A Japan Post-Marketing, Randomized, Double-Blind, Parallel-Group, Flexible Dose Comparative Study to Assess the Non-Inferiority of Duloxetine Compared With Pregabalin in Patients With Diabetic Peripheral Neuropathic Pain
Phase: PHASE4
Conditions: Diabetic Peripheral Neuropathic Pain
Sponsor: Eli Lilly and Company

Title: A Japan Post-marketing, Randomized, Double-blind, Parallel-group, Flexible Dose 
Comparative Study to Assess the Non-inferiority of Duloxetine Compared with Pregabalin in 
Patients with Diabetic Peripheral Neuropathic Pain. 
NCT ID: NCT02417935 
Document Approval Date: 14-Sep-2016 

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1. Protocol F1J-JE-HMHA(1413N0841)(d)
A Japan Post-marketing, Randomized, Double-blind, 
Parallel-group, Flexible Dose Comparative Study to 
Assess the Non-inferiority of Duloxetine Compared with 
Pregabalin in Patients with Diabetic Peripheral 
Neuropathic Pain
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
duloxetine hydrochloride(LY248686), unlesssuch persons are bound by a confidentiality 
agreement with Eli Lilly and Company or its subsidiaries.  This document and its associated 
attachmentsare subject to United States Freedom of Information Act (FOIA) Exemption 4.
Duloxetine hydrochloride(LY248686)
Study F1J-JE-HMHA (1413N0841) will be a post-marketing, Phase 4, multicenter, 
randomized, double-blind, parallel-group, flexible-dose,comparative study to assess the 
non-inferiority ofduloxetine (40 to 60 mg/day) compared with pregabalin (300to 600mg/day)
for 12 weeks in adult outpatients with diabetic peripheral neuropathic pain.
Approval Date: 14-Sep-2016 GMT
Eli Lilly Japan K.K.
Kobe, Japan
Shionogi & Co., Ltd.
Osaka, Japan
Post-marketing Study Protocol Electronically Signed and Approved by Lilly:
29-May-2014
Amendment (a) Electronically Signed and Approved by Lilly:  30-Sep-2014
Amendment (b) Electronically Signed and Approved by Lilly:  17-Apr-2015
Amendment (c) Electronically Signed and Approved by Lilly: 5-Aug-2016
Amendment (d) Electronically Signed and Approved by Lilly
on approval date provided below.

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2.
Synopsis
Study Rationale
Duloxetine was submitted to Pharmaceuticals and Medical Devices Agency (PMDA) for the 
indication of diabetic peripheral neuropathic pain (DPNP) in Japan, and received approval on 
22 February 2012. As part of the new drug application (NDA), 2 double-blind clinical studies 
were conducted in Japan (Phase 2 F1J-JE-HMFE [0512N0821] and Phase 3 F1J-JE-HMFX
[0715N0831]).  Duloxetine efficacy was shown in this Phase 3 study (Yasuda et al. 2011);
however, during the NDA review period, PMDA judged that an additional clinical trial was 
necessary to confirm duloxetine efficacy. Thus, PMDA requested that Shionogi Co., Ltd. 
conduct a post-marketing clinical trial to confirm efficacy.  Shionogi is an alliance partner of 
Lilly and holder of the NDA for Cymbalta in Japan. Following discussion of the study design 
with PMDA and Shionogi, it was agreed that Lilly Japan would conduct a post-marketing, 
Phase 4, multicenter, randomized, double-blind, parallel-group, flexible-dose, comparative study 
to assess the non-inferiority of duloxetine (40 to 60 mg/day) compared with pregabalin (300 to 
600 mg/day) for 12 weeks in adult outpatients with DPNP (Study F1J-JE-HMHA [1413N0841]).

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Clinical Protocol Synopsis:  Study F1J-JE-HMHA (1413N0841)
Name of Study Drug: Duloxetine hydrochloride (LY248686)
Title of Study:  A Japan Post-marketing, Randomized, Double-blind, Parallel-group, Flexible Dose Comparative 
Study to Assess the Non-inferiority of Duloxetine Compared with Pregabalin in Patients with Diabetic Peripheral 
Neuropathic Pain
Number of Planned Patients/Subjects:
   Enrolled/Randomized:  286 (143 per arm)
Phase of Development:  4
Length of Study:  approximately 2 years and 8 months
Estimated first patient visit:  01 October 2014               Estimated last patient visit:  01 June 2017
Primary Objective:
The primary objective of this study is to assess the noninferiority of duloxetine (40 to 60 mg/day) compared to 
pregabalin (300 to 600 mg/day) after 12 weeks of treatment in patients with diabetic peripheral neuropathic pain 
(DPNP), as measured by change from baseline in the weekly mean of the 24-hour average pain score, which will 
be measured using an 11-point numeric rating scale (NRS) in the daily patient diary.
Secondary Objectives:
Secondary objectives of this study are: 

To compare the efficacy of duloxetine (40 to 60 mg/day) versus pregabalin (300 to 600 mg/day) for the 
treatment of patients with DPNP as measured by:
o
Patient Global Impression of Improvement (PGI- I) 
o
Brief Pain Inventory-Severity and Interference rating short form (BPI-SF)
o
Weekly mean of night pain and 24-hour worst pain scores measured using an 11-point NRS in 
the daily patient diary
o
Response to treatment, defined by a 30% and 50% reduction of the weekly mean of the 24-hour 
average pain score measured using an 11-point NRS in the daily patient diary.
o
Neuropathic Pain Symptom Inventory (NPSI) 
o
Clinical Global Impression of Improvement (CGI-I) 
o
EuroQol 5 Dimension (EQ-5D) 
o
Beck Depression Inventory-II (BDI-II) Total score

To evaluate the safety and tolerability of duloxetine compared with pregabalin for the treatment of 
patients with DPNP as measured by frequencies of treatment-emergent adverse events (TEAEs),including 
edema, the discontinuation rates due to adverse events (AEs), and clinical laboratory tests (including
hemoglobin A1c [HbA1c] and glucose).
Study Design:  Study F1J-JE-HMHA (1413N0841) is a post-marketing, Phase 4, multicenter, randomized, double-
blind, parallel-group, flexible-dose, comparative study to assess the noninferiority of duloxetine (40 to 60 mg/day) 
compared with pregabalin (300 to 600 mg/day) for 12 weeks in adult outpatients with DPNP. The study design 
includes a screening period (approximately 1 to 2 weeks), treatment period (12 weeks), tapering period (1 week), 
and follow-up period (1 week) as described below:  

Period 1 - Screening:  The screening period will consist of a minimum of 7 days and a maximum of 
14 days.  During the screening period, no study drug will be administered.

Period 2 - Treatment:  The treatment period will begin at Visit 2 (Day 0) and end at Visit 6 (Week 12).  
At the beginning of Visit 2 (Day 0), patients will be randomly assigned to duloxetine or pregabalin in a 
1:1 ratio.  Duloxetine will be administered at 20 mg/day for 1 week and then 40 mg/day for 3 weeks. 
Pregabalin will be administered at 150 mg/day for 1 week and then 300 mg/day for 3 weeks.  At Visit 4 
(Week 4) and at Visit 5 (Week 8), duloxetine and pregabalin doses may be increased in patients who do
not achieve ≥30 % pain improvement in the BPI-SF average-pain score compared with baseline (Visit 2).  
At either week, duloxetine may be increased to 60 mg/day once daily (QD) and pregabalin may be 
increased to 450 mg/day.  If pregabalin is increased to 450 mg/day at Visit 4 (Week 4), it may be further 
increased to 600 mg/day at Visit 5 (Week 8) in patients who still do not achieve ≥30 % pain improvement 
in the BPI-SF average-pain score compared with baseline (Visit 2).  

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
Period 3 - Tapering:  Period 3 is a 1-week tapering period to minimize discontinuation-emergent AEs. 
Patients receiving a final dose of duloxetine at 60 mg/day during treatment will receive 40 mg/day for the 
first 3 days of the 1-week tapering period and then 20 mg/day for the last 4 days.  Patients receiving a 
final dose of duloxetine at 40 mg/day during double-blind treatment will receive 20 mg/day throughout 
the 1-week tapering period.  Patients receiving a final dose of pregabalin at 600 mg/day or 450 mg/day
during double-blind treatment will receive 300 mg/day for the first 3 days of the 1-week tapering period 
and 150 mg/day for the last 4 days.  Patients receiving a final dose of pregabalin at 300 mg/day during 
double-blind treatment will receive 150 mg/day throughout the 1-week tapering period.

Period 4 - Follow Up:  During the 1-week follow-up period, no study drug will be administered. The 
purpose of this period is to investigate AEs that occurred 1 week after discontinuation of the study drug 
with or without tapering.
Diagnosis and Main Criteria for Inclusion and Exclusions:  Eligible patients are male or female outpatients 
≥20 and 80 years of age that present with pain due to bilateral, peripheral neuropathy as determined by the 
simplified screening criteria from the Working Group for Diabetic Neuropathy on 18 January 2002, partially 
modified version. In addition, patients must have:  (1) HbA1c ≤9.4% (National Glycohemoglobin Standardization 
Program [NGSP]) at Visit 1; (2) a HbA1c that has been measured 42 to 70 days prior to Visit 1, and the range of 
variation in the values measured, thereafter, is within ±1.0% of the value measured at Visit 1; and (3) a score of at 
least 4 on the mean of the 24-hour average pain score measured using the 11-point NRS in the daily patient diary
(should be calculated from records 7 days immediately prior to Visit 2).  Key exclusion criteria include the 
following:  (1) glycemic control has been poor within 70 days immediately prior to Visit 1; (2) past history of 
psychiatric diseases, such as depression, anxiety disorder, eating disorder, etc., that required drug therapy in the 
past 1 year, or current complications of these diseases or any history of manic psychosis or bipolar disorder; 
(3) major depressive disorder (MDD); (4) complications of diseases that are considered to affect the assessment of 
diabetic peripheral neuropathic pain; and (5) neuropathic pain suspected to be caused by alcohol.
Study Drug, Dosage, and Mode of Administration:  Duloxetine 20, 40, or 60 mg/day, given once daily (QD) as 
20 mg capsules orally.
Reference Therapy, Dose, and Mode of Administration:  Pregabalin 150, 300, 450, or 600 mg/day, given twice 
daily (BID) as 25 or 150 mg capsules orally
Planned Duration of Treatment:  13 weeks for a single patient

Treatment period:  12 weeks

Tapering period:  1 week

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Criteria for Evaluation:  
Efficacy:  

The 24-hour average pain, the night pain, and the 24-hour worst pain scores measured using an 11-point 
NRS in the daily patient diary

Patient’s Global Impressions of Improvement (PGI-I)

Brief Pain Inventory (BPI)–Severity and Interference (short form)  (BPI-SF)

Neuropathic Pain Symptom Inventory (NPSI)

Beck Depression Inventory-II (BDI-II)

Clinical Global Impressions of Improvement (CGI-I)
Safety:  

Spontaneously reported AE (including edema), serious adverse events (SAEs), electrocardiograms 
(ECGs), vital signs, body weight, and laboratory measurements (clinical chemistry, hematology, 
urinalysis)

Columbia Suicide Severity Rating Scale (C-SSRS) and self-harm follow-up form

Fall Questionnaire
Health Outcomes:  

EuroQol 5 Dimension (EQ-5D)
Other Measures (Baseline Only):

Patient’s Global Impressions of Severity

Clinical Global Impressions of Severity

Mini-International Neuropsychiatric Interview (MINI): MDD module only
Statistical Methods:
General Considerations:  Efficacy analyses will be conducted on the full analysis set (FAS).  The FAS includes all 
data from all randomized patients receiving at least 1 dose of the study drug according to the treatment the patients 
were assigned. Safety analyses will be conducted on the safety analysis set. This set includes all randomized 
patients who received at least 1 dose of study drug. Safety analyses will be based on the treatment the patients 
actually received.
Efficacy/Health Outcome:  The primary efficacy variable is the change from baseline in the weekly mean of the 
24-hour average pain score measured using the 11-point NRS in the daily patient diary.  A mixed-model repeated 
measures (MMRM) analysis will be the primary analytical technique to assess mean change in the primary efficacy 
measures.  The MMRM model will include the random effect of patient and fixed categorical effects of treatment, 
duration of DPNP (<2 years, ≥2years), week, and treatment-by-week interaction, as well as the continuous fixed 
covariates of baseline value. An unstructured covariance structure will be used to model the within-patient errors.
A Kenward-Rogers correction will be used to estimate denominator degrees of freedom.  The difference in least 
squares (LS) mean between treatments (duloxetine minus pregabalin) at Week 12 along with its 2-sided 95% 
confidence interval (CI) will be calculated based on the model. If the upper bound of the 95% CI does not exceed 
0.51, it will be concluded that duloxetine is not inferior to pregabalin.  An analysis of covariance (ANCOVA) 
model will be also used to analyze the change from baseline to Week 12 in the primary efficacy variable. The 
model will contain the main effects of treatment and duration of DPNP (<2 years, ≥2years) as well as the 
continuous fixed covariates of baseline value.  The LS mean will be used for the statistical comparisons using 
ANCOVA.  For the imputation of the missing values, the last observation carried forward (LOCF) and baseline 
observation carried forward (BOCF) methods will be used.
Safety:  Safety will be assessed by summarizing and analyzing AEs (SAEs, TEAEs, adverse drug reactions), 
discontinuation (rates and reasons), Fall Questionnaire, laboratory measurements, vital signs, weight, and ECGs.
In addition, suicide risk and suicide-related events (behavior and/or ideation) as assessed by the C-SSRS.

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3.
Table of Contents
Section
Page
1.
Protocol F1J-JE-HMHA (1413N0841) (d) A Japan Post-marketing, 
Randomized, Double-blind, Parallel-group, Flexible Dose 
Comparative Study to Assess the Non-inferiority of Duloxetine 
Compared with Pregabalin in Patients with Diabetic Peripheral 
Neuropathic Pain.................................................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................6
4.
Abbreviations and Definitions...........................................................................................12
5.
Introduction ......................................................................................................................16
6.
Objectives.........................................................................................................................18
6.1.
Primary Objective ........................................................................................................18
6.2.
Secondary Objectives...................................................................................................18
7.
Investigational Plan...........................................................................................................19
7.1.
Summary of Study Design............................................................................................19
7.2.
Discussion of Design and Control ................................................................................20
8.
Study Population...............................................................................................................22
8.1.
Inclusion Criteria..........................................................................................................22
8.1.1.
Disease Diagnostic Criteria ..................................................................................22
8.2.
Exclusion Criteria ........................................................................................................23
8.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................25
8.3.
Discontinuations ..........................................................................................................26
8.3.1.
Discontinuation of Inadvertently Enrolled Patients...............................................26
8.3.2.
Discontinuation of Study Drug.............................................................................26
8.3.3.
Patient Discontinuation from the Study ................................................................26
8.3.4.
Discontinuation of Study Sites .............................................................................28
8.3.5.
Discontinuation of the Study................................................................................28
9.
Treatment..........................................................................................................................29
9.1.
Treatments Administered .............................................................................................29
9.2.
Materials and Supplies .................................................................................................31
9.3.
Method of Assignment to Treatment ............................................................................31
9.4.
Rationale for Selection of Doses in the Study...............................................................31
9.5.
Selection and Timing of Doses.....................................................................................31
9.5.1.
Special Treatment Considerations ........................................................................33
9.6.
Continued Access to Study Drug..................................................................................34
9.7.
Blinding .......................................................................................................................34

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9.7.1.
Unbliding for SAEs..............................................................................................34
9.7.2.
Emergency unblinding for AEs ............................................................................35
9.8.
Concomitant Therapy...................................................................................................36
9.9.
Treatment/Diary Compliance .......................................................................................36
10.
Efficacy, Health Outcome/Quality of Life Measures, Safety 
Evaluations, Sample Collection and Testing, and Appropriateness of 
Measurements...................................................................................................................38
10.1. Efficacy Measures........................................................................................................38
10.1.1.
Primary Efficacy Measure....................................................................................38
10.1.2.
Secondary Efficacy Measures...............................................................................38
10.2. Health Outcome/Quality of Life Measures ...................................................................39
10.3. Other Measures............................................................................................................39
10.4. Safety Evaluations........................................................................................................40
10.4.1.
Adverse Events ....................................................................................................40
10.4.1.1.
Serious Adverse Events ..................................................................................41
10.4.2.
Other Safety Measures .........................................................................................42
10.4.2.1.
Electrocardiograms.........................................................................................42
10.4.2.2.
Columbia Suicide Severity Rating Scale (C–SSRS) and 
Self-harm Follow-up Form .............................................................................42
10.4.2.3.
Fall Questionnaire ..........................................................................................43
10.4.3.
Safety Monitoring ................................................................................................43
10.4.4.
Complaint Handling.............................................................................................43
10.5. Sample Collection and Testing.....................................................................................44
10.5.1.
Samples for Study Qualification and Health Monitoring.......................................44
10.6. Appropriateness of Measurements................................................................................44
11.
Data Quality Assurance.....................................................................................................45
11.1. Data Capture System....................................................................................................45
12.
Sample Size and Statistical Methods .................................................................................47
12.1. Determination of Sample Size ......................................................................................47
12.2. Statistical and Analytical Plans.....................................................................................47
12.2.1.
General Considerations ........................................................................................47
12.2.2.
Patient Disposition...............................................................................................48
12.2.3.
Patient Characteristics..........................................................................................48
12.2.4.
Concomitant Therapy...........................................................................................48
12.2.5.
Treatment/Diary Compliance ...............................................................................48
12.2.6.
Primary Outcome and Methodology.....................................................................49
12.2.7.
Efficacy Analyses ................................................................................................50
12.2.8.
Health Outcome/Quality of Life Analyses............................................................50

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12.2.9.
Safety Analyses....................................................................................................50
12.2.10. Interim Analyses..................................................................................................51
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................52
13.1. Informed Consent.........................................................................................................52
13.2. Ethical Review.............................................................................................................52
13.3. Regulatory Considerations ...........................................................................................52
13.3.1.
Investigator Information.......................................................................................53
13.3.2.
Protocol Signatures ..............................................................................................53
13.3.3.
Final Report Signature .........................................................................................53
14.
References ........................................................................................................................54

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List of Tables
Table
Page
Table HMHA.1. Treatment Regimens......................................................................................30
Table HMHA.2. Number of Capsules by Dose Regimen, Treatment, and Time of Day ............32

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List of Figures
Figure
Page
Figure HMHA.1. Illustration of study design for Clinical Protocol F1J-JE-HMHA
(1413N0841). ................................................................................................19
Figure HMHA.2. Process of unblinding for the purpose of reporting SAE information to 
regulatory authorities and a manufacturer overseas during the study 
period ............................................................................................................35

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List of Attachments
Attachment
Page
Attachment 1.
Protocol HMHA Study Schedule ...................................................................57
Attachment 2.
Protocol HMHA Clinical Laboratory Tests....................................................60
Attachment 3.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................61
Attachment 4.
Protocol Amendment F1J-JE-HMHA (1413N0841) (d) Summary [A 
Japan Post-marketing, Randomized, Double-blind, Parallel-group, 
Flexible Dose Comparative Study to Assess the Non-inferiority of 
Duloxetine Compared with Pregabalin in Patients with Diabetic 
Peripheral Neuropathic Pain] .........................................................................62

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4.
Abbreviations and Definitions
Term
Definition
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can, therefore, be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
audit
A systematic and independent examination of the trial-related activities and documents 
to determine whether the evaluated trial-related activities were conducted, and the data 
were recorded, analyzed, and accurately reported according to the protocol, applicable 
standard operating procedures (SOPs), good clinical practice (GCP), and the applicable 
regulatory requirement(s).
BDI-II
Beck Depression Inventory-II
BID
twice daily
blinding
A procedure in which one or more parties to the trial are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the patient are not.  
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the subjects are 
aware of the treatment received.
BOCF
baseline observation carried forward
BPI-SF
Brief Pain Inventory-Short Form
CGI-I
Clinical Global Impression of Improvement 
CGI-S
Clinical Global Impression of Severity
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.

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Term
Definition
compliance
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
CrCL
creatinine clearance
C-SSRS
Columbia Suicide Severity Rating Scale
DPNP
diabetic peripheral neuropathic pain
DSM-IV-TR
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision
ECG
electrocardiogram
eCRF
electronic case report form
ED
early discontinuation
efficacy
Efficacy is the ability of a treatment to achieve a beneficial intended result under 
controlled conditions.
end of trial (study)
End of trial is the date of the last visit or last scheduled procedure shown in the Study 
Schedule for the last patient. 
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
enter
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ePRO
electronic patient-reported outcomes
EQ-5D
EuroQol 5 Dimension
FAS
full analysis set
FDA
Food and Drug Administration
FOIA
Freedom of Information Act
GCP
good clinical practice
HbA1c
hemoglobin A1c
ICD-10
International Statistical Classification of Diseases and Related Health Problems, 10th
revision
ICF
informed consent form
ICH
International Conference on Harmonisation

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Term
Definition
Informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular trial, after having been informed of all aspects of the trial that are relevant 
to the patient’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.  
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
IRB
institutional review board:  A board or committee (institutional, regional, or national) 
composed of medical and nonmedical members whose responsibility is to verify that 
the safety, welfare, and human rights of the patients participating in a clinical study are 
protected.
IWRS
interactive web-response system
JSPC
Japan Society of Pain Clinicians
legal representative
An individual, judicial, or other body authorized under applicable law to consent on 
behalf of a prospective patient, to the patient’s participation in the clinical study.
LOCF
last observation carried forward
LS mean
Least square mean
MAO
Monoamine oxidase
MDD
major depressive disorder
MHLW
Ministry of Health Labor and Welfare
MHLW-PAB
Ministry of Health Labor and Welfare-Pharmaceutical Affairs Bureau
MINI
Mini-International Neuropsychiatric Interview
MMRM
Mixed-model repeated measures
NDA
new drug application
NGSP
National Glycohemoglobin Standardization Program
NIMH
National Institutes of Mental Health
NPSI
Neuropathic Pain Symptom Inventory
NRS
numeric rating scale
patient
A study participant who has the disease or condition for which the study drug is 
targeted.

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Term
Definition
PGI-I
Patient Global Impressions of Improvement
PGI-S
Patient Global Impression of Severity  
PMDA
Pharmaceuticals and Medical Devices Agency
PPS
per-protocol set:  The set of data generated by the subset of patients who sufficiently 
complied with the protocol to ensure that these data would be likely to exhibit the 
effects of treatment, according to the underlying scientific model.
QD
once daily
randomize
The process of assigning patients to an experimental group on a random basis.
re-screen
To screen a patient who was previously declared a screen failure for the same study.
SAE
serious adverse event
SAP
statistical analysis plan
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.  In this study, 
screening involves tests (for example, psychological tests and blood draws).  For this 
type of screening, informed consent for these screening procedures and/or tests shall be 
obtained; this consent may be separate from obtaining consent for the study.
SD
standard deviation
SNRI
serotonin and norepinephrine reuptake inhibitor
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
subject
An individual who is or becomes a participant in clinical research, either as a recipient 
of the study drug(s) or as a control.  A subject may be either a healthy human or a 
patient.
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that either occurs 
or worsens at any time after treatment baseline and that does not necessarily have to 
have a causal relationship with this treatment.
TPO
third-party organization
ULN
upper limit of normal
US
United States
VAS
visual analog scale

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A Japan Post-marketing, Randomized, Double-blind, 
Parallel-group, Flexible Dose Comparative Study to Assess 
the Non-inferiority of Duloxetine Compared with Pregabalin 
in Patients with Diabetic Peripheral Neuropathic Pain
5. Introduction
Recently, the number of patients with diabetes in Japan has increased most likely due to life-style 
changes.  Approximately 9.5 million people in Japan have diabetes, and even more are estimated 
to have either diabetes or preliminary diabetes (20.5 million).  This is approximately one-seventh 
of adults in Japan (MHLW 2013). Three major complications of diabetes are diabetic 
neuropathy, diabetic retinopathy, and diabetic nephropathy. Among these, diabetic neuropathy is
the most common, and approximately 15.6 % of diabetic patients have diabetic neuropathy
(MHLW 2002).  Moreover, diabetic neuropathy causes a painful physical symptom known as 
diabetic peripheral neuropathic pain (DPNP).  With the recent increase in diabetes in Japan, the 
number of diabetic patients with diabetic neuropathy and DPNP is estimated to increase. 
The first and most important treatment for all DPNP patients is maintaining glucose 
concentrations within the normal range.  Tight glycemic control can prevent progression of 
diabetic neuropathy (Amthor et al. 1994) and multiple studies have shown that improving 
glycemic control can reduce pain in DPNP patients (Archer et al. 1983, Boulton et al. 1982, 
Oyibo et al. 2002).  However, DPNP commonly occurs even in patients with good glycemic 
control (Sorensen et al. 2002), and pharmacologic treatments directed at pain are often necessary 
to manage DPNP. 
Historically, epalrestat and mexiletine hydrochloride have been widely used in Japan for the 
treatment of DPNP. Both epalrestat and mexiletine are listed as therapeutic options for DPNP in 
the Japanese guideline for neuropathic pain management (JSPC 2011).  Other medications listed 
in the treatment guideline include antidepressants, anticonvulsants, and sustained-release 
oxycodone. Tricyclic antidepressants, certain anticonvulsants, and opioid analgesics appear to 
also provide temporary relief to patients with DPNP, but use of these medications is limited by 
side effects (McQuay et al. 1996).
Recently, duloxetine and pregabalin have received approval by the Pharmaceuticals and Medical 
Devices Agency (PMDA) in Japan for management of DPNP.  Duloxetine is a serotonin and 
norepinephrine reuptake inhibitor (SNRI), and is thought to reduce the perception of pain by 
increasing the activity of descending pain pathways that dampen pain signals that arise from the 
periphery and are relayed through the spinal cord dorsal horn (Perahia et al. 2006).  Duloxetine is 
indicated for the treatment of multiple diseases in overseas countries including major depressive 
disorder (MDD), generalized anxiety disorder, fibromyalgia, DPNP, and pain from osteoarthritis 
and chronic low back pain (Cymbalta package insert [PI]). In Japan, duloxetine is indicated for 
Depression/Depressive state and DPNP (Cymbalta PI), and used as a first-line medication for 
DPNP.  Pregabalin is an anticonvulsant thought to reduce pain by binding to alpha2-delta 
subunits of presynaptic neuronal calcium channels, and reducing the release of excitatory 

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neurotransmitters involved in pain perception. Overseas, in addition to DPNP, pregabalin is 
indicated for the management of post-herpetic neuralgia, fibromyalgia, generalized anxiety 
disorder, and as an adjunct therapy for epilepsy (Lyrica PI).  In Japan, pregabalin is indicated for 
neuropathic pain and pain associated with fibromyalgia.
Duloxetine was submitted to the PMDA in Japan for the indication of DPNP, and received 
approval on 22 February 2012. As part of the new drug application (NDA), 2 double-blind 
clinical studies were conducted in Japan (Phase 2 F1J-JE-HMFE [0512N0821] and Phase 3 F1J-
JE-HMFX [0715N0831]).  Duloxetine efficacy was shown in this Phase 3 study (Yasuda et al. 
2011); however, during the NDA review period, PMDA judged that an additional clinical trial 
was necessary to confirm duloxetine efficacy.  Thus, PMDA requested that Shionogi Co., Ltd.
conduct a post-marketing clinical trial to confirm duloxetine efficacy (PMDA 2012).  Shionogi is 
an alliance partner of Lilly and holder of the NDA for duloxetine (Cymbalta PI) in Japan. 
Following discussion of the study design with PMDA and Shionogi, it was agreed that Lilly 
Japan would conduct a post-marketing, Phase 4, multicenter, randomized, double-blind, parallel-
group, flexible-dose, comparative study to assess the non-inferiority of duloxetine (40 to 60 
mg/day) compared with pregabalin (300 to 600 mg/day) for 12 weeks in adult outpatients with 
DPNP (Study F1J-JE-HMHA [1413N0841]).  The comparison between duloxetine and 
pregabalin is supported by the fact that both duloxetine and pregabalin are listed as first-line 
treatments in the international treatment guidelines for DPNP (NICE 2013) and in Japanese 
guideline (JSPC 2011), and that both have proven efficacy for the treatment of DPNP (O’Connor 
et al. 2009).
The primary objective of Study F1J-JE-HMHA (1413N0841) is to assess the non-inferiority of 
duloxetine (40 to 60 mg/day) given orally for 12 weeks compared with pregabalin (300 to 
600 mg/day) given orally for 12 weeks in the treatment of patients with DPNP, as measured by 
change from baseline in the weekly mean of the 24-hour average pain score, which will be 
evaluated using an 11-point numeric rating scale (NRS) in the daily patient diary.  
More detailed information about the known and expected benefits and risks of duloxetine 
hydrochloride may be found in the Cymbalta PI.

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6. Objectives
6.1.
Primary Objective
The primary objective of this study is to assess the noninferiority of duloxetine (40 to 60 mg/day)
compared to pregabalin (300 to 600 mg/day) after 12 weeks of treatment in patients with DPNP, 
as measured by change from baseline in the weekly mean of the 24-hour average pain score,
which will be measured using an11-point NRS in the daily patient diary.
6.2.
Secondary Objectives
Secondary objectives of this study are:

To compare the efficacy of duloxetine (40 to 60 mg/day, orally) versus pregabalin 
(300 to 600 mg/day, orally) for the treatment of patients with DPNP as measured by:
o
Patient Global Impression of Improvement (PGI-I) 
o
Brief Pain Inventory–Severity and Interference rating short form (BPI-SF)
o
Weekly mean of night pain and 24-hour worst daily pain scores measured using 
an 11-point NRS in the daily patient diary
o
Response to treatment, defined by a 30% and 50% reduction of the weekly mean 
of the 24-hour average pain score measured using an 11-point NRS in the daily 
patient diary
o
Neuropathic Pain Symptom Inventory (NPSI) 
o
Clinical Global Impressions of Improvement (CGI-I)
o
EuroQol 5 Dimension (EQ-5D) 
o
Beck Depression Inventory-II (BDI-II) Total score

To evaluate the safety and tolerability of duloxetine compared with pregabalin for the 
treatment of patients with DPNP as measured by frequencies of treatment-emergent 
adverse events (TEAEs), including edema, the discontinuation rates due to adverse events
(AEs), and clinical laboratory tests (including hemoglobin A1c [HbA1c] and glucose).

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7. Investigational Plan
7.1.
Summary of Study Design
Study F1J-JE-HMHA (1413N0841) is a post-marketing, Phase 4, multicenter, randomized, 
double-blind, parallel-group, flexible-dose, comparative study to assess the non-inferiority of 
duloxetine (40 to 60 mg/day) compared with pregabalin (300 to 600 mg/day) for 12 weeks in 
approximately 286 adult outpatients with DPNP (143 patients per arm).  
Figure HMHA.1 illustrates the study design, which includes a screening period (approximately 
1 to 2 weeks), treatment period (12 weeks), tapering period (1 week), and follow-up period 
(1 week).  The study periods are further described below.
Dosage is shown as mg/day.  Duloxetine will be administered once daily (QD) and 
Pregabalin will be administered twice daily (BID).
Figure HMHA.1.
Illustration of study design for Clinical Protocol F1J-JE-HMHA
(1413N0841).
Period 1 - Screening (1 to 2 weeks): The screening period will consist of a minimum of 7 days
and a maximum of 14 days.  Patients will not be allowed to use any prohibited medications and 
therapies from Period 1.  During this period, patients will be screened for eligibility.  
An informed consent form (ICF) approved by an institutional review board (IRB) will be signed 

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by the patient.  Informed consent must be obtained before any study procedures are performed
(Attachment 1).  During screening procedures, no study drug will be administered.
Period 2 - Treatment (12 weeks):  The treatment period will begin at Visit 2 (Day 0) and end at 
Visit 6 (Week 12).  At the beginning of Visit 2 (Day 0), patients will be randomly assigned to 
duloxetine or pregabalin in a 1:1 ratio.  Patients will take duloxetine QD orally after breakfast 
and pregabalin BID orally as instructed by each respective package label (See Section 9.5). 
Duloxetine will be administered at 20 mg/day for 1 week and then 40 mg/day for 3 weeks. 
Pregabalin will be administered at 150 mg/day for 1 week and then 300 mg/day for 3 weeks.  
At Visit 4 (Week 4) and at Visit 5 (Week 8), duloxetine and pregabalin doses may be increased 
in patients who do not achieve ≥30 % pain improvement in the BPI-SF average pain score
compared with baseline (Visit 2).  At either week, duloxetine may be increased to 60 mg/day and 
pregabalin may be increased to 450 mg/day.  If pregabalin is increased to 450 mg/day at Visit 4 
(Week 4), it may be further increased to 600 mg/day at Visit 5 (Week 8).  See Section 9 for 
additional dosing details.
Based on clinical judgment and on individual patient tolerability, investigators may decide to 
keep patients, who don’t achieve ≥30 % pain improvement, on the original dose (dose escalation 
is not mandatory). However, efficacy is not expected at lower doses for patients who will not 
receive dosage increases. From an ethical standpoint, these patients will be considered to 
discontinue the study in order to select another therapy option following tapering.
Patients will not be allowed to decrease their dose once increased.  If patients are unable to 
tolerate a dosage increase during Period 2, they should be discontinued from the study.
Period 3 - Tapering (1 week):  Period 3 is a 1-week tapering period to minimize
discontinuation-emergent AEs. Patients receiving a final dose of duloxetine at 60 mg/day during 
double-blind treatment will receive 40 mg/day for the first 3 days of the 1-week tapering period 
and then 20 mg/day for the last 4 days.  Patients receiving a final dose of duloxetine at 40 
mg/day during double-blind treatment will receive 20 mg/ day throughout the 1-week tapering 
period.  Patients receiving a final dose of pregabalin at 600 mg/day or 450 mg/day during 
double-blind treatment will receive 300 mg/day for the first 3 days of the 1-week tapering period 
and 150 mg/day for the last 4 days.  Patients receiving a final dose of pregabalin at 300 mg/day
during double-blind treatment will receive 150 mg/day throughout the 1-week tapering period.
See Section 9.5.1 for additional details, including dose tapering for patients who discontinue 
early.
Period 4 - Follow Up (1 week):  During the follow-up period, no study drug will be 
administered. The purpose of this period is to investigate AEs that occurred 1 week after 
discontinuation of the study drug with or without tapering.
7.2.
Discussion of Design and Control
Pregabalin was chosen as a comparator in this study because it is used as a standard of care for 
DPNP in Japan as well as duloxetine (JSPC 2011).  

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The doses and dosage regimens chosen in this study are based on the current licensed dosages of 
study drugs, used as monotherapy, in Japan. At Visit 4 (Week 4) and at Visit 5 (Week 8), 
duloxetine and pregabalin doses may be increased in patients who do not achieve ≥30 % pain 
improvement in the BPI-SF average pain score compared with baseline (Visit 2).  At either week, 
duloxetine may be increased to 60 mg/day QD and pregabalin may be increased to 450 mg/day.  
If pregabalin is increased to 450 mg/day at Visit 4 (Week 4), it may be further increased to 
600 mg/day at Visit 5 (Week 8).  
Based on clinical judgment and on individual patient tolerability, investigators may decide to 
keep patients, who don’t achieve ≥30 % pain improvement, on the original dose (dose escalation 
is not mandatory). However, efficacy is not expected at lower doses for patients who will not 
receive dosage increases. From an ethical standpoint, these patients will be considered to 
discontinue the study in order to select another therapy option following tapering.
Patients will not be allowed to decrease their dose once increased. If patients are unable to 
tolerate a dosage increase during Period 2, they should be discontinued from the study.
The treatment period chosen for Period 2 is 12 weeks because previous Phase 3 trials of duloxetine 
and pregabalin in Japan were 12 weeks and 13 weeks, respectively.  Although a treatment period 
of 13 weeks was used in a Phase 3 study of pregabalin in Japan, 12 weeks of treatment with 
pregabalin was chosen in the current study based on the following (Satoh et al. 2011):

Improvements in the weekly mean of the pain scores in the daily pain diary were 
observed as early as 1 week after beginning treatment with pregabalin, and these 
improvements were sustained throughout the study period.

In the 600-mg pregabalin group, change in pain scores appeared to reach a plateau at 
4 weeks relative to the start of treatment.

In the 300-mg pregabalin group, pregabalin treatment for 12 weeks showed almost the 
same efficacy as 13 weeks of treatment.
In addition, a foreign double-blind, placebo-controlled study of pregabalin showed that efficacy 
was achieved after 12 weeks of treatment including 1 week of titration (Tölle et al. 2008).  
These studies suggest that a 12-week treatment period is long enough to achieve efficacy with 
pregabalin.
Withdrawal symptoms are common with duloxetine, especially if discontinuation is abrupt, and 
have also been reported with pregabalin. Therefore, all patients will receive a tapered dose 
reduction over 1 week (Period 3). Other discontinued patients should also receive tapered study 
drug, whenever possible.
A randomized, double-blind study has been chosen in order to reduce bias in the collection of 
data. The study population has been chosen based on current use of the study drugs in clinical 
practice.

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8. Study Population
Entered patients who meet the eligibility criteria at Visit 1 will proceed to Visit 2. At Visit 2, 
patients who continue to meet the applicable eligibility criteria will be randomized into double-
blind treatment. Individuals who do not meet the criteria for participation in this study (screen 
failures) may be re-screened.  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
8.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria at 
Visit 1, and Visit 2, where indicated:
[1]
Male or female outpatients ≥20 and 80 years of age at the time of obtaining 
informed consent
[2]
Present with pain due to bilateral, peripheral neuropathy (see disease diagnostic 
criteria below)
[3]
Have a level of understanding sufficient to provide written informed consent and to 
communicate with the investigator and site personnel
[4]
Have HbA1c ≤9.4% (National Glycohemoglobin Standardization Program [NGSP])
at Visit 1 
[5]
Have HbA1c that has been measured 42 to 70 days prior to Visit 1, and the range of 
variation in the values measured, thereafter, is within ±1.0% of the value measured at 
Visit 1
[6]
A score of at least 4 on the mean of the 24-hour average pain score measured using
11-point NRS in the daily patient diary (should be calculated from records 7 days 
immediately prior to Visit 2)
[7]
Have made complete daily patient diary entries 80% or more of the time from Visit 1 
to Visit 2
8.1.1. Disease Diagnostic Criteria
For the purposes of this study, patients with DPNP are defined by:

The presence of pain due to bilateral, peripheral neuropathy, caused by type I or type II 
diabetes mellitus, which has manifested for at least 6 months, and is assessable in the feet, 
legs, or hands, as determined by the following symptoms:
o
Aching pain (including tingling pain, and strangling, punching, hauling, or 
wringing pain)
o
Burning pain
o
Smarting pain (including pricking pain)
o
Pinging and running pain (including keen, stabbing, and electric shock-like pain, 
or paroxysmal pain sustaining for several seconds to several minutes)
o
Pain induced by stimulation that usually causes no pain (allodynia)

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
A diagnosis of diabetic polyneuropathy (distal symmetric polyneuropathy), as determined 
by the simplified screening criteria from the Working Group for Diabetic Neuropathy on 
18 January 2002, partially modified version.
Screening Criteria of Diabetic Polyneuropathy
Prerequisite Condition: 
Must meet the following two items
1. Diagnosis of diabetes
2. Other neuropathies than diabetic neuropathy can be excluded
Criteria: 
Meet any two of following three items
1. Presence of symptoms considered to be due to diabetic polyneuropathy
2. Decreased vibration in bilateral medial malleoli
3. Decrease or disappearance of bilateral ankle reflex
Notes:
1. Symptoms considered to be due to diabetic polyneuropathy include:
1) bilateral pain
2) numbness, pain, paresthesia, or decreased sensation in the tips of toes and 
bottom of feet
Must meet the above two items
Excludes symptoms in only upper extremities or related only to cold, as with 
peripheral vascular disease
2. Ankle reflex is examined on standing position on the knees
3. Decreased vibration sense is considered ≤10 seconds by 128 Hz tuning fork.
4. Take age into consideration in elderly subjects
8.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at 
Visit 1, and Visit 2, where indicated:
[8]
Are investigator site personnel directly affiliated with this study and/or their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted
[9]
Are Lilly employees, or are employees of Shionogi, an alliance partner of 
Lilly, or are employees of a third-party organization (TPO) involved in this 
study
[10]
Are currently enrolled in a clinical trial involving a study drug or nonapproved 
use of a drug or device (other than the study drugs used in this study), or 
concurrently enrolled in any other type of medical research judged not to be 
scientifically or medically compatible with this study
[11]
Have been treated with other investigational drug(s) within 30 days immediately prior 
to Visit 1

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[12]
Have previously completed or withdrawn from any study investigating duloxetine or 
pregabalin or have previously been treated with duloxetine or pregabalin
[13]
Have complications of serious cardiovascular, hepatic, renal, respiratory or 
hematological diseases, or symptomatic peripheral vascular diseases, and whose 
enrollment in this clinical trial is considered inappropriate

“Serious” can be considered as a grade 3 AE as described in the Ministry of 
Health, Labour and Welfare-Pharmaceutical Affairs Bureau (MHLW-PAB)
Notification No. 80 (29 June 1992): “Criteria for Severity Classification of 
Adverse Drug Reactions of Pharmaceutical Products.”
[14]
Have undergone renal transplant, or are currently undergoing renal dialysis. 
[15]
Have uncontrolled narrow-angle glaucoma, history of uncontrolled seizures, or 
uncontrolled or poorly controlled hypertension
[16]
Glycemic control has been poor within 70 days immediately prior to Visit 1 (for 
example, ketoacidosis requiring hospitalization, or hypoglycemia that may cause 
consciousness disorder)
[17]
Pregnant* or lactating female patients, or male patients who are planning for their 
partners to be or become a pregnant during the timeframe of the study
(* detailed information can be found in Attachment 2. Protocol HMHA Clinical 
Laboratory Tests)
[18]
Have hypersensitivity to multiple medications
[19]
Answered “yes” to either Question 4 (Active Suicidal Ideation with Some Intent to 
Act, Without Specific Plan) or Question 5 (Active Suicidal Ideation with Specific 
Plan and Intent) on the “Suicidal Ideation” portion of the Columbia-Suicide Severity 
Rating Scale (C–SSRS) or answered “yes” to any of the suicide-related behaviors 
(actual attempt, interrupted attempt, aborted attempt, preparatory act or behavior) on 
the “Suicidal Behavior” portion of the C–SSRS; and the ideation or behavior occurred 
within the past month
[20]
Have past history of psychiatric diseases, such as depression, anxiety disorder, eating 
disorder, etc., that required drug therapy in the past 1 year, or who are currently 
having complications of these diseases or any history of manic psychosis or bipolar 
disorder
[21]
Have MDD as determined using depression module of the Mini-International 
Neuropsychiatric Interview (MINI)
[22]
Have complications of diseases that are considered to affect the assessment of 
diabetic peripheral neuropathic pain. For example, nerve diseases with pain other 
than diabetic peripheral neuropathic pain (cervical spondylosis, carpal tunnel 
syndrome, spinal canal stenosis, and post-herpetic pain), pain diseases other than 
nerve diseases (collagen diseases, gout, chronic obstructive arteriosclerosis, and 
arthritis), and other pain at the site of evaluation (skin diseases and traumatic injury) 
are excluded. 
[23]
Have neuropathic pain suspected to be caused by alcohol

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[24]
Have past history of drug abuse or dependence (including alcohol dependence) in the 
past 1 year, or who are currently having complication, thereof
[25]
Considered unsuitable to participate in the study as judged by the investigator
[26]
Have been treated with a monoamine oxidase (MAO) inhibitor(s) within 14 days 
immediately prior to Visit 2.  Patients who visited the investigator site 14 days prior 
to Visit 2, those who have been treated with MAO inhibitors(s), thereafter, are 
excluded
[27]
Have alanine aminotransferase (ALT) and aspartate aminotransferase (AST) at a level 
≥100 U/L at Visit 1
[28]
Have total bilirubin at a level ≥1.5 mg/dL at Visit 1
[29]
Have creatinine clearance (CrCL), calculated by Cockroft-Gault, that is <1.0 mL/s 
(<60mL/min) at Visit 1
[30]
Have a white blood cell (WBC) value <2500/mm3, neutrophils <1500/mm3, or 
platelets <100×103/mm3 on their hematology tests at Visit 1
[31]
Introduction of any treatments for diabetes, or a change in dosing regimen of any 
treatments for diabetes (exclude insulin treatment), or resumption of insulin treatment 
after Visit 1
[32]
Have been treated with prohibited concomitant drug(s), or who have undergone 
prohibited concomitant treatment(s) after Visit 1
[33]
Have taken restricted concomitant drugs 27 days immediately before Visit 1, with 
continued use of the restricted concomitant drug prior to Visit 1
[34]
Have taken acetaminophen for 4 days or more 7 days immediately prior to Visit 2
8.2.1. Rationale for Exclusion of Certain Study Candidates
The majority of exclusions are for patient safety reasons, as well as compliance with the 
summary of product characteristics, and to minimize confounding effects on the study data.  
Exclusions [8] and [9] reduce the potential bias that may be introduced at the study site. 
Exclusions [10] and [11] exclude drugs that cannot be mapped to a standard drug dictionary or 
for which few data are known to analyze the potential relationship of AEs or drug interactions. 
Exclusion [12] eliminates patients who have participated in other duloxetine or pregabalin trials 
and/or have had previous exposure to duloxetine or pregabalin to minimize the potential 
response bias. Exclusions [13], [15], [16], [18], [21], [22], [23], [24], [25], [26], [27], [28], [29],
and [30] eliminate potential safety issues. Exclusion [14] is included because patients with 
compromised renal function would need to have individualized dose adjustment for pregabalin, 
and this is not possible in this study. Exclusion [17] is intended to reduce potential risk to the 
infant by preventing lactation exposure, because risks to infants (as well as the fetus) are 
unknown. Exclusion [19] excludes patients with serious mental diseases. Exclusion [20] is to 
demonstrate independent effect on pain. Exclusions [31], [32], [33], and [34] are included 
because some treatments can interfere with pain evaluation.

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8.3.
Discontinuations
8.3.1. Discontinuation of Inadvertently Enrolled Patients
The criteria for enrollment must be followed explicitly. If the investigator site identifies a patient 
who did not meet enrollment criteria, and who was inadvertently enrolled, the sponsor must be 
notified.  If the sponsor identifies a patient who did not meet enrollment criteria, and who was 
inadvertently enrolled, the investigator site will be notified.  A discussion must occur between 
the sponsor clinical research physician or clinical research scientist and the investigator to 
determine whether the patient may continue in the study, with or without study drug.  
Inadvertently enrolled patients may be maintained in the study and on study drug when the Lilly 
clinical research physician or clinical research scientist agree with the investigator that it is 
medically appropriate for that patient.  The patient may not continue in the study with or without 
study drug if the Lilly clinical research physician or clinical research scientist does not agree 
with the investigator’s determination it is medically appropriate for the subject to continue.  The 
investigator must obtain documented approval from the Lilly clinical research physician or 
clinical research scientist to allow the inadvertently enrolled patient to continue in the study with 
study drug.
8.3.2. Discontinuation of Study Drug
Discontinuation of the study drug for abnormal liver tests should be considered by the 
investigator when a patient meets one of the following conditions after consultation with the
Lilly designated medical monitor: 

ALT or AST >8X upper limit of normal (ULN)

ALT or AST >5X ULN for more than 2 weeks 

ALT or AST >3X ULN and total bilirubin level >2X ULN or prothrombin time >1.5X 
ULN

ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, right upper-
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
Patients who discontinue the study drug early will have end-of-therapy procedures performed as 
shown in the Study Schedule (Attachment 1).
8.3.3. Patient Discontinuation from the Study
In addition, patients will be discontinued from the study in the following circumstances:

Enrollment in any other clinical trial involving study drug or enrollment in any other type 
of medical research judged not to be scientifically or medically compatible with this 
study

Investigator Decision
o
The investigator decides that the patient should be discontinued from the study

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o
If the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent

Subject Decision 
o
The patient requests to be withdrawn from the study

Sponsor Decision
o
Lilly, Shionogi, or its designee stops the study or stops the patient’s participation 
in the study for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP

Adverse Event 
o
If the investigator decides that the patient should be withdrawn because of an
SAE or a clinically significant laboratory value, the study drug is to be 
discontinued and appropriate measures are to be taken.  Lilly, Shionogi, or its 
designee is to be alerted immediately.  Refer to Safety Evaluations Section 10.4.

The patient experiences a clinically severe AE, in the opinion of the investigator, that 
would preclude further participation in the study, or the patient does not tolerate the 
planned dosages.

The female patient is willing to become pregnant, or becomes pregnant. The male patient 
is willing to have a child.

There is a significant protocol violation, as determined by the investigator or sponsor.

The patient answers “yes” to either Question 4 (Active Suicidal Ideation with Some 
Intent to Act, Without Specific Plan) or Question 5 (Active Suicidal Ideation with 
Specific Plan and Intent) on the “Suicidal Ideation” portion of the C-SSRS during the 
study period, or answers “yes” to any of the suicide-related behaviors (actual attempt, 
interrupted attempt, aborted attempt, preparatory act or behavior) on the “Suicidal 
Behavior” portion of the C-SSRS.

If an investigator, site personnel performing assessments, or patient is unblinded, the 
patient must be discontinued from the study.  In cases where there are ethical reasons to 
have the patient remain in the study, the investigator must obtain specific approval from a 
Lilly clinical research physician or clinical research scientist for the patient to continue in 
the study.
Patients who discontinue study early will have discontinuation procedures performed as shown 
in the Study Schedule (Attachment 1).

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8.3.4. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, Shionogi, or its designee, the investigator, 
or the IRB of the study site judges it necessary for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and GCP.
8.3.5. Discontinuation of the Study
The study will be discontinued if Lilly, Shionogi, or its designee judges it necessary for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, and GCP.

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9. Treatment
9.1.
Treatments Administered
Information for study drugs is shown below.
Duloxetine:

Name of the study drug: LY248686

Generic name: Duloxetine hydrochloride (JAN)

Chemical name: (+)-(S)-N-Methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine 
hydrochloride

Ingredient/content/formulation type: It is a dark brown, opaque, hard capsule packed 
with lipid-soluble granules containing 20 mg of duloxetine.

Placebo of LY248686: A placebo capsule that is indistinguishable from LY248686 
capsule.
Pregabalin:

Generic name: Pregabalin

Chemical name: (S)-3-(aminomethyl)-5-methylhexanoic acid

Ingredient/content/formulation type: It is a hard capsule packed with 25 or 150 mg of 
pregabalin

Placebo of pregabalin: A placebo capsule that is indistinguishable from pregabalin 
encapsulated capsule
This study involves a comparison of duloxetine (40 to 60 mg QD) given orally for 12 weeks to 
pregabalin (150 to 300 mg BID) given orally for 12 weeks.  Table HMHA.1 shows the treatment 
regimens.
All duloxetine doses will be administered using 20-mg capsules (or matching placebo capsules,
as applicable).
All pregabalin doses will be administered using over-encapsulated 25-mg and 150-mg capsules
(or matching placebo capsules, as applicable).
The investigator or his/her designee is responsible for the following:

explaining the correct use of the investigational agent(s) to the patient and site personnel

verifying that instructions are followed properly

maintaining accurate records of study drug dispensing and collection

returning all unused medication to Lilly, Shionogi, or its designee at the end of the study
Note: In some cases, sites may destroy the material if, during the investigator site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose clinical trial materials.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the study drug so that the situation can be assessed.

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Table HMHA.1.
Treatment Regimens
Dose
Regimen
Screening
Double-Blind Treatment
Tapering
Follow-up
Period 1
Period 2-A
Period 2-B
Period 3
Period 4
Dose
Dose
Weeks 0 to 1
Dose
Weeks 1 to 4
Dose
Weeks 4 to 8
Dose
Weeks 8 to 12
Dose
Weeks 12 to 13
Dose
Weeks 13 to 
14
Duloxetine 
No dose increasea
N/A
20 mg/day
40 mg/day
40 mg/day
40 mg/day
20 mg/day
N/A
Dose increase at Week 4
N/A
20 mg/day
40 mg/day
60 mg/day
60 mg/day
40 to 20 mg/dayb
N/A
Dose increase at Week 8
N/A
20 mg/day
40 mg/day
40 mg/day
60 mg/day
40 to 20 mg/dayb
N/A
Pregabalin 
No dose increasea
N/A
150 mg/day
300 mg/day
300 mg/day
300 mg/day
150 mg/day
N/A
Dose increase at Week 4
N/A
150 mg/day
300 mg/day
450 mg/day
450 mg/day
300 to 150 mg/dayc
N/A
Dose increase at Week 8
N/A
150 mg/day
300 mg/day
300 mg/day
450 mg/day
300 to 150 mg/dayc
N/A
Dose increase at
Weeks 4 and 8
N/A
150 mg/day
300 mg/day
450 mg/day
600 mg/day
300 to 150 mg/dayc
N/A
Abbreviations:  N/A = not available/not applicable.
a
No dose increase during Period 2-B.
b
40 mg/day for the first 3 days of the 1-week tapering period and then 20 mg/day for the last 4 days.
c
300 mg/day for the first 3 days of the 1-week tapering period and 150 mg/day for the last 4 days.

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9.2.
Materials and Supplies
Lilly, Shionogi, or its designee will provide the following study materials:

20-mg capsules of duloxetine hydrochloride

25-mg and 150-mg over-encapsulated capsules of pregabalin

placebo capsules identical in appearance to duloxetine capsules

placebo capsules identical in appearance to pregabalin over-encapsulated capsules
Duloxetine, pregabalin, and matching placebo capsules will be provided to patients in the study.
All study drugs will be handled, stored (for example, at room temperature), and used in accordance 
with this protocol and the respective PI for each study drug.  Study drug will be dispensed to the 
patient at the study site. Patients will be given instructions on how and when to take each dose.
Study drug packaging will be labeled with a unique identifier for drug accountability. Study 
drug packages will contain additional capsules to allow for permitted deviations in visit intervals.  
Clinical trial materials will be labeled according to Japan’s regulatory requirements.
Patients who are discontinuing from the study should attend the site and will receive separate 
drug supplies for tapering down of study drug (see Section 9.5.1).
9.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be randomized to double-blind treatment at 
Visit 2.  Assignment to treatment groups will be determined by a computer-generated random 
sequence using an interactive web-response system (IWRS).  The IWRS will be used to assign
blisterpacks containing double-blind study drug to each patient. The appropriate number of 
blisterpacks will be dispensed at Visit 2, Visit 4, and Visit 5, depending on each dose regimen.  
Site personnel will confirm that they have located the correct blisterpacks by entering a 
confirmation number found on the blisterpacks into the IWRS.
Randomization will be stratified by baseline weekly mean of the 24-hour average pain score 
measured using the 11-point NRS in the dairy patient diary (<6, ≥6) and duration of DPNP 
(<2 years, ≥2years).
9.4.
Rationale for Selection of Doses in the Study
The doses selected for this study are based on the current licensed dosages in Japan (see 
Section 7.2).
9.5.
Selection and Timing of Doses
Patients who take part in all treatment phases will receive double-blind treatment for 12 weeks 
during Period 2 and for 1 week during Period 3.  The number of capsules will vary after Visit 4 
(Week 4), depending on whether or not patients receive dosage increases at Visit 4 and Visit 5
(Week 8).  Table HMHA.2 depicts the number of capsules by dose regimen, treatment, and 
time of day.  Capsules will contain active study drug (duloxetine or pregabalin) or placebo
(see Section 9.2).

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Table HMHA.2.
Number of Capsules by Dose Regimen, Treatment, and Time of Day
Dose Regimen Time
Morning
Evening
Capsule 1
Capsule 2
Total Number 
of Capsules
Capsule 1
Capsule 2
Total Number 
of Capsules
No Dose Increase at Week 4 or 8
Weeks 0 to 1 
○
□□□
4
-
□□□
3
Weeks 1 to 4 
○○
□
3
-
□
1
Weeks 4 to 8 
○○
□
3
-
□
1
Weeks 8 to 12 
○○
□
3
-
□
1
Weeks 12 to 13 
(First 3 days)
○
□□□
4
-
□□□
3
Weeks 12 to 13 
(last 4 days)
○
□□□
4
-
□□□
3
Dose Increase at Week 4
Weeks 0 to 1 
○
□□□
4
-
□□□
3
Weeks 1 to 4 
○○
□
3
-
□
1
Weeks 4 to 8 
○○○
□□□□
7
-
□□□□
4
Weeks 8 to 12 
○○○
□□□□
7
-
□□□□
4
Weeks 12 to 13 
(First 3 days)
○○
□
3
-
□
1
Weeks 12 to 13 
(last 4 days)
○
□□□
4
-
□□□
3
Dose Increase at Week 8
Weeks 0 to 1 
○
□□□
4
-
□□□
3
Weeks 1 to 4 
○○
□
3
-
□
1
Weeks 4 to 8 
○○
□
3
-
□
1
Weeks 8 to 12 
○○○
□□□□
7
-
□□□□
4
Weeks 12 to 13 
(First 3 days)
○○
□
3
-
□
1
Weeks 12 to 13 
(last 4 days)
○
□□□
4
-
□□□
3
Dose Increases at Week 4 and Week 8
Weeks 0 to 1 
○
□□□
4
-
□□□
3
Weeks 1 to 4 
○○
□
3
-
□
1
Weeks 4 to 8 
○○○
□□□□
7
-
□□□□
4
Weeks 8 to 12 
○○○
□□
5
-
□□
2
Weeks 12 to 13 
(First 3 days)
○○
□
3
-
□
1
Weeks 12 to 13 
(last 4 days)
○
□□□
4
-
□□□
3
○: Duloxetine 20 mg (or Duloxetine placebo), □: Pregabalin 25 or 150 mg (or Pregabalin placebo)
Patients assigned to Duloxetine will take active Duloxetine and Pregabalin placebo, and patients assigned to 
active Pregabalin will take Duloxetine placebo and Pregabalin.
For all periods during which patients receive treatment, doses should be taken daily at
approximately the same time of day if possible. Capsules should be swallowed whole and 

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should not be crushed or broken. Patients should take the capsules after a meal (breakfast and 
dinner).
Patients will be asked to retain the empty packaging and to return it, together with any unused 
study drugs, at each visit after the start of dosing. Returned packaging and study drugs will be 
checked by staff at the investigational site at each applicable visit. Details of all study drugs 
dispensed and returned will be recorded (see Section 9.9).
Patients are to remain on a stable dose of duloxetine or pregabalin until the required dosage 
increase at Week 1 and the possible dose increases at Visit 4 (Week 4) and Visit 5 (Week 8). If 
patients experience significant intolerability during dose increases, they are to be discontinued
from the study (with appropriate tapering; see Section 9.5.1). This assessment of intolerability 
will be made by the investigator and the patient. For patients discontinuing from the study, 
separate packages will be provided to taper the dose, if necessary. 
Patients will be informed that they can contact the investigational site at any time during
treatment to discuss side effects and tolerability issues. 
9.5.1. Special Treatment Considerations
To help minimize the risk of discontinuation reactions, study drug doses will be tapered for 
selected dose regimens during Period 3 (Visit 6 [Week 12] to Visit 7 [Week 13]) before study 
drugs are discontinued. The following tapering regimes will apply to patients whose final study 
drug dose, during Period 2, were duloxetine 40/60 mg/day or pregabalin 300/450/600 mg/day.
If a patient discontinues during the first week of double-blind treatment, his/her medication 
should be discontinued abruptly.  
If a patient discontinues during or after the second week of double-blind treatment, his/her 
medication should be tapered over 7 days as follows, depending on the dosage when they 
discontinue.
•
Duloxetine final dose of 40 mg/day 
o
20 mg/day for 7 days 
•
Duloxetine final dose of 60 mg/day
o
40 mg/day for the first 3 days 
o
20 mg/day for the last 4 days
•
Pregabalin final dose of 300 mg/day 
o
150 mg/day for 7 days 
•
Pregabalin final dose of 450 mg/day 
o
300 mg/day for the first 3 days 
o
150 mg/day for the last 4 days
•
Pregabalin final dose of 600 mg/day 
o
300 mg/day for the first 3 days 
o
150 mg/day for the last 4 days

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A patient may be discontinued from the study without being tapered off his/her medication if the 
patient refuses to be tapered,or in the case of a SAE,for patient safety or ethical reasons.
Patients who are discontinuing from the study must attend the study site for an early
discontinuation(ED) visit and to receive study drug for dose tapering (if applicable). 
Thesepatients must attend the study site for a follow-up visit(Visit 301)1 week afterthe end of 
study drugtapering(Visit 7). For patients who discontinue the study drug without tapering, they 
must stillattend the study site for an ED visitand a follow-upvisit (Visit 301).
Restricted medications are summarizedinProtocol Addendum F1J-JE-HMHA (1413N0841).
9.6. Continued Access to StudyDrug
After the conclusion of the study, access to each of the study drugs is possible through 
commercial sources. Treatment of patients after the end of the study will be at the discretion of 
the treating physician.
9.7. Blinding
This is a double-blind study.Double dummy technique is used for retaining the blind.To assure 
the blinding of the study, a minimum number of Lilly
 Japan personnel will see the randomization 
table and treatment assignments before the study is completed (see Section9.7.1). 
9.7.1. Unbliding for SAEs
 
 
 
 
 
 
 
 
 
 
 
 
  
 
CCI
. 

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9.7.2. Emergency unblindingfor AEs
CCI
Emergency unblinding for AEsmay be performed through an IWRS, which may supplement or 
take the place of emergency codes generated by a computer drug-labeling system.  This option 
may be used ONLY if the patient’s well-being requires knowledge ofthepatient’s treatment 
assignment.  All communicationsresulting in an unblinding event are recorded by the IWRS.
If an investigator, site personnel performing assessments, orpatientis unblinded, thepatient
must be discontinued from the study.  In cases where there are ethical reasons to have thepatient
CCI

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remain in the study, the investigator must obtain specific approval from a Lilly clinical research 
physician or clinical research scientist for the patient to continue in the study.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted.  Patient safety must always be the first 
consideration in making such a determination.  If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the Lilly clinical research 
physician prior to unblinding a patient’s treatment assignment.  If a patient’s treatment 
assignment is unblinded, Lilly and Shionogi must be notified immediately.
9.8.
Concomitant Therapy
The list of prohibited and limited medications and therapies is provided in Protocol Addendum 
F1J-JE-HMHA (1413N0841).  
Concomitant medications will be recorded on electronic case report forms (eCRFs), including 
dose and duration of treatment.  In addition, medications that are ongoing at the time of Visit 1 
will be collected as concomitant medications in the eCRF.  Patients requiring excluded 
concomitant drugs will be discontinued from the study, unless approval has been obtained from 
the sponsor clinical research physician or clinical research scientist.
Patients will be instructed to consult with the investigator or other site personnel before taking 
any new prescribed medications, over-the-counter medications, or supplements/herbal 
preparations.  If an investigator directs a patient to discontinue any medication in order to 
comply with this protocol, this instruction should take place only after the patient has signed the 
ICF.
9.9.
Treatment/Diary Compliance
Patient compliance with study medication will be assessed at each visit.  Compliance will be 
assessed by direct questioning and counting returned tablets.  Deviation(s) from the prescribed 
dosage regimen should be recorded in the eCRF.
Diary completion will directly affect primary efficacy data collection; thus, the status of
compliance with diary completion will be assessed at each visit from Visit 2 to Visit 6.  A patient 
will be considered to be compliant with the diary at each visit if he/she has completed at least 
80% of the diaries over the total days since the last visit.
Compliance for each visit interval is defined as taking between 80% and 120% of the study drug 
dosage prescribed for that interval. The first time a patient is noncompliant, the patient will be 
counseled on the importance of taking the prescribed amount of study drug(s). The second time 
(either consecutive or nonconsecutive) that a patient is noncompliant, Lilly or its representative 
will be notified. 
Patients who are significantly noncompliant may be discontinued from the study. A patient will
be considered significantly noncompliant if he/she is judged by the investigator to have 
intentionally or repeatedly taken more than the prescribed amount of medication.

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Patients should be instructed to return all study drug packaging and unused study drugs and 
supplies to the study site at each visit. The study site will keep a record of all study drugs 
dispensed to and returned by the patients throughout the study.  The study site will return all 
unused study dugs to Lilly or its designee.  The investigator (or designee) at each investigational 
site will be responsible for keeping a drug accountability log. A drug reconciliation will be 
performed as appropriate, for example, throughout, and at the end of the study.

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10.
Efficacy, Health Outcome/Quality of Life Measures, 
Safety Evaluations, Sample Collection and Testing, and 
Appropriateness of Measurements
Study procedures and their timing (including tolerance limits for timing) are summarized in the 
Study Schedule (Attachment 1).
10.1. Efficacy Measures
10.1.1. Primary Efficacy Measure 
The primary efficacy measure will be the 11-point NRS in the daily patient diary, ranging from 
0 (no pain) to 10 (pain as bad as you can imagine).  The 11-point NRS measures the severity of 
pain over the previous 24 hours. Patients will be asked to provide 24-hour average pain, 24-hour 
worst pain and night pain scores in the daily patient diary.  Among these, the weekly mean of the 
24-hour average pain score will be the primary endpoint, and the other 2 items will be secondary 
endpoints.
10.1.2. Secondary Efficacy Measures 
The following secondary efficacy measures will be collected at the times shown in the Study
Schedule (Attachment 1).

BPI Short Form  (BPI-SF):  The BPI-SF (Cleeland and Ryan 1994) is a self-reported 
instrument that measures the severity of pain and the interference of pain on function.  
There are a total of 11 questions on the form, which are self-rated by the patient. Each 
question is scored on an 11-point scale, ranging from 0 to 10.  
o
BPI pain severity portion: There are 4 questions, which assess the severity of worst 
pain and least pain in the past 24 hours, average pain, and the pain experienced by the 
patient “right now.” The scores range from 0 (no pain) to 10 (pain as bad as you can 
imagine).
o
BPI interference portion: There are 7 questions, which assess how pain has 
interfered with the patient’s functioning in the past 24 hours on general 
activity, mood, walking ability, normal work, relations with other people, 
sleep, and enjoyment of life. The interference scores range from 0 (does not 
interfere) to 10 (completely interferes). 

The 24-hour worst pain and the night pain scores measured using the 11-point NRS in 
the daily patient diary (see Section 10.1).

Patient Global Impression of Improvement (PGI-I):  The PGI-I (Guy 1976) 
assessments will be completed by the patient.  The patient will record how he/she 
perceives the degree of improvement (or worsening) at the time of assessment since 
taking treatment. The score ranges from 1 (very much better) to 7 (very much 
worse).

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
Neuropathic Pain Symptom Inventory (NPSI):  The NPSI (Bouhassira et al. 2004) 
questionnaire is a 12-item self-administered questionnaire that will be completed by 
the patient. It assesses 5 different dimensions of neuropathic pain: burning 
spontaneous pain, pressing spontaneous pain, paroxysmal pain, evoked pain, and 
paresthesias/dysesthesias.

Clinical Global Impression of Improvement (CGI-I):  The CGI-I (Guy 1976) will 
be completed by the study physician in the presence of the patient or after having 
been in the presence of the patient.  The clinician will record the degree of the 
patient’s improvement (or worsening) since taking treatment (Visit 2), regardless of 
whether the improvement (or worsening) is thought to be entirely due to the drug 
treatment. Improvement is rated on a 7-point scale, ranging from 1 (very much 
improved) to 7 (very much worse).

Beck Depression Inventory-II (BDI-II): The BDI-II (Beck et al. 1996) is a self-
administered scale that serves as an indicator of the presence and degree of depressive 
symptoms consistent with those of the Diagnostic and Statistical Manual of Mental 
Disorders, 4th Edition, Text Revision (DSM-IV-TR). The BDI-II contains 21 items that 
characterize how the patient was feeling in the past 2 weeks.  
10.2. Health Outcome/Quality of Life Measures
The following secondary health outcome measure will be collected at the times shown in the 
Study Schedule (Attachment 1).

EuroQol 5 Dimension (EQ-5D):  The EQ-5D (EuroQol 1990) is a self-reported, 
5-item scale used to assess the patient’s health utility (mobility, self-care, usual 
activities, pain and discomfort, and depression/anxiety).  Scoring is on a 3-point scale.  
In addition, a Quality of Life “thermometer” visual analog scale (VAS) is presented 
that is rated from 0 to 100.
10.3. Other Measures
The following measures will be collected at baseline (Visit 2) only as shown in the Study
Schedule (Attachment 1):

Patient Global Impression of Severity (PGI-S): The PGI-S (Guy 1976) 
assessments will be completed by the patient.  The patient will record how he/she 
feels at the current time. It will be completed at baseline (Visit 2) only. Severity is 
rated on a 7-point scale, ranging from 1 (normal, not at all ill) to 7 (among the most 
extremely ill patients).

Clinical Global Impression of Severity (CGI-S):  The CGI-S (Guy 1976) will be 
completed by the study physician in the presence of the patient, or after having been 
in the presence of the patient.  The clinician will record how ill the patient is at the 
current time, in relation to the clinician’s total experience with this patient population. 
It will be completed at baseline (Visit 2) only. Severity is rated on a 7-point scale, 
ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill patients).

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
Mini-International Neuropsychiatric Interview (MINI):  The MINI (Sheehan et al. 
1998) is a short structured diagnostic interview, developed jointly by psychiatrists and 
clinicians in the United States (US) and Europe, for DSM-IV-TR and International 
Statistical Classification of Diseases and Related Health Problems, 10th revision 
(ICD-10) psychiatric disorders. With an administration time of approximately 
15 minutes, it was designed to meet the need for a short, but accurate, structured 
psychiatric interview for multicenter clinical trials.  Only the MDD module of the 
MINI will be completed at baseline (Visit 2).
10.4. Safety Evaluations
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious, considered related to the study treatment or the study, or that caused the 
patient to discontinue before completing the study.  The patient should be followed until the 
event is resolved or explained.  Frequency of follow-up evaluation is left to the discretion of the 
investigator.
10.4.1. Adverse Events
The sponsor has standards for reporting AEs that are to be followed, regardless of applicable 
regulatory requirements that may be less stringent.  
Cases of pregnancy that occur during maternal or paternal exposures to study drug should be 
reported.  Data on fetal outcome and breast-feeding are collected for regulatory reporting and 
drug safety evaluation.
Study site personnel will record the occurrence and nature of each patient’s preexisting 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study.
After the ICF is signed, site personnel will record any change in the condition(s) and the 
occurrence and nature of any AEs.  All AEs related to protocol procedures are reported to the 
sponsor via electronic data entry (Inform).  In addition, all AEs occurring after the patient 
receives the first dose of study drug must be reported to the sponsor or its designee via electronic 
data entry.
Any clinically significant findings from ECGs, labs, vital sign measurements, and other 
procedures that result in a diagnosis should be reported to sponsor.
Investigators will be instructed to report to the sponsor their assessment of the potential 
relatedness of each AE to protocol procedure, studied disease state, study drug, via electronic 
data entry/designated data transmission methods.

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The investigator decides whether he or she interprets the observed AEs as either related to 
disease, to the study medication, study procedure, or other concomitant treatment or pathologies.  
To assess the relationship of the AE to the study drug, the following terminologies are defined:

Related:  a direct cause-and-effect relationship between the study treatment and 
the AE is likely

Possibly related:  a cause-and-effect relationship between the study treatment and 
the AE has not been demonstrated at this time and is not probable, but is also not 
impossible

Unrelated:  without question, the AE is definitely not associated with the study 
treatment
As per sponsor’s SOPs, all “related” and “possibly related” AEs and SAEs will be defined as 
related to study drug.
Adverse events that have occurred during the time from Visit 1 to the follow-up visit (Visit 301), 
are surveyed (Attachment 1).
10.4.1.1. Serious Adverse Events
Serious adverse event collection begins after the patient has signed informed consent and has 
received study drug.  If a patient experiences an SAE after signing informed consent, but prior to 
receiving study drug, the event will NOT be reported as serious, unless the investigator feels the 
event may have been caused by a protocol procedure. Serious adverse events will be reported 
the same period for AE report.
Planned surgeries should not be reported as SAEs, unless the underlying medical condition has 
worsened during the course of the study.
Study site personnel must alert Lilly of any SAE within 24 hours of investigator awareness of the 
event via a sponsor-approved method.  If alerts are issued via telephone, they are to be 
immediately followed with official notification on study-specific SAE forms.  This 24-hour 
notification requirement refers to the initial SAE information and all follow-up SAE 
information. Lilly should report all SAE information to Shionogi for their safety evaluations 
within 48 hours of Lilly awareness of the event.
An SAE is any AE from this study that results in one of the following outcomes:

death 

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon appropriate 

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medical judgment, they may jeopardize the patient, and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.
Serious adverse events that occur up to and including the patient’s last study visit will be 
collected, regardless of the investigator’s opinion of causation, in the clinical data collection 
database and the pharmacovigilance system at Lilly.  The investigator does not need to actively 
monitor patients for AEs once the trial has ended, unless provided otherwise in the protocol.  
If an investigator becomes aware of SAEs occurring to a patient after the patient’s participation 
in the trial has ended, the investigator should report the SAEs to Lilly, regardless of the 
investigator’s opinion of causation, and the SAEs will be entered in the pharmacovigilance 
system at Lilly.
10.4.2. Other Safety Measures
10.4.2.1. Electrocardiograms
For each patient, 12-lead digital electrocardiograms (ECGs) will be collected locally at the 
investigative site according to the Study Schedule (Attachment 1) as single ECG evaluation.
Patients must be supine for approximately 5 to 10 minutes before ECG collection, and remain 
supine, but awake, during ECG collection.
Electrocardiograms may be obtained at additional times, when deemed clinically necessary.  
Collection of more ECGs than expected at a particular time point is allowed when needed to 
ensure high quality records.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
patient is still present, to determine whether the subject meets entry criteria and for immediate 
subject management, should any clinically relevant findings be identified.
The investigator (or qualified designee) must document his/her review of the ECG printed at the 
time of evaluation.
Electrocardiograms will be evaluated for patients who have a risk of cardiovascular events based 
on the investigator’s decision at baseline to determine subject eligibility, at Visit 7 during the 
safety evaluation for tapering/discontinuation, or at early discontinuation.  Electrocardiograms
may be obtained at additional times depending on the investigator’s decision.
10.4.2.2. Columbia Suicide Severity Rating Scale (C–SSRS) and Self-harm 
Follow-up Form
The C-SSRS (Posner et al. 2007, 2011) captures the occurrence, severity, and frequency of 
suicide-related thoughts and behaviors during the assessment period.  The scale includes 
suggested questions to solicit the type of information needed to determine if a suicide-related 
thought or behavior occurred.  The C-SSRS will be administered by an investigator/study 
physician according to the Study Schedule (Attachment 1).  The tool was developed by the 
National Institutes of Mental Health (NIMH) trial group for the purpose of being a counterpart to 
the Food and Drug Administration’s (FDA’s) categorization of suicidal events.

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10.4.2.3. Fall Questionnaire
According to the Study Schedule (Attachment 1), patients will respond yes/no to a simple 
unpublished questionnaire that solicits fall events.  If the patient responds yes, additional 
questions will be asked regarding the status of the patient when the fall occurred, whether or not 
the patient used walking aids, what physical complaints the patient had at the time of the fall, and 
the outcome of the fall.
If the patient responds yes on the questionnaire, the event will be 
reported as an AE or SAE depending on the outcome of the fall.
10.4.3. Safety Monitoring
The Lilly clinical research physician or clinical research scientist will monitor safety data 
throughout the course of the study.
Edema and its related events will be monitored carefully, per PMDA, because angiotensin 
converting enzyme inhibitors and thiazolidines are not prohibited in this study. There are 
precautions for these drugs in the pregabalin PI; however, there is no obvious evidence for the 
relationship between these drugs and edema.  Moreover, there is no report that these drugs will 
influence the efficacy evaluation for duloxetine and pregabalin.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly clinical 
research physician will, as is appropriate, consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical scientist and Shionogi.
If a study patient experiences elevated ALT or AST >3X ULN, or elevated total bilirubin >2X 
ULN, clinical and laboratory monitoring should be initiated by the investigator.  Details for 
hepatic monitoring depend upon the severity and persistence of observed laboratory test 
abnormalities.  To ensure patient safety and comply with regulatory guidance, the investigator is 
to consult with Lilly regarding collection of specific recommended clinical information and 
follow-up laboratory tests. See Attachment 3.
10.4.4. Complaint Handling
Lilly collects product complaints on study drugs and drug delivery systems used in clinical 
studies in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.
All product complaints associated with material packaged, labeled, and released by the sponsor
will be reported.
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

Recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

Faxing the completed product complaint form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.

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10.5. Sample Collection and Testing
Attachment 1 lists the schedule for sample collections in this study.
Attachment 2 lists the laboratory tests that will be performed for this study.  
10.5.1. Samples for Study Qualification and Health Monitoring
Blood and urine samples will be collected to determine whether patients meet 
inclusion/exclusion criteria and to monitor patient health.
Investigators must document their review of each laboratory safety report.
Laboratory/analyte results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
10.6. Appropriateness of Measurements
The measures of efficacy and safety are standard measures used in clinical trials of DPNP and 
depression and are well documented and reliable.

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11.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

Provide instructional material to the study sites, as appropriate

Sponsor start-up training to instruct the investigators and study coordinators.  
This training will give instruction on the protocol, the completion of the eCRFs, and 
study procedures.

Make periodic visits to the study site

Be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax

Review and evaluate eCRF data and use standard computer edits to detect errors in data 
collection

Conduct a quality review of the database
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Shionogi,
Lilly, or its representatives, and/or regulatory agencies at any time.  Investigators will be given 
notice before an audit occurs.
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study.  If requested, the 
investigator will provide the sponsor, applicable regulatory agencies, and applicable IRBs with 
direct access to original source documents.
11.1. Data Capture System
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Electronic patient-reported outcome (ePRO) measures are entered into an ePRO instrument at the 
time that the information is obtained.  In these instances where there is no prior written or 
electronic source data at the site, the ePRO instrument record will serve as the source.
In this study, the patient diary will be reported via ePRO.  An 11-point NRS in the daily patient
diary, such as the 24-hour average pain and 24-hour worst pain and night pain scores, will be 
entered into an ePRO.   
If ePRO records are stored at a TPO, investigator sites will have continuous access to the source 
documents during the study and will receive an archival copy at the end of the study for 
retention.
Any data for which the ePRO instrument record will serve to collect source data will be 
identified and documented by each site in that site’s study file.

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Case report form data collected by the TPO will be encoded by the TPO and stored electronically 
in the TPO’s database system.  Validated data will subsequently be transferred to Lilly’s data 
warehouse, using standard Lilly file transfer processes.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system.  Data will subsequently be transferred from the central 
vendor to the Lilly’s database.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.

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12.
Sample Size and Statistical Methods
12.1. Determination of Sample Size
Approximately 286 (143 per arm) patients will be randomized.
Sample size was calculated in order to have enough statistical power to confirm the 
non-inferiority of duloxetine to pregabalin based on the primary endpoint, the change from 
baseline to Week 12 in the weekly mean of the 24-hour average pain score, which will be 
evaluated using an 11-point NRS in the daily patient diary. Assuming that the treatment 
difference of the primary endpoint is 0.1 (i.e. duloxetine is superior to pregabalin by 0.1) and that 
the common standard deviation (SD) is 1.82 with a non-inferiority margin of 0.51, 141 patients 
per group (282 in total) would have a statistical power of 80% to confirm the non-inferiority with 
a 1-sided significance level of 0.025.
The treatment difference could be assumed to be at least 0.1 in this study based on the results 
such as the double-blind randomized study to comparing duloxetine and pregabalin (the 
treatment difference [95% confidence interval (CI)]: 0.61 [0.33, 0.90]) (Bouhassira et al. 2014, 
Marchettini et al. 2016, Tesfaye et al. 2013) and the results of the meta-analysis comparing them
indirectly (the treatment difference [95% credible interval]: 0.25 [-0.16, 0.67]) (Quilici et al. 
2009) even though there are differences such as treatment periods among the studies.
The SD was assumed to be 1.82, based on the pooled analysis results of 1 pregabalin trial and 2
duloxetine trials conducted in Japan.
The non-inferiority margin was estimated based on a meta-analysis that applied the
DerSimonian-Laird method.  Utilizing a phase 3 trial of pregabalin in Japan, which was treated 
as an evaluation-test in either Japan or the US, this meta-analysis looked at the difference of 
variation in the average pain score between placebo and pregabalin after 12 weeks of treatment.
It was estimated that the difference of the mean value and its 95% CI was 1.03 (0.69, 1.37).  The 
non-inferiority margin for the current study was set using half of the difference of the mean value, 
0.51 (that is, 1.03/2).  
12.2. Statistical and Analytical Plans
12.2.1. General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly.
Efficacy analyses will be conducted on the full analysis set (FAS).  The FAS includes all data 
from all randomized patients receiving at least 1 dose of the study drug according to the 
treatment the patients were assigned. When mean change from baseline to endpoint is assessed, 
data will be included in the analysis only if there is a baseline and a corresponding postbaseline 
measure.  
Analyses based on the per-protocol set (PPS) will be performed to examine the robustness of the 
primary efficacy analysis. The PPS will be defined as a subset of patients in FAS who did not 
have major protocol deviations. 

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Safety analyses will be conducted on the safety analysis set. This set includes all randomized 
patients who received at least 1 dose of study drug. Safety analyses will be based on the 
treatment the patients actually received.
All tests of hypotheses will be considered statistically significant if the 2-sided p-value is <0.05, 
unless otherwise stated. No adjustments for multiple comparisons will be made.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the clinical study report.  Additional exploratory analyses of the data will be conducted as 
deemed appropriate.
12.2.2. Patient Disposition
All patients who discontinue from the study will be identified, and the extent of their 
participation in the study will be reported.  If known, a reason for their discontinuation will be 
given.  The reasons for patient discontinuation (completed the study, discontinued due to AEs, 
discontinued due to lack of efficacy, etc) will be summarized with counts and percentages within 
each of the 2 treatment groups. Treatment-group differences will be evaluated using Fisher’s 
exact tests.
12.2.3. Patient Characteristics
Patient characteristics, disease severity, and history will be summarized by treatment group.
12.2.4. Concomitant Therapy
Previous medications (that is, those taken and stopped before baseline) and concomitant 
medication used during the study will be summarized by treatment group. For previous and 
concomitant medications, treatment group differences in the frequency of usage for each 
medication will be analyzed by Fisher’s exact test.
12.2.5. Treatment/Diary Compliance
At each visit, patients’ compliance with the study medication will be calculated based on the 
number of capsules taken (calculated from the number of capsules dispensed and returned) and 
the number of days between visits as a percentage of the number of capsules prescribed for a 
period of that length. Percentage compliance will be summarized using means, standard 
deviations, medians etc. by treatment group and visit and additionally, counts and percentages of 
patients with compliance <80%, between 80% and 120%, and so forth, will be presented.
In addition, percentage of diary completion will be summarized using means, standard 
deviations, medians etc. by treatment group and visit and percentages of patients with 
compliance <80%, ≥80%, will be presented.

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12.2.6. Primary Outcome and Methodology
The primary efficacy variable is the change from baseline in the weekly mean of the 24-hour 
average pain score measured using an 11-point NRS in the daily patient diary.
A mixed-model repeated measures (MMRM) analysis will be the primary analytical technique to 
assess mean change in efficacy measures. The MMRM model will include the random effect of 
patient and fixed categorical effects of treatment, duration of DPNP (<2 years, ≥2years), week, 
and treatment-by-week interaction, as well as the continuous fixed covariates of baseline value.
An unstructured covariance structure will be used to model the within-patient errors. 
A Kenward-Rogers correction (Kenward and Roger 1997) will be used to estimate denominator 
degrees of freedom.  
The difference in LS mean between treatments (duloxetine minus pregabalin) at Week 12, along 
with its 2-sided 95% CI, will be calculated, based on the model. If the upper bound of the 
95% CI does not exceed 0.51, it will be concluded that duloxetine is not inferior to pregabalin.
If the model with unstructured covariance structure fails to converge, the sandwich estimator (Lu 
and Mehrotra 2010) will be used to estimate the standard errors of the fixed effects parameters 
and the model will be fit using covariance structures of the following order until convergence is 
met:

heterogeneous toeplitz type = toeph

heterogeneous autoregressive (1st order) type = arh(1)

heterogeneous compound symmetric type = cs(h)

toeplitz type = toep

autoregressive (1st order) type = ar(1)

compound symmetric type = cs
If the sandwich estimator is used, the Kenward-Roger approximation for denominator degrees of 
freedom cannot be used; instead, the denominator degrees of freedom will be partitioned into 
between-subject and within-subject portions (denoted by DDFM= BETWITHIN in the MODEL 
statement).  
An analysis of covariance (ANCOVA) model will be used to analyze the change from baseline
to Week 12 in the weekly mean of the 24-hour average pain score measured using an 11-point 
NRS in the daily patient diary. The model will contain the main effects of treatment and 
duration of DPNP (<2 years, ≥2years) as well as the continuous fixed covariates of baseline 
value.  The LS mean will be used for the statistical comparisons using ANCOVA. For the 
imputation of the missing values, the following 2 methods will be used. Both analyses will be 
performed as a secondary analysis to examine the robustness of the primary analysis result.

The last observation carried forward (LOCF) method for all the missing cases

The baseline observation carried forward (BOCF) method for the patients who 
discontinued due to treatment-related reasons, such as AE or lack of efficacy, and the 
LOCF method for all the other missing cases

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12.2.7. Efficacy Analyses
The secondary efficacy objectives will be addressed by conducting MMRM and/or ANCOVA 
analyses (as described in Section 12.2.6, but without the baseline score in the model for CGI-I
and PGI-I, and week will be replaced by visit except for items from diary) to compare treatment 
differences for the following:

From the BPI-SF, each of the 4 questions assessing the severity of worst pain, least pain, 
and average pain in the past 24 hours, and the pain right now

From the BPI-SF, each of the 7 questions assessing the interference of pain with activities 
and the mean of the seven questions

Weekly mean of night pain and worst pain scores measured using 11-point NRS in the 
daily patient diary

BDI-II total score

CGI-I and PGI-I

From the NPSI questionnaire, the total score and each of the 5 subscores:  burning 
spontaneous pain, pressing spontaneous pain, paroxysmal pain, evoked pain, and 
paresthesias/dysesthesias
Further secondary objectives will be addressed by comparing treatment groups with respect to 
the proportions of patients achieving each of the following at Visit 6 (Week 12) using Fisher’s 
exact test. In this analysis, missing data will be imputed using LOCF method:

A ≥30% reduction on the weekly mean of the 24-hour average pain score measured using 
an 11-point NRS in the daily patient diary

A ≥50% reduction on the weekly mean of the 24-hour average pain score measured using 
an 11-point NRS in the daily patient diary
12.2.8. Health Outcome/Quality of Life Analyses
The secondary efficacy objectives for health outcome/quality of life measures will be addressed 
by conducting ANCOVA analyses (as described in Section 12.2.6) to compare treatment 
differences on the EQ-5D.
12.2.9. Safety Analyses
Safety will be assessed by summarizing and analyzing AEs (SAEs, TEAEs, adverse drug 
reactions), discontinuations due to AEs, Fall Questionnaire, laboratory measurements, vital 
signs, weight, and ECGs. In addition, suicide risk and suicide-related events (behavior and/or 
ideation) as assessed by the C-SSRS.
For key variables, statistical comparison between treatments will be conducted.  For binomial 
data, such as the proportion of patients with TEAEs, etc, Fisher’s exact test will be used.  
For continuous data, such as change from baseline-to-endpoint (LOCF) in laboratory 
measurements, etc, ANCOVA, including treatment and baseline value in the model, will be used.

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12.2.10.
Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the appropriate Lilly regulatory scientist will be consulted to determine whether it is 
necessary to amend the protocol.
Unblinding details are specified in the unblinding plan section of the statistical analysis plan 
(SAP) or a separate unblinding plan document.

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13.
Informed Consent, Ethical Review, and Regulatory 
Considerations
13.1. Informed Consent
The investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the study, including answering any questions the patient may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the patient’s willingness to continue his or her participation in the trial.
The ICF will be used to explain the potential risks and benefits of study participation to the 
patient in simple terms before the patient is entered into the study, and to document that the 
patient is satisfied with his or her understanding of the risks and benefits of participating in the 
study and desires to participate in the study.
The investigator is responsible for ensuring that informed consent is given by each patient or 
legal representative.  This includes obtaining the appropriate signatures and dates on the ICF 
prior to the performance of any protocol procedures and prior to the administration of study drug.
13.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at investigative sites(s).  
All ICFs must be compliant with the ICH guideline on GCP.  
Documentation of IRB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  The IRB(s) will review the protocol as required.
The study site’s IRB(s) should be provided with the following:

current PI and updates during the course of the study

ICF

relevant curricula vitae
13.3. Regulatory Considerations
This study will be conducted in accordance with:

consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines

International Conference on Harmonisation (ICH) GCP Guideline [E6]

applicable laws and regulations
The investigator or designee will promptly submit the protocol to applicable IRB(s).
Some of the obligations of the sponsor will be assigned to a TPO.
An identification code assigned by the investigator to each patient will be used in lieu of the 
patient’s name to protect the patient’s identity when reporting AEs and/or other trial-related data.

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13.3.1. Investigator Information
Physicians with a specialty in internal medicine or diabetes will participate as investigators in 
this clinical trial.
13.3.2. Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his/her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
13.3.3. Final Report Signature
The clinical study report coordinating investigator will sign the final clinical study report for this 
study, indicating agreement that, to the best of his/her knowledge, the report accurately describes 
the conduct and results of the study. 
An investigator will be chosen by Lilly to serve as the clinical study report coordinating 
investigator.
The sponsor’s responsible medical officer and statistician will approve the final clinical study 
report for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.

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14.
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Tesfaye S, Wilhelm S, Lledo A, Schacht A, Tölle T, Bouhassira D, Cruccu G, Skljarevski V, 
Freynhagen R. Duloxetine and pregabalin: high-dose monotherapy or their combination? The 
"COMBO-DN study"-a multinational, randomized, double-blind, parallel-group study in 
patients with diabetic peripheral neuropathic pain. Pain. 2013;154(12):2616-2625.
Tölle T, Freynhagen R, Versavel M, Trostmann U, Young JP Jr. Pregabalin for relief of 
neuropathic pain associated with diabetic neuropathy: a randomized, double-blind study. 
Eur J Pain. 2008;12(2):203-213.
Yasuda H. Nigishi H, Kazuwa N, Masato K, Atsunori K, Ryuzo K. Superiority of duloxetine to 
placebo in improving diabetic neuropathic pain: Results of a randomized controlled trial in 
Japan. J Diabetes Invest. 2011;2(2):132-139.

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Attachment 1.Protocol HMHA Study Schedule

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F1J-JE-HMHA (1413N0841) (d) Clinical Protocol
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Study Schedule, Protocol F1J-JE-HMHA (1413N0841)
Perform procedure as indicated. 
Period 1
Screening
Period 2
Treatment
Period 3
Tapering
Period 4
Follow up
Visit
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 301
Week
Weeks
-2 to -1
Week 0
Week 2
Week 4
Week 8
Week 12
ED
Week 13/ 
discontinuationa
Week 14/ 
discontinuationb
Day
Day 
-14 to -7
Day 0
Day 14
Day 28
Day 56
Day 84
-
-
-
Allowable range
-
-
± 7 days
± 7 days
± 7 days
+ 7 days
+ 3 
daysc
+ 3 days
+ 3 days
Patient characteristics/ diagnosis
Consent obtainment
Y
Patient characteristics
Y
Diagnosis of diabetic neuropathy
Y
Past history/ complications
Y
Y
Treatments
Drug allocation
Y
Prescription of the investigational 
drugs
Y
Y
Y
Y
Y
Y
Recovery of the investigational drugs/ 
confirmation of remaining drugs
Y
Y
Y
Y
Y
Y
Concomitant (previous) 
drugs/treatments
Y
Y
Y
Y
Y
Y
Y
Y
Efficacy evaluation
11-point NRS in the daily patient diary
24-hour average pain
Worst pain
Night pain
PGI-S
Y
PGI-I
Y
Y
Y
Y
Y
BPI-SF
Y
Y
Y
Y
Y
Y
BDI-II
Y
Y
Y
Y
Y
MINI
Y
CGI-S
Y
CGI-I
Y
Y
Y
Y
Y

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F1J-JE-HMHA (1413N0841) (d) Clinical Protocol
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Period 1
Screening
Period 2
Treatment
Period 3
Tapering
Period 4
Follow up
Visit
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 301
Week
Weeks
-2 to -1
Week 0
Week 2
Week 4
Week 8
Week 12
ED
Week 13/ 
discontinuationa
Week 14/ 
discontinuationb
Day
Day 
-14 to -7
Day 0
Day 14
Day 28
Day 56
Day 84
-
-
-
Allowable range
-
-
± 7 days
± 7 days
± 7 days
+ 7 days
+ 3 
daysc
+ 3 days
+ 3 days
NPSI
Y
Y
Y
EQ-5D
Y
Y
Y
Safety evaluation
Adverse events
Hematology/clinical chemistry
Y
Y
Y
Ye
Yf
Y
HbA1cd
Y
Y
Y
Y
Yf
Y
Urinalysis
Y
Y
Y
Y
Y
CrCL
Y
Pregnancy test
Y
The test is performed, as appropriate, when 
the possibility of pregnancy is suspected.
Sitting blood pressure/heart rate
Y
Y
Y
Y
Y
Y
Y
Y
Electrocardiographyg
Y
Y
Y
C-SSRS
Y
Y
Y
Y
Y
Y
Y
Y
Body weight
Y
Y
Y
Y
Y
Fall Questionnaire
Y
Y
Y
Y
Y
Y
Y
Abbreviations: BDI-II = Beck Depression Inventory-II; BPI-SF = Brief Pain Inventory-Short Form; CGI-I = Clinical Global Impression of Improvement;
CGI-S = Clinical Global Impression of Severity; CrCL = Creatinine Clearance; C-SSRS = Columbia Suicide Severity Rating Scale; EQ-5D = EuroQol 
5 Dimension; ED = Early Discontinuation; MINI = Mini-International Neuropsychiatric Interview; NPSI = Neuropathic Pain Syndrome Inventory;
NRS = numeric rating scale; PGI-I = Patient Global Impression of Improvement; PGI-S = Patient Global Impression of Severity.
a
Visit 7 occurs 7 days (+3) after Visit 6 or early discontinuation visit. Patients who discontinue the study drug without tapering do not require this visit.  (See 
Section 9.5.1.) 
b
Visit 301 occurs 7 days (+3) after Visit 7 or ED Visit without tapering.
c
ED is considered as the same day of the last administration. Variables for ED visit will be evaluated within 3 days after the last administration.
d
When there are multiple HbA1c values measured at different institutes, the value measured at the same institute at Visit 1 is used for this eligibility judgment.  
If both values measured by the central laboratory are available, the most recent data should be used for this eligibility judgment.
e
Glucose (fasting), Clinical chemistry only.
f
This will be applied to patients who discontinue the study without tapering.
g
ECG will be evaluated for patients who have a risk of cardiovascular events based on the investigator’s decision.

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Attachment 2.Protocol HMHA Clinical Laboratory Tests
Clinical Laboratory Tests (collected centrally)
Hematology:
Clinical Chemistry:
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte (red blood cell) count (RBC)
Potassium
Leukocyte (white blood cell) count (WBC)
Chloride
Neutrophils, segmented
Total bilirubin
Lymphocytes
Direct bilirubin
Monocytes
Alkaline phosphatase
Eosinophils
Alanine aminotransferase (ALT)
Basophils
Aspartate aminotransferase (AST)
Platelets
Gamma-glutamyltransferase (GGT)
Lactate Dehydrogenase (LDH)
Urinalysis:
Total protein
Protein
Blood urea nitrogen (BUN)
Glucose
Creatinine
Blood
Uric acid
Urobilinogen
Calcium
Albumin  
Glucosec
Creatinine    
Albumin
Albumin- Creatinine ratio
Total cholesterol
Low-density lipoprotein- (LDL-) cholesterol
Serum Pregnancy Testa
High-density lipoprotein- (HDL-) cholesterol
Triglyceride (TG)
Others
Creatine kinase (CK)
Hemoglobin A1c (HbA1c)
Creatinine clearanceb
a
The serum pregnancy test applies to females of child-bearing potential (not surgically sterilized and between 
menarche and 1-year postmenopausal) only.  Patients, who have test negative for pregnancy at the time of 
screening (Visit 1) based on this serum pregnancy test, are eligible for this study.
b
Cockcroft-gault method will be used for estimating the Creatinine clearance.
C
Glucose can be evaluated with the random glucose tests except for Visit 6.

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Attachment 3.Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow up with patients in consultation with the Lilly, or its designee, clinical 
research physician.
Hepatic Monitoring Tests (collected centrally)
Hepatic Hematology
Haptoglobin
Hemoglobin
Hematocrit
Hepatic Coagulation
Erythrocyte (red blood cell) count (RBC)
Prothrombin Time
Leukocyte (white blood cell) count (WBC)
Prothrombin Time, International Normalized Ratio 
(INR)
Neutrophils, segmented
Lymphocytes
Hepatic Serologies
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, immunoglobulin (Ig) M
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistry
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
Alanine aminotransferase (ALT)
Anti-nuclear antibody
Aspartate aminotransferase (AST)
Gamma-glutamyltransferase (GGT)
Anti-smooth muscle antibody
Creatinine kinase (CK)

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Attachment 4.
Protocol Amendment F1J-JE-HMHA 
(1413N0841) (d) Summary [A Japan Post-marketing, 
Randomized, Double-blind, Parallel-group, Flexible Dose 
Comparative Study to Assess the Non-inferiority of 
Duloxetine Compared with Pregabalin in Patients with 
Diabetic Peripheral Neuropathic Pain]

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Overview
Protocol F1J-JE-HMHA (1413N0841) [A Japan Post-marketing, Randomized, Double-blind, 
Parallel-group, Flexible Dose Comparative Study to Assess the Non-inferiority of Duloxetine 
Compared with Pregabalin in Patients with Diabetic Peripheral Neuropathic Pain] has been 
amended.  The new protocol is indicated by amendment (d) and will be used to conduct the study 
in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:
Guideline for Diabetes Management recommends both duloxetine and pregabalin as the first 
choice for treatment of DPNP (The Japan Diabetes Society, 2016) and the sample size was 
calculated assuming that the efficacies of duloxetine and pregabalin are equal because data that 
directly compare duloxetine and pregabalin wasn’t published in a manuscript during this study’s 
planning phase. The target number of patients has been recalculated based on the manuscripts 
which have been published after this study’s planning phase including the randomized double-
blind clinical study with DPNP to compare duloxetine and pregabalin (Bouhassira et al. 2014, 
Marchettini et al. 2016, Tesfaye et al. 2013) and also the results of the meta-analysis comparing 
them indirectly were reconsidered (Quilici et al. 2009). As the results we believe that the 
statistical power to confirm the non-inferiority will be maintained even after the target number of 
patients is reduced to 286. From the above, we decided to change the target number of patients 
from 410 to 286. 
Reference: 
The Japan Diabetes Society. Guideline for Diabetes Management. Japan: Nankodo; 2016: 226-
227, ISBN 978-4-524-25857-4. 

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
2.
Synopsis
Number of Planned Patients/Subjects:
Enrolled/Randomized:  286410 (143205 per arm)
7.1.
Summary of Study Design
Study F1J-JE-HMHA (1413N0841) is a post-marketing, Phase 4, multicenter, randomized, 
double-blind, parallel-group, flexible-dose, comparative study to assess the non-inferiority of 
duloxetine (40 to 60 mg/day) compared with pregabalin (300 to 600 mg/day) for 12 weeks in 
approximately 286410 adult outpatients with DPNP (143205 patients per arm).  
12.1. Determination of Sample Size
Approximately 286410 (143205 per arm) patients will be randomized.
Sample size was calculated in order to have enough statistical power to confirm the non-
inferiority of duloxetine to pregabalin based on the primary endpoint, the change from baseline 
to Week 12 in the weekly mean of the 24-hour average pain score, which will be evaluated using 
an 11-point NRS in the daily patient diary.  Assuming that the treatment difference of the 
primary endpoint is 0.1 (i.e. the efficacy of duloxetine is superior to and pregabalin by 0.1) are 
equal and that the common standard deviation (SD) of the primary endpoint is 1.82 with a non-
inferiority margin of 0.51, 141201 patients per group (282402, in total) would have a statistical 
power of 80% to confirm the non-inferiority with a 1-sided significance level of 0.025. 
The treatment difference could be assumed to be at least 0.1 in this study based on the results 
such as the double-blind randomized study to comparing duloxetine and pregabalin (the 
treatment difference [95% confidence interval (CI)]: 0.61 [0.33, 0.90]) (Bouhassira et al. 2014, 
Marchettini et al. 2016, Tesfaye et al. 2013) and the results of the meta-analysis comparing them 
indirectly (the treatment difference [95% credible interval]: 0.25 [-0.16, 0.67]) (Quilici et al. 
2009) even though there are differences such as treatment periods among the studies.
The SD was assumed to be 1.82, based on the pooled analysis results of 1 pregabalin trial and 2 
duloxetine trials conducted in Japan. 
The non-inferiority margin was estimated based on a meta-analysis that applied the DerSimonian 
Laird method.  Utilizing a phase 3 trial of pregabalin in Japan, which was treated as an 
evaluation-test in either Japan or the US, this meta-analysis looked at the difference of variation 
in the average pain score between placebo and pregabalin after 12 weeks of treatment.  It was 
estimated that the difference of the mean value and its 95% confidence interval (CI) was 1.03 

F1J-JE-HMHA (1413N0841) (d) Clinical Protocol
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(0.69, 1.37).  The non-inferiority margin for the current study was set using half of the difference 
of the mean value, 0.51 (that is, 1.03/2).  The SD was assumed to be 1.82, based on the pooled 
analysis results of 1 pregabalin trial and 2 duloxetine trials conducted in Japan.
14.
References
Bouhassira D, Wilhelm S, Schacht A, Perrot S, Kosek E, Cruccu G, Freynhagen R, Tesfaye S, 
Lledó A, Choy E, Marchettini P, Micó JA, Spaeth M, Skljarevski V, Tölle T. Neuropathic pain 
phenotyping as a predictor of treatment response in painful diabetic neuropathy: Data from the 
randomized, double-blind, COMBO-DN study. Pain. 2014;155(10):2171-2179.
Marchettini P, Wilhelm S, Petto H, Tesfaye S, Tölle T, Bouhassira D, Freynhagen R, Cruccu G, 
Lledo A, Choy E, Kosek E, Mico JA, Spath M, Skljarevski V, Lenox-Smith A, Perrot S. Are 
there different predictors of analgesic response between antidepressants and anticonvulsants in 
painful diabetic neuropathy? Eur J Pain. 2016;20(3):472-482.
Quilici S, Chancellor J, Löthgren M, Simon D, Said G, Le TK, Garcia-Cebrian A, Monz B. 
Meta-analysis of duloxetine vs. pregabalin and gabapentin in the treatment of diabetic 
peripheral neuropathic pain. BMC Neurol. 2009;9:6.
Tesfaye S, Wilhelm S, Lledo A, Schacht A, Tölle T, Bouhassira D, Cruccu G, Skljarevski V, 
Freynhagen R. Duloxetine and pregabalin: high-dose monotherapy or their combination? The 
"COMBO-DN study"-a multinational, randomized, double-blind, parallel-group study in 
patients with diabetic peripheral neuropathic pain. Pain. 2013;154(12):2616-2625.

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