Conditions: Depressive Disorder
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 151
Healthy volunteers: no

Brief summary:
The purpose of this long-term study is to evaluate the safety and efficacy of duloxetine hydrochloride in Japanese children and adolescents with depressive disorder.

Detailed description:

Arms:
arm 1: Duloxetine hydrochloride administered orally.

Interventions: intervention 1: Duloxetine Hydrochloride
Intervention descriptions: intervention 1: Administered orally

Protocol document:
Prot_000.pdf: 
Study Protocol 
 
This is the translated version of the Study Protocol (Version 4) written in Japanese 
 
Study title: 
 
Phase-3 clinical study of duloxetine hydrochloride in children and 
adolescent patients with depressive disorder: An open-label 
extension study 
Study No.: 
1702A3632 
Development phase: 
3 
Product No.: 
LY248686 
Sponsor: 
Shionogi & Co., Ltd. (Head Office) 
3-1-8 Doshomachi, Chuo-ku, Osaka, 541-0045, Japan 
Contact information for the 
sponsor: 
 
 
 
 
Emergency contact: 
 
 
 
 
 
 
 
Preparation dates 
 
First version (Version 1): 
September 25, 2017 
Version 2 
October 20, 2017 
Version 3 
February 23, 2018 
Version 4 
August 8, 2018 
 
 
This protocol contains confidential information belonging to Shionogi & Co., Ltd. 
The information in this protocol should not be disclosed to a third party without permission from Shionogi 
& Co., Ltd. Reproduction of this protocol by photocopying, etc., is also prohibited. 
 


 
 
 
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Overview of the study 
Study title: 
Phase-3 clinical study of duloxetine hydrochloride in children and adolescent 
patients with depressive disorder: An open-label extension study 
Study No.: 
1702A3632 
Development 
phase: 
3 
Primary objective: 
To evaluate the long-term safety of duloxetine in children and adolescent patients 
with depressive disorder. 
Secondary 
objectives: 
• 
To evaluate the long-term efficacy of duloxetine in children and adolescent 
patients with depressive disorder. 
• 
To evaluate the pharmacokinetics of duloxetine in Japanese children and 
adolescent patients with depressive disorder. 
- 
To compare the plasma duloxetine concentrations at steady state obtained 
at 5 time points (including at least one predose level [trough]) in children 
and adolescent patients with depressive disorder with those of adult 
patients with depressive disorder. 
- 
To examine the potential factors that affect the pharmacokinetic properties 
of duloxetine (e.g., age, body weight, and sex) and their effects in the 
population pharmacokinetics analysis. 
• 
To evaluate the relationship between duloxetine exposure at steady state and 
Children’s Depression Rating Scale-Revised (CDRS-R) total score, one of the 
efficacy endpoints. 
Study design: 
This study is a multicenter, open-label, uncontrolled, long-term treatment study in 
children and adolescent patients with depressive disorder. This study will include a 
total of 135 patients; consecutive subjects who have completed the preceding study 
“Phase-3 clinical study of duloxetine hydrochloride in children and adolescent 
patients with depressive disorder: Superiority study versus placebo” (Study No.: 
1701A3631) then wish to continue the study treatment will be enrolled, as well as 
additional subjects who have child and adolescent depressive disorder, with a target 
of 100 subjects completing a 1-year treatment.  
This study will consist of the following four periods (a total of 53 to 56 weeks): 
screening period (1 to 3 weeks), treatment period (50 weeks), tapering period (1 to 
2 weeks), and follow-up period (1 week). Note that consecutive subjects will 
undergo three periods (a total of 52 to 53 weeks), excluding the screening period. 
New subjects whose eligibility has been confirmed after obtaining informed consent 
will be pre-registered (Visit 1), and, after completion of the 1- to 3-week screening 
period, their eligibility will be confirmed again and they will be registered (Visit 2). 


 
 
 
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Consecutive subjects will give consent for this study before completing the 
observation at Visit 9 in the preceding study, and, after completing the observation 
at Visit 9 in the preceding study and the eligibility of this study is confirmed, be 
enrolled in this study from Visit 2 (registration). 
After registration, the study drug will be administered orally, once daily after 
breakfast. 
Study subjects: 
The subjects must meet the following criteria: (i) aged ≥9 to <18 at the time of 
obtaining consent and assent (consecutive subjects are allowed to be enrolled if they 
are aged ≥9 to <18 in the preceding study); (ii) diagnosed as having depression or 
persistent depressive disorder as defined in the Diagnostic and Statistical Manual of 
Mental Disorders, version 5 (DSM-5), with onset at the age of ≥7; and (iii) fully 
meeting the criteria for a depressive episode. The Mini-International 
Neuropsychiatric 
Interview 
for 
Children 
and Adolescents 
(MINI-KID; 
version 7.0.2) will be used for diagnosis on the basis of DSM-5. 
Inclusion/exclusion 
criteria: 
Subjects must meet all the following criteria: 
Inclusion criteria 
Consecutive 
subjects 
New 
subjects 
1) Have completed 7-week treatment in the preceding 
study and wish to continue treatment with duloxetine. 
X 
 
2) Have been diagnosed with depression or persistent 
depressive disorder, as defined in DSM-5, and fully 
meet the criteria for a depressive episode. MINI-KID 
(version 7.0.2) should be used for diagnosis of 
depression. 
 
X 
3) Are aged ≥9 to <18 at the time of obtaining consent and 
assent, and must have been ≥7 at the initial onset of 
depression episode. Are male or female and are 
hospitalized or out-patients. 
 
X 
4) Have a legal representative capable of providing 
written informed consent for this study. In addition, for 
patients aged ≥13, a written, informed assent must also 
be obtained from the patient him/herself. For patients 
aged ≥9 to <13, a written, informed assent should also 
be obtained from the patient him/herself if possible. 
X 
X 
5) For post-menarchic females, a pregnancy test result 
must be negative at Visit 1 (or Visit 2 for consecutive 
subjects). In addition, the patient must agree to use one 
X 
X 


 
 
 
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of the following contraceptive methods from Visit 1 (or 
Visit 2 for consecutive subjects) until 1 month after the 
final administration. However, this requirement does 
not apply to females for whom it can be confirmed in 
writing that 6 weeks or more has passed since bilateral 
ovariectomy. 
Estrogen- and progesterone-containing, combined-
hormonal contraceptive agents with ovulation-
suppressing 
effects 
(administered 
orally, 
intravaginally, subcutaneously, etc.), progesterone-
containing 
hormonal 
contraceptive 
agents 
(administered 
orally, 
intravenously, 
by 
implantation, etc.), intrauterine device, intrauterine 
system, bilateral tubal ligation, male partner’s 
vasectomy, or sexual abstinence. 
6) The principal investigator or sub-investigator judges 
that the subject’s legal representative can ensure that the 
subject him/herself will comply with all hospital visits, 
tests, and other procedures stipulated in this protocol. 
In addition, the principal investigator or sub-
investigator judges that the subject him/herself will be 
able to comply with all the hospital visits, tests, and 
other procedures stipulated in this protocol. 
 
X 
7) The principal investigator or sub-investigator judges 
that the subject’s legal representative has sufficient 
comprehension and cognitive ability to communicate as 
appropriate with the principal investigator or sub-
investigator, and other persons involved with the study. 
In addition, the principal investigator or sub-
investigator confirms that the subject him/herself has a 
cognitive level appropriate to his/her age, and judges 
that he/she has sufficient comprehension and cognitive 
ability to communicate as appropriate with the principal 
investigator or sub-investigator, and other persons 
involved with the study. 
 
X 
8) Have ability to swallow the capsules without opening, 
crushing, dissolving, or breaking them. In addition, 
 
X 


 
 
 
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he/she can take up to three capsules per day. 
 
Patients who meet any of the following criteria will be excluded: 
Exclusion criteria 
Consecutive 
subjects 
New 
subjects 
1) 
Judged by the principal investigator or sub-
investigator to have complications diagnosed as 
belonging to one or more of the following categories 
in DSM-5, or to have a history of such disorders:  
• 
Neurodevelopmental disorders 
• 
Schizophrenia-spectrum disorder or other 
psychotic disorders 
• 
Bipolar or related disorders 
• 
Trauma and stressor-related disorders 
• 
Disruptive, impulse‒control, and conduct 
disorders 
X 
X 
2) 
Judged by the principal investigator or sub-
investigator to have complications diagnosed as 
belonging to one or more of the following categories 
in DSM-5: 
• 
Obsessive-compulsive disorder or related 
disorders 
• 
Anorexia nervosa, bulimia nervosa, or binge-
eating disorder 
• 
Sleep-wake disorders 
• 
Neurocognitive disorders 
• 
Disruptive mood dysregulation disorder 
X 
X 
3) 
Judged by the principal investigator or sub-
investigator to have a personality disorder. 
X 
X 
4) 
Treatment with two or more antidepressants has 
previously been tried, and, despite treatment of a 
single depressive episode with the optimal clinical 
dose for 4 weeks or more, there has been no response. 
Alternatively, the depressive episode has been treated 
previously or is currently being treated with 
duloxetine, but without response. 
 
X 
5) 
The principal investigator or sub-investigator judges 
X 
X 


 
 
 
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that systematic psychotherapy must be initiated 
between Visits 1 and 18. 
6) 
One or more of the patient’s parents and/or siblings has 
been diagnosed with bipolar disorder. 
X 
X 
7) 
A history of epileptic or other convulsive attacks. 
However, patients with a history of febrile convulsions 
can be enrolled. 
X 
X 
8) 
Administered electroconvulsive therapy within 1 year 
before Visit 1. 
 
X 
9) 
Uncontrolled diabetes or collagen disease. 
 
X 
10) Have initiated, changed or discontinued hormonal 
therapy within 3 months before Visit 1. Patients with 
thyroid dysfunction are excluded. But patients can be 
enrolled if they (i) have undergone thyroid hormone 
supplementation at a consistent dose for at least 3 
months as of Visit 1; (ii) show medically appropriate 
thyroid hormone (TSH, FT3, FT4) concentrations; and 
(iii) have clinically normal thyroid function. 
 
X 
11) Currently have or have a history of malignant 
tumors/cancer. 
X 
X 
12) For new subjects, either (i) suicidal ideation and/or 
suicidal attempt within 1 year before Visit 1; or (ii) at 
Visits 1 and 2 (or Visit 2 for consecutive subjects), 
answer “Yes” to questions 4 and/or 5 about suicidal 
ideation, and/or any of the questions about suicidal 
behaviors (except those about non-suicidal self-
injurious behavior), on the Columbia suicide severity 
rating scale (C-SSRS). 
X 
X 
13) Body weight below 20 kg at Visit 2. 
X 
X 
14) Serious*1 
or 
medically 
unstable*2 
disease 
(cardiovascular disease, hepatic disease, respiratory 
disease, hematologic disease, endocrine disease, 
peripheral vascular disorder, neuropsychiatric disease, 
renal disease), or clinically problematic abnormal 
laboratory 
test 
results 
or 
abnormal 
electrocardiography (ECG) findings*3. 
*1: 
Grade 3 in ''Concerning classification criteria for 
X 
X 


 
 
 
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seriousness of adverse drug reactions to pharmaceutical 
products, etc.” (Drug Safety Notification no. 80; June 29, 
1992). 
*2:  Judged by the principal investigator or sub-investigator to 
have the potential to disrupt study participation, or to 
necessitate hospitalization during the study period. 
*3: 
Judged by the principal investigator or sub-investigator to 
suggest serious medical problems, or to necessitate 
aggressive therapy. 
15) Meeting one or more of the following criteria: 
• 
At Visit 2, latest ALT or AST of 100 U/L or 
higher, or latest total bilirubin of 1.6 mg/dL or 
higher. 
• 
Latest serum creatinine level of 2.0 mg/dL or 
higher at Visit 2. Or have severe renal 
impairment, history of renal transplantation, 
and/or currently undergoing renal dialysis. 
X 
X 
16) Glaucoma, elevated intraocular pressure, and/or 
prostatic hypertrophy or other types of dysuria. 
X 
X 
17) Depression or depressive state due to organic brain 
disorder. 
X 
X 
18) Hemorrhagic tendency or hemorrhagic diathesis. 
X 
X 
19) Treatment with monoamine oxidase (MAO) inhibitor 
within 14 days before Visit 2, and/or potential for 
MAO inhibitor treatment during the study period or 
within 5 days after completion of study drug 
administration. 
X 
X 
20) Hypersensitivity to duloxetine or inactive ingredients 
of duloxetine formulation. 
X 
X 
21) Allergic to two or more drugs, or a history of serious 
allergic reactions to one or more drugs. 
X 
X 
22) Judged by the principal investigator or sub-
investigator to have the complication of substance-
related and/or addictive disorders, as defined in DSM-
5, or a history of such disorders. However, patients 
with caffeine-related disorder can be enrolled. 
 
X 
23) One or more substances of abuse (phencyclidines, 
 
X 


 
 
 
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benzodiazepines, cocaine-type drugs, stimulants, 
cannabis, 
opioids, 
barbiturates, 
tricyclic 
antidepressants, etc.) detected by urinary drug 
screening at Visit 2. 
24) Intension to travel overseas between Visit 1 (or Visit 2 
for consecutive subjects) and Visit 6. 
X 
X 
25) Pregnant* or possibly pregnant, breastfeeding, hoping 
to become pregnant during the study period. Or 
recently given birth. 
* Pregnancy: Pregnancy tests (blood or urine human chorionic 
gonadotropin) will be performed in all post-menarche females. 
X 
X 
26) Previously administered the study drug during 
participation in this study, or during participation in a 
different clinical study on duloxetine. 
 
X 
27) Have received another study drug within 30 days 
before Visit 1 or are currently receiving it. 
 
X 
28) Participation judged to be inappropriate for any other 
reason by the principal investigator or sub-
investigator. 
X 
X 
Study drug dosage 
and administration 
method: 
All subjects will receive 1 to 3 oral capsules of duloxetine 20 mg once daily after 
breakfast from the day after the registration (Visit 2). 
During the treatment period, subjects will receive duloxetine 20 mg/day for one 
week then 40 mg/day for one week, and subsequently receive 40 mg/day or 60 
mg/day for 48 weeks depending on the symptoms. 
During the tapering period, the subjects whose duloxetine dose at discontinuation or 
completion of the treatment period is 60 mg/day will receive 40 mg/day for one 
week then 20 mg/day for one week. The subjects whose duloxetine dose at 
discontinuation or completion of the treatment period is 40 mg/day will receive 20 
mg/day for one week. 
Administration 
period: 
51 or 52 weeks (50-week treatment period and 1- to 2-week tapering period) 
Prohibited 
drugs 
and therapies: 
Use of the below drugs, or over-the-counter drugs with equivalent effects, is 
prohibited from Visit 1 (or after completing the observation period at the completion 
of the tapering period in the preceding study for consecutive subjects) through to 
Visit 18 (completion of the tapering period): 
Prohibited drugs that may affect therapeutic evaluation: 
1) 
Antidepressants 


 
 
 
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2) 
Anxiolytics 
3) 
Soporific agents, other than the “Permitted soporific agents” in Section 
6.2.2  
4) 
Antipsychotics 
5) 
Antiparkinsonian agents 
6) 
Anticonvulsants 
7) 
Mood-stabilizers (lithium carbonate, carbamazepine, sodium valproate) 
8) 
Psychostimulants 
9) 
Adrenal corticosteroids (excluding topical agents, such as ear drops, nose 
drops, eye drops, topical skin formulations, and inhaled formulations). 
10) Interferon formulations 
11) Any of the following drugs, which might affect the metabolic/agonistic 
activities of serotonin or noradrenaline: 
Cyproheptadine hydrochloride (Periactin®, etc.) 
Dimetotiazine mesilate (Migristene®) 
Ifenprodil tartrate (Cerocral®, etc.) 
5-HT3 inhibitors (Zofran®, etc.) 
5-HT4 stimulants (Gasmotin®, etc.) 
5-HT1B/1D receptor agonists (Imigran®, etc.) 
Adrenergic agents (Noradrenaline®, etc.) 
12) St. John’s wort 
13) Chinese herbal medicines administered to treat central nervous conditions 
such as insomnia, neurosis or anxiety. 
14) Other agents judged to act on the central nervous system, and thus affect 
therapeutic evaluation. 
 
Prohibited drugs that present safety-related problems: 
1) 
MAO inhibitors** (FP®, Azilect®, etc.) 
**Administration of these is contraindicated from 14 days before Visit 2 (or after 
completing the observation period at the completion of the tapering period in the 
preceding study for consecutive subjects) until 5 days after completion of study drug 
administration. 
2) 
Other investigational drugs 
 
Unless specifically stated otherwise, use of the following treatments is 
contraindicated from Visit 1 (or after completing the observation period at the 
completion of the tapering period in the preceding study for consecutive subjects) 
through to Visit 18 (completion of the tapering period): 


 
 
 
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1) 
Electroconvulsive therapy 
2) 
Bright-light therapy, i.e. therapy using irradiation devices approved as 
medical devices. 
3) 
Systematic psychotherapy, such as systematically organized cognitive 
therapy, cognitive behavioral therapy, and interpersonal psychotherapy. 
For new subjects, this study will use educational tools, consistently in all 
institutions, for the psycho-education of subjects and guardians. 
4) 
Exercise therapy 
5) 
Hormone therapy is contraindicated. However, in accordance with 
exclusion criterion 10, treatment can be continued at the same dose in 
thyroid dysfunction patients who meet the following three criteria: (i) 
having undergone thyroid hormone supplementation for at least 3 months 
as of Visit 1 (or Visit 2 for consecutive subjects); (ii) showing medically 
appropriate concentrations of thyroid hormones (TSH, FT3 and FT4); and 
(iii) having attained a clinically normal state of thyroid function. 
Efficacy endpoints: 
CDRS-R, Clinical Global Impression of Severity (CGI-S) 
Pharmacokinetic 
endpoint: 
Plasma duloxetine concentrations 
Safety endpoints: 
Adverse events, adverse drug reactions, C-SSRS score, laboratory test results, blood 
pressure, pulse rate, body weight, ECG 
Statistical methods: The summary statistics will be calculated for the observed efficacy endpoints 
(CDRS-R total score and CGI-S) and their changes from baseline at each time-point 
after study drug administration. In principle, the baseline for each endpoint is 
defined as the subject’s initiation of this study (Visit 2). 
Study period: 
Study period for each subject: Up to 56 weeks (consisting of a 1- to 3-week 
Screening period, a 50-week treatment period, a 1- to 2-week tapering period, and a 
1-week follow-up period). 
Scheduled study period: From November 2017 to March 2021. 
Date of preparation 
of the first version: 
September 25, 2017 
Date of preparation 
of 
the 
latest 
version: 
August 8, 2018 (Version 4): 
 
 


 
 
 
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Table of contents 
Overview of the study .......................................................................................................................... 2 
Table of contents ................................................................................................................................. 11 
List of Tables ...................................................................................................................................... 14 
List of Figures .................................................................................................................................... 14 
List of abbreviations and definitions of terms .................................................................................... 15 
1. Background information ................................................................................................................ 16 
2. Study objectives ............................................................................................................................. 19 
2.1 Primary objective ..................................................................................................................... 19 
2.2 Secondary objectives ................................................................................................................ 19 
3. Study plan ....................................................................................................................................... 20 
3.1 Study design ............................................................................................................................. 20 
3.2 Rationale for setting the study design ...................................................................................... 21 
3.3 Study period: ............................................................................................................................ 21 
3.3.1 Study period for each subject ............................................................................................ 21 
3.3.2 Scheduled period of entire study ....................................................................................... 21 
4. Eligibility of subjects and discontinuation of study ....................................................................... 22 
4.1 Study subjects ........................................................................................................................... 22 
4.2 Inclusion criteria ....................................................................................................................... 22 
4.3 Exclusion criteria...................................................................................................................... 23 
4.4 Screening dropouts ................................................................................................................... 26 
4.5 Withdrawal from study or discontinuation of administration ................................................... 26 
5. Treatments ...................................................................................................................................... 28 
5.1 Study drug ................................................................................................................................ 28 
5.1.1 Investigational product ...................................................................................................... 28 
5.2 Dosage and regimen ................................................................................................................. 28 
5.3 Selection of dose and timing of administration for each subject .............................................. 28 
5.4 Allocation method for each subject .......................................................................................... 29 
5.5 Blinding .................................................................................................................................... 29 
5.6 Packaging and labeling ............................................................................................................. 29 
5.7 Storage and management of study drug ................................................................................... 29 
5.8 Study drug management at the study site ................................................................................. 29 
5.9 Treatment compliance .............................................................................................................. 29 
6. Restrictions on subjects .................................................................................................................. 30 
6.1 Prior treatment (prior drugs/therapies) ..................................................................................... 30 
6.2 Treatment during study treatment period (concomitant drugs/therapies) ................................. 30 
6.2.1 Prohibited drugs and therapies: ......................................................................................... 30 


 
 
 
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6.2.2 Restricted drugs and therapies ........................................................................................... 32 
6.2.3 Drugs with which care required ........................................................................................ 32 
6.3 Other restrictions ...................................................................................................................... 33 
7. Study procedures and evaluation methods ..................................................................................... 34 
7.1 Obtaining informed consent ..................................................................................................... 34 
7.2 Confirmation of demographic factors and medical history ...................................................... 34 
7.3 Registration of subjects and prescription of study drug ........................................................... 35 
7.4 Psycho-education ..................................................................................................................... 35 
7.5 Efficacy evaluation ................................................................................................................... 35 
7.5.1 Children’s Depression Rating Scale-Revised (CDRS-R) .................................................. 35 
7.5.2 Clinical Global Impression of Severity (CGI-S) ............................................................... 36 
7.6 Pharmacokinetic evaluation ..................................................................................................... 36 
7.7 Safety evaluation ...................................................................................................................... 36 
7.7.1 Physical examination ......................................................................................................... 36 
7.7.2 Columbia Suicide Severity Rating Scale (C-SSRS) .......................................................... 37 
7.7.3 Body weight ...................................................................................................................... 37 
7.7.4 Blood pressure and pulse rate ............................................................................................ 37 
7.7.5 Electrocardiogram ............................................................................................................. 37 
7.7.6 Laboratory tests ................................................................................................................. 38 
7.7.6.1 Laboratory test items .................................................................................................. 38 
7.7.6.2 Methods for collection, storage, and shipment of samples ......................................... 39 
7.7.7 Evaluation of adverse events ............................................................................................. 39 
7.7.7.1 Evaluation methods for adverse events ...................................................................... 39 
7.7.7.2 Assessment period ...................................................................................................... 40 
7.7.7.3 Severity ....................................................................................................................... 40 
7.7.7.4 Causal relationship with study drug ........................................................................... 40 
7.7.7.5 Predictable adverse drug reactions ............................................................................. 41 
7.7.7.6 Adverse events of special concern .............................................................................. 41 
7.7.7.7 Adverse events such as laboratory test results ............................................................ 41 
7.7.7.8 Serious adverse events ................................................................................................ 42 
7.7.7.9 Abuse, misuse, overdose, and medication error (special situations) .......................... 43 
7.7.7.10 Pregnancy ................................................................................................................. 44 
7.7.7.11 Adverse events during study drug administration..................................................... 44 
7.8 Appropriateness of test items ................................................................................................... 44 
7.9 Permitted range of test times .................................................................................................... 44 
8. Statistical analysis .......................................................................................................................... 46 
8.1 Statistical analysis methods ...................................................................................................... 46 
8.2 Target number of subjects ........................................................................................................ 46 


 
 
 
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8.3 Analysis sets ............................................................................................................................. 46 
8.4 Handling of missing data .......................................................................................................... 46 
8.5 Subject characteristics .............................................................................................................. 47 
8.6 Demographic and baseline characteristics................................................................................ 47 
8.7 Study drug administration period, dosage, and treatment compliance ..................................... 47 
8.8 Prior treatment .......................................................................................................................... 47 
8.9 Concomitant treatment ............................................................................................................. 47 
8.10 Analysis of efficacy ................................................................................................................ 47 
8.11 Safety analysis ........................................................................................................................ 47 
8.11.1 Adverse events ................................................................................................................. 47 
8.11.2 Blood pressure, pulse rate, and body weight ................................................................... 48 
8.11.3 Laboratory test results ..................................................................................................... 48 
8.11.4 ECG ................................................................................................................................. 48 
8.11.5 Columbia Suicide Severity Rating Scale (C-SSRS) ........................................................ 48 
8.12 Pharmacokinetic analysis ....................................................................................................... 48 
8.13 Interim analysis ...................................................................................................................... 49 
9. Management-related items requiring attention ............................................................................... 50 
9.1 Principal investigator and study management system .............................................................. 50 
9.2 Institutional review board (IRB) .............................................................................................. 51 
9.3 Ethics ........................................................................................................................................ 52 
9.4 Providing information to patients and obtaining informed consent ......................................... 52 
9.5 Protection of subjects’ confidentiality ...................................................................................... 52 
9.6 Monitoring ................................................................................................................................ 53 
9.7 Case report forms and source documents ................................................................................. 53 
9.7.1 Case Report forms ............................................................................................................. 53 
9.7.2 Source documents and raw data ........................................................................................ 53 
9.7.3 External data ...................................................................................................................... 54 
9.8 Committees, meetings, etc. ...................................................................................................... 54 
9.8.1 Case review committee ..................................................................................................... 54 
9.8.2 Safety monitoring committee ............................................................................................ 54 
9.9 Study discontinuation or suspension ........................................................................................ 55 
9.9.1 Discontinuation or suspension of entire study ................................................................... 55 
9.9.2 Discontinuation or suspension of study at each study site ................................................ 55 
9.10 Modifications to and deviations from the protocol ................................................................ 55 
9.11 Data management ................................................................................................................... 56 
9.12 Storage of records ................................................................................................................... 56 
9.13 Study quality control and quality assurance ........................................................................... 56 
9.14 Decisions relating to publication ............................................................................................ 56 


 
 
 
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10. References .................................................................................................................................... 57 
Appendix 1: Study Schedule .............................................................................................................. 58 
Appendix 2: Management of abnormal hepatic function test results, and discontinuation criteria .... 60 
 
List of Tables 
Table 5-1. Treatment Regimens .......................................................................................................... 28 
Table 7-1. Children’s Depression Rating Scale-Revised .................................................................... 35 
Table 7-2. Routine laboratory tests ..................................................................................................... 38 
Table 7-3. Permitted range of time of examinations, observations and tests ...................................... 45 
 
List of Figures 
Fig. 3-1. Schematic diagram of study schedule .................................................................................. 21 
 
 


 
 
 
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List of abbreviations and definitions of terms 
 
Abbreviation and terms 
Definition 
5-HT 
5-hydroxytryptamine (serotonin) 
CDRS-R 
Children’s Depression Rating Scale-Revised 
CGI-S 
Clinical Global Impression of Severity 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
DSM-IV-TR 
Diagnostic and Statistical Manual of Mental Disorders Fourth Edition – Text 
Revision 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders Fifth Edition 
EDC 
electronic data capture 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FT3 
free triiodothyronine 
FT4 
free thyroxine 
IRB 
institutional review board 
LOCF 
last observation carried forward 
MAO 
monoamine oxidase 
MINI-KID 
Mini International Neuropsychiatric Interview for children and adolescents 
NA 
noradrenaline 
SNRI 
serotonin noradrenaline reuptake inhibitor 
SSRI 
selective serotonin reuptake inhibitor 
TSH 
thyroid stimulating hormone 


 
 
 
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1.  Background information 
Depression is a psychiatric disorder, with the principal symptoms being depressive mood, and 
mood/affective disorders such as anxiety and irritation, and it is often associated with volitional and 
behavioral disorders, and also generalized symptoms such as sleep disorders, anorexia, and fatigue. The 
etiology and pathology of depression have not been fully elucidated (1), but one fundamental concept of 
the mechanism of onset of depression is the monoamine hypothesis, according to which deficiency of 
monoamines, such as serotonin and noradrenaline, which are neurotransmitters at cerebral nerve terminals, 
results in decreased synaptic transmission (2). 
Before 1980, very little attention was given to pediatric depression, and it was thought to be a very rare 
condition. However, when the operational diagnostic criteria in DSM Version 3 (DSM-III), published by 
the American Psychiatric Association in 1980, were applied, it was found that there are children with 
depressive symptoms just as there are adults, and it is now clear that pediatric depression patients are far 
more numerous than previously thought (3). Overseas epidemiological studies have shown that the 
frequency of initial depressive episodes increases rapidly from the age of 12, and from that age the 
incidence of depression is approximately the same as in adults (4, 5). In addition, although the symptoms 
of depression change with developmental stage, it has been reported that from the age of 10 they 
increasingly resemble those of adults (6). In recent years, considerable attention has been given to 
pediatric/adolescent depression in Japan, and the number of patients diagnosed has increased (7). The 
progression and prognosis of pediatric depression are not good, as, according to a prognostic survey of 65 
patients by Kovacs (1984), 92% showed recovery within 18 months after onset, but with 40% of these the 
condition recurred within 2 years after recovery, and with 70% it recurred within 5 years after onset (8, 9). 
According to Fombonne (2001), a 20-year outcome survey of 149 patients with depression onset before 
the age of 18 showed recurrence of major depression with 62.4% (10). In other words, pediatric depression 
is readily cured, but also recurs readily (11); it is a condition showing both high incidence and ready 
recurrence. In addition, it is considered that it results in considerable psychosocial dysfunction, and also 
has major effects on family members (3). For these reasons, as with adult depression, prompt and 
appropriate diagnosis and treatment are important for pediatric depression. However, it cannot really be 
said that appropriate, evidence-based drug therapy is currently in use (7). In Japan, clinical studies of 
children and adolescent depression have not shown any safe and effective antidepressants, and no drugs 
are currently indicated for pediatric depression. However, based on the results of overseas clinical studies, 
the package insert of escitalopram has no description of careful administration to patients aged 12 to 17. 
The latest version of Treatment Guideline II: Major Depressive Disorder, amended from the previous 
version (amended 2013) by the Japanese Society of Mood Disorders in July 2016 (7) includes a new section, 
titled “Pediatric/adolescent depression”, which is an area of ongoing research, and the unmet medical needs 
for pediatric/adolescent antidepressants are thus proposed. In the USA also, on the basis of observational 
research on and reanalysis of clinical studies on serotonin/noradrenaline reuptake inhibitors and selective 
serotonin reuptake inhibitors, several reports have suggested that the risks of not prescribing 
antidepressants to juveniles are higher than the risks of prescribing them. Therefore, in July 2016, the 


 
 
 
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American Academy of Pediatrics amended its treatment guidance (Guidance for the Clinician in Rendering 
Pediatric Care) to recommend appropriate antidepressant treatment even for juveniles (12). 
Duloxetine is a compound that is classified as a serotonin/noradrenaline reuptake inhibitor and shows 
marked inhibition of both serotonin (5-HT) and noradrenaline reuptake. In Japan, after approval for 
treatment of depression and depressive state was achieved in January 2010, approval was achieved for the 
following indications: (i) pain associated with diabetic neuropathy; (ii) pain associated with fibromyalgia; 
(iii) pain associated with chronic low back pain; and (iv) pain associated with osteoarthritis. In worldwide 
terms, since approval for major depressive disorder was achieved in the USA in August 2004, it has been 
approved in more than 100 countries, including Japan, and is now in wide use. In addition, as of May 2017, 
in addition to major depressive disorder, it has been approved for numerous indications, including (i) pain 
associated with diabetic neuropathy; (ii) fibromyalgia; (iii) chronic musculoskeletal pain, including 
chronic low back pain and chronic osteoarthritis; (iv) stress urinary incontinence; and (v) generalized 
anxiety disorder. Most of the above indications are for adults, but in October 2014 generalized anxiety 
disorder was achieved as a pediatric indication in the USA. In addition, in March 2015 the Duloxetine 
Pediatric-Focused Safety Review (Cymbalta® [Duloxetine] Pediatric Advisory Committee Meeting) was 
held in the USA, no new safety-related concerns were identified, and the Food and Drug Administration 
(FDA)’s conclusion was that the usual safety monitoring should be continued (13). 
On the other hand, in the HMCK and HMCL studies, which were overseas, Phase-3, double-blind, parallel-
group, comparative studies with pediatric/adolescent major depressive disorder patients diagnosed on the 
basis of DSM Version 4 (amended version; DSM-IV-TR), although no particular safety-related problems 
were found, there were high placebo responses in both studies, and superiority over the placebo was not 
found with either duloxetine or the positive control, fluoxetine. However, on the basis of the results of a 
supplementary analysis performed before a Japanese study was planned, in a population of patients with 
treatment initiation at the age of ≥9 and depression onset at the age of ≥7, the changes in CDRS-R total 
scores in the duloxetine 30- and 60-mg groups were significantly higher than in the placebo group (in the 
HMCL study, this was the change at the final evaluation time-point, at week 10, by the LOCF method). In 
addition, as a tendency toward differences in placebo response between institutions was found, it is 
considered that performance of the study with a relatively small number of subjects, at an institution 
selected as having a low placebo response, is a method that is appropriate from the point of view of a 
clinical study, and that it should increase the probability of success. In addition, both the pediatric subjects 
enrolled in the study and their guardians are to be given basic psycho-education about treatment of 
depression, which will be systematic, and have the same contents, and this is expected to minimize the 
variation between subjects, thus increasing the detection power. At the same time, the psycho-education is 
to be provided consistently from the screening period, and subjects with high placebo response are to be 
excluded, thus reducing the mean placebo response. 
Under such background, the preceding study “Phase-3 clinical study of duloxetine hydrochloride in 
children and adolescent patients with depressive disorder: Superiority study versus placebo” (Study No.: 
1701A3631) will be conducted to evaluate the efficacy and safety of duloxetine in children and adolescent 


 
 
 
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patients with depressive disorder. Additionally, an extended long-term treatment study is planned in 
participants of the preceding study and new patients in order to confirm the long-term safety and efficacy 
of duloxetine. 
The duloxetine package insert includes, as drug-class labeling, the following requirement to take care: 
“There have been reports of an increased risk for suicidal ideation and/or suicidal attempt in antidepressant-
treated patients aged 24 years or younger, so consideration should be given to the risk/benefit relationship 
when this drug is to be administered”. Therefore, the intention is to take great care during performance of 
this study with the followings. Sufficient warning, especially about suicide-related adverse events is to be 
given to the principal investigator or sub-investigator. In addition, information about adverse events, 
especially those relating to suicide, as well as the evaluation by C-SSRS is to be gathered, and the Safety 
Evaluation Committee is to assess them. 


 
 
 
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2.  Study objectives 
To evaluate the long-term safety and efficacy of duloxetine in children and adolescent patients with 
depressive disorder. 
 
2.1  Primary objective 
• 
To evaluate the long-term safety of duloxetine in children and adolescent patients with depressive 
disorder. 
 
2.2  Secondary objectives 
• 
To evaluate the long-term efficacy of duloxetine in children and adolescent patients with depressive 
disorder. 
• 
To evaluate the pharmacokinetics of duloxetine in Japanese children and adolescent patients with 
depressive disorder. 
- 
To compare the plasma duloxetine concentrations at steady state obtained at 5 time points 
(including at least one predose level [trough]) from children and adolescent patients with 
depressive disorder with those of adult patients with depressive disorder. 
- 
To examine the potential factors that affect the pharmacokinetic properties of duloxetine (e.g., 
age, body weight, and sex) and their effects in the population pharmacokinetics analysis. 
• 
To evaluate the relationship between duloxetine exposure at steady state and Children’s Depression 
Rating Scale-Revised (CDRS-R) total score, one of the efficacy endpoints. 
 


 
 
 
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3.  Study plan 
3.1  Study design 
This study is a multicenter, open-label, uncontrolled, long-term treatment study in children and adolescent 
patients with depressive disorder. This study will include a total of 135 patients; consecutive subjects who 
have completed the preceding study then wish to continue the study treatment will be enrolled, as well as 
additional subjects who have child and adolescent depressive disorder, with a target of 100 subjects 
completing a 1-year treatment. 
As shown below, this study will consist of the following four periods (a total of 53 to 56 weeks): screening 
period (1 to 3 weeks), treatment period (50 weeks), tapering period (1 to 2 weeks), and follow-up period 
(1 week). Note that consecutive subjects will undergo three periods (a total of 52 to 53 weeks) excluding 
the screening period. 
Consecutive subjects will give consent to this study before completing the observation at Visit 9 in the 
preceding study, and, after completing the observation at Visit 9 in the preceding study and the eligibility 
of this study is confirmed, be enrolled to this study from Visit 2 (registration). 
• 
Screening period (for new subjects only): After obtaining informed consent, subjects for whom 
eligibility is confirmed will be pre-registered (at Visit 1) and the first session of psycho-education 
will be provided in addition to the subjects’ condition assessment. 
• 
Treatment period: Subjects for whom eligibility is confirmed will be registered (at Visit 2) and the 
study drug will be administered orally, once daily after breakfast, for 50 weeks. The administration 
of duloxetine will be initiated at 20 mg/day, then the dose will be increased to 40 mg/day from 1 
week after treatment initiation. From 2 weeks after treatment initiation, if there are no concerns 
about safety, the dose may be increased to 60 mg/day. Subsequently, until 50 weeks after treatment 
initiation, the dose may be increased to 40 mg/day or 60 mg/day as appropriate, depending on the 
symptoms. 
• 
Tapering period: In order to minimize the occurrence of adverse events due to discontinuation of 
administration, a 1- to 2-week tapering period is set for subjects who complete the treatment period, 
or who withdraw from it during the second week or later. Subjects whose duloxetine dose at 
discontinuation or completion of the treatment period is 60 mg/day will receive 40 mg/day for one 
week then 20 mg/day for one week. If the dose at discontinuation or completion is 40 mg/day, 20 
mg/day will be administered for one week. 
• 
Follow-up period: No study drugs will be administered during the 1-week follow-up period. This 
period is set to enable evaluation of any adverse events during the week after completion of study 
drug administration, irrespective of whether or not the dose was tapered. If administration is 
discontinued during the treatment period, and there is then no administration during the tapering 
period, a 1-week follow-up period will be set after administration discontinuation. 
 
The study design is shown in Fig. 3-1. The study schedule is shown in Appendix 1. 




 
 
 
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4.  Eligibility of subjects and discontinuation of study 
4.1  Study subjects 
Children and adolescent patients with depressive disorder who meet all of the following inclusion criteria 
and do not meet any of the exclusion criteria will be included in this study. 
 
4.2  Inclusion criteria 
Subjects must meet all the following criteria: 
Inclusion criteria 
Consecutive 
subjects 
New 
subjects 
1) 
Have completed a 7-week treatment in the preceding study and wish to 
continue treatment with duloxetine. 
X 
 
2) 
Have been diagnosed with depression or persistent depressive disorder, 
as defined in the Diagnostic and Statistical Manual of Mental 
Disorders, version 5 (DSM-5), and fully meet the criteria for a 
depressive episode. MINI-KID (version 7.0.2) is used for diagnosis of 
depression. 
 
X 
3) 
Are aged ≥9 to <18 at the time of obtaining consent and assent, and 
must have been ≥7 at the initial onset of depression episode. Are male 
or female and are hospitalized or out-patients. 
 
X 
4) 
Have a legal representative capable of providing written informed 
consent for this study. In addition, for patients aged ≥13, a written, 
informed assent must also be obtained from the patient him/herself. For 
patients aged ≥9 to <13, a written, informed assent should also be 
obtained from the patient him/herself if possible. 
X 
X 
5) 
For post-menarchic females, a pregnancy test result must be negative 
at Visit 1 (or Visit 2 for consecutive subjects). In addition, the patient 
must agree to use one of the following contraceptive methods from 
Visit 1 (or Visit 2 for consecutive subjects) until 1 month after the final 
administration. However, this requirement does not apply to females 
for whom it can be confirmed in writing that 6 weeks or more has 
passed since bilateral ovariectomy. 
Estrogen- 
and 
progesterone-containing, 
combined-hormonal 
contraceptive 
agents 
with 
ovulation-suppressing 
effects 
(administered 
orally, 
intravaginally, 
subcutaneously, 
etc.), 
progesterone-containing 
hormonal 
contraceptive 
agents 
(administered orally, intravenously, by implantation, etc.), 
intrauterine device, intrauterine system, bilateral tubal ligation, male 
X 
X 


 
 
 
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Inclusion criteria 
Consecutive 
subjects 
New 
subjects 
partner’s vasectomy, or sexual abstinence. 
6) 
The principal investigator or sub-investigator judges that the subject’s 
legal representative can ensure that the subject him/herself will comply 
with all hospital visits, tests, and other procedures stipulated in this 
protocol. In addition, the principal investigator or sub-investigator 
judges that the subject him/herself will be able to comply with all the 
hospital visits, tests, and other procedures stipulated in this protocol. 
 
X 
7) 
The principal investigator or sub-investigator judges that the subject’s 
legal representative has sufficient comprehension and cognitive ability 
to communicate as appropriate with the principal investigator or sub-
investigator, and other persons involved with the study. In addition, the 
principal investigator or sub-investigator confirms that the subject 
him/herself has a cognitive level appropriate to his/her age, and judges 
that he/she has sufficient comprehension and cognitive ability to 
communicate as appropriate with the principal investigator or sub-
investigator, and other persons involved with the study. 
 
X 
8) 
Have ability to swallow the capsules without opening, crushing, 
dissolving, or breaking them. In addition, he/she can take up to three 
capsules per day. 
 
X 
 
4.3  Exclusion criteria 
Patients who meet any of the following criteria will be excluded: 
Exclusion criteria 
Consecutive 
subjects 
New 
subjects 
1) 
Judged by the principal investigator or sub-investigator to have 
complications diagnosed as belonging to one or more of the following 
categories in DSM-5, or to have a history of such disorders: 
• 
Neurodevelopmental disorders 
• 
Schizophrenia-spectrum disorder or other psychotic disorders 
• 
Bipolar or related disorders 
• 
Trauma and stressor-related disorders 
• 
Disruptive, impulse‒control, and conduct disorders 
X 
X 
2) 
Judged by the principal investigator or sub-investigator to have 
complications diagnosed as belonging to one or more of the following 
categories in DSM-5: 
X 
X 


 
 
 
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Exclusion criteria 
Consecutive 
subjects 
New 
subjects 
• 
Obsessive-compulsive disorder or related disorders 
• 
Anorexia nervosa, bulimia nervosa, or binge-eating disorder 
• 
Sleep-wake disorders 
• 
Neurocognitive disorders 
• 
Disruptive mood dysregulation disorder 
3) 
Judged by the principal investigator or sub-investigator to have a 
personality disorder. 
X 
X 
4) 
Treatment with two or more antidepressants has previously been tried, 
and, despite treatment of a single depressive episode with the optimal 
clinical dose for 4 weeks or more, there has been no response. 
Alternatively, the depressive episode has been treated previously or is 
currently being treated with duloxetine, but without response. 
 
X 
5) 
The principal investigator or sub-investigator judges that systematic 
psychotherapy must be initiated between Visits 1 and 18. 
X 
X 
6) 
One or more of the patient’s parents and/or siblings has been diagnosed 
with bipolar disorder. 
X 
X 
7) 
A history of epileptic or other convulsive attacks. However, patients with 
a history of febrile convulsions can be enrolled. 
X 
X 
8) 
Administered electroconvulsive therapy within 1 year before Visit 1. 
 
X 
9) 
Uncontrolled diabetes or collagen disease. 
 
X 
10) Have initiated, changed or discontinued hormone replacement therapy 
within 3 months before Visit 1. Patients with thyroid dysfunction are 
excluded. But patients can be enrolled if they (i) have undergone thyroid 
hormone supplementation at a consistent dose for at least 3 months as of 
Visit 1; (ii) show medically appropriate thyroid hormone (TSH, FT3, FT4) 
concentrations; and (iii) have clinically normal thyroid function. 
 
X 
11) Currently have or have a history of malignant tumors/cancer. 
X 
X 
12) For new subjects, either (i) suicidal ideation and/or suicidal attempt 
within 1 year before Visit 1; or (ii) at Visits 1 and 2 (or Visit 2 for 
consecutive subjects), answer “Yes” to questions 4 and/or 5 about 
suicidal ideation, and/or any of the questions about suicidal behaviors 
(except those about non-suicidal self-injurious behavior), on the 
Columbia suicide severity rating scale (C-SSRS). 
X 
X 
13) Body weight below 20 kg at Visit 2. 
X 
X 
14) Serious*1 or medically unstable*2 disease (cardiovascular disease, hepatic 
X 
X 


 
 
 
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Exclusion criteria 
Consecutive 
subjects 
New 
subjects 
disease, respiratory disease, hematologic disease, endocrine disease, 
peripheral vascular disorder, neuropsychiatric disease, renal disease), or 
clinically problematic abnormal laboratory test results or abnormal 
electrocardiography (ECG) findings*3. 
*1: 
Grade 3 in ''Concerning classification criteria for seriousness of adverse drug 
reactions to pharmaceutical products, etc.” (Drug Safety Notification no. 80; June 
29, 1992). 
*2:  Judged by the principal investigator or sub-investigator to have the potential to 
disrupt study participation, or to necessitate hospitalization during the study 
period. 
*3: 
Judged by the principal investigator or sub-investigator to suggest serious 
medical problems, or to necessitate aggressive therapy. 
15) Meeting one or more of the following criteria: 
• 
At Visit 2, latest ALT or AST of 100 U/L or higher, or latest total 
bilirubin of 1.6 mg/dL or higher. 
• 
Latest serum creatinine level of 2.0 mg/dL or higher at Visit 2. Or 
have severe renal impairment, history of renal transplantation, 
and/or currently undergoing renal dialysis. 
X 
X 
16) Glaucoma, elevated intraocular pressure, and/or prostatic hypertrophy or 
other types of dysuria. 
X 
X 
17) Depression or depressive state due to organic brain disorder. 
X 
X 
18) Hemorrhagic tendency or hemorrhagic diathesis. 
X 
X 
19) Treatment with monoamine oxidase (MAO) inhibitor within 14 days 
before Visit 2, and/or potential for MAO inhibitor treatment during the 
study period or within 5 days after completion of study drug 
administration. 
X 
X 
20) Hypersensitivity to duloxetine or inactive ingredients of duloxetine 
formulation. 
X 
X 
21) Allergic to two or more drugs, or a history of serious allergic reactions to 
one or more drugs. 
X 
X 
22) Judged by the principal investigator or sub-investigator to have the 
complication of substance-related and/or addictive disorders, as defined 
in DSM-5, or a history of such disorders. However, patients with 
caffeine-related disorder can be enrolled. 
 
X 
23) One or more substances of abuse (phencyclidines, benzodiazepines, 
 
X 


 
 
 
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Exclusion criteria 
Consecutive 
subjects 
New 
subjects 
cocaine-type drugs, stimulants, cannabis, opioids, barbiturates, tricyclic 
antidepressants, etc.) detected by urinary drug screening at Visit 2. 
24) Intension to travel overseas between Visit 1 (or Visit 2 for consecutive 
subjects) and Visit 6. 
X 
X 
25) Pregnant* or possibly pregnant, breastfeeding, hoping to become 
pregnant during the study period. Or recently given birth. 
* Pregnancy: Pregnancy tests (blood or urine human chorionic gonadotropin) will be 
performed in all post-menarchic females. 
X 
X 
26) Previously administered the study drug during participation in this study, 
or during participation in a different clinical study on duloxetine. 
 
X 
27) Have received another study drug within 30 days before Visit 1 or are 
currently receiving it. 
 
X 
28) Participation judged to be inappropriate for any other reason by the 
principal investigator or sub-investigator. 
X 
X 
 
4.4  Screening dropouts 
A subject who gives informed consent to participate in the study but is not registered in the study will be 
considered as a screening dropout. The following are entered in these patients’ case report forms (CRFs): 
date of obtaining legal representative’s written, informed consent; date of obtaining the patient’s written 
assent (if applicable); demographic factors; information about meeting inclusion criteria and violating 
exclusion criteria; dropout date; reasons for dropping out; and adverse events leading to dropping out and 
serious adverse events. 
 
4.5  Withdrawal from study or discontinuation of administration 
The principal investigator or sub-investigator will as far as possibly encourage subjects to complete the 
study, but subjects can withdraw for any reason. The principal investigator or sub-investigator will notify 
the sponsor about all discontinuations. If one or more of the following is applicable, the principal 
investigator or sub-investigator will discontinue study drug administration to the subject, and then 
discontinue the study. Note that the study will be considered completed when administrations and 
observations up to Visit 19 are completed. 
• 
The principal investigator or sub-investigator judges discontinuation to be necessary due to one or 
more serious or intolerable adverse events. 
• 
The principal investigator or sub-investigator judges that insufficient efficacy of the study drug has 
resulted in aggravation of the primary disease, making discontinuation necessary. 
• 
Pregnancy of the subject. 


 
 
 
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• 
The subject or his/her legal representative expresses the wish to withdraw from the study. 
• 
The ineligibility of the subject is revealed after registration. 
• 
Administration of duloxetine at a dose of 40 mg/day or higher is difficult at or after Visit 3. 
• 
The subject is unable to visit hospital due to moving home, transferring to a different hospital, etc. 
• 
Death of the subject. 
• 
It is judged that management of abnormal hepatic function test results is necessary, as is withdrawal 
on the basis of the discontinuation criteria (Appendix 2). 
• 
Discontinuation is judged by the principal investigator or sub-investigator to be necessary for any 
other reason. 
If a subject is withdrawn, the principal investigator will promptly report the withdrawal to the sponsor, and 
will as far as possible perform the assessments and tests for discontinuation of the treatment period or 
tapering period. Subjects withdrawn during the treatment period will be transferred to the tapering period. 
In the case of subjects withdrawn during the tapering period, the assessments for the follow-up period will 
be performed. All subjects withdrawn because of adverse events will be followed up until one of the 
following: (i) recovery from the adverse event to the state pertaining before administration initiation; (ii) 
the investigator or sub-investigator judges that the symptoms have stabilized or become chronic; and (iii) 
it is not possible to maintain communications with the subject. In addition, the date of completion or 
discontinuation of the treatment period or tapering period (as applicable), and the reasons for 
discontinuation (if applicable), will be recorded in the CRF. 
 
 


 
 
 
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5.  Treatments 
5.1  Study drug 
5.1.1  Investigational product 
• 
Product name:  
LY248686 
• 
Nonproprietary name:  
Duloxetine hydrochloride (JAN) 
• 
Chemical name:  
(+)-(S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine 
monohydrochloride 
• 
Components, content, and dosage form:  Dark brown, opaque, hard capsule, packed with enteric 
granules, containing 20 mg of duloxetine per capsule 
 
5.2  Dosage and regimen 
All subjects will receive oral duloxetine once daily after breakfast for 51 or 52 weeks (a 50-week treatment 
period and 1- to 2-week tapering period) from the day after registration (Visit 2). Note that, once or twice 
between Visits 5 and 17, the subjects should visit the study site without taking a dose to collect a blood 
sample for pre-dose PK (refer to Section 7.6 ). Table 5-1 shows the treatment regimens for the study drug. 
During the treatment period, the subjects will receive duloxetine 20 mg/day for one week then 40 mg/day 
for one week, and subsequently receive either 40 mg/day or 60 mg/day for 48 weeks as appropriate. 
Subjects who complete the treatment period or who withdraw from it during Week 2 or later of treatment 
period will be transferred to the tapering period. During the tapering period, subjects whose duloxetine 
dose at discontinuation or completion of the treatment period is 60 mg/day will receive 40 mg/day for one 
week then 20 mg/day for one week. Subjects whose duloxetine dose at discontinuation or completion of 
the treatment period is 40 mg/day will receive 20 mg/day for one week. However, tapered administration 
may be omitted if serious adverse drug reactions occur, there are safety-related problems, or the subject or 
his/her legal representative refuses the tapered administration. 
 
Table 5-1. Treatment Regimens 
Treatment period 
Tapering period 
Week 1 
Week 2 
Weeks 3 - 50 
Week 51 
Week 52 
20 mg/day 
40 mg/day 
60 mg/day 
40 mg/day 
20 mg/day 
1 x 20 mg LY248686 
capsule 
2 x 20 mg LY248686 
capsule 
3 x 20 mg LY248686 
capsule 
2 x 20 mg LY248686 
capsule 
1 x 20 mg LY248686 
capsule 
40 mg/day 
20 mg/day 
- 
2 x 20 mg LY248686 
capsule 
1 x 20 mg LY248686 
capsule 
- 
 
5.3  Selection of dose and timing of administration for each subject 
During Weeks 3 to 50 of the treatment period, the subjects will receive duloxetine 40 mg/day or 60 mg/day 
for 48 weeks depending on symptoms. As described in Section 5.2 , the tapering period will be 1 or 2 
weeks based on the dose at discontinuation or completion of the treatment period. 
 


 
 
 
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5.4  Allocation method for each subject 
This study is not a randomized study and all enrolled subjects will receive duloxetine. 
 
5.5  Blinding 
This study is an open-label study in which no one is blinded. 
 
5.6  Packaging and labeling 
One Press Through Package (PTP) sheet contains 10 capsules of the study drug (LY248686 20 mg) and a 
box contains 10 PTP sheets. Each study drug box is labeled with the investigational material development 
number (LY248686), manufacturing number, expiration date, storage condition, a statement that it is for 
investigational use, and the sponsor’s name and address. 
 
5.7  Storage and management of study drug 
LY248686 should be stored in a tight container at room temperature. 
The sponsor will supply the study drug to the study drug manager designated by the director of the study 
site, in accordance with the contract between the sponsor and the study site. The study drug manager will 
store/manage 
the 
study 
drug 
according 
to 
the 
separately 
prepared 
procedures 
for 
handling/storage/management of the study drug, and record the use of study drug. 
 
5.8  Study drug management at the study site 
Unused study drug does not have to be stored under the conditions stipulated in this protocol, but all such 
materials will be stored at the study site. The study drug manager will accurately record the amount of 
unused study drug at study completion, place all unused study drug in appropriate boxes, and return it to 
the sponsor together with a photocopy of the study drug management table. 
 
5.9  Treatment compliance 
At each study site visit, the subjects should return unused study drugs to the study site. The investigator or 
sub-investigator will confirm treatment compliance, ascertaining the exact amount of the drug taken since 
the previous visit. At each visit, the duration of study drug administration, dosage, and a number of unused 
capsules will be entered in the CRF. If the prescription is changed, the change of prescription and its reason 
should also be entered. If unused study drug is found when checking the treatment compliance, the 
investigator or sub-investigator will instruct the subject about the importance of treatment compliance. 
The subject is taken to be noncompliant when, since the previous visit, the proportion of days on which 
the drug has not been taken as stipulated exceeds 30%. On the other hand, if the drug taken exceeds the 
stipulated dose on even one occasion, this is taken to constitute noncompliance, and a Special Situations 
Report is submitted to the sponsor. 


 
 
 
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6.  Restrictions on subjects 
6.1  Prior treatment (prior drugs/therapies) 
For new subjects, a treatment received prior to the observation of Visit 1 will be considered as a prior 
treatment (prior drug/therapy). The restrictions on prior treatment are stipulated in Section 4.3 . 
For all depression treatments performed for new subjects within 2 weeks before Visit 1, including ethical 
drugs, over-the-counter drugs, and non-pharmaceutical therapies, the name of the drug or therapy, dosage, 
administration route, and duration of treatment will be recorded in the CRF. For consecutive subjects, the 
prior treatment will be based on the information obtained in the CRF of the preceding study. 
 
6.2  Treatment during study treatment period (concomitant drugs/therapies)  
Concomitant treatments (concomitant drugs/therapies) will include treatments performed after the 
observation at Visit 1 (or after completing the observation at the completion of the tapering period in the 
preceding study for consecutive subjects). 
The investigator or sub-investigator will record in the CRF the following information about treatments 
(ethical drugs, over-the-counter drugs, and non-pharmaceutical therapies) administered to the relevant 
subject between Visit 1 (or after completing the observation at the completion of the tapering period in the 
preceding study for consecutive subjects) and Visit 19 (completion of the follow-up period): 
• 
Name of the concomitant drug or non-pharmaceutical therapy 
• 
Administration route 
• 
Occurrence or non-occurrence of dosage changes, and whether use is as-needed basis or not 
• 
Duration of treatment 
• 
Reasons for use 
However, the following drugs do not have to be recorded in the CRF unless they are the cause of adverse 
events: 
• 
Drugs for diluting solutions, such as physiological saline solution 
• 
Drugs used in medical procedures, etc., with the drug itself not being for treatment, such as alcohol 
disinfection, and heparin lock. 
• 
Items that are not recognized as drugs, such as foods. However, health foods, etc., with ingredient 
of contraindicated drugs or restricted drugs have to be recorded in the CRF. 
• 
Fluid replacement or infusion solution, unless used to treat adverse events. 
• 
Drugs used for tests, such as contrast agents and pre- and post-medication 
 
6.2.1  Prohibited drugs and therapies: 
Use of the below drugs, or over-the-counter drugs with equivalent effects, is prohibited from Visit 1 (or 
after completing the observation at the completion of the tapering period in the preceding study for 
consecutive subjects) through to Visit 18 (completion of the tapering period): 
Prohibited drugs that may affect therapeutic evaluation: 
1) 
Antidepressants 


 
 
 
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2) 
Anxiolytics 
3) 
Soporific agents, other than the “Permitted soporific agents” in Section 6.2.2  
4) 
Antipsychotics 
5) 
Antiparkinsonian agents 
6) 
Anticonvulsants 
7) 
Mood-stabilizers (lithium carbonate, carbamazepine, sodium valproate) 
8) 
Psychostimulants 
9) 
Adrenal corticosteroids (excluding topical agents, such as ear drops, nose drops, eye drops, topical 
skin formulations, and inhaled formulations). 
10) Interferon formulations 
11) Any of the following drugs, which might affect the metabolic/agonistic activities of serotonin or 
noradrenaline: 
Cyproheptadine hydrochloride (Periactin®, etc.) 
Dimetotiazine mesilate (Migristene®) 
Ifenprodil tartrate (Cerocral®, etc.) 
5-HT3 inhibitors (Zofran®, etc.) 
5-HT4 stimulants (Gasmotin®, etc.) 
5-HT1B/1D receptor agonists (Imigran®, etc.) 
Adrenergic agents (Noradrenaline®, etc.) 
12) St. John’s wort 
13) Chinese herbal medicines administered to treat central nervous conditions such as insomnia, 
neurosis or anxiety. 
14) Other agents judged to act on the central nervous system, and thus affect therapeutic evaluation. 
 
Prohibited drugs that present safety-related problems: 
1) 
MAO inhibitors (FP®, Azilect®, etc.) 
**Administration of these is contraindicated from 14 days before Visit 2 (or after completing the observation 
at the completion of the tapering period in the preceding study for consecutive subjects) until 5 days after 
completion of study drug administration. 
2) 
Other investigational drugs 
 
Unless specifically stated otherwise, use of the following treatments is contraindicated from Visit 1 (or 
after completing the observation at the completion of the tapering period in the preceding study for 
consecutive subjects) through to Visit 18 (completion of the tapering period): 
1) 
Electroconvulsive therapy 
2) 
Bright-light therapy, i.e. therapy using irradiation devices approved as medical devices. 
3) 
Systematic psychotherapy, such as systematically organized cognitive therapy, cognitive 
behavioral therapy, and interpersonal psychotherapy. For new subjects, this study will use 


 
 
 
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educational tools, consistently in all institutions, for the psycho-education of subjects and guardians. 
4) 
Exercise therapy 
5) 
Hormone therapy is contraindicated. However, in accordance with exclusion criterion 10, treatment 
can be continued at the same dose with thyroid dysfunction patients show meet the following three 
criteria: (i) having undergone thyroid hormone supplementation for at least 3 months as of Visit 1 
(or Visit 2 for consecutive subjects); (ii) showing medically appropriate concentrations of thyroid 
hormones (TSH, FT3 and FT4); and (iii) having attained a clinically normal state of thyroid function. 
 
6.2.2  Restricted drugs and therapies 
The following permitted soporific agents and restricted drugs and therapies may only be used under the 
stipulated conditions from Visit 1 (or after completing the observation at the completion of the tapering 
period in the preceding study for consecutive subjects) to Visit 18 (completion of the tapering period): 
Permitted soporific agents: 
The following soporific agent may be used in subjects aged ≥15: 
Ramelteon (Rozerem ®) 
 
Restricted drugs: 
Antihistamine agents (e.g. pseudoephedrine, diphenhydramine) and commercially available drugs 
containing antihistamine agents should only be used 12 hours or more before CDRS-R or Clinical Global 
Impression of Severity (CGI-S) evaluation (except in the case of topical agents, such as ear drops, nose 
drops, eye drops, topical skin formulations, and inhaled formulations). 
If antihistamine agents or commercially available drugs containing antihistamine agents are used, the time 
of use is confirmed with the subject, and at least 12 hours is allowed to pass after use of these drugs before 
the CDRS-R or CGI-S evaluation. 
 
6.2.3  Drugs with which care required 
Sufficient care about subjects’ safety should be taken when using any of the following drugs between Visit 
1 (or after completing the observation at the completion of the tapering period in the preceding study for 
consecutive subjects) and Visit 18 (completion of the tapering period): 
1) 
Hypotensive agents (central sympathetic suppressors), such as clonidine hydrochloride. 
2) 
Drugs with high protein-binding rates, such as warfarin potassium and clofibrate 
3) 
CYP1A2-inhibitors, such as cimetidine. 
4) 
CYP2D6-inhibitors and substrates, such as quinidine sulfate®, Pronon tablets®, and Tambocor 
tablets®  
5) 
Formulations containing serotonin precursors such as L-tryptophan and 5-hydroxytryptophan 
6) 
Tramadol 
7) 
Linezolid 
8) 
Nonsteroidal anti-inflammatory drugs 


 
 
 
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9) 
Pimozide 
10) Alcohol 
11) Ciprofloxacin 
12) Triptan-based agents 
13) Methylene blue 
 
6.3  Other restrictions 
It will be explained to subjects that they should comply with the following points from Visit 1 (or after 
completing the observation at the completion of the tapering period in the preceding study for consecutive 
subjects) to Visit 18 (completion of tapering period): 
1) 
If an over-the-counter drug is to be taken, obtain approval by the investigator or sub-investigator 
first. 
2) 
Do not drink alcohol. 
3) 
Do not operate potentially dangerous machinery. 
4) 
Use contraception (in the case of post-menarchic females only). 
 
It will be explained to subjects that they should comply with the following points after completion of study 
drug administration: 
1) 
MAO inhibitor should not be used within 5 days of completion of dosing of the study drug. 
2) 
Use reliable contraception until 1 month after completion of study drug administration (in the case 
of post-menarchic females only). 
 


 
 
 
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7.  Study procedures and evaluation methods 
The performance times are shown in Appendix 1. 
 
7.1  Obtaining informed consent 
The principal investigator or sub-investigator will give a sufficient explanation about the details of this 
study to subjects and their legal representatives, using informed consent explanatory documents and assent 
documents approved by the Institutional Review Board (IRB), and will obtain written, informed consent 
from the legal representatives before initiation of the study. Subjects will be given explanations about the 
details and duration of the study, using information, words and technical terms appropriate to their 
comprehension ability, and signatures on assent forms will be obtained from those aged ≥13. Written assent 
will also be obtained from subjects <13 years old if possible, but oral assent is acceptable if obtaining 
written assent is difficult. Each subject’s legal representative will, after signing the informed consent form, 
enter a statement that written or oral assent has been obtained from the subject. Photocopies of the signed 
or sealed informed consent form and assent form will be provided to the relevant subject or his/her legal 
representative, and the principal investigator will store the original. Informed consent must be obtained 
from all subjects’ legal representatives. Subjects can be enrolled in this study once their legal 
representatives have signed or sealed the informed consent forms. The following will be entered in the 
patients’ case report forms (CRFs): date of obtaining legal representative’s written, informed consent; and 
date of obtaining the patient’s written assent (if applicable). 
The principal investigator or sub-investigator must enable the subject and his/her legal representative to 
understand the risks and benefits associated with participation in the study, not only when giving an 
explanation before study initiation, but also in response to questions from the subject or his/her legal 
representative at any time during the study. If any information that may affect the wish of a subject and/or 
his legal representative to continue with study participation is obtained during the study, this information 
must be promptly explained to the subject and his/her legal representative. 
 
7.2  Confirmation of demographic factors and medical history 
(1) 
Baseline subject characteristic and medical history 
For new subjects, the following baseline subject characteristics will be obtained at Visit 1 and entered in 
the CRF: date of birth; sex; height; ethnicity; race; hospitalization status; history of current condition (age 
at onset of depression, number of depressive episodes to date, timing of onset of current episode); disease 
category according to DSM-5; and medical history. As to medical history, important aspects of medical 
history necessitating hospitalization and/or surgery, all complications continuing as of the time of obtaining 
informed consent, and surgical history are determined. 
For consecutive subjects, the baseline subject characteristics and medical history will be based on the 
information obtained in the CRF of the preceding study. 
 


 
 
 
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(2) 
Urinary drug screening 
For new subjects, urinary drug tests will be performed at Visit 2, and the presence or absence of substances 
of abuse (phencyclidine, benzodiazepines, cocaine-type drugs, stimulants, cannabis, opioids, barbiturates, 
tricyclic antidepressants, etc.) will be determined. 
 
7.3  Registration of subjects and prescription of study drug 
After confirming the eligibility of subjects on the basis of the inclusion and exclusion criteria, the principal 
investigator, sub-investigator, or study collaborators will enter the necessary information in Electronic 
Data Capture (EDC) then pre-register and register subjects at Visits 1 (new subjects only) and 2, 
respectively. After enrolling subjects in the study, the principal investigator, sub-investigator, or study drug 
manager will prescribe the study drug in accordance with the stipulations in Section 5.  
 
7.4  Psycho-education 
Fundamental psycho-education about depression treatment will be provided systematically, with the same 
contents, to new subjects only (consecutive subjects have taken the sessions in the preceding study). The 
principal investigator, sub-investigator, or clinical psychologist will hold sessions with the subjects and 
guardians at Visits 1, 2, 5, and 6. Psycho-education is provided after evaluation of CDRS-R and CGI-S. At 
each session, the subjects and guardians will watch a DVD, followed by a question and answer session 
with the principal investigator or sub-investigator, and a clinical psychologist or similar. The session date 
and name will be recorded in the CRF. The details of the psycho-education are stipulated in a separately 
specified procedures. 
 
7.5  Efficacy evaluation 
7.5.1  Children’s Depression Rating Scale-Revised (CDRS-R) 
At Visits 1 (or Visit 2 for consecutive subjects) to 17 (or at discontinuation of treatment), the severity of 
symptoms for the below 17 items will be judged using CDRS-R (Table 7-1). The date and results of 
evaluation will be recorded in the CRF. At discontinuation of treatment, evaluation will be performed if 
possible, and recorded in the CRF. 
 
Table 7-1. Children’s Depression Rating Scale-Revised 
Endpoints 
Score range 
Endpoints 
Score range 
1. Impaired Schoolwork 
1 to 7 
11. Depressed Feelings 
1 to 7 
2. Difficulty Having Fun 
1 to 7 
12. Morbid Ideation 
1 to 7 
3. Social Withdrawal 
1 to 7 
13. Suicidal Ideation 
1 to 7 
4. Sleep Disturbance 
1 to 5 
14. Excessive Weeping 
1 to 7 
5. Appetite Disturbance 
1 to 5 
15. Depressed Facial Affect 
1 to 7 
6. Excessive Fatigue 
1 to 7 
16. Listless Speech 
1 to 5 
7. Physical Complaints 
1 to 7 
17. Hypoactivity 
1 to 7 
8. Irritability 
1 to 7 
 
 
 
9. Excessive Guilt 
1 to 7 
 
 
 
10. Low Self-Esteem 
1 to 7 
Total 
17 to 113 


 
 
 
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7.5.2  Clinical Global Impression of Severity (CGI-S) 
At Visits 1 (or Visit 2 for consecutive subjects) to 17 (or at discontinuation of treatment), the principal 
investigator or sub-investigator will evaluate the disease severity in terms of the below grades 1 to 7. The 
date and results of evaluation will be recorded in the CRF. At discontinuation of treatment, evaluation will 
be performed if possible, and recorded in the CRF. 
 
1. Normal / no disease 
2. Bordering on disease 
3. Mild disease 
4. Moderate disease 
5. Marked disease 
6. Severe disease 
7. Extremely severe disease 
 
7.6  Pharmacokinetic evaluation 
Random blood samples for quantitation of plasma concentrations of duloxetine will be collected from all 
subjects five times between Visit 5 and the completion of study drug administration during the treatment 
period. Note that, for one or two of the five collections, subjects should visit the study site without taking 
the study drug to collect pre-dose blood samples. If the dose is increased or decreased, blood samples 
should be collected at least 2 weeks after the dose adjustment. The date and time of blood collection and 
the date and time of the last dose of study drug prior to blood collection will be recorded in the CRF. 
A 2 mL blood sample will be collected in a heparin containing tube and should be centrifuged at 3,000 x 
g for 15 minutes at room temperature or 4°C within 30 minutes after collection. The separated blood 
plasma will be dispensed into two polypropylene tubes at approximately 0.3 mL each and stored at −20°C 
or below. Samples will be collected by 
 (refer to Section 7.7.6.2 ). 
 will store samples (0.3 mL each) at −20°C or below and send to the drug concentration 
laboratory (
) with dry ice. 
The drug concentration laboratory will analyze the plasma samples within 13 months after collection. 
 
 
 
 
 
 
 
 
 
 
7.7  Safety evaluation 
7.7.1  Physical examination 
At Visits 1 (or Visit 2 for consecutive subjects) to 18 (or discontinuation of the treatment or tapering period) 
and Visit 19, the principal investigator or sub-investigator will examine the subject by the standard methods 
in use at the relevant institution, and will ascertain the occurrence or non-occurrence of adverse events. 
When an adverse event is found, the details will be recorded in the CRF. If necessary, examination 
appropriate to the signs and symptoms will also be performed, as judged appropriate by a physician. For 
2 weeks after the initial administration of the study drug, the subject’s progression will be monitored with 
special care. 


 
 
 
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7.7.2  Columbia Suicide Severity Rating Scale (C-SSRS) 
At Visits 1 (or Visit 2 for consecutive subjects) to 18 (or discontinuation of the treatment or tapering period), 
the principal investigator or sub-investigator will evaluate suicidal thinking using a questionnaire. For 
consecutive subjects, a measurement at Visit 9 in the preceding study may be used as a measurement at 
Visit 2 of this study. The date and results of evaluation will be recorded in the CRF. The principal 
investigator or sub-investigator will judge whether any abnormal change from baseline (Visit 2) is 
clinically significant (refer to Section 7.7.7.7 ) and will record any changes judged to be clinically 
significant as adverse events. 
 
7.7.3  Body weight 
Body weight (kg) will be measured at Visits 2, 5, 8, 11, 14, 17 (or at discontinuation of the treatment 
period) and Visit 18 (or at discontinuation of the tapering period). For consecutive subjects, a measurement 
at Visit 9 in the preceding study may be used as a measurement at Visit 2 of this study. The date and result 
of measurement will be recorded in the CRF. The principal investigator or sub-investigator will judge 
whether any abnormal change from baseline (Visit 2) is clinically significant (refer to Section 7.7.7.7 ) and 
will record any changes judged to be clinically significant as adverse events. 
 
7.7.4  Blood pressure and pulse rate 
The blood pressure (systolic and diastolic) and pulse rate, at rest, will be measured at Visits 1 (new subjects 
only), 2, 5, 8, 11, 14, 17 (or at discontinuation of the treatment period) and Visit 18 (or at discontinuation 
of the tapering period). For consecutive subjects, a measurement at Visit 9 in the preceding study may be 
used as a measurement at Visit 2 of this study. The date and result of measurement will be recorded in the 
CRF. The principal investigator or sub-investigator will judge whether any abnormal change from baseline 
(Visit 2) is clinically significant (refer to Section 7.7.7.7 ) and will record any changes judged to be 
clinically significant as adverse events. 
 
7.7.5  Electrocardiogram 
Standard, 12-lead electrocardiogram (ECG) will be performed at Visits 1 (or Visit 2 for consecutive 
subjects), 5, 11, and 18 (or at discontinuation of the tapering period; if not transferred to the tapering period, 
at completion or discontinuation [Visit 17] of the treatment period). For consecutive subjects, a 
measurement at Visit 9 in the preceding study may be used as a measurement at Visit 2 of this study. The 
principal investigator or sub-investigator will judge whether ECG results are normal or abnormal, and will 
record the date of ECG, the judgment, and any abnormal findings in the CRF. 
If there are abnormal findings, the principal investigator or sub-investigator will judge whether the 
abnormal change from baseline (i.e., Visit 1 for new subjects or Visit 2 for consecutive subjects) is 
clinically significant (refer to Section 7.7.7.7 ), and will record any changes judged to be clinically 
significant as adverse events. 


 
 
 
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7.7.6  Laboratory tests 
7.7.6.1  Laboratory test items 
At Visits 1 (or Visit 2 for consecutive subjects), 5, 8, 11, 14, and 18 (or at discontinuation of the tapering 
period; if not transferred to the tapering period, at completion or discontinuation [Visit 17] of the treatment 
period), blood samples will be collected for laboratory tests, the volumes being 2 mL for hematology tests, 
and 8 mL and 5 mL for blood chemistry tests, at Visit 1 and other visits, respectively; and urine samples 
will also be collected. The samples will then be sent to the clinical laboratory facility specified in Section 
7.7.6.2 . Details of the collection, handling, storage, and shipment of samples are stipulated in a separate 
document. For new subjects, blood samples and urine samples at Visit 1 will be collected after obtaining 
informed consent, between 3 weeks before the initial administration of the study drug and Visit 2. For 
consecutive subjects, a measurement at Visit 9 in the preceding study may be used as a measurement at 
Visit 2 of this study. Both new subjects and consecutive subjects will be registered after the latest 
measurements at Visit 2 are confirmed. 
The principal investigator or sub-investigator will judge whether the abnormal change from baseline (i.e., 
Visit 1 for new subjects or Visit 2 for consecutive subjects) is clinically significant (refer to Section 7.7.7.7 ), 
and will record any changes judged to be clinically significant as adverse events. The sample collection 
dates will be recorded in the CRF for each sample type (blood or urine). 
 
7.7.6.1.1  Routine tests 
Table 7-2 shows the routine hematology test, blood chemistry test, and urinalysis parameters. 
 
Table 7-2. Routine laboratory tests 
Classification 
Parameter 
Hematology 
Leukocyte count, erythrocyte count, hemoglobin, hematocrit, leukocyte 
fractions (eosinophils, basophils, neutrophils, monocytes, lymphocytes), platelet 
count 
Blood chemistry 
AST, ALT, LDH, γ-GTP, ALP, creatine kinase, total bilirubin, total protein, 
blood urea nitrogen, serum creatinine, uric acid, total cholesterol, 
triglycerides, Na, K, Cl, Ca, blood glucose, HbA1ca, TSHa, FT33a, FT44a 
Urinalysis (qualitative) 
Urinary protein, urinary glucose, urobilinogen, urinary occult blood 
a 
For new subjects, measurements will be obtained at Visit 1 only. 
 
7.7.6.1.2  Pregnancy test 
Pregnancy will be determined by the test for human chorionic gonadotropin (HCG) in urine or serum (only 
with post-menarchic females) at Visits 1 (or Visit 2 for consecutive subjects) and 18 (or at discontinuation 
of the tapering period; if not transferred to the tapering period, at completion or discontinuation of the 
treatment period [Visit 17]). For consecutive subjects, a measurement at Visit 9 in the preceding study may 
be used as a measurement at Visit 2 of this study. 
 


 
 
 
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7.7.6.2  Methods for collection, storage, and shipment of samples 
An principal investigator, sub-investigator, nurse, or medical technician will collect blood and urine 
samples at the stipulated times, and send them to the below clinical laboratory facility. Details of the 
collection, handling, storage, and shipment of samples are specified in a separate document. 
 
 
 
 
 
 
 
 
 
 
 
 
7.7.7  Evaluation of adverse events 
7.7.7.1  Evaluation methods for adverse events 
An adverse event is any unfavorable medical event suffered by someone administered a pharmaceutical 
product (including a study drug) and does not necessarily have a causal relationship with the relevant 
pharmaceutical product. In other words, an adverse event is any unfavorable and/or unexpected sign 
(including abnormal laboratory test result), symptom, or disease associated with the administration of a 
drug, irrespective of any causal relationship with that drug. Surgery that was already planned is not 
considered to be an adverse event, unless it leads to exacerbation of an existing disease, and is therefore 
not considered to be a serious adverse event even if it necessitates hospitalization. However, if an additional 
surgery is performed in connection with the planned surgery, this is taken to be an adverse event, and to 
be a serious adverse event if prolongation of hospitalization is required, or if any other criterion for being 
a serious adverse event is met. Hospitalization or prolongation of hospitalization for reasons other than 
adverse events is not considered to constitute a serious adverse event. 
The presence or absence of an adverse event will be confirmed on the basis of the subject’s spontaneous 
complaint, non-inductive questions, examination, C-SSRS, blood pressure, pulse rate, body weight, and 
ECG or laboratory test results. Adverse events include new onset of an event, increase in the severity or 
frequency of an event since administration initiation, and diagnostic abnormality, including abnormal 
laboratory test results. A symptom recorded as a medical history at study initiation will be handled as an 
adverse event only when symptoms are aggravated. In addition, loss of efficacy, and changes in the primary 
disease (depression) or scores for any of the CDRS-R items, will not be handled as adverse events in this 
study, unless judged to be serious adverse events. 
The principal investigator or sub-investigator will evaluate adverse events. The principal investigator or 
sub-investigator will carefully investigate each adverse event, and record in the CRF the date of onset, 
time of onset, date of cessation (if the outcome is recovery or death), severity, seriousness (including the 
reason for judging seriousness), causal relationship with the study drug, actions taken for the adverse event, 
and outcome of the adverse event. 
 


 
 
 
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7.7.7.2  Assessment period 
Adverse events occurring between obtaining the legal representative’s informed consent (for new subjects) 
or initiation of study drug administration in this study (for consecutive subjects) and 7 days after the final 
administration of study drug (the follow-up period) as well as adverse events consecutive from the 
preceding study at the initiation of study drug administration in this study (only if applicable) will be 
assessed. For consecutive subjects, adverse events that occurred between obtaining informed consent for 
this study and initiation of study drug administration in this study will be assessed in the preceding study. 
In the case of withdrawn subjects, the principal investigator or sub-investigator will assess adverse events 
up to 7 days after final administration of the study drug. Appropriate follow-up will be continued until one 
of the following, and the outcome will be determined on that basis: (i) the relevant adverse event recovers 
to the pre-administration state (if consecutive from the preceding study, it should be recovered to the pre-
administration of the preceding study); (ii) the subject’s condition stabilizes or becomes chronic; (iii) the 
subject is lost to follow-up; or (iv) the principal investigator or sub-investigator judges further assessment 
to be unnecessary. In addition, if the subject stops visiting hospital during the study, he/she will be followed 
up by an appropriate method such as by telephone, and the findings will be entered in the CRF. 
If the above adverse event follow-up has to be continued for 28 days or more after completion of 
administration, the outcome at the earliest date after 28 days after completion of administration will be 
recorded in the CRF. 
 
7.7.7.3  Severity 
The principal investigator or sub-investigator will judge the severity of adverse events in accordance with 
the below definitions. The highest severity of each event during its period of occurrence will be recorded 
as the severity in the CRF. 
• 
Mild:  
Signs or symptoms are found, but activities of daily life are not disturbed. 
• 
Moderate:  
Activities of daily life are disturbed due to discomfort, and/or abnormality is 
clinically demonstrated. 
• 
Severe:  
Activities of daily life are impossible, and/or major clinical effects are 
demonstrated. 
 
7.7.7.4  Causal relationship with study drug 
The principal investigator or sub-investigator will judge the causal relationship with the study drug in 
accordance with the following criteria: 
• 
Not related:  
The adverse event can be clearly explained by a factor other than the 
study drug, and/or there is no valid chronological relationship between 
the study drug and the adverse event. 
• 
Possibly related:  
The adverse event may have been caused by a factor other than the 
study drug, but a causal relationship with the study drug cannot be 
ruled out. 


 
 
 
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• 
Probably related:  
It is unlikely that the adverse event was caused by a factor other than 
the study drug. 
• 
Related:  
There is a valid chronological relationship between administration of 
the study drug and onset of the adverse event, and the event cannot be 
explained by a factor other than the study drug 
 
Adverse events judged to be “Possibly related”, “Probably related” or “Related” are taken to be adverse 
drug reactions. 
 
7.7.7.5  Predictable adverse drug reactions 
Adverse drug reactions listed in the most recent investigator’s brochure for duloxetine, or in any reports 
about adverse drug reactions submitted separately to the IRB, study site, or the principal investigator, are 
taken to be predictable adverse drug reactions. 
 
7.7.7.6  Adverse events of special concern 
7.7.7.6.1  Suicide-related adverse events 
The duloxetine package insert, includes, as drug-class labeling, the following requirement to take great 
care: “There have been reports of increases in the risks of suicidal ideation and suicidal planning in patients 
aged under 24 administered antidepressants, so consideration should be given to the risk/benefit 
relationship when this drug is to be administered”. Therefore, the principal investigator or sub-investigator 
will evaluate any suicidal thinking using the C-SSRS questionnaire, as detailed in Section 7.7.2 , and will 
record any suicide-related adverse events. 
The principal investigator or sub-investigator will perform sufficient monitoring of subjects who suffer 
from adverse events that are clearly or possibly suicide-related. 
If a subject suffers a suicide-related adverse event, and/or if requested by the sponsor, the principal 
investigator will report the details of the relevant adverse event to the sponsor, by fax, email or telephone, 
or orally. After the sponsor has received the relevant information, he/she will promptly request the Safety 
Evaluation Committee to perform a review. If necessary, the sponsor can also request the principal 
investigator to provide additional information. 
 
7.7.7.7  Adverse events such as laboratory test results 
The principal investigator or sub-investigator will judge whether or not any changes from the baseline by 
laboratory test results (hematology, blood chemistry, and urinalysis) and abnormalities in other safety 
endpoints (e.g. examination findings, body weight, blood pressure, pulse rate, ECG findings) are clinically 
significant. Laboratory test results that deviate from the reference range will be handled as abnormal values. 
If a baseline value is abnormal, but worsens after study initiation, the principal investigator or sub-
investigator will judge whether or not this is clinically significant. Events judged by the principal 
investigator or sub-investigator to be clinically significant will be recorded as adverse events. When an 


 
 
 
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abnormal test result is accompanied by disease or other toxicity, the disease name and/or details of toxicity 
will be reported as an adverse event. 
An event will be considered clinically significant if one or more of the following criteria is met, and 
judgment about clinical significance in other situations will be at the discretion of the principal investigator 
or sub-investigator: 
• 
The criterion for a serious adverse event is met (refer to Section 7.7.7.8 ). 
• 
Study drug discontinuation or dose reduction is required. 
• 
Drug administration or another procedure is required for treatment. 
• 
An additional test or other medical procedure is required. 
• 
Management of abnormal hepatic function test results is necessary, and the discontinuation criteria 
(Appendix 2) are met. 
If management of abnormal hepatic function test results is necessary, and the discontinuation criteria 
(Appendix 2) are met, evaluation and additional assessment will be performed, and records will be made 
in the follow-up assessment form for abnormal hepatic function. 
 
7.7.7.8  Serious adverse events 
7.7.7.8.1  Definition 
Of the adverse events observed after study initiation, an adverse event meeting one or more of the 
following criteria will be handled as a serious adverse event: 
• 
Leading to death. 
• 
Life-threatening. 
• 
Requiring hospitalization or prolongation of hospitalization. 
• 
Leading to permanent and/or significant disability or dysfunction (according to the opinion of the 
reporting physician). 
• 
Leading to congenital anomaly. 
• 
Other medically major event. 
If an adverse event exposes a subject to danger, or requires medical procedures to prevent one of the results 
defined above, even if the event does not lead to death, is not life-threatening, and does not require 
hospitalization, it will be handled as a serious adverse event on the basis of appropriate medical judgment. 
For example, bronchial asthma which requires intensive therapy at emergency department, etc., vascular 
disorder or convulsion not requiring hospitalization, drug dependency or abuse are included. In addition, 
all events meeting the below criterion are taken to be serious adverse events. The principal investigator or 
sub-investigator will judge the seriousness of adverse events. 
− 
AST and/or ALT >3 times the upper limit of the respective reference values, and total bilirubin 
>2 times the upper limit of the reference values. 
 
7.7.7.8.2  Reports of serious adverse events 
The principal investigator will report the details of all serious adverse events to the sponsor, using the 


 
 
 
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serious adverse event report form, within 24 hours after the relevant events are judged to be serious. All 
serious adverse events will be reported, irrespective of the causal relationship with the study drug. The 
sponsor can also request additional information about serious adverse events. 
As far as possible, the principal investigator will report all serious adverse events using the diagnostic 
names. If the diagnostic name has not been fixed at the time of reporting, the report will state the individual 
signs and symptoms. 
 
Serious adverse event reports and contact person for 
reporting 
 
 
 
 
 
 
 
 
 
 
If the sponsor judges follow-up to be necessary, the principal investigator will report to the above contact 
person by fax or email, using a serious adverse event form, and will provide any new information to the 
sponsor. The principal investigator will evaluate photocopies of relevant documents, such as discharge 
summaries, medical records from other departments and institutions, and autopsy reports, and will include 
any relevant information in a supplementary serious adverse event report. The sponsor can also request 
photocopies of such reports. 
The principal investigator will establish appropriate measures for medical treatment of serious adverse 
events, on the basis of medical judgment. Measures taken with serious adverse events, and their results, 
will be recorded. The principal investigator will establish the necessary measures, and will also elucidate 
the causes of serious adverse events as far as possible. 
If a serious adverse event during or after the assessment period stipulated in Section 7.7.7.2 is judged by 
the principal investigator to have a causal relationship with study drug, he will report it to the sponsor. 
The principal investigator will also report all serious adverse events to the IRB in accordance with the 
regulatory requirements. The sponsor will report all reported serious adverse events to the regulatory 
authority, in accordance with the regulatory requirements. 
 
7.7.7.9  Abuse, misuse, overdose, and medication error (special situations) 
In the event of abuse, misuse, overdose, or medication error associated with the study drug (special 
situations), as defined below, the principal investigator will promptly report it to the sponsor by fax or 
email, using the form stipulated by the sponsor (Special Situation Report Form). The principal investigator 
will also submit reports to the sponsor about any serious adverse events associated with the special 
situation. 
• 
Abuse: Intentional overdose of the study drug, associated with adverse physical or mental effects, 


 
 
 
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irrespective of whether this is continuous or sporadic. 
• 
Misuse: Inappropriate use of the study drug at doses other than those instructed or on the label, 
intentionally by the subject. 
• 
Overdose: Accidental or intentional use of the study drug at a dose exceeding that prescribed. 
• 
Medication error: An accidental medication error, including cases that have been prevented from 
occurring, during the process of prescription, dispensing or administration. A medication error due 
to the subject forgetting to take one or more doses is not reportable. 
 
7.7.7.10  Pregnancy 
The principal investigator or sub-investigator will instruct female subjects that, if they become pregnant 
during the study, they must stop taking the study drug, and immediately inform the principal investigator 
or sub-investigator. If a subject is found to be pregnant, the principal investigator or sub-investigator will 
withdraw her form the study. Information about the pregnancy will be reported to the sponsor as detailed 
below. 
For all pregnancies that occur between initiation of study drug administration and completion of the follow-
up period, the principal investigator will send a pregnancy follow-up report to the sponsor by fax or email 
within 24 hours after the pregnancy comes to light. Pregnancy complications and terminations for medical 
reasons will be reported appropriately, as adverse events or serious adverse events. Miscarriages will be 
reported as serious adverse events. In addition, pregnancies will be followed, and pregnancy follow-up 
reports will be submitted to the sponsor by fax or email. Even after completion of the follow-up period, if 
a pregnancy comes to light within 1 month after the final study drug administration, the study site will 
report it to the sponsor. At completion of pregnancy, by birth, miscarriage or termination, the outcome will 
be reported to the sponsor. 
 
7.7.7.11  Adverse events during study drug administration 
Adverse events with onset after the initial study drug administration are taken to be treatment-emergent 
adverse events (TEAE). For consecutive subjects, of adverse events consecutive from the preceding study 
at initiation of study drug administration in this study, adverse events that started after initiation of study 
drug administration in the preceding study are also taken to be TEAEs of this study. 
 
7.8  Appropriateness of test items 
Efficacy endpoints chosen in this study are similar to those in the preceding study in order to study and 
examine various aspects of long-term efficacy. 
Safety endpoints chosen in this study are also similar to that in the preceding study. 
 
7.9  Permitted range of test times 
Examination, observation and tests will be performed in accordance with Appendix 1. If performance at 
the date and time shown in Appendix 1 is impossible, for unavoidable reasons, performance within the 


 
 
 
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permitted range shown in Table 7-3 will be acceptable. Data collected outside the permitted range will be 
taken to be missing for that visit. When the dose is to be increased from 20 to 40 mg/day, or from 40 to 60 
mg/day for the first time, the pre-increase dose must be administered for at least 7 days. 
 
Table 7-3. Permitted range of time of examinations, observations and tests 
 
Visit 
Week 
Stipulated date of visit 
Permitted 
range 
(days) 
Range 
(Day) 
Screening 
period 
1 
-3 to -1 
-21 to -7 
- 
- 
Treatment 
period 
2 
0 
0 (Registration) 
0 
- 
 
3 
1 
7 
±3 
4 to 10 
 
4 
2 
14 
±3 
11 to 17 
 
5 
4 
28 
±7 
21 to 35 
 
6 
8 
56 
±7 
49 to 63 
 
7 
12 
84 
±7 
77 to 91 
 
8 
16 
112 
±7 
105 to 119 
 
9 
20 
140 
±7 
133 to 147 
 
10 
24 
168 
±7 
161 to 175 
 
11 
28 
196 
±7 
189 to 203 
 
12 
32 
224 
±7 
217 to 231 
 
13 
36 
252 
±7 
245 to 259 
 
14 
40 
280 
±7 
273 to 287 
 
15 
44 
308 
±7 
301 to 315 
 
16 
48 
336 
±7 
329 to 343 
 
17 
50 
350 
±3 
347 to 353 
 
At 
discontinuation 
- 
Date of final administration in 
treatment period 
+3 
- 
Tapering 
period 
18 
51 
If the last dose 
is 40 mg 
On Day 7, taking Visit 17 (or the time 
of discontinuation during the 
treatment period) to be Day 0. 
 
±3 
- 
52 
If the last dose 
is 60 mg 
On Day 14, taking Visit 17 (or the 
time of discontinuation during the 
treatment period) to be Day 0. 
±3 
- 
 
At 
discontinuation 
- 
Final administration in tapering 
period 
+3 
- 
Follow-up 
period 
19 
52 to 53 
On day 7 or later, taking the final 
administration date to be day 0. 
 
- 
 


 
 
 
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8.  Statistical analysis 
8.1  Statistical analysis methods 
The sponsor will commission a contract organization to perform the statistical analysis. The sponsor will 
perform the pharmacokinetic analysis. The details of the analysis will be stipulated in the “Statistical 
analysis plan” and “Pharmacokinetic analysis plan”, which will be prepared on the basis of this section. 
When any change is made to the analysis planned in the protocol, reason for a change will be specified in 
the statistical analysis plan or pharmacokinetic analysis plan without fail. 
Number of subjects, arithmetic mean, standard deviation, minimum, median, and maximum will be 
calculated as summary statistics for the items measured by continuous data in principle. Number of 
subjects and proportion of each category will be calculated as summary statistics for the items measured 
by discrete value. 
Level of significance at 0.05 (two-sided) will be used for statistical tests in this study unless otherwise 
specified. There will be no multiplicity adjustment for the statistical tests. 
SAS of Version 9.2 or higher will be used for all analyses and for creation of tables. 
 
8.2  Target number of subjects 
The target number of subjects is set as at least 100 subjects to collect data from, who receive duloxetine 
for one year. Assuming that 25% of subjects dropout from this study, the target total number of registered 
subjects is 135, including consecutive subjects and new subjects. Blood samples for plasma drug 
concentration measurements will be collected five times for each subject to evaluate the pharmacokinetics 
in Japanese children and adolescent patients with depressive disorder. 
 
8.3  Analysis sets 
The following analysis sets are defined: 
(1) 
Full-analysis set (FAS)  
This comprises all subjects to whom the study drug has been administered at least once, and with whom 
the CDRS-R total score has been determined at baseline and at least once after initiation of study drug 
administration. 
(2) 
Safety-analysis set 
This comprises all subjects to whom the study drug is administered at least once.  
(3) 
Pharmacokinetic analysis set 
This comprises all subjects to whom the study drug is administered at least once and the plasma duloxetine 
concentration is measured at least once. The pharmacokinetic analysis set will be used for preparing and 
summarizing the list of drug concentrations. 
 
8.4  Handling of missing data 
In principle, missing data will not be imputed. However, if missing data is imputed for analysis at the final 
evaluation time point, LOCF may be used. 


 
 
 
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8.5  Subject characteristics 
Of the subjects registered, the number and proportion who complete the study, and the number and 
proportion withdrawn will be summarized. In addition, the reasons for withdrawal will be summarized. 
The number and proportion of subjects included in each analysis set will also be shown. 
 
8.6  Demographic and baseline characteristics 
The summary statistics will be used to summarize the demographic and baseline characteristics of the 
safety analysis set. 
 
8.7  Study drug administration period, dosage, and treatment compliance 
The study drug administration period, administration rate, and total dose will be summarized on the safety 
analysis set.  
 
8.8  Prior treatment 
Drugs used in prior treatment will be coded for using the WHO Drug Dictionary. With the safety analysis 
set, the subjects who received prior treatment will be tabulated. 
 
8.9  Concomitant treatment 
Drugs used in concomitant treatment will be coded for using the WHO Drug Dictionary. For the safety 
analysis set, the subjects who receive concomitant therapy will be tabulated. 
 
8.10  Analysis of efficacy 
The summary statistics will be calculated using the FAS for the observed efficacy endpoints (CDRS-R 
total score and CGI-S) and their changes from baseline at each time-point after study drug administration. 
The baseline for each endpoint is defined as the subject’s initiation of this study (Visit 2). Changes from 
the start of the preceding study will be summarized similarly by treatment group in the preceding study. 
 
8.11  Safety analysis 
Safety analysis will be conducted on the safety analysis sets. 
 
8.11.1  Adverse events 
Adverse events will be classified by system organ class and preferred term, in accordance with MedDRA. 
Of the adverse events reported using CRFs, TEAEs will be used for safety analysis. TEAEs are defined in 
Section 7.7.7.11 . 
The number of subjects suffering TEAEs, and the numbers suffering death, other serious TEAEs, TEAEs 
leading to discontinuation of administration, and TEAEs leading to dose reduction will be determined. The 
TEAE rate and 95% confidence interval will be calculated by the Clopper-Pearson method. The number 


 
 
 
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of adverse events will also be included. Adverse drug reactions will be summarized in the same manner as 
TEAEs. Adverse drug reactions are defined in Section 7.7.7.4 . 
As summarization of TEAEs by system organ class and preferred term, the number and proportion of 
subjects suffering these events will be shown. In addition, TEAEs will be summarized by severity, onset 
timing, and outcome. Adverse drug reactions will be summarized similarly. 
 
8.11.2  Blood pressure, pulse rate, and body weight 
Summary statistics will be calculated for the measurements and change from baseline at each time-point. 
The baseline is defined as the subject’s initiation of this study (Visit 2). 
 
8.11.3  Laboratory test results 
Summary statistics will be calculated for the measurements and change from baseline at each time-point. 
The baseline is defined as Visit 1 for new subjects or Visit 2 for consecutive subjects. 
The category distribution of the qualitative laboratory test data at each time-point will be summarized. 
 
8.11.4  ECG 
The distribution of ECG findings (normal or abnormal) will be summarized for observation time-point. 
 
8.11.5  Columbia Suicide Severity Rating Scale (C-SSRS) 
The distribution of the presence or absence of suicidal ideation and suicidal behavior will be summarized 
for observation time-point. 
 
8.12  Pharmacokinetic analysis 
Plasma duloxetine concentrations and time from the last administration will be listed for each subject. 
Trough plasma concentrations, which are 18 to 30 hours after the last administration of duloxetine, for 
each subject will be collected and summarized for each dose group by the number of subjects with 
measurements, arithmetic mean (Mean), standard deviation (SD), coefficient of variation (CV% = 
SD/Mean × 100), median, minimum (Min), and maximum (Max). The plasma concentration below 
quantifiable limit will be substituted with 0. The plasma duloxetine concentrations at steady state from 
children and adolescent patients with depressive disorder will be compared with those of adult patients 
with depressive disorder. The relationship between the trough concentration of duloxetine and CDRS-R 
total score will be displayed in a graph. 
Data considered by the pharmacokinetic analysts to be clearly inappropriate to include in the analysis will 
be excluded from the analysis. If excluded, the reason for exclusion shall be described in the clinical study 
report. 
The population pharmacokinetic analysis will be conducted using a nonlinear mixed effect model, with 
NONMEM version 7.3 or higher. The report of population pharmacokinetic analysis will be prepared 
separately. 


 
 
 
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8.13  Interim analysis 
After completing registration of subjects, once all subjects complete (or withdraw) observation at Visit 11 
(Week 28), an interim analysis may be performed to assess the safety and efficacy of duloxetine 
administered for 6 months. The method of interim analysis should follow that of the analysis at the end of 
study. 
 


 
 
 
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9.  Management-related items requiring attention 
9.1  Principal investigator and study management system 
Sponsor 
Shionogi & Co., Ltd. (Head Office) 
3-1-8 Doshomachi, Chuo-ku, Osaka, 541-0045, Japan 
Contact information of sponsor  
 
 
 
 
 
 
 
 
Medical Expert 
 
 
 
 
 
 
 
 
 
 
Coordinating investigator 
 
 
 
 
 
Safety Monitoring committee members 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Study sites and principal investigators 
See separate sheet 
Clinical research associate (CRA) 
See separate sheet 
Emergency contact 
 
 
 
Clinical research organization (CRO) 
  
 
 
 
  
 
Clinical laboratory facility 
 
 
 
 
Drug Concentration Laboratory 
 
 
 
 
 
 
 
 
Data management 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical analysis 
 
 
 
 
 
 
 
 
 
9.2  Institutional review board (IRB) 
The IRB will protect the human rights, safety and welfare of subjects by reviewing study-related 
documents (including revised versions when any important amendments are made to these documents) 
such as the protocol, informed consent form and explanatory documents (or assent documents), materials 


 
 
 
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relating to subject recruitment (when applicable), other documents provided to subjects, the investigator’s 
brochure, safety information, and annual reports of study performance (when applicable), as submitted by 
the principal investigator or sponsor. The IRB will be established on the basis of the GCP and various 
regulations. This study will be initiated after the principal investigator has obtained written approval by 
the IRB. 
Revision of the protocol should be deliberated as done for the initial deliberation. The principal investigator 
will submit all periodic reports and updated information upon request by the IRB. The principal 
investigator will report all the applicable adverse events to the IRB. 
 
9.3  Ethics 
The clinical study will be performed in accordance with the appropriate regulatory requirements and the 
protocol approved by the IRB, and in compliance with the latest GCP, all appropriate requirements for 
protection of subjects’ confidentiality, and ethical principles based on the Declaration of Helsinki. 
 
9.4  Providing information to patients and obtaining informed consent 
After accepting the sponsor’s proposal about the explanatory documents and informed consent form, or 
assent document, in accordance with GCP and the regulatory requirements, the principal investigator will 
prepare the explanatory documents and informed consent form, or assent document. The sponsor must 
agree with the revisions pointed out by the principal investigator in relation to the explanatory documents 
and informed consent form, or assent document, before submitting these documents to the IRB. The 
principal investigator must provide the sponsor with the explanatory documents and informed consent 
form, or assent document, after the documents have been appropriately reviewed and approved by the IRB. 
The principal investigator or sub-investigator will use the explanatory documents and informed consent 
form, or assent document, approved by the IRB to explain the quality, purpose, methods, foreseeable 
benefits, and potential risks to subjects before study participation, using readily understandable vocabulary. 
The method for obtaining written consent or assent should be in accordance with the GCP and appropriate 
regulatory requirements. 
 
9.5  Protection of subjects’ confidentiality 
Laws about appropriate data privacy protection must be complied with in relation to subjects’ personal 
information. CRFs, study drug management table, reports, letters, etc. should be identified by subject code 
to protect the personal information of subjects. The principal investigator will permit access to all source 
documents for monitors of the sponsor, auditors, and regulatory authority to confirm data of the CRF and 
verify procedures of data collection. However, personal information of subjects will be protected within 
the scope of appropriate laws and regulations. The principal investigator and sponsor must ensure that 
handling of confidential information is in accordance with any local regulatory requirements. If there is 
potential for anonymized subjects’ information to be used, made public, or transferred, appropriate consent 
or approval must be obtained. 


 
 
 
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The information of subjects will be identified by subject ID code during the study and coded information 
will be recorded in the CRF. Personal information of subjects will be protected even when a subject must 
be identified for reasons such as safe conduct of a clinical study or instructions of regulatory authority. 
 
9.6  Monitoring 
The sponsor and contract monitoring organization will perform monitoring to ensure that the study is 
performed in compliance with the GCP requirements and the protocol. Monitoring will be performed by 
the sponsor or by monitors who are representatives of the contract monitoring organization, by means of 
on-site monitoring, at the appropriate frequency, and with frequent communication by e-mail, mail, 
telephone, or fax. Monitors will check the data recorded in the CRF; verify the items recorded in the CRF 
by direct access to source documents; collect information on the safety and efficacy of subjects; perform 
inspections to ensure that the quantity of unused study drug is accurate; and confirm that the source 
documents and essential documents have been stored. 
 
9.7  Case report forms and source documents 
9.7.1  Case Report forms 
The sponsor will provide the CRF. The CRF will be prepared using an EDC system. A CRF will be 
prepared for each new subject who has signed informed consent or for each consecutive subject who has 
registered to this study, and subjects’ demographic information stipulated in the protocol and data relating 
to the study will be recorded. Subjects’ data relating to the study will be recorded in the source documents, 
and then promptly recorded in the CRF in accordance with the procedures relating to the CRF. The 
principal investigator or sub-investigator, and other study collaborators designated in writing, will make 
entries in the CRF. 
If the sponsor has uncertainties about data from a study site, either the data in the CRF will be revised in 
accordance with the appropriate procedures, or a response to the question will be recorded. The principal 
investigator will ensure that the data recorded in CRF are accurate, complete, and legible and that the 
timing of submission is appropriate. The principal investigator will sign CRF to verify completeness of the 
recorded data. 
The sponsor will obtain in writing a list of site reference values for all laboratory test items before study 
initiation. When the site reference values are changed after study initiation, the list will be obtained in 
writing. If all or some tests are performed at a central laboratory, reference values will be obtained for all 
items measured by that laboratory. 
 
9.7.2  Source documents and raw data 
Source documents are the basic materials for data recorded in the CRF. Participation of subjects in the 
study, details and date of study performance, adverse events, and the condition of subjects will be recorded. 
However, for the following types of data, the data recorded in the CRFs may be used as raw data: 
Reasons for use of prior and concomitant treatment. 


 
 
 
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Adverse events: severity, seriousness, and causal relationships with the study drug 
Comments recorded in CRFs. 
In addition, for data managed solely with CRFs (calculated automatically by the EDC), there is the 
following item: 
Age at the time of obtaining informed consent (new subjects only) 
Age at the time of obtaining assent (new subjects only) 
CDRS-R total score. 
 
The principal investigator will store source documents, such as laboratory test reports, and detailed subjects’ 
medical history and medical records. All source documents should be made available for direct access by 
monitors, auditors, and IRB and inspection by regulatory authorities. Therefore, the principal investigator, 
sub-investigator, or study collaborators must make arrangements enabling appropriate direct access. The 
sponsor and study site personnel will ascertain the source documents in which information required for 
completing CRFs is recorded, and where they are stored. In the case of storage by electronic recording, 
the access method for verification must be stipulated in a document stipulated by the study site. 
 
9.7.3  External data 
The following data will be reported separately from CRFs: 
• 
Plasma concentrations of duloxetine (measured at 
 
according to the separately prepared procedures) 
• 
Results of pharmacokinetic analysis 
• 
Laboratory test results 
 
9.8  Committees, meetings, etc. 
9.8.1  Case review committee 
Before the database lock, at a case review meeting, the sponsor, together with a medical expert, will check 
all data for all subjects recorded in CRFs. The subjects to be included in the analysis set will be decided 
upon on the basis of the outcome of the case review meeting and the definition of the analysis set in the 
protocol. Appropriateness of medical judgment of the principal investigator for the significant data 
affecting the safety or efficacy endpoint will also be evaluated during a case review meeting. 
 
9.8.2  Safety monitoring committee 
Depending upon the sponsor’s requirements, reported interim safety data will be evaluated, and the sponsor 
will be notified as to whether the study should be continued, modified or discontinued. The evaluation will 
be performed in accordance with the Safety Monitoring Committee’s standard operating procedures, which 
are set separately. 
 


 
 
 
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9.9  Study discontinuation or suspension 
9.9.1  Discontinuation or suspension of entire study 
The sponsor may discontinue or suspend the study when one or more of the following conditions is 
applicable: 
• 
Ensuring the safety of the study is difficult, for reasons such as multiple occurrence of serious 
adverse drug reactions. 
• 
It is not considered possible to achieve the study objectives, for reasons such as not being able to 
enroll a sufficient number of subjects. 
 
When disconsecutive or suspending the study, the sponsor must report promptly to the principal 
investigator. The principal investigator or sub-investigator must promptly explain about study 
discontinuation or suspension to the participating subjects, and transfer them to other appropriate treatment. 
Discontinuation criteria for each subject are shown in Section 4.5 . 
 
9.9.2  Discontinuation or suspension of study at each study site 
When ensuring the safety of the study is difficult, for reasons such as multiple occurrence of serious 
adverse drug reactions, the principal investigator may discontinue or suspend the study at the relevant 
study site after obtaining approval by the sponsor. If a major deviation from the protocol (including other 
procedures) and/or the GCP occurs, and is not resolved, the sponsor may request the principal investigator 
to discontinue or suspend the study at the relevant study site. 
If the study is discontinued or suspended, the principal investigator or sub-investigator must promptly 
explain about the discontinuation or suspension to the participating subjects and the IRB, and transfer the 
subjects to other appropriate treatment. 
 
9.10  Modifications to and deviations from the protocol 
The principal investigator will perform the study in accordance with the study protocol approved by the 
IRB and regulatory authority, and provided by the sponsor. Protocol amendments require agreement by the 
principal investigator and sponsor. For any protocol amendment, written approval must be obtained from 
the IRB beforehand, unless such amendments are medically essential for avoiding immediate risk to the 
subject. 
The principal investigator or sub-investigator must record deviations from the protocol and the reasons for 
these. In the event of an amendment to or deviation from the protocol in order to avoid immediate risk to 
the subject, the principal investigator must immediately submit a record of the deviation or amendment to 
the sponsor, study site, and IRB, and promptly obtain approval by the IRB. After obtaining approval by 
the IRB, the principal investigator will obtain written agreement by the sponsor, via the study site. 
If deviation from the protocol is required as an emergency, in a medically unavoidable situation, such as 
in order to avoid immediate risk to the subject, the principal investigator will contact the sponsor in 
advance wherever possible to discuss how this should be handled. All deviations from the protocol should 


 
 
 
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be recorded in the source documents. 
 
9.11  Data management 
The sponsor will commission data management tasks to a contract data management organization. Details 
of data management tasks will be defined in a separately specified procedure. 
 
9.12  Storage of records 
Study-related documents must be stored in accordance with the GCP and regulatory requirements. The 
principal investigator and study site must take measures to prevent accidental or premature disposal of the 
documents. When manufacture and marketing of the study drug has been approved, the sponsor will 
promptly report this in writing to the director of the study site. 
The duration of storage of records will be until the later of the following: 
• 
Three years after the date of achieving study drug marketing approval or after the decision to 
discontinue study drug development. 
• 
Three years after study discontinuation or completion. 
The above period of storage can be extended if necessary, as agreed upon with the sponsor. If the principal 
investigator cannot be responsible for storage of study-related records, this responsibility will be 
transferred to an appropriate successor. 
 
9.13  Study quality control and quality assurance 
The sponsor will define the procedures for quality control and quality assurance in the standard operation 
procedures in order to ensure that the study is performed, and that data, documents and reports are prepared 
in accordance with the protocol, GCP, and appropriate regulatory requirements. This study will be 
performed in accordance with ethical principles based on the Declaration of Helsinki, GCP, and other 
appropriate regulatory requirements. 
The sponsor will hold explanatory meetings with the principal investigator and each study site before study 
initiation, and will provide education and training as required for study performance. 
 
9.14  Decisions relating to publication 
All information about duloxetine provided by the sponsor to the principal investigator is confidential 
information, and must not be disclosed to any third party. The principal investigator must not use this 
information for purposes other than the study without obtaining the consent of the sponsor. All the 
information obtained during the study should be provided to the sponsor. The information obtained during 
the study will be used for development of duloxetine and will be disclosed to the regulatory authority, other 
principal investigators, joint development company, and consulting company, etc. as necessary. The 
sponsor possesses the right to all data. Approval of the sponsor should be obtained before making public 
the information obtained in this study. 
Overview of this protocol is made available on the clinical study registry site. 


 
 
 
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10.  References 
1. Guideline for clinical evaluation of antidepressants. Pharmaceutical and Food Safety Bureau notification 
no. 1116-1. November 16, 2010  
2. Tanabe A, Nomura S. Pathology and pathophysiology. Jpn J Clin Med 2007; 65: 1585-90. 
3. Denda K. Current status of pediatric depression in Japan. Jpn J Clin Psychopharmacol 2004; 7: 1567-77. 
4. Zisook S, Lesser I, Stewart JW, et al. Effect of age at onset on the course of major depressive disorder. 
Am J Psychiatry 2007; 164: 1539-46. 
5. Hasin DS, Goodwin RD, Stinson FS, Grant BF. Epidemiology of major depressive disorder: results from 
the National Epidemiologic Survey on Alcoholism and Related Conditions. Arch Gen Psychiatry 2005; 
62: 1097-106. 
6. Carlson GA, Kashani JH. Phenomenology of major depression from childhood through adulthood: 
analysis of three studies. Am J Psychiatry 1988; 145: 1222-5. 
7. Japanese Society of Mood Disorders Guidelines (II): Depression (DSM-5) and major depressive disorder, 
2016. 
8. Kovacs M, Feinberg TL, Crouse-Novak MA, Paulauskas SL, Finkelstein R. Depressive disorders in 
childhood. I. A longitudinal prospective study of characteristics and recovery. Arch Gen Psychiatry 1984; 
41: 229-37. 
9. Kovacs M, Feinberg TL, Crouse-Novak M, Paulauskas SL, Pollock M, Finkelstein R. Depressive 
disorders in childhood. II. A longitudinal study of the risk for a subsequent major depression. Arch Gen 
Psychiatry 1984; 41: 643-9. 
10. Fombonne E, Wostear G, Cooper V, Harrington R, Rutter M. The Maudsley long-term follow-up of child 
and adolescent depression. 1. Psychiatric outcomes in adulthood. Br J Psychiatry 2001; 179: 210-7. 
11. Denda K. Epidemiology, diagnosis and treatment of pediatric/adolescent depression. Jpn J Clin 
Psychopharmacol 2006; 9: 780-90. 
12. Shain B. American Academy of Pediatrics Committee on Adolescence. Clinical report: Guidance for the 
Clinician in Rendering Pediatric Care. Suicide and suicide attempts in adolescents. Pediatrics 2016; 138 
(1) (accessed 2016-10-13). 
13. U.S. Food and Drug Administration (FDA). MINUTES OF THE PEDIATRIC ADVISORY 
COMMITTEE March 24, 2015. 
 
 
 


 
 
LY248686; Shionogi & Co., Ltd. 
Protocol: 1702A3632; August 8, 2018 
Appendix 1: Study Schedule 
 
Screening 
period 
Treatment period 
Tapering 
period 
Follow-up 
period 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9, 10 
11 
12, 13 
14 
15,16 17/disconti
nuation 
18/discon
tinuation 
19 
Week 
-3 to -1 
0 
1 
2 
4 
8 
12 
16 
20, 24 
28 
32, 36 
40 
44, 48 
50 
51 to 52 52 to 53 
Visit date 
 
0 
7 
14 
28 
56 
84 
112 
140, 168 
196 224, 252 
280 
308, 336 
350 
364 
371 
Obtaining informed 
consent or assent 
Xa 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic factors 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MINI-KID 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of 
inclusion/exclusion 
criteria 
Xa 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xj 
Registration 
Xa 
Pre-
registration 
Xc 
Registrat
ion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CDRS-R 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Psycho-education 
Xa, d 
Xa, d 
 
 
Xa, d, g 
Xa, d, g 
 
 
 
 
 
 
 
 
 
 
CGI-S 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
C-SSRS 
Xa 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug 
administered 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xk 
 
 
Adherence of drug 
administration 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Laboratory testse 
Xa 
Xb, f 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
Xl 
 
Blood pressure, 
pulse rate 
Xa 
Xf 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
ECG 
Xa 
Xb, f 
 
 
X 
 
 
 
 
X 
 
 
 
 
Xl 
 
Body weight 
 
Xf 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Urinary drug 
screening 
 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testh 
Xa 
Xb, f 
 
 
 
 
 
 
 
 
 
 
 
 
Xl 
 
Plasma 
concentration 
 
 
 
 
Xi (5 times) 
 
 
Adverse events 
X 
a 
Will be performed only in new subjects. 
b 
Will be performed only in consecutive subjects. Informed consent/assent will be obtained before completing the observation at Visit 9 in the preceding study. 
c 
Consecutive subjects should be enrolled (registered) in this study within 3 days after the final administration of study drug in the preceding study. 


 
 
LY248686; Shionogi & Co., Ltd. 
Protocol: 1702A3632; August 8, 2018 
d 
Psycho-education is provided after evaluation of CDRS-R and CGI-S. 
e 
Hematology tests, blood chemistry tests, and urinalysis. HbA1c, TSH, FT3, and FT4 will also be measured at Visit 1 for new subjects only. 
f 
For consecutive subjects, results at Visit 9 in the preceding study may be used. 
g 
Will be performed at discontinuation if a subject discontinues the study before Visit 6. 
h 
Will be performed only in post-menarche females. 
i 
Blood samples for quantitation of plasma concentrations of duloxetine will be collected for five times at any timing between Visit 5 and the completion of study drug administration 
during the treatment period. If the dose is increased or decreased, blood samples should be collected at least 2 weeks after the dose adjustment. Of five random blood samples, one or two 
samples should be collected before dosing. 
j 
Adverse events occurring within 7 days after the final administration of the study drug will be investigated. The subject is checked by telephone or other appropriate method, even if 
he/she fails to make a visit. 
k 
Dispense study drugs for tapering period. 
l 
If the tapering period is not conducted, the pregnancy test will be performed at Visit 17 or at the time of discontinuation during the treatment period. 


 
 
 
LY248686; Shionogi & Co., Ltd. 
Protocol: 1702A3632; August 8, 2018 
- 60 - 
Appendix 2: Management of abnormal hepatic function test results, and 
discontinuation criteria 
In order to ensure subjects’ safety , as well as to evaluate the causes of any hepatic dysfunction found, 
management on the basis of abnormal hepatic function test results, and the discontinuation criteria, are 
defined, on the basis of the FDA’s July 2009 guidance (Guidance for Industry Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation). 
 
(1) 
Hepatic dysfunction criteria 
The principal investigator or sub-investigator confirms whether or not the subject’s laboratory test results 
meet any of the following criteria: 
a. AST and/or ALT >5 times the upper limit of normal (ULN). 
b. AST and/or ALT >3 times the upper limit of normal (ULN), and total bilirubin >2 times the upper 
limit of normal (ULN). 
c. AST and/or ALT >3 times the upper limit of normal (ULN), and signs and/or symptoms consistent 
with hepatitis or hypersensitivity (e.g. fatigue, nausea, vomiting, right upper abdominal pain or 
tenderness, jaundice, fever, rash, eosinophil increase by more than 5%). 
 
(2) 
Principal investigator’s actions 
If one or more of the above hepatic dysfunction criteria is met, the principal investigator or sub-investigator 
will act as follows: 
• 
Immediately ensure that the subject stops taking the study drug. 
• 
If possible, have the subject visit hospital within 72 hours after the abnormalities are first found, to 
repeat the hepatic function tests for a supplementary evaluation of hepatic function. 
• 
Until the hepatic function test result (ALT, AST, ALP, and total bilirubin) abnormalities cease, 
stabilize, or return to within the reference range or to the baseline, the subject’s progression is 
observed two to three times per week, if possible. 
• 
Report to the sponsor using the hepatic dysfunction follow-up assessment form, within 72 hours 
after the relevant abnormalities coming to the principal investigator’s attention. 
• 
Look into the option of consulting a hepatologist or other specialist. 
• 
Look into the option of performing hepatic imaging, such as ultrasonography, magnetic resonance 
imaging, or computed tomography. 
• 
Report all events that meet criterion b (above) as serious adverse events. 
 
(3) 
Follow-up assessment 
If one or more of the above hepatic dysfunction criteria is met, items including the following will be 
assessed at the time of the follow-up assessment visit, and the results will be entered in the hepatic 
dysfunction follow-up assessment form: 
• 
Clinical symptom. 


 
 
 
LY248686; Shionogi & Co., Ltd. 
Protocol: 1702A3632; August 8, 2018 
- 61 - 
• 
Alcohol intake. 
• 
Risk factors for nonalcoholic steatohepatitis (NASH) (e.g. diabetes, obesity, and 
hypertriglyceridemia). 
• 
Autoimmune hepatitis and cholangitis. 
• 
Wilson's disease. 
• 
Laboratory tests: 
− 
The following serum tests relating to viral hepatitis:  
 
Hepatitis A IgM antibody  
 
Hepatitis B surface antigen and hepatitis B core antibody  
 
Hepatitis C RNA  
 
Hepatitis E IgA antibody  
 
Cytomegalovirus IgM antibody  
 
Epstein-Barr virus capsid antigen IgM antibody 
− 
In the case of subjects with total bilirubin >1.5 times the upper limit of the reference values, 
conjugated bilirubin will be measured. 
− 
Blood cell measurement will be carried out, including leukocyte fractions. 
 


 
 
 
LY248686; Shionogi & Co., Ltd. 
Protocol: 1702A3632; August 8, 2018 
- 62 - 
Appendix 3: Sponsor’s signature 
 
Approval of the Protocol 
 
 
Product Name: LY248686 
Study Protocol Title: Phase-3 clinical study of duloxetine hydrochloride in children and 
adolescent patients with depressive disorder: An open-label extension 
study 
Study Protocol Number: 1702A3632 
Version Number: 4 
Issue Date: 8 August 2018 
 
 
 
 
Sponsor signatory: 
 
This clinical study protocol was subject to critical review and has been approved by the sponsor: 
 
 
 
 
Refer to electronic signature page 
 
Refer to electronic signature page 
 
 
 
 
 
Date: day-month-year 
 


 
 
 
 
 
 
 
Final Approval 
 
 
08-Aug-2018 08:44:31 GMT+0000 
 
 

SAP_001.pdf: 
 
 
 
 
 
Phase-3 clinical study of duloxetine hydrochloride in children and adolescent 
patients with depressive disorder: An open-label extension study 
 
Protocol No. 1702A3632 
 
Statistical Analysis Plan 
Version 1.1 
 
 
 
 
 
 
This is the translated version of the Statistical Analysis Plan (Version 1.1) written in Japanese 
 
 


 
Signatures 
Company name and roles 
Approver 
Date 
 
 
 
(Refer to the flag page) 
Refer to the flag page 
 
 
 
(Refer to the flag page) 
Refer to the flag page 
 
 
 


 
Preparation and amendment history 
Version Date 
Author, 
amender 
Comments 
1.0 
January 22, 2018 
 
New preparation 
1.1 
August 25, 2020 
 
Addition of abbreviations; revision of handling of the 
tests at discontinuation and at the final evaluation; 
addition of categories in the maximum and final doses 
during the treatment period; deletion of “consecutive 
from the preceding study” from onset timing category 
for adverse events during the treatment period; 
addition of CGI-S score category distribution analysis; 
addition of status of occurrence of adverse events and 
adverse drug reactions, classified by dosage at onset; 
addition of shift tables for the analyses of Columbia 
suicide severity rating scale; deletion of “performance 
of interim analysis”. 
 
 


 
 
Table of contents 
1. Introduction ...................................................................................................................................... 1 
2. Study summary ................................................................................................................................. 1 
3. Study objectives ............................................................................................................................... 2 
3.1 Primary objective ....................................................................................................................... 2 
3.2 Secondary objectives .................................................................................................................. 2 
4. Study design ..................................................................................................................................... 2 
4.1 Observation schedule ................................................................................................................. 2 
4.2 Allocation method ...................................................................................................................... 2 
4.3 Target number of subjects .......................................................................................................... 2 
5. Analysis sets ..................................................................................................................................... 2 
5.1 FAS ............................................................................................................................................. 2 
5.2 Safety-analysis set ...................................................................................................................... 2 
6. Issues with statistical analysis, and data handling ............................................................................ 3 
6.1 Reporting of analysis results ...................................................................................................... 3 
6.2 Statistical tests ............................................................................................................................ 3 
6.3 Assessments, observations and tests: Permitted timing and handling in statistical analyses ..... 3 
6.4 Handling of missing data ............................................................................................................ 3 
6.5 Baseline ...................................................................................................................................... 3 
7. Subject composition and backgrounds ............................................................................................. 4 
7.1 Disposition of patients ................................................................................................................ 4 
7.1.1 Patient composition in efficacy evaluation .......................................................................... 4 
7.1.2 Patient composition in safety evaluation ............................................................................. 4 
7.2 Analysis of demographic factors ................................................................................................ 4 
8. Treatment course and compliance .................................................................................................... 5 
8.1 Compliance ................................................................................................................................ 5 
8.1.1 Duration of administration and total dose ........................................................................... 5 
8.1.2 Compliance rate ................................................................................................................... 5 
8.2 Concomitant treatment ............................................................................................................... 5 
9. Efficacy evaluation ........................................................................................................................... 6 
9.1 Endpoints .................................................................................................................................... 6 
9.1.1 Analysis of efficacy endpoints............................................................................................. 6 
10. Safety evaluation ............................................................................................................................ 7 
10.1 Adverse events and adverse drug reactions .............................................................................. 7 
10.2 Analyses of vital signs and body weight ................................................................................ 10 
10.3 Analysis of laboratory test results .......................................................................................... 10 
10.4 Analysis of ECG ...................................................................................................................... 11 
10.5 Analysis of Columbia suicide severity rating scale ................................................................. 11 


 
 
11. Performance of interim analysis ................................................................................................... 13 
12. Data handling in analyses ............................................................................................................. 13 
12.1 Number of decimal places for calculated values .................................................................... 13 
Appendix 1. Schedule ........................................................................................................................ 14 
Appendix 2. Permitted range of timing of examinations, observations and tests ............................... 16 
Appendix 3: Endpoint Scoring ........................................................................................................... 17 
1. 
Calculation methods for CDRS-R total score and subscale scores ......................................... 17 
 


 
 
List of abbreviations and terms 
 
Abbreviation and 
terms 
Definition 
BOCF 
baseline observation carried forward 
CDRS-R 
Children’s Depression Rating Scale-Revised 
CGI-S 
Clinical Global Impression of Severity  
C-SSRS 
Columbia Suicide Severity Rating Scale 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders Fifth Edition 
FAS 
Full Analysis Set 
FT3 
free triiodothyronine 
FT4 
free thyroxine 
LOCF 
last observation carried forward  
MedDRA 
Medical Dictionary for Regulatory Activities 
MINI-KID 
Mini International Neuropsychiatric Interview for children and adolescents 
SMQ 
Standardised MedDRA Queries 
 
 
 




 
2 
3.  Study objectives 
3.1  Primary objective 
To evaluate the long-term safety of duloxetine in children and adolescent patients with depressive disorder. 
 
3.2  Secondary objectives 
⚫ To evaluate the long-term efficacy of duloxetine in children and adolescent patients with depressive 
disorder. 
⚫ To evaluate the pharmacokinetics of duloxetine in Japanese children and adolescent patients with 
depressive disorder. 
⚫ To evaluate the relationship between duloxetine exposure at steady state and Children’s Depression 
Rating Scale-Revised (CDRS-R) total score, one of the efficacy endpoints. 
 
4.  Study design 
4.1  Observation schedule 
A schedule table is presented in Appendix 1. 
 
4.2  Allocation method 
This study is not a randomized study and all enrolled subjects will receive duloxetine. 
 
4.3  Target number of subjects 
135 subjects (targeting 100 subjects complete one year-administration) 
 
Rationale for the target sample size: 
In this study, the target number of subjects is set as at least 100 subjects to collect data from, who will 
receive duloxetine for one year. Assuming that 25% of subjects drop out of this study, the target total 
number of registered subjects is 135, including consecutive subjects and new subjects. 
 
5.  Analysis sets 
The efficacy analysis set is defined as the full-analysis set (FAS). In addition, the safety-analysis set will 
be defined for the analysis of safety. 
 
5.1  FAS 
This comprises all subjects to whom the study drug has been administered at least once, and with whom 
the CDRS-R total score has been determined at baseline and at least once after initiation of study drug 
administration. 
 
5.2  Safety-analysis set 
This comprises all subjects to whom the study drug is administered at least once. 


 
3 
 
6.  Issues with statistical analysis, and data handling 
6.1  Reporting of analysis results 
The numbers of subjects, arithmetic means, standard deviations, minima, medians, and maxima will in 
principle be calculated as summary statistics for the endpoints measured as continuous data. Items 
observed as discrete values will be summarized as the number and proportion of subjects in each category. 
While the results of the analysis will be presented using the entire analysis sets, unless otherwise specified, 
the analysis of data from the initiation of the preceding study throughout this study will include the 
consecutive subjects and the results will be presented by the treatment group in the preceding study. 
The software used for statistical analyses in this study will be SAS, Version 9.4. 
 
6.2  Statistical tests 
If a statistical test is performed, the level of significance will be 0.05 (two-sided), unless stated otherwise. 
There will be no multiplicity adjustment for the statistical tests. 
 
6.3  Assessments, observations and tests: Permitted timing and handling in statistical 
analyses 
In principle, data obtained at the time-points shown in the case report forms, and collected in accordance 
with the performance schedule shown in the study protocol, will be used for the statistical analysis. In the 
case of data reported at the discontinuation visit, the time-points for use in analyses will be determined on 
the basis of the permitted ranges in the performance schedule. If there is duplication by data obtained at 
the scheduled visits and data obtained at the discontinuation tests, the data obtained closest to the scheduled 
date will be used. If this does not eliminate duplication, data from the scheduled visit will be used. 
Unscheduled visits will not be included in the time-points for analysis. For the permitted ranges for the 
observation, test, and evaluation time-points shown in the study protocol, refer to Appendix 2. 
For the final evaluation, data obtained at weeks 51 to 52 or at discontinuation of the treatment/tapering 
period will be used, except for CDRS-R and CGI-S scores, for which those obtained at week 50 or at 
discontinuation of the treatment period are used. However, if none of the above data are available, the 
latest data among reported data collected at scheduled visits are used for the final evaluation. 
 
6.4  Handling of missing data 
In principle, missing data will not be imputed. However, if missing data is imputed for analysis at the final 
evaluation time point, LOCF may be used. 
 
6.5  Baseline 
Data obtained before initiation of study drug administration (Visit 2) in this study will be used as baseline 
data, unless otherwise specified. As with laboratory test results of new subjects, if data from Visit 2 are 
missing, data from Visit 1 (screening period) will be used as baseline data. The baseline for the analysis of 


 
4 
data from the preceding study throughout this study will be the observed values obtained before initiation 
of study drug administration in the preceding study. 
 
7.  Subject composition and backgrounds 
7.1  Disposition of patients 
With registered subjects, the number who complete the treatment period and the number of withdrawals 
are calculated, and in the case of the withdrawals the disposition of the reasons for discontinuation is shown. 
Among subjects transferred to the tapering period, the number who complete the tapering period and the 
number of withdrawals are calculated, and the disposition of the reasons for discontinuation is summarized. 
 
7.1.1  Patient composition in efficacy evaluation 
With registered subjects, the numbers of subjects included in and excluded from the FAS will be calculated, 
and the disposition of the reasons for exclusion will be shown. 
 
7.1.2  Patient composition in safety evaluation 
With registered subjects, the numbers of subjects included in and excluded from the safety-analysis set 
will be calculated, and the disposition of the reasons for exclusion will be shown. 
 
7.2  Analysis of demographic factors 
With the safety-analysis set, summary statistics will be determined for the following continuous data items; 
and the frequencies and proportions of subjects in each category will be determined for discrete values: 
For the consecutive subjects, each demographic factor will also be summarized by the treatment group in 
the preceding study. Demographic factors will also be calculated separately for new subjects. 
 
Data type 
Item 
Continuous 
Age on date of obtaining legal representative’s informed consent,  
age at initial onset of depression,  
height, body weight, 
CDRS-R total score baseline value, 
CDRS-R subscale (mood, somatic, subjective, behavior) baseline values, 
CGI-S score baseline value 
Discrete 
Sex (male, female), ethnicity, race, 
age on date of obtaining legal representative’s informed consent (<12, ≥12), 
depressive episode ordinal number (first time, second time, third to seventh time, eighth 
time or more, not known), 
duration of current depressive episode (0 to 2 weeks, 2 to 4 weeks, 4 to 8 weeks, more 
than 8 weeks, not known), disease class according to DSM-5 (depression, persistent 
depressive disorder), 
hospitalization status category (hospitalized, out-patient), 
medical and surgical history (present, absent), 
complications (present, absent), 
previous drug treatment (present, absent), 
previous therapy (present, absent) 
 


 
5 
The dispositions of medical and surgical history, complications, previous drug treatment, and previous 
therapy will be shown. Drugs used previously will be coded for using the WHO Drug Dictionary, and 
summarized on the basis of consistently selected noncommercial names. 
 
8.  Treatment course and compliance 
8.1  Compliance 
8.1.1  Duration of administration and total dose 
The following analyses will be performed for the administration in this study with the safety-analysis set: 
1) 
Summary statistics for study drug administration duration will be calculated. Administration 
duration is defined as follows: 
   Administration duration (days)  
        = (administration completion date) − (administration initiation date) + 1.  
In addition, times (days) will be converted to week units, and the distributions in the following 
categories will be summarized: 12 or less weeks; more than 12 to 24 weeks; more than 24 to 
50 weeks; and more than 50 weeks. 
2) 
Summary statistics will be calculated for the total dose of study drug. 
3) 
For the maximum and final doses during the treatment period, the distribution in the following 
categories will be summarized: 20 mg, 40 mg, 60 mg, 80 mg, and 540 mg. 
 
8.1.2  Compliance rate 
In the safety-analysis set, summary statistics for compliance rate during the treatment period will be 
calculated. Distribution in the following categories will be summarized: less than 70%, and 70% or more. 
Compliance rate is defined as follows: 
 
Compliance rate [%] =
{𝑇𝑜𝑡𝑎𝑙 𝑃𝑟𝑒𝑠𝑐𝑟𝑖𝑝𝑡𝑖𝑜𝑛 −  20 × (𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑢𝑛𝑡𝑎𝑘𝑒𝑛 𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠)}
(𝑇𝑜𝑡𝑎𝑙 𝑃𝑟𝑒𝑠𝑐𝑟𝑖𝑝𝑡𝑖𝑜𝑛)
× 100
 
 
8.2  Concomitant treatment 
The following analyses will be performed with the safety-analysis set: Concomitant drugs will be coded 
for using the WHO Drug Dictionary, and then summarized on the basis of consistently selected 
noncommercial names. 
1) 
The number and proportion of subjects who have taken any concomitant medication at least once 
during the study period will be calculated. In addition, the disposition of the concomitant 
medication(s) will be shown. If use of the same concomitant medication has been reported more 
than once with the same subject, this will be taken to be one concomitant medication. 
2) 
The number and proportion of subjects who have had any concomitant therapy at least once during 
the study period will be calculated. In addition, the disposition will be shown by the name of 
concomitant therapy. If use of the same concomitant therapy has been reported more than once 
with the same subject, this will be taken to be one concomitant therapy. 


 
6 
 
9.  Efficacy evaluation 
Efficacy analyses will be performed with the FAS. Efficacy endpoints are summarized in Table 1. The 
statistical analysis will be mainly descriptive; when changes from the initiation of the preceding study or 
from the initiation of the open-label extension study are evaluated, the 95% confidence interval for the 
mean will be calculated. 
 
Table 1. Summary of endpoints and analysis methods 
 
Observed values 
Changes 
 
Summary statistics 
95% confidence 
interval for mean  
Summary statistics 
95% confidence 
interval for mean 
CDRS-R total score. 
○ 
○ 
○ 
○ 
CGI-S  
○ 
○ 
○ 
○ 
CDRS-R 
subscales 
and item 13 (suicidal 
ideation) 
○ 
○ 
○ 
○ 
○: to be calculated 
 
9.1  Endpoints 
1) 
CDRS-R total score. 
The CDRS-R total score will be calculated by adding together the scores for answers to all 
questions in the 17 items (refer to Appendix 3). 
2) 
CDRS-R subscales and item 13 (suicidal ideation) 
The CDRS-R subscales are defined as mood, somatic, subjective and behavior (refer to Appendix 
3). 
3) 
CGI-S 
Disease severity will be evaluated on the basis of seven grades, from 1 (no disease or abnormality) 
to 7 (extremely severe disease). The analysis of CGI-S will be based on the score. 
 
9.1.1  Analysis of efficacy endpoints 
The following analyses will be performed for the efficacy endpoints. 
1) 
Analysis of CDRS-R total score, CGI-S, CDRS-R subscales, and item 13 (suicidal ideation) 
A) Summary statistics will be calculated at each evaluation time-point in this study. 
B) Summary statistics for changes from baseline in this study will be calculated at each evaluation 
time-point and the 95% confidence interval for the mean will be calculated. 
C) Time-course graph for mean changes (standard deviation) from baseline will be prepared, where 
the baseline is Visit 2 of this study. 
D) The CGI-S score category distribution will be summarized at baseline (Visit 2 of this study) and 
at the final evaluation (week 50 of administration or discontinuation of the treatment period). 
2) 
Analysis of CDRS-R total score, CGI-S, CDRS-R subscales, and item 13 (suicidal ideation) from 
the initiation of the preceding study throughout this study 


 
7 
The following analyses will be performed only in consecutive subjects: 
A) Summary statistics will be calculated at each evaluation time-point in the preceding study and 
this study. 
B) Summary statistics for changes from baseline in the preceding study will be calculated at each 
evaluation time-point in the preceding study and this study and the 95% confidence interval for 
the mean will be calculated. 
C) Time-course graph for mean changes (standard deviation) from baseline in the preceding study 
will be prepared. 
D) The CGI-S score category distribution will be summarized at baseline in the preceding study and 
at the final evaluation (week 50 of administration or discontinuation of the treatment period). 
 
10.  Safety evaluation 
Safety analyses will be performed with the safety-analysis set. 
 
10.1  Adverse events and adverse drug reactions 
Adverse events occurring at or after the initiation of the open-label extension study and continuing from 
the preceding study will be evaluated. Reported adverse events will be converted to Medical Dictionary 
for Regulatory Activities (MedDRA) terms, and tabulated by system organ class and preferred term. 
 
1) 
The number of subjects with a given adverse event and the number of cases will be determined, 
and the incidence rate and 95% confidence interval will be calculated. The incidence rate will be 
obtained as the proportion of subjects in the analysis set with a specific adverse event, and the 
confidence interval for the incidence rate will be determined by the Clopper-Pearson method. 
Totaling will be performed in a similar manner to above with deaths, other serious adverse events, 
adverse events leading to administration discontinuation, adverse events leading to dose reduction, 
adverse drug reactions, deaths as adverse drug reactions, other serious adverse drug reactions, 
adverse drug reactions leading to administration discontinuation, and adverse drug reactions 
leading to dose reduction. The relevant definitions are shown below. 
 


 
8 
Death 
Adverse event with “Death” as the outcome 
Other serious 
adverse event 
Adverse event in the seriousness category “Serious”, except for death 
Adverse event leading to 
administration 
discontinuation 
Adverse event for which the study drug action is “Administration 
discontinuation” 
Adverse event  
leading to dose reduction 
Adverse event for which the study drug action is “Dose reduction” 
Adverse drug reaction 
Adverse event with the causal relationship with the study drug judged 
to be other than “Not related” 
Death as adverse drug 
reaction 
Death, with the causal relationship with the study drug judged to be 
other than “Not related” 
Other serious 
adverse drug reaction 
Other serious adverse event with the causal relationship with the study 
drug judged to be other than “Not related” 
Adverse drug reaction 
leading to administration 
discontinuation 
Adverse event leading to administration discontinuation, with the 
causal relationship with the study drug judged to be other than “Not 
related” 
Adverse drug reaction 
leading to dose reduction 
Adverse event leading to dose reduction, with the causal relationship 
with the study drug judged to be other than “Not related” 
 
2) 
The number of subjects with a given adverse event, the number of cases, and the incidence rate 
will be determined by adverse event system organ class and preferred term. However, when 
calculating the number of subjects with a given adverse event and the incidence rate, if the same 
adverse event occurs more than once with the same subject, these events will be taken to be have 
affected one subject. Adverse drug reactions will be tabulated similarly. 
3) 
With respect to adverse events with an incidence of 2% or more, the number of subjects, number 
of cases, and incidence rate will be calculated for each adverse event preferred term. Adverse drug 
reactions will be tabulated similarly. 
4) 
The number of subjects and incidence rate will be calculated for each severity and outcome 
category, by adverse event system organ class and preferred term. If the same adverse event occurs 
more than once in different categories with the same subject, it will be taken to have occurred once, 
in the category with the highest of the below priority ranks. Adverse drug reactions will be tabulated 
similarly. 
 


 
9 
 
Survey item category 
Priority rank 
Severity 
Outcome 
1 
Severe 
Death 
2 
Moderate 
Recovery with sequelae 
3 
Mild 
No improvement 
4 
 
Partial recovery 
5 
 
Recovery 
6 
 
Unknown 
 
5) 
The number of subjects and the incidence rate will be calculated for each onset timing category 
(weeks 0 to 8; weeks 8 to 16, weeks 16 to 24, weeks 24 to 32; weeks 32 to 40; weeks 40 to 48; 
weeks 48 to 50; later than week 50) for adverse events during the treatment period, by system organ 
class and preferred term. The denominator of the incidence rate will be the number of subjects with 
administration duration no shorter than the lower limit of each onset time category. The onset 
timing will be calculated as follows: 
   Onset timing [day] 
     
 = (onset date) − (administration initiation date in the open-label extension study) + 1 
When calculating the number of subjects and the incidence rate, if the same adverse event occurs 
in different categories more than once in the same subject, it will be taken to have occurred with 
one subject in each of the relevant categories. Adverse drug reactions will be tabulated similarly. 
6) 
With subjects in the safety analysis set who are transferred to the tapering period, adverse events 
that occur during the tapering period will be summarized. The number of subjects with a given 
adverse event, the number of cases, and the incidence rate will be determined by adverse event 
system organ class and preferred term. However, when calculating the number of subjects with a 
given adverse event and the incidence rate, if the same adverse event occurs more than once with 
the same subject, these events will be taken to be have affected one subject. Adverse drug reactions 
will be tabulated similarly. 
7) 
With respect to adverse events for which the following standard MedDRA queries (SMQ) are 
applicable, the number of subjects, number of cases, and incidence rate will be determined by 
system organ class and preferred term. However, when calculating the number of subjects with a 
given adverse event and the incidence rate, if the same adverse event occurs more than once with 
the same subject, these events will be taken to be have affected one subject. 
 
SMQ 
Range 
Suicide/self-injury 
Broad search 
Hostility/aggression 
Broad search 
 
8) 
The number of subjects and incidence rate will be calculated for each study drug dose category 
(20 mg, 40 mg, 60 mg, 540 mg) at the onset date of adverse event occurring after the initiation of 
the open-label extension study, by system organ class and preferred term. When calculating the 
number of subjects and the incidence rate, if the same adverse event occurs in different categories 


 
10 
more than once in the same subject, it will be taken to have occurred with one subject in each of 
the relevant categories. Adverse drug reactions will be tabulated similarly. 
 
10.2  Analyses of vital signs and body weight 
Blood pressure (systolic and diastolic), pulse rate, and body weight will be analyzed. The time-points for 
evaluation of vital signs and body weight are taken to be the baseline, weeks 4, 16, 28, 40, and 50 after 
administration initiation, and the final evaluation time (weeks 51 to 52, or at discontinuation of the 
treatment period or tapering period). 
1) With respect to blood pressure (systolic and diastolic), pulse rate, and body weight, summary statistics 
of observed values at each evaluation time-point and changes from baseline will be calculated. 
2) For consecutive subjects, summary statistics of observed values at each evaluation time-point in the 
preceding study and this study and changes from baseline in the preceding study will be calculated. 
 
10.3  Analysis of laboratory test results 
The below laboratory test results will be analyzed. The time-points for evaluation of laboratory test results 
are taken to be baseline (Visit 1 for new subjects, Visit 2 for consecutive subjects), weeks 4, 16, 28, and 
40 after administration initiation, and the final evaluation time (weeks 51-52, or at discontinuation of the 
treatment period or tapering period). However, for HbA1c TSH, FT3 and FT4, evaluation is solely during 
the screening period. 
 
Classification 
Parameter 
Hematology tests 
Leukocyte count, erythrocyte count, hemoglobin, hematocrit, leukocyte fractions 
(eosinophils, basophils, neutrophils, monocytes, lymphocytes), platelet count 
Blood chemistry 
AST, ALT, LDH, γ-GTP, ALP, creatine kinase, total bilirubin, total protein, blood 
urea nitrogen, serum creatinine, uric acid, total cholesterol, triglycerides, Na, K, Cl, 
Ca, blood glucose, HbA1c, TSH, FT3, FT4 
Urinalysis 
(qualitative) 
Urinary protein, urinary glucose, urobilinogen, urinary occult blood 
 
1) 
With respect to laboratory test results obtained as continuous values, summary statistics of observed 
values at each evaluation time-point and changes from baseline will be calculated. 
2) 
With respect to urinalysis parameters obtained as qualitative values, the number and proportion of 
subjects in each category at each evaluation time-point will be determined. 
3) 
As evaluation of liver function, the numbers and proportions of subjects meeting the following 
criteria at each evaluation time-point, and the numbers and proportions meeting these criteria at 
least one evaluation time-point after administration initiation, will be determined: 
• 
AST >5 times the upper limit of the reference values. 
• 
ALT >5 times the upper limit of the reference values. 
• 
AST or ALT >3 times the upper limit of the reference values, and total bilirubin >2 times the 


 
11 
upper limit of the reference values 
• 
AST >3 times the upper limit of the reference values. 
• 
ALT >3 times the upper limit of the reference values. 
4) 
For consecutive subjects, summary statistics of observed values at each evaluation time-point in 
the preceding study and this study and changes from baseline in the preceding study will be 
calculated. 
 
10.4  Analysis of ECG 
The presence or absence of ECG abnormalities will be analyzed. The time-points for evaluation of ECG 
are taken to be baseline (Visit 1 for new subjects, Visit 2 for consecutive subjects), weeks 4 and 28 after 
administration initiation, and the final evaluation time (weeks 51-52, or at discontinuation of the tapering 
period). 
1) With respect to the presence or absence of ECG abnormalities, the frequency of each category 
before and after administration initiation as well as before administration initiation and the final 
evaluation time (weeks 51-52, or at discontinuation of the treatment period or tapering period) 
will be summarized in the form of a shift table. With respect to categories after administration 
initiation, events will be taken to have occurred once, in the category with the highest of the below 
priority ranks. 
 
 
Survey item category 
Priority rank 
Judgment 
1 
Abnormal, clinically significant 
2 
Abnormal, not clinically significant 
3 
Normal 
4 
Not observed 
 
2) With respect to the presence or absence of ECG abnormalities, the number and proportion of 
subjects in each category at each evaluation time-point will be determined. 
 
10.5  Analysis of Columbia suicide severity rating scale 
Columbia Suicide Severity Rating Scale (C-SSRS) will be analyzed. The time-points for evaluation of C-
SSRS are taken to be the screening period and all scheduled visits during the treatment period, and the 
final evaluation time (weeks 51-52 or at discontinuation of the treatment period or tapering period). 
1) The distribution of categories (yes, no) on the below evaluation scale will be summarized in the 
form of a shift table before and after administration initiation as well as before administration 
initiation and the final evaluation time (weeks 51-52, or at discontinuation of the treatment period 
or tapering period). For categories before administration initiation, subjects with at least one “yes” 
assessment at any one evaluation time-point in the screening period or before administration 
initiation will be classified as ”yes”, and other subjects will be classified as “no”. For categories 


 
12 
after administration initiation, subjects with at least one “yes” assessment at any one evaluation 
time-point after administration initiation will be classified as “yes”, and other subjects will be 
classified as “no”. Both before and after administration initiation as well as the final evaluation time, 
subjects with missing observed values at all evaluation time-points will be classified as “non-
assessed subjects”. 
2) The number and proportion of subjects in each category at each evaluation time-point will be 
determined. 
Columbia suicide severity rating scale 
Suicidal 
ideation 
1. Wish to be dead 
2. Non-specific Active suicidal thoughts. 
Suicidal 
behavior 
1. Actual attempt 
2. Non-Suicidal Self-Injurious Behavior 
3. Self-Injurious Behavior, intent unknown 
4. Interrupted attempt 
5. Aborted attempt 
6. Preparatory Act or Behavior 
7. Suicidal behavior 
8. Completed suicide 
 
3) For the following five questions about suicidal ideation, the distribution on the highest question 
number with at least one “yes” answer will be summarized in the form of a shift table of before 
versus after administration initiation. 
Question 
No. 
Questions 
1 
Wish to be dead 
2 
Non-specific Active suicidal thoughts. 
3 
Active suicidal ideation with any methods (not plans) but without 
intent to act 
4 
Active suicidal ideation with some intent to act, without specific plan 
5 
Active suicidal ideation with specific plan and intent 
 
4) For the following six questions about suicidal behavior, the distribution of yes/no will be 
summarized in the form of a shift table of before versus after administration initiation, where “yes” 
represents there is at least one answer of “yes” to a question, and “no” represents there is no answer 
of “yes” to a question. 
 
 
 
 
Questions 
Actual attempt 
Interrupted attempt 
Aborted attempt 
Preparatory Act or Behavior 
Suicidal behavior 
Completed suicide 


 
13 
11.  Performance of interim analysis 
In this study, no interim analysis will be performed. 
 
12.  Data handling in analyses 
12.1  Number of decimal places for calculated values 
In principle, the number of decimal places to which calculated summary statistics and proportions are 
expressed will be as shown below. 
 
Index 
Rules for data expression 
p-Value 
Rounded off to the fourth decimal place. If below 0.0001, expressed as 
“<.0001”. 
Mean, standard deviation, 
median 
Rounded off to one significant figure of the raw data. 
Maximum, minimum 
The same number of significant figures as the raw data. 
Proportion (%) 
Rounded off to the first decimal place. 
 
 


 
14 
Appendix 1. Schedule 
 
Screening 
period 
Treatment period 
Tapering 
period 
Follow-up 
period 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9, 10 
11 
12, 13 
14 
15,16 17/discontin
uation 
18/discont
inuation 
19 
Week 
− 3 to −1 
0 
1 
2 
4 
8 
12 
16 
20, 24 
28 
32, 36 
40 
44, 48 
50 
51 to 52 
52 to 53 
Visit date 
 
0 
7 
14 
28 
56 
84 
112 
140, 168 
196 
224, 252 
280 
308, 336 
350 
364 
371 
Obtaining informed 
consent or assent 
Xa 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic factors 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MINI-KID 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of 
inclusion/exclusion 
criteria: 
Xa 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xj 
Registration 
Xa 
(pre-
Registration) 
Xc 
(Registra
tion) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CDRS-R 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Psycho-education 
Xa, d 
Xa, d 
 
 
Xa, d, g 
Xa, d, g 
 
 
 
 
 
 
 
 
 
 
CGI-S 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
C-SSRS 
Xa 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug 
administered 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xk 
 
 
Adherence of drug 
administration 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Laboratory testse 
Xa 
Xb, f 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
Xl 
 
Blood pressure and 
heart rate 
Xa 
Xf 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
ECG 
Xa 
Xb, f 
 
 
X 
 
 
 
 
X 
 
 
 
 
Xl 
 
Body weight 
 
Xf 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Urinary drug screening 
 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testh 
Xa 
Xb, f 
 
 
 
 
 
 
 
 
 
 
 
 
Xl 
 
Plasma concentration 
 
 
 
 
Xi (5times) 
 
 
Adverse events 
X 
 
a 
Will be performed only in new subjects. 


 
15 
b 
Will be performed only in consecutive subjects. Informed consent/assent will be obtained before completing the observation at Visit 9 in the preceding study. 
c 
Consecutive subjects should be enrolled (registered) in this study within 3 days after the final administration of study drug in the preceding study. 
d 
Psycho-education is provided after evaluation of CDRS-R and CGI-S. 
e 
Hematology tests, blood chemistry tests, and urinalysis. HbA1c, TSH, FT3, and FT4 will also be measured at Visit 1 for new subjects only. 
f 
For consecutive subjects, results at Visit 9 in the preceding study may be used. 
g 
Will be performed at discontinuation if a subject discontinues the study before Visit 6. 
h 
Will be performed only in post-menarche females. 
i 
Blood samples for quantitation of plasma concentrations of duloxetine will be collected five times at any timing between Visit 5 and the completion of study drug administration during 
the treatment period. If the dose is increased or decreased, blood samples should be collected at least 2 weeks after the dose adjustment. Of five random blood samples, one or two 
samples should be collected before dosing. 
j 
Adverse events occurring within 7 days after the final administration of the study drug will be investigated. The subject is checked by telephone or other appropriate method, even if 
he/she fails to make a visit. 
k 
Dispense study drugs for tapering period. 
l 
If the tapering period is not conducted, the pregnancy test will be performed at Visit 17 or at the time of discontinuation during the treatment period. 


 
16 
Appendix 2. Permitted range of timing of examinations, observations and tests 
 
Visit 
Week 
Stipulated date of visit 
Permitted 
range (day) 
Range (Day) 
Screening 
period 
1 
−3 to −1 
−21 to −7 
- 
- 
Treatment 
period 
2 
0 
0 (Registration) 
0 
- 
 
3 
1 
7 
±3 
4 to 10 
 
4 
2 
14 
±3 
11 to 17 
 
5 
4 
28 
±7 
21 to 35 
 
6 
8 
56 
±7 
49 to 63 
 
7 
12 
84 
±7 
77 to 91 
 
8 
16 
112 
±7 
105 to 119 
 
9 
20 
140 
±7 
133 to 147 
 
10 
24 
168 
±7 
161 to 175 
 
11 
28 
196 
±7 
189 to 203 
 
12 
32 
224 
±7 
217 to 231 
 
13 
36 
252 
±7 
245 to 259 
 
14 
40 
280 
±7 
273 to 287 
 
15 
44 
308 
±7 
301 to 315 
 
16 
48 
336 
±7 
329 to 343 
 
17 
50 
350 
±3 
347 to 353 
 
At 
discontinuation 
- 
Date of final dosing of treatment 
period 
+3 
- 
Tapering 
period 
18 
51 
If the last 
dose is 40 
mg 
On Day 7, taking Visit 17 (or the 
time of discontinuation during the 
treatment period) to be Day 0. 
±3 
- 
 
 
52 
If the last 
dose is 60 
mg 
On Day 14, taking Visit 17 (or the 
time of discontinuation during the 
treatment period) to be Day 0. 
±3 
- 
 
At 
discontinuation 
- 
Date of final dosing of tapering 
period 
+3 
- 
Follow-up 
period 
19 
52 to 53 
On day 7 or later, taking final 
administration date to be day 0. 
 
- 


 
17 
Appendix 3: Endpoint Scoring 
1. Calculation methods for CDRS-R total score and subscale scores 
The scores for items 1 to 17 will be totaled, and the CDRS-R total score calculated. 
  
Endpoints 
Score range 
Endpoints 
Score range 
1. Impaired Schoolwork 
1～7 
11. Depressed Feelings 
1～7 
2. Difficulty Having Fun 
1～7 
12. Morbid Ideation 
1～7 
3. Social Withdrawal 
1～7 
13. Suicidal Ideation 
1～7 
4. Sleep Disturbance 
1～5 
14. Excessive Weeping 
1～7 
5. Appetite Disturbance 
1～5 
15. Depressed Facial Affect 
1～7 
6. Excessive Fatigue 
1～7 
16. Listless Speech 
1～5 
7. Physical Complaints 
1～7 
17. Hypoactivity 
1～7 
8. Irritability 
1～7 
 
 
 
9. Excessive Guilt 
1～7 
 
 
 
10. Low Self-Esteem 
1～7 
Total 
17～113 
 
The CDRS-R subscale scores will be calculated as shown below. 
 
Subscale 
Calculation method 
Mood 
Total of items 8, 11, 14 and 15 
Somatic 
Total of items 4, 5, 6, 7, 16 and 17 
Subjective 
Total of items 9, 10, 12 and 13 
Behavior 
Total of items 1, 2 and 3 
 
 
 


 
18 
 
 
 
Reason for signing: Approved 
Name: 
 
 
Role: Approver 
Date of signature: 01-Sep-2020 06:57:05 
GMT+0000 
 
Reason for signing: Approved 
Name: 
 
 
Role: Approver 
Date of signature: 01-Sep-2020 08:22:57 
GMT+0000