation ratio (control group:Trintellix 
group) of 7:1, the two-sided significance level (α) of 0.05, and the power (1-β) of 0.8 (with the 
one-sided significance level of 0.05, the sample sizes are 10,644 and 74,508 patients, 
respectively). 
Therefore, considering future data accumulation and other factors, the DB should be adequately 
studied. 
 
*1: Appendix 4. Information on the Number of Patients to Be Studied That Is Available From the 
Medical Information Database (Part 2) 
 
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 Limitations of the Study 
 
The DB includes members of health insurance societies; therefore, it does not include older 
adults aged 75 years or older. The number of individuals aged 65 years or older is small; 
however, the number of patients with depression in Japan is highest in their 40s.14) 
Therefore, the DB is considered a suitable database for the comparison of adverse events 
between Trintellix and SSRIs. 
 
Although the study has high traceability, members are lost to follow-up owing to withdrawal 
from health insurance societies or termination of contracts with individual health insurance 
societies. 
 
If the name of the injury or disease is entered for insurance claims or other purposes, the 
name may differ from the actual diagnosis. 
 
The analyses are performed using prescription data and do not capture the actual status of 
drug administration. 
 
Key data on the risk factors of intracranial hemorrhage (e.g., drinking and smoking 
histories) are available only for certain members. However, drinking and smoking histories 
have a lower priority as a confounding factor than age, sex, antithrombotic drug 
administration, NSAID administration, and hypertension, which are included in the primary 
analysis. Therefore, drinking and smoking histories will be included in the additional 
propensity score analysis only. 
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 Retention of Records 
Records will be stored appropriately in accordance with written procedures. 
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 References 
1) 
Treatment Guidelines by the Japanese Society of Mood Disorders. II. Depression (DSM-5)/Major 
Depressive Disorder 2016. Introduction revised on 24 July 2019. Mood Disorder Treatment 
Guideline Preparation Committee, the Japan Society of Mood Disorders 
2) 
Tyrka A, et al., Psychotic major depression: a benefit-risk assessment of treatment options. Drug Saf 
29:491-508,2006. 
3) 
Christel R, et al., Association of Selective Serotonin Reuptake Inhibitors With the Risk for 
Spontaneous Intracranial Hemorrhage. JAMA Neurol. 2017;74(2):173-180 
4) 
Sacco R, et al. An updated definition of stroke for the 21st Century. A statement for healthcare 
professionals from the American Heart Association / American Stroke Association. Stroke. 2013; 
44: 2064-2089. 
5) 
Kazuya F, et al., Accuracy of Japanese claims data in identifying diabetes-related complications. 
Pharmacoepidemiol Drug Saf. 2021;30:594–601. 
6) 
Japan Stroke Society Guideline 2021 for the Treatment of Stroke, the Japan Stroke Society, 
Guideline for the Treatment of Stroke Committee 
7) 
Masao I, et al., Gastrointestinal bleeding risk of selective serotonin reuptake inhibitors by level of 
kidney function: A population-based cohort study. Br J Clin Pharmacol 2018; 84:2142–2151. 
8) 
Masao Iwagami, Report of “Task force on validation of indicators obtained from health insurance 
claims information mainly consisting of injury/disease names in Japan” 
9) 
Sigrid B, et al., Risk of intracerebral hemorrhage associated with phenprocoumon exposure: a 
nested case–control study in a large population-based German database. pharmacoepidemiology and 
drug safety 2010; 19: 722–730 
10) Vittinghoff, E, et al., Relaxing the Rule of Ten Events per Variable in Logistic and Cox Regression. 
American Journal of Epidemiology 2007;  165(6): 710–718 
11) Mendel D, et al., Cyclooxygenase Selectivity of Nonsteroidal Anti-inflammatory Drugs and Risk of 
Stroke. Arch Intern Med. 2008;168(11):1219-1224 
12) Masatsugu Hori, Learn about characteristics of Japanese from large-scale clinical studies. Heart Vol. 
47 No. 2 (2015) 
13) Sample Sizes for Clinical, Laboratory and Epidemiology Studies, Kyoto University Press 
14) Patient Survey/2011 Patient Survey First Volume (Nationwide): http://www.e-
stat.go.jp/SG1/estat/List.do?lid=000001103073 (Accessed Sep 5, 2022) 
 
 
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 Appendices 
 
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