Effect of Duloxetine 30/60 mg Once Daily Versus Placebo in Adolescents With Juvenile Primary Fibromyalgia Syndrome
Phase: PHASE3
Conditions: Fibromyalgia
Sponsor: Eli Lilly and Company

Title: Effect of Duloxetine 30/ 60 mg Once Daily versus Placebo in Adolescents with Juvenile 
Primary Fibromyalgia Syndrome. 
NCT ID: NCT01237587 
Document Approval Date: 25 Oct 2010 

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1.
Protocol F1J-MC-HMGW
Effect of Duloxetine 30/60 mg Once Daily versus Placebo 
in Adolescents with Juvenile Primary Fibromyalgia 
Syndrome
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 (LY248686), unless such persons are bound by a confidentiality agreement with 
Eli Lilly and Company or its subsidiaries.  This document and its associated attachments 
and appendices are subject to United States Freedom of Information Act Exemption 4.
Duloxetine (LY248686)
Phase IIIb, randomized, double-blind, placebo-controlled, 13-week clinical trial to assess 
the efficacy and safety of duloxetine 30/60 mg QD compared to placebo in adolescents with 
Juvenile Primary Fibromyalgia Syndrome. Continued efficacy and safety of duloxetine 
30/60 mg QD will be assessed in a 26-week, open-label treatment extension period.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Approved by Lilly:  25 Oct 2010
  

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2.
Synopsis
Study Rationale
There is little published research on Juvenile Primary Fibromyalgia Syndrome (JPFS), yet 
available literature suggests this condition is associated with significant morbidity and disability 
in adolescents. Prevalence rates in some countries are estimated from 1.2% to 6.2%, with the 
rate in the United States not known.  To date, there are no published drug efficacy studies in this 
population, nor is there a drug approved for FM or JPFS in the adolescent age range.  
Duloxetine is approved for the management of fibromyalgia (FM) in adults. Upon approval of 
that indication, the US Food and Drug Administration (FDA), under the Pediatric Research 
Equity Act (PREA), required Lilly to conduct a deferred study to assess safety and effectiveness 
of duloxetine in pediatric patients with FM aged 13 to 17 years. Specific facets of this protocol 
and study design were employed to address the requirements of that deferred research. 
Clinical Protocol Synopsis:  Study F1J-MC-HMGW
Name of Investigational Product:
Duloxetine (LY248686)
Title of Study:  Effect of Duloxetine 30/ 60 mg Once Daily versus Placebo in Adolescents with Juvenile 
Primary Fibromyalgia Syndrome
Number of Planned Patients/Subjects:
Entered:  300
Enrolled/Randomized:  210
Completed (Acute Period):  163
Phase of Development: Phase 3b 
Length of Study:  
Planned first patient visit:  February 2011               
Planned last patient visit (Acute Period):  September 2014
Planned last patient visit (Extension Period):  April 2015
Objectives:  
The primary objective is to evaluate the efficacy of duloxetine 30/60 mg once daily (QD) compared with 
placebo on the reduction of average pain severity as measured by the Brief Pain Inventory (BPI) –
Modified Short Form: Adolescent Version 24-hour average pain severity rating (for simplicity, it is 
referred to as the BPI average pain severity here after) during a 13-week, double-blind treatment phase in 
adolescents (aged 13 to 17 years) with Juvenile Primary Fibromyalgia Syndrome (JPFS).
The secondary objectives of the study are:

To evaluate the efficacy of duloxetine 30/60 mg QD compared with placebo for the treatment of 
JPFS in adolescents during a 13-week, double-blind treatment phase, as assessed by the change 
from baseline on the following measures:
o
Brief Pain Inventory (BPI) Modified Short Form: Adolescent Version severity (worst pain, 
least pain, pain right now) and interference.
o
Response to treatment, as defined by a 30% and 50% reduction in the BPI average pain 
severity.
o
Pediatric Pain Questionnaire (PPQ) pain right now, and worst pain and average pain items.
o
Clinical Global Impression of Severity, Overall (CGI-Severity: Overall) scale.

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o
Clinical Global Impression of Severity for Mental Illness (CGI-Severity: Mental Illness) 
scale.
o
Functional Disability Inventory-child version scale (FDI-child).
o
Functional Disability Inventory-parent version scale (FDI-parent).
o
Children's Depression Inventory (CDI).
o
Multidimensional Anxiety Scale for Children (MASC).

To evaluate the safety and tolerability of duloxetine 30/60 mg QD compared with placebo for the 
treatment of JPFS in adolescents during a 13-week, double-blind treatment phase.

To evaluate the efficacy and safety of duloxetine 30/60 mg QD during a 26-week, open-label, 
extension treatment phase, as assessed by the following:
o
Maintenance effect of duloxetine 30/60 mg QD during the open-label extension treatment 
phase. Maintenance effect will be assessed using the BPI average pain severity in only the 
acute phase responders (defined as those patients with ≥30% pain reduction from baseline on 
the BPI average pain severity measure).
o
Effect of duloxetine 30/60 mg QD during extension treatment phase as measured by the 
following: BPI, PPQ, CGI-Severity: Overall, CGI-Severity: Mental Illness, FDI-child, FDI-
parent, CDI, and MASC.
o
Safety of duloxetine 30/60 mg QD during extension treatment phase.
The exploratory objectives of the study are:

To evaluate the correlation between BPI severity pain items and PPQ pain items.

To evaluate the appropriateness of the American College of Rheumatology (ACR) fibromyalgia 
(FM) criteria in an adolescent population.
Study Design:  This is a Phase 3b study of duloxetine versus placebo for the treatment of JPFS in 
adolescents. The study consists of 4 periods: Period I is a 1-week screening period; Period II is a 13-
week, double-blind, placebo-controlled treatment period of duloxetine 30/60 mg QD; Period III is a 26-
week, open-label extension period of flexible duloxetine 30/60 mg QD; Period IV is a 1-week drug 
tapering period.
Diagnosis and Main Criteria for Inclusion and Exclusions:
Main inclusion criteria:

Male and female outpatients aged 13 through 17 years.

Meet criteria for JPFS as defined by Yunus and Masi (1985).

Score of ≥4 on BPI average pain severity (Item 3) at Visit 1 and Visit 2.
Main exclusion criteria:

Pain symptoms related to traumatic injury, past surgery, structural bone or joint disease (such as 
bursitis, tendonitis), or regional pain syndrome that will interfere with interpretation of outcome 
measures.

Current or previous diagnosis of rheumatologic disorder, rheumatoid arthritis (RA), 
inflammatory arthritis, or infectious arthritis, or an autoimmune disease (for example, systemic 
lupus erythematosus). 

Have a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-
IV) Axis I condition, currently or within the past year, except major depressive disorder 
(MDD) and/or generalized anxiety disorder (GAD), adjustment disorder or specific 

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phobias with primary investigator approval.

Have a current secondary DSM-IV Axis I condition of attention-deficit/hyperactivity 
disorder (ADHD) that requires pharmacologic treatment.

Have any lifetime DSM-IV Axis I diagnosis of psychosis, bipolar disorder, or schizoaffective 
disorder.

Have a family history of 1 or more first-degree relatives (parents or siblings) with diagnosed 
bipolar I disorder.

Have a history of substance abuse or dependence within the past 6 months, excluding nicotine 
and caffeine.

Have any DSM-IV Axis II disorder which, in the judgment of the investigator, would interfere 
with compliance with the study protocol.

Have a significant suicide attempt within 1 year of Visit 1 or are currently at suicidal risk in the 
opinion of the investigator (Columbia-Suicide Severity Rating Scale [C-SSRS] criteria to help).

Have been treated with duloxetine within the past 6 months. 

Have had prior nonresponse or inadequate tolerance to duloxetine. 

Body weight <20 kg at any screening period visit.

Have initiated, stopped, or changed the type or intensity of psychotherapy within 3 months prior 
to Visit 1.  Patients who anticipate a change to psychotherapy (start, stop, or change in type, 
intensity, or frequency) during study Period II will be excluded.

Have a history of seizure disorder (other than febrile seizures).

Have uncontrolled narrow-angle glaucoma.

Have acute liver injury (such as hepatitis) or severe cirrhosis (Child-Pugh Class C).

Have serious or unstable medical illness.

Are pregnant or breast-feeding.

Are taking any excluded medications (eg. stimulants, antidepressants) that cannot be 
discontinued at Visit 1. 
Investigational Product, Dosage and Mode of Administration:  
Duloxetine 30 or 60 mg QD by mouth.
Planned Duration of Treatment:  
Screening period: approximately 1 week, depending on length of medication washout period
Double-blind treatment period:  13 weeks 
Open-label extension treatment period: 26 weeks (6 months)
Drug taper period: 1 week

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Reference Therapy, Dose and Mode of Administration:  
Matched placebo capsules given QD by mouth.
Criteria for Evaluation:
Efficacy:  

Brief Pain Inventory (BPI) Modified Short Form: Adolescent Version

Pediatric Pain Questionnaire (PPQ)

Clinical Global Impression of Severity, Overall (CGI-Severity: Overall)

Clinical Global Impression of Severity for Mental Illness (CGI-Severity: Mental Illness)

Functional Disability Inventory-child version (FDI-child)

Functional Disability Inventory-parent version (FDI-parent)

Children's Depression Inventory (CDI)

Multidimensional Anxiety Scale for Children (MASC)
Safety:  

Treatment-emergent adverse events (TEAEs)

Vital signs, height, and weight

Electrocardiograms (ECGs)

Rates and reasons for early discontinuation

Laboratory measurements

Suicide risk and suicide-related events (behavior and/or ideation) as assessed by the C-SSRS.

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Statistical Methods:  
This is a randomized, double-blind, parallel, placebo-controlled comparison trial with 4 study periods 
(screening period, double-blind treatment period, open-label extension period, drug taper period) to assess 
the efficacy and safety of duloxetine 30/60 mg QD in this adolescent population.  Approximately 210 
patients will be randomized in a 1:1 ratio to the duloxetine and placebo treatment groups. This study will
assess the difference of the mean change in BPI average pain severity from baseline to the last time point
(Visit 8, Week 13) in Study Period II between treatment groups. Assuming that there will be some 
missing post-baseline data, this sample size will provide at least 80% power to detect the treatment 
difference with α=.05. All the parameters used in the sample size calculations were based on the mixed 
model repeated measures (MMRM) analysis of data from 3-month, placebo-controlled, acute treatment 
period in 2 adult FM studies: Study F1J-MC-HMCA and Study F1J-MC-HMCJ.
All analyses will be conducted on an intent-to-treat basis.  Treatment and interaction effects will be 
evaluated based on a 2-sided significance level of 0.05.  No adjustments for multiple comparisons will be 
made.  Unless otherwise specified, when a total score is calculated from individual items, it will be 
considered missing if any of the individual items are missing.  When an average score is computed from 
individual items, it is calculated from nonmissing values.
A restricted maximum likelihood-based, MMRM analysis will be used to analyze the primary efficacy 
variable (change from baseline in BPI average pain rating).  An analysis of covariance (ANCOVA) model 
with terms for treatment, investigator, and continuous covariate of baseline BPI average pain severity will 
also be used to test treatment difference for the primary efficacy variable (using last-observation-carried-
forward [LOCF] approach and baseline-observation-carried-forward [BOCF] approach).  The significance 
of treatment-by-investigator interaction will be evaluated in a separate model when it is necessary.  Type 
III sum of squares from least-squares means will be used for statistical comparison using analysis of 
variance (ANOVA) or ANCOVA models when no interaction terms are involved.  Type II sum of squares 
will be used for the LSMeans when an interaction term is included.  
ANCOVA and MMRM models similar to those described above will be used to analyze change from 
baseline for continuous secondary efficacy measures.  Treatment differences for categorical efficacy 
variables will be evaluated using Fisher’s exact test.
Analyses of categorical safety variables (adverse events, treatment-emergent changes in vital signs, and 
labs) will be conducted using Fisher’s exact test.  Continuous safety data will be analyzed using ANOVA
or ANCOVA model.
In the double-blind treatment period, duloxetine will be compared with placebo using statistical inference. 
In the open-label extension period, descriptive statistics will be used to summarize data for patients who 
entered the open-label period.

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3.
Table of Contents
Effect of Duloxetine 30/60 mg Once Daily versus Placebo in 
Adolescents with Juvenile Primary Fibromyalgia Syndrome
Section
Page
1.
Protocol F1J-MC-HMGW Effect of Duloxetine 30/60 mg Once 
Daily versus Placebo in Adolescents with Juvenile Primary 
Fibromyalgia Syndrome......................................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................7
4.
Abbreviations and Definitions...........................................................................................11
5.
Introduction ......................................................................................................................15
6.
Objectives.........................................................................................................................17
6.1.
Primary Objective ........................................................................................................17
6.2.
Secondary Objectives...................................................................................................17
6.3.
Exploratory Objectives.................................................................................................18
7.
Investigational Plan...........................................................................................................19
7.1.
Summary of Study Design............................................................................................19
7.1.1.
Study Period I – Screening Phase .........................................................................20
7.1.2.
Study Period II – Double-Blind Treatment Phase .................................................20
7.1.3.
Study Period III – Open-Label Extension Treatment Phase ..................................21
7.1.4.
Study Period IV – Taper/Discontinuation Phase ...................................................22
7.2.
Discussion of Design and Control ................................................................................22
8.
Study Population...............................................................................................................23
8.1.
Inclusion Criteria..........................................................................................................23
8.1.1.
Disease Diagnostic Criteria ..................................................................................24
8.2.
Exclusion Criteria ........................................................................................................24
8.2.1.
Exclusion Criteria for Regions with Prevalence of Chronic 
Hepatitis B Virus..................................................................................................26
8.2.2.
Rationale for Exclusion of Certain Study Candidates ...........................................26
8.3.
Discontinuations ..........................................................................................................27
8.3.1.
Discontinuation of Patients...................................................................................27
8.3.2.
Discontinuation of Study Sites .............................................................................28
8.3.3.
Discontinuation of the Study................................................................................28
9.
Treatment..........................................................................................................................29

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9.1.
Treatments Administered .............................................................................................29
9.2.
Materials and Supplies .................................................................................................30
9.3.
Method of Assignment to Treatment ............................................................................30
9.4.
Rationale for Selection of Doses in the Study...............................................................30
9.5.
Selection and Timing of Doses.....................................................................................30
9.6.
Continued Access to Investigational Product................................................................31
9.7.
Blinding .......................................................................................................................31
9.8.
Concomitant Therapy...................................................................................................31
9.9.
Treatment Compliance .................................................................................................32
10.
Efficacy, Health Outcome/Quality of Life Measures, and Safety 
Evaluations, and Appropriateness of Measurements..........................................................34
10.1. Efficacy Measures........................................................................................................34
10.1.1.
Primary Efficacy Measure....................................................................................34
10.1.2.
Secondary Efficacy Measures...............................................................................34
10.2. Safety Evaluations........................................................................................................35
10.2.1.
Adverse Events ....................................................................................................36
10.2.1.1.
Serious Adverse Events ..................................................................................37
10.2.2.
Other Safety Measures .........................................................................................38
10.2.2.1.
Columbia Suicide Severity Rating Scale and Self-Harm 
Follow-up Form..............................................................................................38
10.2.2.2.
Clinical Laboratory Tests................................................................................38
10.2.2.3.
Vital Signs Data..............................................................................................38
10.2.2.4.
Electrocardiograms.........................................................................................38
10.2.3.
Safety Monitoring ................................................................................................39
10.2.4.
Complaint Handling.............................................................................................39
10.3. Sample Collection and Testing.....................................................................................40
10.3.1.
Samples for Standard Laboratory Testing.............................................................40
10.3.2.
Exploratory Work ................................................................................................40
10.3.2.1.
Pharmacogenetic Evaluations .........................................................................40
10.4. Appropriateness of Measurements................................................................................41
11.
Data Quality Assurance.....................................................................................................42
11.1. Data Capture System....................................................................................................42
12.
Sample Size and Statistical Methods .................................................................................43
12.1. Determination of Sample Size ......................................................................................43
12.2. Statistical and Analytical Plans.....................................................................................43
12.2.1.
General Considerations ........................................................................................43
12.2.2.
Patient Disposition...............................................................................................44
12.2.3.
Patient Characteristics..........................................................................................44

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12.2.4.
Concomitant Therapy...........................................................................................45
12.2.5.
Treatment Compliance .........................................................................................45
12.2.6.
Primary Outcome and Methodology.....................................................................45
12.2.7.
Efficacy Analyses ................................................................................................46
12.2.8.
Safety Analyses....................................................................................................48
12.2.9.
Subgroup Analyses ..............................................................................................51
12.2.10. Interim Analyses..................................................................................................51
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................53
13.1. Informed Consent.........................................................................................................53
13.2. Ethical Review.............................................................................................................53
13.3. Regulatory Considerations ...........................................................................................54
13.3.1.
Investigator Information.......................................................................................54
13.3.2.
Protocol Signatures ..............................................................................................54
13.3.3.
Final Report Signature .........................................................................................54
14.
References ........................................................................................................................55

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Table of Contents (concluded)
Attachment
Page
Attachment 1.
Protocol HMGW Study Schedule ...................................................................57
Attachment 2.
Protocol HMGW Clinical Laboratory Tests....................................................62
Attachment 3.
Protocol HMGW Sampling Summary.............................................................64

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4.
Abbreviations and Definitions
Term
Definition
ACR
American College of Rheumatology
ADHD
attention-deficit/hyperactivity disorder 
adolescent
Aged 13 to 17 years
adverse event (AE)
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and 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.
ANCOVA
analysis of covariance
ANOVA
analysis of variance
assent
Agreement from a child or other individual who is not legally capable of 
providing consent, but who can understand the circumstances and risks involved 
in participating in a study (required by some institutional review boards [IRBs]). 
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).
blinding
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 [subject/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
BMI
body mass index
BOCF
Baseline observation carried forward
BPI
Brief Pain Inventory
electronic case 
report form (eCRF)
Sometimes referred to as clinical report form:  A printed or electronic form for 
recording study participants’ data during a clinical study, as required by the 
protocol.
CDI
Children's Depression Inventory
CGI-Severity
Clinical Global Impression of Severity 
clinical research 
physician (CRP)
Individual responsible for the medical conduct of the study.  Responsibilities of 
the CRP may be performed by a physician, clinical research scientist, global 
safety physician or other medical officer.
CNS
Central nervous system

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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.
compliance
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality 
requirements defined by the laboratory generating the data and that Lilly is 
confident that results are accurate.  Confirmation will either occur immediately 
after initial testing or will require that samples be held to be retested at some 
defined time point, depending on the steps required to obtain confirmed results.
consent
The act of obtaining informed consent for participation in a clinical trial from 
patients deemed eligible or potentially eligible to participate in the clinical trial.  
Patients entered into a trial are those who sign the informed consent form
directly or through their legally acceptable representatives.
CRF
case report form
CS
Clinically significant
C-SSRS
Columbia-Suicide Severity Rating Scale
DCAE
Discontinuation due to adverse event
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
ECG
Electrocardiogram
end of study (trial)
End of study (trial) is the date of the last visit or last scheduled procedure shown 
in the Study Schedule for the last active subject in the study.  
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.
ethical review 
board (ERB)
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 trial are 
protected.
FDA
US Food and Drug Administration
FDI
Functional Disability Inventory
FM
Fibromyalgia
GAD
Generalized anxiety disorder
GCP
Good clinical practice
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation

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interim analysis
Interim analysis typically refers to an analysis of clinical trial data that is 
conducted prior to completion of all phases of a study and its full reporting 
database.  For the purpose of this study, the Interim Analysis section of the 
protocol (12.2.10) describes the planned analysis of data that will be performed 
upon completion of the double-blind treatment period (Study Period II).  For 
that analysis, the database will be locked and the unblended data will be 
analyzed and reported. It will be considered the final data lock/analysis for 
Study Period I-II.
investigational
product (IP)
Study drug/medication provided for this clinical trial (duloxetine and/or 
placebo).
investigator
A person responsible for the conduct of the clinical trial at a trial site.  If a trial 
is conducted by a team of individuals at a trial site, the investigator is the 
responsible leader of the team and may be called the principal investigator.
IVRS
Interactive Voice Response System
JPFS
Juvenile Primary Fibromyalgia Syndrome
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 trial.
LOCF
Last observation carried forward
LS
least squares
MAOI
Monoamine oxidase inhibitor
MASC
Multidimensional Anxiety Scale for Children
MDD
Major depressive disorder
MINI-KID
Mini International Neuropsychiatric Interview for children and adolescents
MMRM
Mixed model repeated measures
NCS
Not clinically significant
NSAID
non-steroidal anti-inflammatory drug
OTC
Over-the-counter
patient
A study participant who has the disease or condition for which the 
investigational product is targeted.
PI
principal investigator
PPQ
Pediatric Pain Questionnaire
PREA
Pediatrics Research Equity Act

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PRO
Patient-reported outcome
QD
Once daily
RA
Rheumatoid arthritis
SAE
Serious adverse event
SAS
Statistical application software
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 trial.  In this 
study, screening involves invasive or diagnostic procedures and/or tests (for 
example, diagnostic psychological tests, x-rays, 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.
subject
An individual who is or becomes a participant in clinical research, either as a 
recipient of the investigational product(s) or as a control.  A subject may be 
either a healthy human or a patient.
TPO
Third Party Organization
treatment-
emergent adverse 
event (TEAE)
Any untoward medical occurrence that either occurs or worsens at any time 
after treatment baseline and which does not necessarily have to have a causal 
relationship with this treatment
TSH
Thyroid-stimulating hormone
UDS
urine drug screen
ULN
upper limit of normal
VAS
Visual Analog Scale  

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Effect of Duloxetine 30/60mg Once Daily versus Placebo in 
Adolescents with Juvenile Primary Fibromyalgia Syndrome
5.
Introduction
Fibromyalgia (FM) is a common condition in adults that is often challenging to treat.  It is 
defined by the American College of Rheumatology (ACR) as widespread pain, with a duration of 
at least 3 months, in combination with tenderness at 11 or more of 18 specific sites on the body 
(Wolfe et al. 1990).  
Fibromyalgia can also be observed in adolescents.  Some authors have published specific 
diagnostic criteria for Juvenile Primary Fibromyalgia Syndrome (JPFS) that are derived from the 
ACR criteria but require fewer tender point sites (at least 4 out of the 18).  These criteria also 
include other features such as chronic anxiety, fatigue, and sleep troubles (Yunus and Masi 
1985).  
Currently, there is very little published research on JPFS, but available scientific literature 
suggests that JPFS often leads to substantial morbidity and disability.  For example, adolescents 
with JPFS report significantly greater functional disability and a greater number of school 
absences than those with other rheumatic diseases, such as juvenile rheumatoid arthritis (RA) or 
lupus (Varni et al. 2002).  The presence of high levels of pain and disability at this critical 
developmental stage places adolescents with JPFS at a greater risk for long-term social and 
occupational difficulties.  
Small, uncontrolled studies from Israel, Mexico, and Italy have estimated that the prevalence rate 
of JPFS in school children ranges from 1.24% to 6.20%, with girls making up the majority of 
cases, but those data are only indicative and need to be confirmed by larger adequate studies 
(Buskila et al. 1993; Clark et al. 1998; Sardini et al. 1996).  Information from a national registry 
in the United States indicates that JPFS accounts for about 7.7% of new patient diagnoses in 
pediatric rheumatology settings (Siegel et al. 1998).  However, the prevalence of JPFS in 
children and adolescents in the general population of the United States is still not available.  The 
mean age of onset of JPFS is 12 years.  To date, there is no published clinical trial that studied 
drug efficacy in this population, nor is there a drug approved or marketed for FM in this 
population. 
As in adults, children and adolescents with FM commonly report depressive symptoms, and 
depression and anxiety disorders are common comorbid disorders (Gedalia et al. 2000, 
Mikkelsson 1999).  The duloxetine studies in adults with FM allowed major depressive disorder 
(MDD) comorbidity because of its high prevalence (26% to 31% of adult FM patients suffer also 
from MDD [Russell et al. 2008]).  In adolescents, empirical experience suggests the high 
prevalence of the MDD and the anxiety disorders comorbidity.  Duloxetine has demonstrated 
efficacy in FM, MDD, and general anxiety disorder (GAD) in adults.  No study has been 
conducted with duloxetine in children or adolescents with GAD.  There is 1 completed open-
label duloxetine study in children and adolescents with MDD, and it suggests clinical benefit of 

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duloxetine in those patients (March et al. 2009).  The current duloxetine study will enroll patients 
with JPFS, including those with comorbid primary diagnoses of MDD and/or GAD.
At the time of approval of duloxetine for the management of FM, the US Food and Drug 
Administration (FDA), under the Pediatric Research Equity Act (PREA), required Lilly to 
conduct a deferred FM study to assess safety and effectiveness of duloxetine in pediatric patients 
with FM aged 13 to 17 years.  Based on the above considerations, Lilly has designed this 
randomized, double-blind, placebo-controlled study to assess the efficacy, safety, and tolerability 
of duloxetine in this population.  Safety/tolerability will be assessed based on clinical judgment 
and comparison to the known safety profile of duloxetine that has been observed in adult patients 
with FM and adolescents with other conditions such as MDD.  
More detailed information about the known benefits and risks of duloxetine may be found in the 
Investigator’s Brochure (IB).

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6.
Objectives
6.1.
Primary Objective
The primary objective of this study is to evaluate the efficacy of duloxetine 30/60 mg once daily 
(QD) compared with placebo on the reduction of average pain severity as measured by the Brief 
Pain Inventory (BPI) – Modified Short Form: Adolescent Version 24-hour average pain severity 
rating (for simplicity, it is referred to as the BPI average pain severity hereafter) during a 13-
week, double-blind treatment phase in adolescents (aged 13 to 17 years) with JPFS, as defined 
by Yunus and Masi (Yunus and Masi 1985).
6.2.
Secondary Objectives
The secondary objectives of the study are as follows:

To evaluate the efficacy of duloxetine 30/60 mg QD in the treatment of adolescents with 
JPFS during a 13-week, double-blind treatment phase, based on the improvement of the 
following measures:
o
Brief Pain Inventory (BPI) Modified Short Form: Adolescent Version severity 
(worst pain, least pain, pain right now) and interference.
o
Response to treatment, as defined by a 30% and 50% reduction in the BPI average 
pain severity.
o
Pediatric Pain Questionnaire (PPQ) pain right now, worst pain and average pain 
items.  
o
Clinical Global Impression of Severity, overall (CGI-Severity: Overall) scale.
o
Clinical Global Impression of Severity for Mental Illness (CGI-Severity:  Mental 
Illness) scale.
o
Functional Disability Inventory - child version scale (FDI-child).
o
Functional Disability Inventory - parent version scale (FDI-parent).
o
Children's Depression Inventory (CDI).
o
Multidimensional Anxiety Scale for Children (MASC).

To evaluate the safety and tolerability of duloxetine 30/60 mg QD in the treatment of 
adolescents with JPFS during a 13-week, double-blind treatment phase.

To evaluate the efficacy and safety of duloxetine 30/60 mg QD during a 26-week, open-
label, extension treatment phase, as assessed by the following:
o
Maintenance effect of duloxetine 30/60 mg QD during the open-label extension 
treatment phase.  Maintenance effect will be assessed using the BPI average pain 
severity in only the acute phase responders (defined as those patients with ≥30% 
pain reduction from baseline on the BPI average pain severity measure).

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o
Effect of duloxetine 30/60 mg QD during an extension treatment phase as 
measured by the following: BPI, PPQ, CGI-Severity: Overall, CGI-Severity: 
Mental Illness, FDI-child, FDI-parent, CDI, and MASC.
o
Safety of duloxetine 30/60 mg QD during an extension treatment phase.  
6.3.
Exploratory Objectives
Exploratory objectives of the study are as follows:

To evaluate the correlation between BPI pain severity items and PPQ pain items.

To evaluate the appropriateness of the ACR FM criteria (Wolfe 1990) in an adolescent 
population.

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7.
Investigational Plan
7.1.
Summary of Study Design
Study F1J-MC-HMGW (HMGW) is a Phase 3b, multicenter, randomized clinical trial of 
duloxetine versus placebo for the treatment of JPFS in adolescents. The study design includes
4 study periods.  Following Study Period I (screening phase), eligible patients enter Study Period 
II, the acute 13-week parallel, randomized, double-blind, placebo-controlled treatment period of 
duloxetine 30/60 mg QD.  Upon completion of the 13-week double-blind period, patients enter 
Study Period III, a 26-week, open-label extension  phase of duloxetine 30/60 mg QD.  A 1-week 
drug taper period (Study Period IV) is required for all patients who discontinue for any reason 
between Visit 4 to Visit 8 during Study Period II, or who complete/discontinue Study Period III 
on duloxetine 60 mg QD. .
Figure HMGW.1 illustrates the study design.
Abbreviations:  DB = double-blind; DLX = duloxetine; OL = open-label; QD = once-daily
a
After Visit 3, patients increased to 60 mg duloxetine can have their dose decreased 1 time, at a scheduled or 
unscheduled Visit. Once 60 mg dose is decreased to 30 mg, it cannot be increased again during Study Period II. 
b
At Visits 4 through 8, patients randomized to placebo or DLX 30 mg who  discontinue prior to entering the 
open-label extension treatment period (Study Period III) will receive placebo in the drug taper period.
c
At Visits 9 through 14 in Study Period III, dose increases are permitted at scheduled visits (to a maximum dose 
of 60 mg QD) and dose decreases are permitted at scheduled or unscheduled visits (to a minimum dose of 
30 mg QD). 
d
Patients who complete/discontinue Study Period III on DLX 30 mg do not need to enter the drug taper period. 
Figure HMGW.1.
Illustration of study design for Protocol F1J-MC-HMGW.
0
14
16
3a
2
1
4
10
6
9
7
7
5
23
14
12
13
1
-1
Study Period I     
Screening Phase
33
4b
8
10
Study Period II  
DB Treatment Phase
Study Period III
OL Extension Treatment Phasec
Week
Visit
1
2
15
39
13
28
11
19
301
40
No 
Study 
Drug
Placebo QD
DLX 30 mg QD
DLX 60 mg QD
DLX 60 mg QD
DLX 30 mg QD
Study Period IV
Taper Phased

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7.1.1. Study Period I – Screening Phase 
Study Period I (Visit 1 to Visit 2) is a screening phase in which patients will be screened for 
study entry eligibility.
At or before Visit 1, the study and its potential risks will be explained to patients and 
parents/legal representatives.  The parent/legal representative will then sign and date the 
informed consent form (ICF), and the patient will sign and date the assent document.  The ICF 
must be signed before any study procedures are conducted and before patients discontinue any 
excluded medications.  Patients will then be assigned a patient number and undergo screening.  
Visit 1 procedures typically require more than 1 day to complete.  At Visit 1, patients will be 
evaluated by the investigator to determine if they meet the diagnostic criteria for JPFS, based 
upon Yunus and Masi’s criteria.  Patients will undergo a physical examination and multiple 
screening procedures that need to be assessed prior to initiating a “washout period” for any 
excluded medications.  This information will be evaluated to ensure consistency with study 
inclusion and exclusion criteria. See Attachment 1 for a complete list of Visit 1 procedures.
If a study patient is taking medication(s) at Visit 1 that are excluded by this protocol, the patient 
must complete a washout period for the excluded medications.  The length of the washout period 
must allow adequate  time for the medication(s) to be eliminated from the patient's body 
(generally about 5 half-lives), and may range from 2 to 28 days.  The medication washout period 
must be completed before performing 3 specific Visit 1 procedures: 1) blood chemistries, 2) 
electrocardiogram (ECG), and 3) urine drug screen (UDS).  The overall period of time to 
complete all Visit 1 procedures, including medication washout, should not exceed 30 days.  The 
day on which the last Visit 1 procedure is completed (for example, scheduled laboratory tests and 
ECG) will be considered the date of Visit 1.  All criteria for enrollment, including the results of 
ECG, safety, and laboratory analyses, must be reviewed by the principal investigator (PI) prior to 
enrollment at Visit 2.  Patients who do not meet entry criteria (inclusion and exclusion criteria) at 
Visit 2 will not be enrolled into the study.  Visit 2 should be scheduled 5 to 9 days after 
completion of Visit 1 procedures.
7.1.2. Study Period II – Double-Blind Treatment Phase
Study Period II (Visit 2 to Visit 8) is a 13-week, randomized, double-blind treatment phase.  
During Study Period II, patients will initially have visits weekly (Visits 3 and 4), then biweekly 
(Visit 5), and then every 3 weeks (Visits 6 to 8).  
At Visit 2, patients who met entry criteria in Study Period I will be randomized in a 1:1 ratio to 
duloxetine or placebo by a computer-generated random sequence using an interactive voice 
response system (IVRS).  All patients will receive investigational product beginning at Visit 2 
and will be instructed to start taking their investigational product the morning after Visit 2.  
Patients randomly assigned to placebo will remain on placebo throughout Study Period II.

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Patients randomly assigned to the duloxetine treatment group will remain on duloxetine 
throughout Study Period II.  Duloxetine patients will initially take a 30 mg QD dose of 
duloxetine for 1 week.  Starting at Visit 3 through Visit 6, the dose can be increased  from 30 mg 
QD to 60 mg QD.  By Visit 4, comorbid MDD and/or GAD patients receiving a 30-mg QD dose 
should be increased to a 60-mg QD dose, unless the patient is experiencing significant 
intolerance to the 30-mg dose.  Beginning at Visit 7, no dose increases can be made.
Dose-escalation criteria for all patients is based on investigator’s clinical judgment of the 
following:  
1) Patient has inadequate treatment response to the 30-mg dose
2) Patient has adequate tolerability to 30-mg dose.  
3) For patients diagnosed with comorbid MDD and/or GAD at baseline, the 30-mg dose 
should be increased to 60 mg, unless the patient is experiencing significant 
intolerance to the 30-mg dose.
Dose adjustments are to be performed through dispensing the appropriate investigational product 
packaging at the site.  Dose increases can only occur at scheduled study visits.  The maximum 
dose level permitted for this study is 60 mg QD.  If necessary due to intolerability, for those 
patients on a 60-mg QD dose, a one-time dose decrease to 30 mg may occur at a scheduled or 
unscheduled visit.  In order to determine whether a dose decrease is needed, the patient must 
return to the study site for assessment.  If a determination is made at the site to decrease the 
patient’s dose, then a new investigational product package will be dispensed using the IVRS.  
Once the 60-mg dose is decreased to 30 mg, it cannot be increased again during Study Period II. 
At the unscheduled visits, procedures are to be performed as indicated in the Study Schedule 
(Attachment 1).  All dosing modifications in this Study Period are implemented in a blinded 
manner using IVRS.
If the patient has already had their 1 dose decrease, and at a subsequent time cannot tolerate the 
investigational product dose well enough to remain compliant, the patient should be 
discontinued. 
It is unknown if duloxetine is efficacious in treating MDD or GAD in this adolescent population.  
The investigator is responsible for assessing the patient’s mental status at each visit.  The CGI-
Severity of Mental Illness will be administered at every visit during Study Period II.
See Attachment 1 for the timing of events and the measures to be assessed.
7.1.3. Study Period III – Open-Label Extension Treatment Phase
Study Period III is a 26-week, open-label extension treatment phase.  Patients initially have visits 
weekly (Visits 8 to 9), then biweekly (Visits 9 to 10), then every 3 to 6 weeks (Visits 10 to 15).   
Patients randomized to either the duloxetine or placebo treatment groups during Study Period II 
will enter Study Period III on a 30-mg dose of duloxetine for 1 week.  The duloxetine dose may 
be increased to 60 mg QD only at a scheduled Visit starting at Visit 9 (Week 14).  As in Study 
Period II, additional dose-escalation consideration should be given to all patients with comorbid 

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MDD and/or GAD at study entry.  At Visit 9, the comorbid MDD and/or GAD patients should 
have their 30-mg dose increased to 60 mg, unless the patient is experiencing significant 
intolerance to the 30-mg dose.  
From Visit 9 to Visit 14, dose modifications are allowed, and patients must return to the study 
site for assessment of all dose changes.  Dose increases (up to 60 mg QD) are only permitted at 
scheduled visits.  Dose decreases (down to 30 mg QD) are permitted at either scheduled or 
unscheduled visits.  Dose adjustments are to be based on the investigator’s clinical judgment of 
treatment response and tolerability at the patient’s current dose.  Procedures will be performed as 
indicated in the Study Schedule (Attachment 1).
7.1.4. Study Period IV – Taper/Discontinuation Phase
Study Period IV is a 1-week taper phase to minimize the occurrence of discontinuation-emergent 
adverse events (AEs).  Patients who complete Study Period III or discontinue after Visit 9 of 
Study Period III while on duloxetine 60 mg QD, will receive duloxetine 30 mg QD for 1 week.  
The 1-week taper is not required for patients in Study Period III who complete or discontinue 
early on a 30-mg QD dose of duloxetine .
Patients who discontinue between Visits 4 to 8 of Study Period II should enter into the 1-week 
drug taper period.  However, tapering of IP should be based on the investigator’s determination 
of safety for his or her patient.  Patients on duloxetine 60 mg QD will receive 30 mg QD for 
1 week.  Patients on duloxetine 30 mg QD will receive placebo for 1 week.  Patients on placebo 
will receive placebo for 1 week.  The 1-week taper is implemented in a blinded manner using the 
IVRS.  The taper period is not required for patients who discontinue at Visit 3 and therefore have 
not received 2 weeks of treatment.
See Attachment 1 for the timing of events and the measures to be assessed.
7.2.
Discussion of Design and Control
The study is designed based on the current knowledge of duloxetine safety and efficacy in FM 
and relevant clinical practice. 
The screening period is intended for diagnosing and assessing the patient for possible inclusion 
in the study and for providing an adequate washout period for excluded medications, which is 
consistent with periods typical of clinical practice.
Double-blind, placebo-controlled studies are the standard used to assess efficacy in randomized 
clinical studies.  The 13-week treatment period allows a sufficient amount of time to demonstrate 
efficacy of treatment, while keeping patients on placebo for as short a time as possible.
The 26-week, open-label period will allow for patients initially randomized to placebo during 
Study Period II to have the opportunity to receive benefit from treatment.
A 1-week tapering period will allow adequate time to gradually decrease the dose and minimize 
discontinuation symptoms.

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8.
Study Population
Entered patients who meet all of the inclusion criteria and are not excluded by exclusion criteria 
will proceed to Visit 2.  At Visit 2, patients who are not excluded will be randomized and 
proceed to Visit 3.
8.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1]
Outpatient male or female aged 13 to 17 years at the time of screening.  
Patients cannot turn 18 before the date of Visit 1 completion.
[2]
Meet criteria for primary JPFS as defined by Yunus and Masi (1985).
[3]
Have a score of ≥4 on Brief Pain Inventory (BPI) average pain severity 
(Item 3) at Visit 1 and Visit 2.  
[4]
Female patients must have a negative serum pregnancy test during screening.  
Furthermore, female patients must agree to abstain from sexual activity or to 
use a reliable method of birth control as determined by the investigator during 
the study.  Examples of reliable birth control methods include:  the use of oral 
contraceptives (for 3 months prior to study enrollment); a reliable barrier 
method of birth control (diaphragms with contraceptive jelly, cervical caps 
with contraceptive jelly, condoms with contraceptive foam, intrauterine 
devices); partner with vasectomy; or abstinence.  
[5]
Patient’s parent/legal representative and patient are judged to be reliable by 
the investigator to keep all appointments for clinical visits, tests, and 
procedures required by the protocol.  
[6]
Patient’s parent/legal representative and patient, if capable, must have a 
degree of understanding such that they can communicate intelligently with the 
investigator and study coordinator.  
[7]
Patients must be capable of swallowing investigational product whole 
(without, for example, chewing, crushing, dissolving, or dividing the 
investigational product).  
[8]
Patients must have venous access sufficient to allow blood sampling and be 
compliant with blood draws as per the protocol.

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8.1.1. Disease Diagnostic Criteria
Patients must have a diagnosis of JPFS.  The diagnosis of JPFS, as defined by Yunus and Masi 
(1985), requires the following 3 criteria to be met:
1) generalized musculoskeletal aching at 3 or more sites for 3 or more months in the 
absence of an underlying condition
2) the presence of at least 3 or more of the following 10 features present: chronic anxiety 
or tension, fatigue, poor sleep, chronic headaches, irritable bowel syndrome, 
subjective soft tissue swelling, numbness, pain modulation by physical activities, pain 
modulation by weather factors, and pain modulation by anxiety/stress
3) 5 or more typical tender points.  Note that 4 tender points will satisfy diagnostic 
criteria provided that the patient has 5 of the 10 features listed under Criterion 2 
above.
8.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[9]
Are children of 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.
[10] Are children of Lilly employees or employees of the designated Clinical 
Research Organization assisting with the conduct of the study. 
[11] Are currently enrolled in, or discontinued within the last 30 days from, a 
clinical trial involving an investigational drug or device or off-label use of a 
drug or device (other than the investigational product/device 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.
[12] Have previously completed or withdrawn from this study or any other study 
investigating duloxetine.
[13] Have a known hypersensitivity to duloxetine or any of the inactive 
ingredients, or have frequent or severe allergic reactions to multiple 
medications.  
[14] Have been treated with duloxetine within the last 6 months.
[15] Will not likely benefit from duloxetine treatment, in the opinion of the 
investigator or have had prior nonresponse or inadequate tolerance to 
duloxetine for any clinical use.
[16] Have pain symptoms related to traumatic injury, past surgery, structural bone 
or joint disease (such as bursitis, tendonitis), or regional pain syndrome that, 
in the opinion of the investigator, will interfere with interpretation of outcome 
measures.  

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[17] Currently have evidence of rheumatologic disorder or have a current or 
previous diagnosis of rheumatoid arthritis, inflammatory arthritis, or 
infectious arthritis, or an autoimmune disease (for example, systemic lupus 
erythematosus).  
[18] Have a DSM-IV Axis I condition, currently or within the past year, except 
major depressive disorder (MDD) and/or generalized anxiety disorder (GAD), 
adjustment disorder or specific phobias with primary investigator approval.
[19] Have a current secondary DSM-IV Axis I condition of attention-
deficit/hyperactivity disorder that requires pharmacologic treatment.
[20] Have any lifetime DSM-IV Axis I diagnosis of psychosis, bipolar disorder, or 
schizoaffective disorder.  
[21] Have any DSM-IV Axis II disorder which, in the judgment of the investigator, 
would interfere with protocol compliance.  
[22] Have a history of substance abuse or dependence within the past 6 months, 
excluding nicotine and caffeine.  
[23] Have a positive urine drug screen (UDS) for any substances of abuse or 
excluded medication.  Note:  If the patient has a positive urine drug screen at 
Visit 1 for an excluded medication that may not have had an adequate 
washout period, a re-test may be performed and evaluated prior to Visit 2.  
[24] Have a family history of 1 or more first-degree relatives (parents or siblings) 
with diagnosed bipolar I disorder (assessed by family member interview).  
[25] Have a significant suicide attempt within 1 year of Visit 1 or are currently at 
suicidal risk in the opinion of the investigator.  Note:  Suicidal risk assessment 
should be facilitated by the Columbia-Suicide Severity Rating Scale (C-
SSRS).  Patients answering "yes" to any of the questions about active suicidal 
ideation/intent/behaviors occurring within the past 6 months must be excluded 
(C-SSRS Suicide Ideation section - Questions 4 and 5; C-SSRS Suicidal 
Behavior section, any of the suicide behaviors questions).    
[26] Have a body weight <20 kg at any screening period visit.
[27] Have initiated, stopped, or changed the type or intensity of psychotherapy 
within 3 months prior to Visit 1.  Patients who anticipate a change to 
psychotherapy (start, stop, or change in type, intensity, or frequency) during 
study Period II are excluded. 
[28] Have a history of seizure disorder (other than febrile seizures) 
[29] Are taking any excluded medications (for example, stimulants, 
antidepressants) that cannot be discontinued at Visit 1.  
[30] Have had treatment with fluoxetine within 30 days prior to Visit 1.  

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[31] Have had treatment with a monoamine oxidase inhibitor (MAOI) within 
14 days of Visit 1; or the potential need to use an MAOI during the study or 
within 5 days of discontinuation of investigational product.  
[32] Have abnormal thyroid-stimulating hormone (TSH) concentrations.  Note:  
Patients previously diagnosed with hypothyroidism, who have been treated on 
a stable dose of thyroid supplement for at least the past 3 months and have 
medically appropriate TSH concentrations (on replacement therapy the TSH 
value may be below the reference range), and are clinically euthyroid may 
participate in the study.  
[33] Have uncontrolled narrow-angle glaucoma.  
[34] Have acute liver injury (such as hepatitis) or severe cirrhosis (Child-Pugh 
Class C).  
[35] Have a serious or unstable medical illness, including any cardiovascular, 
hepatic, renal, respiratory, hematologic, endocrinologic, or neurologic disease, 
or clinically significant laboratory abnormality or electrocardiogram (ECG) 
result that is not stabilized or is anticipated to require hospitalization within 
6 months, or would compromise participation in the study in the opinion of 
the investigator.  A serious or unstable medical condition is one that, in the 
judgment of the investigator, is likely to require intervention, hospitalization, 
or use of excluded medications during the course of the study.  
[36] Have initiated or discontinued hormone therapy within the previous 3 months.  
[37] Female patients who are either pregnant, nursing or have recently given birth.
8.2.1. Exclusion Criteria for Regions with Prevalence of Chronic 
Hepatitis B Virus
[38] History of hepatic dysfunction, current jaundice, or positive Hepatitis B 
surface antigen (Dane particle) (HBsAg) or positive Hepatitis C antibody 
(HCV-Ab).  Note:  only for regions as determined by the Center for Disease 
Control (CDC 2010) with a prevalence of chronic hepatitis B virus (HBV).
[39] Patients with an alanine transaminase (ALT) ≥2 times the upper limit of 
normal (ULN) based on central lab reference range.
8.2.2. Rationale for Exclusion of Certain Study Candidates
Exclusion Criteria [9] and [10] reduce the potential bias that may be introduced at the study site.  
Exclusion Criterion [11] eliminates drugs that cannot be mapped to a standard drug dictionary, or 
for which little data are known to analyze the potential relationship of AEs or drug interactions.  
Exclusion Criteria [16] and [17] are intended to avoid other confounding pain conditions or 
rheumatologic diagnoses and exclude patients with rheumatologic disorders.  
Exclusion Criteria [18], [20], [21], and [24] are intended to avoid confounding psychiatric 
diagnoses and exclude patients with serious mental diseases.  

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Exclusion Criterion [15] is intended to avoid enrolling patients with a history of JPFS who have 
been nonresponsive to drug treatment or are unable to tolerate drug treatment.  
Exclusion Criterion [27] is intended to avoid other therapy that can confound the evaluation of 
treatment response.  
Exclusion Criteria [30] and [31] are intended to prevent the development of serotonin syndrome.  
Exclusion Criteria [12], [14] and [15] reduce potential bias in patients who have been exposed to 
duloxetine. 
Exclusion Criteria [22] and [23] are intended to exclude patient that are likely to use central 
nervous system-active drugs that might confound efficacy and safety assessments.  Exclusion 
Criteria [19] and [29] eliminates patients likely to use central nervous system (CNS)-active drugs 
that might adversely affect the safety assessments of duloxetine or place patients at an increased 
risk of AEs due to drug-drug interactions.  
Exclusion Criteria [13], [25], [26], [28], [33], [34], and [37] are intended to avoid any potential 
safety issues.  Exclusion Criterion [35] excludes patients who have significant medical 
conditions or diseases that are unrelated to therapy but may need to be treated during the course 
of the study by an excluded medication or procedure.  
Exclusion Criterion [32] is intended to exclude patients with thyroid disease, which may 
confound symptomatology.  
Exclusion Criterion [36] is intended to prevent patients enrolling in the study who present with 
potentially confounding symptoms resulting from hormone imbalance.
8.3.
Discontinuations
8.3.1. Discontinuation of Patients
The criteria for enrollment must be followed explicitly.  If a patient who does not meet 
enrollment criteria is inadvertently enrolled, that patient is discontinued from the study, and Lilly 
or its designee must be contacted.
In addition, patients will be discontinued from the investigational product and/or from the study 
in the following circumstances.

Enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study

The investigator decides that the patient should be withdrawn.  If this decision is 
made because of a serious adverse event or a clinically significant laboratory 
value, the investigational product is to be discontinued and appropriate measures 
are to be taken.  Lilly or its designee is to be alerted immediately.  Refer to 
Section 10.2 Safety Evaluations.

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
The patient, patient’s parent/legal representative, or attending physician requests 
that the patient be withdrawn from the study.

The patient for any reason, requires treatment with another therapeutic agent that 
has been demonstrated to be effective for treatment of the study indication.  In 
this case, discontinuation from the study occurs prior to introduction of the new 
agent.

The investigator or Lilly 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 good clinical practice.

If the patient becomes pregnant.

If the patient’s body weight decreases to <20 kg.
In addition, patients may be discontinued in the following circumstances:

If an exclusion criterion develops after investigational product initiation, Lilly or 
its designee will be contacted to determine the appropriate evaluation and follow-
up, which may include discontinuation of the patient.

If the patient is unable to tolerate the investigational product as judged by the 
investigator, the investigators should use clinical judgment on whether to continue 
or decrease investigational product dose, or discontinue the patient’s participation 
in the study.

If the patient is significantly noncompliant with investigational product or study 
procedures, they should be discontinued from the study.

The patient, for any reason, requires treatment with another therapeutic excluded 
of concomitant use with duloxetine for the trial.  In this case, Lilly or its designee
should be contacted and the patient may be discontinued.
Patients who discontinue the investigational product and/or study early will have end-of-therapy 
and/or end-of-study procedures performed as shown in the Study Schedule (Attachment 1).
8.3.2. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review board 
(ERB) of the study site judges it necessary for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and GCP.
8.3.3. Discontinuation of the Study
The study will be discontinued if Lilly 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
During Study Period II (Double-Blind Treatment Period), patients will be randomly assigned to 
duloxetine or placebo to be taken once daily (QD), preferably in the morning.  Patients assigned 
to duloxetine will begin at 30 mg QD for 1 week.  Starting at Visit 3, through Visit 6, the dose 
may be increased to 60 mg QD.  Dose escalation should follow GCP.  Dose increases can only 
occur at scheduled study visits (Visits 3, 4, 5, or 6).  Additional dose-escalation consideration 
should be given to all patients with comorbid MDD/GAD at study entry.  At Visit 4, patients 
with comorbid MDD/GAD on a 30-mg QD dose should have their dose increased to 60 mg QD, 
unless the patient is experiencing significant intolerance to the 30-mg dose.  If necessary, due to 
intolerability, a one-time dose decrease (down to 30 mg QD) may occur at scheduled or 
unscheduled visits.  To determine whether a dose decrease is needed, the patient must return to 
the study site for assessment.  If a determination is made at the site to decrease the patient’s dose, 
a new investigational product package will be dispensed using the IVRS.  A dose decrease can 
occur anytime throughout the course of Study Period II (to a minimum dose of 30 mg QD).  
Once a patient’s dose has been decreased, it cannot be increased again in Study Period II.
During Study Period III (Open-Label Extension Treatment Period), patients who were 
randomized to either the duloxetine or placebo treatment groups during Study Period II will 
receive a 30-mg QD dose of duloxetine for 1 week.  The duloxetine dose may be increased to 
60 mg QD only at scheduled Visits starting at Visit 9  As in Study Period II, additional dose-
escalation consideration should be given to all patients with comorbid MDD/GAD at study entry.  
At Visit 9, patients with comorbid MDD/GAD should have their 30-mg dose increased to 60 mg, 
unless the patient is experiencing significant intolerance to the 30-mg dose.  From Visit 9 to Visit 
14, dose modifications are allowed, and patients must return to the study site for assessment of 
all dose changes.  Dose increases (up to 60 mg QD) are only permitted at scheduled visits.  Dose 
decreases (down to 30 mg QD) are permitted at either scheduled or unscheduled visits.  Dose 
increases or decreases are to be based on the investigator’s clinical judgment of treatment 
response and tolerability at the patient’s current dose.  Patients unable to tolerate a 30-mg dose 
should be discontinued from this study.  Patients discontinuing the study between Visits 9 to 15 
on duloxetine 30 mg QD do not need to enter the drug taper period.
The investigator or his/her designee is responsible for explaining the correct use of the 
investigational product(s) to the patient and patient’s parent/legal representative, verifying that 
instructions are followed properly, maintaining accurate records of investigational product 
dispensing and collection, and returning all unused medication to Lilly or its designee at the end 
of the study.
Patients and patient’s parent/legal representative will be instructed to contact the investigator as 
soon as possible if he or she has a complaint or problem with the investigational product, so that 
the situation can be assessed.

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9.2.
Materials and Supplies
Lilly will provide the following investigational products:

30-mg capsules of duloxetine hydrochloride

placebo capsules identical in appearance to duloxetine capsules
Investigational product will be dispensed to patients at the study site.  Investigational product 
will be labeled with a unique identifier for drug accountability.  Investigational product 
packaging will contain a sufficient quantity of investigational product to last to the next visit and 
additional capsules to allow for sufficient investigational product in case of a longer visit 
window.
9.3.
Method of Assignment to Treatment
After the informed consent form (ICF) is signed and dated, a patient is considered to be 
“entered” into the study and will be assigned a patient number.  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 IVRS.  The IVRS 
will be used to assign investigational product packages containing double-blind investigational 
product to each patient during Study Period II, and open-label investigational product during 
Study Period III.  Site personnel will confirm that they have located the correct investigational 
product packages by entering a confirmation number found on the investigational product 
packages into the IVRS.
To achieve between-group comparability for site factor, the randomization will be stratified by 
site.
9.4.
Rationale for Selection of Doses in the Study
The two doses of duloxetine, 30 mg and 60 mg QD, administered orally, were selected based on 
the recommended adult dose and current clinical and pharmacokinetic data.  For adults, the 
recommended dose of duloxetine is 60 mg administered QD, with treatment initiating at a 30-mg 
QD dose for 1 week. Some adults respond to the 30-mg starting dose. 
Study F1J-MC-HMFN (HMFN) is an open-label study of duloxetine safety and 
pharmacokinetics in children and adolescents with MDD.  The pharmacokinetic results from 
Study HMFN suggest that differential dosing based on age or body weight is not warranted.  The 
range of duloxetine concentrations in children (7 through 11 years) and adolescents (12 through 
17 years) are similar to those observed in adults, with median values being lower in pediatric 
patients than in adults.  Therefore, differential dosing in the pediatric population compared with 
the adult population may not be warranted.
9.5.
Selection and Timing of Doses
At Visit 2, patients will be instructed to take the investigational product starting the day after 
Visit 2.  The investigational product should be taken QD, preferably in the morning.  Patients 
will take a 30-mg dose QD from the day after Visit 2 to Visit 3; and either a 30-mg or a 60-mg 

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dose QD from Visit 3 to Visit 8 during Study Period II.  Dose changes will occur as described in 
Section 7.1.
Starting at Visit 8, patients completing Study Period II will be allowed to enter the open-label 
extension treatment period (Study Period  III) and will begin receiving duloxetine 30 mg QD for 
1 week, preferably in the morning.  The duloxetine dose may be increased to 60 mg QD starting 
at Visit 9.  From Visit 9 to Visit 14, dose increases are permitted at scheduled visits (to a 
maximum dose of 60 mg QD) and dose decreases are permitted at scheduled or unscheduled 
visits (to a minimum dose of 30 mg QD).  Dose adjustments are to be based on the investigator’s 
clinical judgment of treatment response and tolerability at the patient’s current dose. 
9.6.
Continued Access to Investigational Product
Investigational product will not be provided after the conclusion of the study as it is 
commercially available in the countries where this study will be conducted.
9.7.
Blinding
This is a double-blind study.
To preserve the blinding of the study, a minimum number of Lilly personnel will see the 
randomization table and treatment assignments before the study is complete.
Emergency unblinding for adverse events may be performed through an IVRS, 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 of the patient’s 
treatment assignment.  All calls resulting in an unblinding event are recorded and reported by the 
IVRS.
The investigator should make every effort to contact the Lilly clinical research physician (CRP) 
prior to unblinding a patient’s treatment assignment.  If a patient’s treatment assignment is 
unblinded, Lilly must be notified immediately by telephone.
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 CRP for the 
patient to continue in the study.
9.8.
Concomitant Therapy
In general, concomitant medications with primarily CNS activity are not allowed in this study.  
Ongoing use of nonsteroidal anti-inflammatory drugs (NSAIDs) is allowed during the study, in 
accordance with the guidelines specified on the HMGW List of Concomitant Medications that is 
provided with this protocol.  Site personnel should call a designated representative with any 
questions regarding medications not specifically cited in the list of excluded medications.  
Patient’s parent/legal representative must sign the ICF before patients stop any excluded 
medications.  Any changes in the list of allowed/not allowed medications will be communicated 
to investigators and will not constitute a protocol amendment.

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All nonstudy medications taken during the study will be recorded on the case report form (CRF), 
including the administration date and dosage.  Patients will be instructed to consult with the 
investigator or study coordinator at the site before taking any new prescribed medications, over-
the-counter (OTC) medications, or supplements/herbal preparations.  
For a detailed list of specifically excluded medications, see the HMGW List of Concomitant 
Medications that is provided to the sites with the protocol and is updated as necessary by Lilly.  
If any changes to the list are made after the protocol has been approved by Lilly, an ERB, or a 
regulatory agency, these changes will not be considered modifications to the protocol, but the 
HMGW List of Concomitant Medications will be updated to provide this information.
Patients who are taking any disallowed medications at the time of screening will need to undergo 
a washout period prior to completing Visit 1.  Ongoing use of NSAIDs is allowed during the 
study, in accordance with the guidelines specified on the HMGW List of Concomitant 
Medications that is provided with this protocol.  After Visit 2, episodic use of some analgesics is 
allowed for break-through pain, acute injury, or surgery.  Episodic use is defined as no more than 
3 consecutive days and no more than 20 cumulative days during Study Period II (Visit 2 to Visit 
8), and 3 consecutive days and no more than 40 cumulative days during Study Period III.  
Analgesics, including acetaminophen and herbal remedies/medicines, are not provided by the 
sponsor.
9.9.
Treatment Compliance
Each patient and parent/legal representative should be instructed to return all investigational 
product packaging and material to the study site at each visit.  The study site will keep a record 
of all drug dispensed and returned throughout the study.  The study site will return all 
investigational product packaging and unused investigational product for all patients, following 
completion of drug accountability procedures by Lilly or designee.  Patient compliance with 
investigational product will be assessed at each visit after Visit 2.  Compliance will be assessed 
by direct questioning and counting returned capsules.  Compliance with the prescribed regimen 
will be recorded in the CRF.
During Study Periods II and III, compliance for each visit interval is defined as taking between 
80% and 120% of the prescribed capsules of investigational product.  If a patient is not 
compliant during an interval, the patient and parent/legal representative will be counseled 
regarding the importance of compliance in this study.  The patient may be discontinued at this 
time if, in the opinion of the investigator, the patient is deemed unlikely to become compliant 
and data obtained from the patient will be unreliable.  The second time that a patient is 
noncompliant with his or her dosage schedule; he or she must be discontinued from the study 
unless noncompliance results from unforeseen circumstances (for example, a blizzard or illness).  
In such instances, the Lilly CRP or designee who is responsible for monitoring the study may 
grant permission for the patient to continue.
In addition, patients who are consistently noncompliant with having their laboratory tests done or 
their procedures completed as indicated in the Study Schedule (Attachment 1), or who do not 

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attend visits within the stated study intervals, may be deemed noncompliant by Lilly or 
investigator and may be discontinued from the study.

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10. Efficacy, Health Outcome/Quality of Life Measures, and 
Safety Evaluations, 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 Brief Pain Inventory (BPI) – Modified Short Form: Adolescent Version.  The primary 
efficacy measure for this study is the BPI “24-hour average pain severity” item (Question 3) of 
the BPI (Cleeland and Ryan 1994), while the other 3 BPI pain severity items and the interference 
items will be considered secondary efficacy measures (see Section 10.1.2 below).  The BPI is a 
self-reported scale that measures the severity of pain and the interference of pain on function.  
For the BPI 24-hour average pain item, the ratings range from 0 (no pain) to 10 (pain as severe as 
you can imagine).  The BPI average pain severity item was selected as the primary outcome 
measure based on past experience with this measure in adult duloxetine FM clinical trials.
10.1.2. Secondary Efficacy Measures
The following secondary efficacy measures will be collected at the times shown in the Study 
Schedule (Attachment 1).

The Brief Pain Inventory (BPI) - Modified Short Form: Adolescent Version 
(Severity and Interference ) is a self-reported scale that measures the severity of 
pain and the interference of pain on function (Cleeland and Ryan 1994).  The 
Severity scores range from 0 (no pain) to 10 (pain as bad as you can imagine).  
There are 4 questions assessing the severity for worst pain, least pain, average 
pain in the past 24 hours (which is the primary efficacy measure), and the pain 
right now.  The Interference scores range from 0 (does not interfere) to 10 
(completely interferes).  There are 7 original questions assessing the interference 
of pain in the past 24 hours on the following:  general activity, mood, walking 
ability, normal work, relations with other people, sleep, and enjoyment of life. 
The BPI: Adolescent Version added an eighth interference question to assess 
interference of pain on school work.  This scale has  not been formally validated 
in adolescents.

The Pediatric Pain Questionnaire (PPQ) is a self-reported scale that measures 
the severity for “pain now,” worst pain, and average pain in the past week with 
100 mm VAS (Visual Analog Scale) (Varni et al. 1987).  The severity scores 
range from 0 (no hurting, no discomfort, no pain) to 100 (hurting a whole lot, very 
uncomfortable, severe pain).  The PPQ has been formally validated in 
adolescents.

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
The Clinical Global Impression of Severity: Overall (CGI-Severity: Overall) scale 
evaluates the severity of overall illness at the time of assessment (Guy 1976).  The score 
ranges from 1 (normal, not at all ill) to 7 (among the most extremely ill patients).  The 
CGI-Severity:  Overall must be administered by a study physician in the presence of the 
patient or after having been in the presence of the patient.  

The Clinical Global Impression of Severity:  Mental Illness (CGI-Severity:  
Mental) scale evaluates the severity of mental illness at the time of assessment 
(Guy 1976).  The score ranges from 1 (normal, not at all ill) to 7 (among the most 
extremely ill patients).  The CGI-Severity:  Mental must be administered by a 
study physician in the presence of the patient or after having been in the presence 
of the patient

Functional Disability Inventory-child form (FDI-child) is a self-reported scale to 
assess the physical trouble or difficulty the child has doing regular activities (Walker and 
Greene 1991).  This scale contains 15 items.  Each item is scored on a 0- to-4-point scale 
(0 = no trouble, 1 = a little trouble, 2 = some trouble, 3 = a lot of trouble, 4 = impossible).  
The total score ranges from 0 to 60.  The higher the score, the more physical trouble or 
difficulty the child has doing regular activities.

Functional Disability Inventory-parent form (FDI-parent) contains the same items as
FDI-child, but is reported by parent/legal representative (Walker and Greene 1991).  The 
total score range from 0 to 60.  The higher the score, the more physical trouble or 
difficulty the child has doing regular activities.

Children's Depression Inventory (CDI) is modeled after the Beck Depression 
Inventory and is a 27-item self-reported, symptom-oriented scale designed for school-
aged children and adolescents (Kovacs 1985).  Each item is scored on a 0-to-2-point scale 
(in increasing severity) and thus the total score ranges from 0 to 54.  The higher the score, 
the more severe the depression.

Multidimensional Anxiety Scale for Children (MASC) is a self-reported scale 
developed to assess anxiety in children and adolescents (March et al. 1997).  The MASC 
consists of 39 items that comprise 4 factors, 3 of which can be separated into 2 subfactors 
each.  Main factors (subfactors) include:  1) physical symptoms (tense/restless and 
somatic/autonomic); 2) social anxiety (humiliation/rejection and public performance 
fears); 3) harm avoidance (perfectionism and anxious coping); and 4) separation anxiety.  
Each item is scored on a 0-to-3-point scale.  Total score range from 0 to 117.  The higher 
the total score, the more severe the anxiety.
10.2. 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 or that caused the patient to discontinue before completing the study.  The 

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patient should be followed until the event is resolved or explained.  Frequency of follow-up 
evaluation is left to the discretion of the investigator.
Patients with clinically relevant abnormal ECGs or laboratory findings should be followed at the 
discretion of the investigator until resolved or explained.  Weight and vital signs will be 
measured at each visit throughout the study, preferably at the same time each visit.  Height will 
be measured by stadiometer three times during the study as indicated in the Study Schedule 
(Attachment 1).  All measurements will be made without shoes and after the removal of any 
heavy personal items (such as large jewelry, wallets, or coats).  Preferably, the same observer 
should measure the patients throughout the study using the same instruments.
Instruments used for measuring height and weight must be in compliance with the study sites’ 
institutional calibration standards.  Compliance with institutional calibration(s) guidelines must 
be appropriately documented.
If a suicide-related event is identified at any time during the study, a thorough evaluation should 
be performed by a study physician and appropriate medical care should be provided.  In some 
patients taking antidepressants, worsening of depression, suicidal events (suicidal thinking and/or 
behavior), or unusual changes in behavior have been reported, especially at the beginning of the 
drug therapy, at the time of dose changes, or early after treatment discontinuation.  It is important 
that parent/legal representatives and patients are instructed to notify their doctor immediately if 
the patient has any distressing thoughts or feelings at any time.
10.2.1. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish drug effect.
Cases of pregnancy that occur during maternal or paternal exposures to investigational product 
or drug delivery system 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 informed consent form (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 Lilly or designee.
In addition, all AEs occurring after the patient receives the first dose of investigational product 
must be reported to Lilly or its designee via CRF.
Any clinically significant findings from ECGs, labs, vital sign measurements, and other 
procedures that result in a diagnosis should be reported to Lilly or its designee.

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Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure and/or investigational product via CRF.
Study site personnel must alert Lilly or its designee within 24 hours of the investigator 
unblinding a patient’s treatment group assignment for any reason.
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via CRF the circumstances and data leading 
to any such dosage reduction or discontinuation of treatment.
10.2.1.1. Serious Adverse Events
Serious adverse event (SAE) collection begins after the patient has signed informed consent and 
has received investigational product.  If a patient experiences an SAE after signing informed 
consent, but prior to receiving investigational product, the event will NOT be collected unless the 
investigator feels the event may have been caused by a protocol procedure.
Previously planned (prior to signing the ICF) 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 or its designee of any serious adverse event (SAE) within 
24 hours of investigator awareness of the event via a Sponsor-approved method.  Alerts issued 
via telephone are to be immediately followed with official notification on study-specific SAE 
forms.  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 
medical judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.
Serious adverse events occurring after a patient has taken the last dose of investigational product 
will be collected for 30 days after the last dose of investigational product, regardless of the 
investigator’s opinion of causation.  Thereafter, SAEs are not required to be reported unless the 
investigator feels the events were related to either investigational product, or drug delivery 
system, or a protocol procedure.

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10.2.2. Other Safety Measures
10.2.2.1. Columbia Suicide Severity Rating Scale and Self-Harm Follow-up Form
The Columbia Suicide Severity Rating Scale (C-SSRS) 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 tool was developed by the Columbia group (Posner 
2007) to prospectively categorize suicide related events.  
Suicide-related events (behavior and/or ideations) will be assessed and evaluated at every visit 
with the administration of the C-SSRS.  The Self-Harm Follow-up Form will be completed at 
any visit, including baseline visit, when a suicidal or nonsuicidal self-injurious behavior is 
identified.  If a suicide-related event is identified at any time during the study, a thorough 
evaluation should be performed by a study physician and appropriate medical care should be 
provided.  
10.2.2.2. Clinical Laboratory Tests
Standard clinical laboratory tests will be performed at times specified in the Study Schedule 
(Attachment 1).
Investigators must document their review of each laboratory report.  To ensure patient safety 
during this study, laboratory values that fall outside a clinically accepted reference range, or 
values that differ significantly from previous values, must be evaluated and commented on by 
the investigator by marking each value clinically significant (CS) or not clinically significant 
(NCS). 
10.2.2.3. Vital Signs Data
A comprehensive physical examination will be performed at Visit 1.
Blood pressure and pulse will be collected in triplicate at every visit, with readings at least 
3 minutes apart.  Prior to taking the blood pressure reading, the patient should be seated in a 
calm, quiet location for at least 5 minutes or until the investigator believes the patient is 
sufficiently relaxed.
Investigators will use the following guidelines when measuring vital signs:

Use the same arm for blood pressure collection throughout the study.

Measure blood pressure and pulse before any blood draws.

Support arm with cuff at approximately the heart level.

Ensure blood pressure cuff length is >2/3 circumference of arm size.  (Note: a larger or 
smaller cuff may be required for larger and smaller patients).
10.2.2.4. Electrocardiograms
Twelve-lead ECGs will be obtained according to the Study Schedule (Attachment 1).  Triplicate 
ECGs will be collected approximately 1 minute apart as specified in Attachment 1.  Subjects 

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must be supine for approximately 5 to 10 minutes before ECG collection and remain supine but 
awake during ECG collection.
The ECGs 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, for immediate patient management and to determine whether the patient meets entry 
criteria.  If a clinically significant increase in the corrected QT (QTc) interval from baseline is 
present, then the investigator should assess the patient for symptoms (such as palpitations, near 
syncope, syncope).
The ECGs will subsequently be electronically transmitted via modem to the centralized ECG 
vendor designated by Lilly.  The centralized ECG vendor’s cardiologist will then complete the 
ECG overread.  The central ECG vendor’s overread will be used for data analysis and report 
writing purposes.
After the overread ECG is returned from the centralized ECG vendor, the investigator or 
qualified designee is responsible for determining if any change to the patient management is 
needed and must document his/her review.
If there are differences in ECG interpretation between the investigator or qualified designee and 
the ECG vendor cardiologist, the investigator or qualified designee’s interpretation will prevail 
for study entry and immediate patient management purposes, and the ECG vendor cardiologist’s 
interpretation will prevail for data analysis purposes.
The investigator (or qualified designee) must document his/her review of one of the replicate 
ECGs printed at the time of collection, the final overread ECG report issued by the central ECG 
laboratory, and any alert reports.
10.2.3. Safety Monitoring
The Lilly CRP will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CRP, 
will, as is appropriate, consult with the functionally independent Global Patient Safety 
therapeutic area physician or clinical scientist, and review trends and laboratory analytes.
In the event that safety monitoring uncovers a potential safety signal, experts outside of the study
team will be asked to evaluate the data.
10.2.4. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical trials in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.
Complaints related to unblinded comparator drugs are reported directly to the manufacturers of 
those drugs/devices in accordance with the package insert.
For blinded studies, all product complaints associated with material packaged, labeled, and 
released by Lilly or delegate will be reported.

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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.
10.3. Sample Collection and Testing
Attachment 1 lists the schedule for sample collections in this study.
Attachment 2 lists the specific tests that will be performed for this study.
Attachment 3 provides a summary of the maximum number and volume of invasive samples, for
all sampling, during the study.  Fewer invasive sampling may actually occur, but this will not 
require a protocol amendment.  
10.3.1. Samples for Standard Laboratory Testing
Blood and urine samples will be collected at the times specified in the Study Schedule 
(Attachment 1).  Standard laboratory tests, including chemistry, hematology, and urinalysis 
panels, will be collected non-fasting and analyzed. A serum pregnancy test will be performed (if 
applicable).  All clinical laboratory tests will be analyzed by a central laboratory.  Attachment 2
lists the specific tests that will be performed for this study.  
Investigators must document their review of each laboratory safety report.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Certain samples may be retained for a longer period, if necessary, to 
comply with applicable laws, regulations, or laboratory certification standards.
Approximately 5 to 10 mL of blood for serum and plasma will be collected by venipuncture per 
the Study Schedule (Attachment 1).  See Attachment 3 for the summary of sample amounts.
Approximately 40 mL of urine will be collected.
Supplies required for the collection and shipment of the patients’ stored samples will be supplied 
by the sponsor.  Sample handling and shipment to the central laboratory will occur per 
instructions given to the study site.
10.3.2. Exploratory Work
10.3.2.1. Pharmacogenetic Evaluations
There is growing evidence that genetic variation may impact a patient’s response to therapy.  
Variable response to therapy may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion, the mechanism of action of the drug, the disease 

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etiology and/or the molecular subtype of the disease being treated.  Therefore, where local 
regulations allow, a 10-mL blood sample will be collected for potential pharmacogenetic 
analysis.  It is a one-time collection, as noted in the Study Schedule (Attachment 1).
Samples will be stored and analysis may be performed on genetic variants thought to play a role
in catecholamine signaling including, but not limited to, catechol-O-methyltransferase to
evaluate their association with observed clinical outcomes to duloxetine.
In the event of an unexpected AE or the observation of unusual response, the samples may be 
genotyped and analysis may be performed to evaluate a genetic association with response to 
LY248686.  These investigations may be limited to a focused candidate gene study or, if 
appropriate, genome wide association studies may be performed to identify regions of the 
genome associated with the variability observed in drug response.  Samples will only be used for 
investigations related to disease and drug or class of drugs under study in the context of this 
clinical program.  They will not be used for broad exploratory unspecified disease or population 
genetic analysis.
Samples will be identified by the patient number (coded) and stored for up to 15 years after the 
last patient visit for the study at a facility selected by the sponsor.  The sample and any data 
generated from it can only be linked back to the patient by investigator site personnel.
10.4. Appropriateness of Measurements
All safety and efficacy assessments have been well documented and are generally regarded as 
reliable, accurate, and relevant in this patient population.

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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 a start-up training session to instruct the investigators and study 
coordinators.  This session will give instruction on the protocol, the completion of 
the CRFs, 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 CRF 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 may periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by 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 ERBs with 
direct access to original source documents.
11.1. Data Capture System
An electronic data capture system will be used in this trial.  The site maintains a separate source
for the data entered by the site into the sponsor-provided electronic data capture system.
Case report form data will be encoded and stored in a clinical trial database.  Data managed by a 
central vendor, such as laboratory test data or ECG data, will be stored electronically in the 
central vendor’s database system.  Data will subsequently be transferred from the central vendor 
to the Lilly generic labs system.
Any data for which the CRF or paper documentation provided by the patient or parent/legal 
representative will serve as the source document will be identified and documented by each site 
in that site’s study file.  Paper documentation provided by the patient or parent/legal 
representative may include, for example, a rating scale to collect patient-reported outcome (PRO) 
measures.
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 210 patients will be randomized in a 1:1 ratio to the duloxetine and placebo 
treatment groups. This study is to assess the difference of the mean change in BPI average pain 
severity from baseline to the last time point (Visit 8, Week 13) in Study Period II between 
treatment groups. Assuming that there will be some missing post-baseline data, this sample size 
will provide at least 80% power to detect the treatment difference with α=.05. All the parameters 
used in the sample size calculations were based on the MMRM analysis of data from 3-month, 
placebo-controlled, acute treatment period in 2 adult FM studies: Study F1J-MC-HMCA and 
Study F1J-MC-HMCJ.
12.2. Statistical and Analytical Plans
12.2.1. General Considerations
All analyses will be conducted on an intent-to-treat basis, meaning that data will be analyzed by 
the treatment groups to which patients are randomly assigned, even if the patient does not take 
the assigned treatment, does not receive the correct treatment, or does not comply with the 
protocol.
Treatment effects and interaction effects will be evaluated based on a 2-sided significance level 
of 0.05.  No adjustments for multiple comparisons will be made.
A repeated measures analysis refers to a restricted maximum likelihood-based, mixed-effects
repeated measures analysis, using all the longitudinal observations at each post-baseline visit.
Unless otherwise specified, when an ANOVA model is used to analyze a continuous variable, 
the model will contain the terms of treatment and investigator.  The significance of treatment-by-
investigator interaction will be evaluated in a separated model when it is necessary.  Similar 
logic is applied to an analysis of covariance (ANCOVA) model, which in general refers to the 
ANOVA model with baseline values added as a covariate.  Type III sum-of-squares for the least-
squares means (LSMeans) will be used for the statistical comparisons using ANOVA or 
ANCOVA when there is no interaction term involved.  For the ANOVA or ANCOVA models 
where the interaction term is included, the Type II sum-of-squares for the LSMeans will be 
employed. 
Unless otherwise specified, when a total score is calculated from individual items, it will be 
considered missing if any of the individual items are missing; when an average score is 
computed from individual items, it is calculated from nonmissing values. 
Unless otherwise specified, for all analyses for Study Period II, baseline is defined as the last 
nonmissing observation at or before the randomization visit (Visit 2).  For analyses using the 
last-observation-carried-forward (LOCF) approach, endpoint is defined as the last nonmissing 
observation obtained from Visit 3 through Visit 8.

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In some analyses for Study Period II, the baseline-observation-carried-forward (BOCF) endpoint 
is specified.  The BOCF endpoint is defined as follows:

For randomized patients who complete the treatment period (that is, complete the 
scheduled Visit 8), the BOCF endpoint is defined as the last nonmissing observation, or 
for randomized patients who discontinue early (that is, do not complete the scheduled 
Visit 8) but with at least one non-missing baseline value, the BOCF endpoint is defined 
as the baseline value.
In Study Period II, all patients who randomized to duloxetine will be considered as being in 
duloxetine treatment group, and duloxetine will be compared with placebo using statistical 
inference. In Study Period III, descriptive statistics will be used to summarize for patients who 
entered Study Period III. The treatment groups for Study Period III will be defined as follows: 
placebo/duloxetine (PLA/DLX) for those who are randomized to placebo during Study Period II 
and who enter Study Period III taking duloxetine, and DLX/DLX for those who are randomized 
to duloxetine during Study Period II and who enter Study Period III taking duloxetine.
When investigator sites are used in an analysis, investigators with fewer than 2 patients 
randomized to placebo and 2 patients randomized to duloxetine (each patients has nonmissing 
BPI average pain severity score) will be pooled within countries for statistical analysis purposes.  
If the pooled site still has fewer than 2 patients randomized to placebo and 2 patients randomized 
to duloxetine, these sites will be pooled with the next smallest site in the same country, or if there 
are none, then the next smallest site in the study overall in another country.
Categorical comparisons between treatment groups will be performed using Fisher’s exact test.
Any changes to the analysis plan, both those prior to unblinding the data and those subsequent to 
unblinding, will be documented and justified in the final study report.  Exploratory analyses of 
the data will be conducted as deemed appropriate.
SAS software will be used to perform all statistical analyses. Statistical analysis of this study 
will be the responsibility of Eli Lilly and Company or designee.
12.2.2. Patient Disposition
Patient disposition (reasons for discontinuation from the study) will be summarized overall and 
by visit for each treatment group.  The reasons for discontinuation will be compared between 
treatment groups using Fisher’s exact test in Study Period II. Reasons for discontinuation in 
Study Period III will be summarized by treatment groups.
12.2.3. Patient Characteristics
Patient demographics (age, gender, racial origin, country, body mass index [BMI], height, and 
weight), duration of fibromyalgia and baseline efficacy measures (BPI average pain severity, 
PPQ average pain rating, CGI-Severity, FDI-child, FDI-parent) will be summarized for all 
randomized patients for Study Period II and all patients who entered the extension period for 
Study Period III.  In addition, baseline assessment for depression (CDI) will be summarized by 
MDD and non-MDD status, and baseline assessment for anxiety (MASC) will be summarized by 

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GAD and non-GAD status for all randomized patients for Study Period II and all patients who 
entered extension period for Study Period III.  For Study Period II, the baseline comparability 
among treatment groups will be examined using an ANOVA model with the terms of treatment 
and investigator for continuous measures, and using Fisher’s exact test for categorical data. 
Patient characteristics in Study Period III will be summarized by treatment groups without 
statistical comparison.
12.2.4. Concomitant Therapy 
Previous medications for the treatment of FM, MDD, and GAD will be summarized by treatment 
group.  The frequency of concomitant medication usage during the double-blind treatment period
will also be summarized by treatment group and the comparison will be conducted using Fisher’s 
exact test for Study Period II. Concomitant therapy in Study III will be summarized by 
treatments groups without any statistical comparison.
12.2.5. Treatment Compliance 
A patient will be considered to be compliant with investigational product for each visit interval if 
they take between 80% and 120% of investigational product capsules prescribed for that interval.
Overall compliance is defined as having been compliant at all visits.  The percentage of patients 
who are compliant at each visit and overall will be summarized by treatment group for Study 
Period II and III.
12.2.6. Primary Outcome and Methodology
The primary objective of this study is to assess the efficacy of duloxetine 30/60 mg QD versus 
placebo in the treatment of adolescents with JPFS.
The primary efficacy measure is the BPI average pain severity in Study Period II.  The primary 
efficacy analysis will be the contrast between duloxetine and placebo at the last visit in Study 
Period II (Visit 8, Week 13) from a MMRM analysis on change from baseline in the BPI average 
pain severity. The model for this analysis will include the fixed class effects of treatment, 
investigative site, visit, and treatment-by-visit interaction, as well as the continuous, fixed 
covariates of baseline value and baseline value-by-visit interaction.  The Kenward-Roger 
(Kenward and Roger, 1997) approximation will be used to estimate denominator degrees of 
freedom.  An unstructured covariance structure will be used to model the within-patient errors.  
If the default Newton-Raphson algorithm used by SAS PROC MIXED does not converge, then 
the Fisher scoring algorithm will be applied. If the model with unstructured covariance structure 
fails to converge, the sandwich estimator (Diggle et al. 1994; 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: 
1. heterogeneous toeplitz
type = toeph
2. heterogeneous autoregressive (1st order)
type = arh(1)
3. heterogeneous compound symmetric
type = cs(h)
4. toeplitz
type = toep
5. autoregressive (1st order)
type = ar(1)
6. compound symmetric
type = cs

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When 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.  SAS® PROC MIXED will be used 
to perform the analysis. In addition, sensitivity analysis will also be performed to address the 
impact of missing data on the primary efficacy analysis.  The intent of this sensitivity analysis is 
to compare the results from assuming Missing at Random (MAR) versus Missing Not at Random 
(MNAR) and to check for consistency of treatment contrasts.  More details will be described in 
the Statistical Analysis Plan (SAP).
12.2.7. Efficacy Analyses 
Table HMGW.1 presents the additional analyses for the primary efficacy variable and the 
analyses for the secondary efficacy variables in Study Period II, either collected directly from 
CRFs or derived from raw observations.
Descriptive statistics will be used to summarize these variables, as applicable, by treatment 
group (PLA/DLX and DLX/DLX) during Study Period III. The details of baseline definition of 
the secondary efficacy measures for Study Period III will be discussed in SAP. Maintenance 
effect of duloxetine 30/60 mg QD during Study Period III will be assessed using the BPI average 
pain severity in only the acute phase responders (defined as those patients with ≥30% pain 
reduction from baseline on the BPI average pain severity measure). The null hypothesis that the 
treatment effect of duloxetine was not maintained during the extension treatment phase was 
tested using T-test by evaluating if upper bound of the 97.5% CI of the change from baseline to 
endpoint for patients in the extension treatment phase who responded to duloxetine 30 mg QD to 
60 mg QD in Study Period II (acute phase duloxetine responders) is less than or equal to the pre-
specified margin of 1.5. In this analysis, baseline was defined as the last non-missing observation 
during Visit 3 to Visit 8, and endpoint was defined as the last non-missing observation in the 
Study Period III. The non-inferiority margin of 1.5 is chosen based on past experience from 
duloxetine Diabetic Peripheral Neuropathic Pain (DPNP) study F1J-MC-HMEM and Chronic 
Low Back Pain (CLBP) study F1J-MC-HMEN, both of those studies used 1.5 as margin to 
assess maintenance of effect under duloxetine 60/120 mg treatment as measured by 24-hour 
average pain in 0-10 scale. 

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Table HMGW.1.
Secondary Efficacy Analysis 
Efficacy Variable
Derivation and Details
Analysis
1.  Area under the curve of pain 
relief (AUC)
a. BPI average pain severity 
The relief score at a visit is 
defined as the BPI average pain 
score at the particular visit minus 
the baseline score. The area under 
the curve of relief (AUC) is the 
sum of each trapezoidal area 
circumscribed by the sides of 
relief scores at two consecutive
nonmissing visits and the side of 
days between the two visits.
Variable 1.a will be analyzed by 
the ANCOVA model described in 
Section 12.2.1 (using baseline 
BPI average pain severity as 
covariate)
2.  Change from baseline to 
LOCF endpoint:
a. BPI worst pain, least pain, 
average pain, and pain right now; 
BPI-Interference items
b. PPQ average pain, pain right 
now, and worst pain rating
c. CGI-S: Mental Illness
d. CGI-S: Overall
e. FDI-child
f. FDI-parent
g. CDI
h. MASC
a-d. eCRF data.
e-f. FDI total score is the sum of 
15 individual item scores.
g. CDI total score is the sum of 
27 individual item scores.
h. MASC physical symptoms, 
social anxiety, harm avoidance 
and separation anxiety subscale 
scores and total score.
       
The Variable 2.a to 2.h will be 
analyzed by the ANCOVA 
models as described in Section 
12.2.1
3.  Change from baseline to 
BOCF endpoint:
a. BPI average pain severity
b. PPQ average pain rating
a-b. eCRF data.
The Variable 3.a to 3.b will be 
analyzed by the ANCOVA 
models as described in Section 
12.2.1
4.  Change from baseline to each 
post-baseline visit:
a. BPI worst pain, least pain, and 
pain right now; BPI-Interference 
items
b. CGI-Severity: Overall and 
CGI-Severity: Mental Health
a-b. eCRF data.
Variables 4.a to 4.b will be 
analyzed by a repeated measures 
analysis as described in Section 
12.2.1

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Table HMGW.1.
Analysis for the Secondary Efficacy Variables (concluded)
5.   Categorical variable:
a. 30% Response rate (LOCF)
b. 30% Response rate (BOCF)
c. 50% Response rate (LOCF)
d. 50% Response rate (BOCF)
e. Sustained response rate (LOCF)
f. Cumulative distribution of BPI 
average pain score reduction
a-b. Response: at least 30% reduction 
from baseline to endpoint (LOCF or 
BOCF) for BPI average pain score.
c-d. Response: at least 50% reduction 
from baseline to endpoint (LOCF or 
BOCF) for BPI average pain score.
e. Sustained response: at least 30% 
reduction from baseline to endpoint; 
with a 30% reduction from baseline at 
an earlier visit than the last visit, and
remains at least 20% reduction from 
baseline in every visit in between, if 
there are any intervening visits (based 
on BPI average pain score).
f. The percentage of patients who have 
reached each threshold of BPI average 
pain reduction from baseline to BOCF 
endpoint (from >0% to 100% with a 
10% increase) will be calculated. 
Discontinued patients will be 
considered as “no change”.
For Variables 5.a to 5.e, 
proportions will be 
summarized by treatment 
group and will be analyzed 
by a Fisher’s exact test.
For Variable 5.f, the 
treatment group difference 
in the empirical cumulative 
distribution of the 
percentage pain reduction 
will be evaluated using 
Van der Waerden test.
6.  Time to event variable:
a. Time to first 30% reduction in 
BPI average pain score
b. Time to first 50% reduction in 
BPI average pain score
c. Time to sustained response
a. For the patients with a 30% reduction 
at a visit in the treatment phase, time = 
days from the date of the visit that the 
earliest 30% reduction is observed to 
the randomization date.
b. For the patients with a 50% 
reduction at a visit in the treatment 
phase, time = days from the date of the 
visit that the earliest 30% reduction is 
observed to the randomization date.
c. For the sustained responders defined 
above, time = the days from the date of 
the visit which is the earlier visit from 
which the sustained response is 
observed to the randomization date
For Variables 6.a to 6.c, the 
Kaplan-Meier survival 
curves of time to event will 
be calculated by treatment 
group. In the calculation, 
patients who do not have 
the event will be 
considered as right-
censored observation. The 
comparison of the survival 
curves between treatment 
groups will be conducted 
by a log-rank test and 
stratified log-rank test 
controlling for pooled 
investigator. 
Abbreviations:  ANCOVA = analysis of covariance; BOCF = baseline observation carried forward; BPI = Brief Pain 
Inventory; CDI = Children’s Depression Inventory; CGI-S = Clinical Global Impressions of Severity; eCRF = 
electronic case report form; FDI = Functional Disability Inventory; LOCF = last observation carried forward; 
MASC = Multidimensional Anxiety Scale for Children; PPQ = Pediatric Pain Questionnaire.
12.2.8. Safety Analyses
Safety will be assessed by summarizing and analyzing treatment-emergent AEs, SAEs, death, 
rates and reasons for discontinuation, laboratory measurements, vital signs, height, weight, and 

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ECGs. In addition, suicide risk and suicide-related events (behavior and/or ideation) will be 
assessed by the C-SSRS. The safety analyses will be conducted for both Study Period II and 
Study Period III. In Study Period II, duloxetine will be compared with placebo using statistical 
inference. In Study Period III, descriptive statistics will be used to summarize for patients who 
entered Study Period III. The details of baseline definition of the safety measures for Study 
Period III will be discussed in SAP.
Categorical Safety Variables
Comparisons between treatment groups for all categorical safety measures will be made by 
Fisher’s exact test.
Treatment-emergent adverse events (TEAEs) are the reported events that first occurred or 
worsened during the treatment period.  For each AE, the severity level is recorded according to 
the patient’s or investigator’s perceived severity of the event (mild, moderate, severe, or more 
severe than baseline), the category of ‘more severe than baseline’ only applies to the AE with 
baseline severity of severe and worsened during the study.  The incidence rates of TEAEs will be 
analyzed by Fisher’s exact test.  Moreover, TEAEs will be summarized by their maximum 
severity and system organ class and analyzed by Fisher’s exact test.
The death, SAEs, and AEs reported as reasons for discontinuation (DCAE) will be summarized 
by treatment group and compared among the treatment groups using Fisher's exact tests.
For laboratory measurements, the incidence rates of treatment-emergent abnormally high or low 
laboratory values at endpoint will be assessed using Fisher’s exact test.  A “treatment-emergent 
high value at endpoint” is defined as a change from a value less than or equal to the high limit at 
all baseline visits to a value greater than the high limit at endpoint.  A “treatment-emergent low 
value at endpoint” is defined as a change from a value greater than or equal to the low limit at all 
baseline visits to a value less than the low limit at endpoint.
Categorical analysis of weight will be performed and treatment difference will be assessed using 
Fisher's exact test.
The incidence of patients meeting criteria for potentially clinically significant (PCS) changes in 
vital signs, and incidence of patients with sustained elevation in blood pressure, as defined in the 
SAP, will be compared between treatment groups. Patients with abnormal vital signs baseline 
assessment will be excluded from the analysis of that measure.
The incidence of patients meeting criteria for PCS changes in ECG intervals and heart rate, as 
defined in the SAP, will also be compared between treatment groups.
Suicide-related thoughts and behaviors based on the C-SSRS will be summarized by treatment.  
In particular, for each of the following suicide-related events, the number and percent of patients 
with the event will be enumerated by treatment:  completed suicide, nonfatal suicide attempt, 
interrupted attempt, aborted attempt, preparatory acts or behavior, active suicidal ideation with 
specific plan and intent, active suicidal ideation with some intent to act without specific plan, 
active suicidal ideation with any methods (no plan) without intent to act, nonspecific active 
suicidal thoughts, and wish to be dead. In addition, the number and percent of patients who 

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experienced at least one of various composite measures will be presented.  These include suicidal 
acts (completed suicide and nonfatal suicidal attempts), suicidal behavior (suicidal acts, 
interrupted attempts, aborted attempts, and preparatory acts or behavior), treatment-emergent 
suicidal ideation, or treatment-emergent suicidal behavior.  Fisher’s exact test will be used for 
treatment comparisons. For each event, p-values will only be displayed if at least 4 events 
occurred in at least 1 treatment group.
Continuous Safety Measures
Mean change from baseline to endpoint in laboratory analytes will be assessed using the 
ANOVA model (see Section 12.2.1). Rank-transformed data will be used for the laboratory 
analysis.
Change from baseline to endpoint in vital signs, ECGs, and weight/height will be analyzed using 
the ANCOVA model with baseline safety value as covariate.
Time to Event
Time to event data for important safety endpoints (such as DCAE, onset of the important 
TEAEs) will be analyzed combining data from Study Period II and Study Period III for patients 
who received duloxetine at anytime during the entire study.  Details of the analysis will be 
provided in the SAP.
Analysis of Drug Taper Period
Similar to the Double-Blind Treatment Period, patient disposition, deaths, SAEs, and taper-
emergent AEs will be summarized by treatment groups  and analyzed using Fisher’s exact test.
Taper-emergent AEs are defined as the new or worsened events reported at Visit 301 compared 
with events reported at baseline (baseline is the last 2 visits before Visit 301). 
Suicide-related thoughts and behaviors based on the C-SSRS will be summarized by treatment 
group.
Change from baseline (last nonmissing value before Visit 301) to endpoint in vital signs and 
weight in the taper period will be analyzed using the ANCOVA model (see Section 12.2.1).

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12.2.9. Subgroup Analyses
Table HMGW.2 lists the subgroup analysis variables by which the analyses for the BPI average 
pain severity will be conducted for Study Period II.
Table HMGW.2.
Definition of Subgroup Variables
Subgroup Variable Categories
Categories
1. Gender
2. Race Origin
3. Baseline Pain Severity
4. Family history of Fibromyalgia
5. Onset age of Fibromyalgia (yr.)
6. Comorbid MDD
7. Comorbid GAD
8. Country
1. Female or Male
2. 
White
American Indian or Alaska Native
Asian
Black or African American
Native Hawaiian or Other Pacific Islander
Multiple
3. ≤6 vs. >6 on BPI average pain severity at baseline
4. Yes/No
5. ≤12 vs. >12
6. Yes/No
7. Yes/No
8. Country name
Abbreviations: BPI = Brief Pain Inventory; MDD = major depressive disorder; GAD = generalized anxiety disorder; 
vs. = versus.
To analyze a specific subgroup’s impact, change from baseline to endpoint (LOCF and BOCF) 
in BPI average pain will be analyzed using an ANCOVA model with all the terms described 
generally in Section 12.2.1 with additional terms of the subgroup and the subgroup-by-treatment 
interaction.  The primary statistical test will be for the treatment-by-subgroup interaction, which 
will be tested at the significance level of 0.05.
Furthermore, treatment group differences will be evaluated within each category of a subgroup 
regardless of the significance level of the treatment-by-subgroup interaction.  For the subgroup 
of Race Origin, all the categories that have <10% of the patients in the study will be combined in 
the analysis.
Subgroup analysis for other efficacy and safety variables will be conducted as deemed 
appropriate and necessary.
12.2.10.
Interim Analyses
An analysis of data will be performed when all patients have completed or discontinued early 
from Study Period II.  For this analysis, the database will be locked and unblinded data from 
Study Period I Study Period II will be analyzed and reported.  This is considered the final data 
lock for the Study Period II, and  will not be considered an interim analysis that requires a formal 

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data monitoring committee (DMC) and no further adjustment to the final analysis significance 
level is needed.
The remainder of the analyses will be performed when all patients have completed Study Period 
IV or have been discontinued from the 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.

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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 informed consent form (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 
investigational product.
A legal representative must give informed consent for a child to participate in this study.  In 
addition to informed consent given by the legal representative, the child may be required to give 
documented assent, if capable.
As used in this protocol, the term “informed consent” includes all consent and assent given by 
patients or their legal representatives.
13.2. Ethical Review
Lilly must agree with all ICFs before they are submitted to the ERB and are used at investigative 
sites(s).  All ICFs must be compliant with the ICH guideline on GCP.  Informed consent 
obtained under special circumstances may occur only if allowed by local laws and regulations 
and performed in accordance with a written process approved by Lilly.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly.  The 
ERB(s) will review the protocol as required.
Any member of the ERB who is directly affiliated with this study as an investigator or as site 
personnel must abstain from the ERB’s vote on the approval of the protocol.
The study site’s ERB(s) should be provided with the following:

the current IB or package labeling and updates during the course of the study

ICF

relevant curricula vitae.

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13.3. Regulatory Considerations
This study will be conducted in accordance with:
1) consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences
(CIOMS) International Ethical Guidelines
2) the ICH GCP Guideline [E6]
3) applicable laws and regulations
The investigator or designee will promptly submit the protocol to applicable ERB(s).
Eli Lilly and Company certifies that this study is being conducted under an active US 
investigational drug application (IND 63,615) at clinical sites within the United States.  All 
investigators (at IND and non-IND sites) are expected to comply with GCP and all applicable 
local clinical trial regulations.
All or some of the obligations of the sponsor will be assigned to a third party organization 
(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.
13.3.1. Investigator Information
Physicians with experience in treating FM 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 or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
After reading the protocol, each PI 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 (CSR) coordinating investigator will sign the final CSR for this study, 
indicating agreement that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study. 
An experienced investigator will serve as the CSR coordinating investigator.  If this investigator 
is unable to fulfill this function, another investigator will be chosen by Lilly to serve as the CSR
coordinating investigator.
The sponsor’s responsible medical officer will approve the final CSR 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. References
Buskila D, Press J, Gedalia A, Klein M, Neumann L, Boehm R, Sukenik S. Assessment of 
nonarticular tenderness and prevalence of fibromyalgia in children. J Rheumatol.
1993;20(2):368-370.
[CDC] Centers for Disease Control.  Travelers’ Health – Yellow Book.  2010.  Available at:  
http://wwwnc.cdc.gov/travel/yellowbook/2010/chapter-2/hepatitis-b.aspx#849. Accessed June, 
14 2010.
Clark P, Burgos-Vargas R, Medina-Palma C, Lavielle P, Marina FF. Prevalence of fibromyalgia 
in children:  a clinical study of Mexican children. J Rheumatol. 1998;25(10):2009-2014.
Cleeland CS, Ryan KM. Pain assessment:  global use of the Brief Pain Inventory. Ann Acad 
Med Singapore. 1994;23(2):129-138.
Diggle PJ, Liang KY, Zeger SL. Analysis of Longitudinal Data. Oxford: Clarendon Press; 
1994.Gedalia A, Garcia CO, Molina JF, Bradford NJ, Espinoza LR. Fibromyalgia syndrome:  
experience in a pediatric rheumatology clinic. Clin Exp Rheumatol. 2000;18(3):415-419. 
Guy W. ECDEU assessment manual for psychopharmacology, revised 1976. Rockville, MD: 
(NIMH) National Institute of Mental Health, Psychopharmacology Research Branch. 1976;p 
217-222; 313-331.
Kovacs M. The children’s depression, inventory (CDI). Psychopharmacol Bull. 1985;21(4):995-
998.
Lu K, Mehrotra DV. Specification of covariance structure in longitudinal data analysis for
randomized clinical trials. Stat Med. 2010;29:474-488.
March JS, Emslie GJ, Kratochvil CJ, Pangallo B, Lobo E, Tamura R, Kogut S, Quinlan T, 
Prakash A. An open-label study of tolerability, safety, and pharmacokinetics of duloxetine in 
children (7-11 years) and adolescents (12-17 years) with MDD.  Presented at NCDEU:  New 
Research Approaches for Mental Health Interventions – 49th Annual Meeting. 2009.  
Hollywood, FL. 
March JS, Parker JD, Sullivan K, Stallings P, Conners CK. The multidimensional anxiety scale 
for children (MASC): factor structure, reliability, and validity. J Am Acad Child Adolesc 
Psychiatry. 1997;36(4):554-565.
Mikkelsson M. One year outcome of preadolescents with fibromyalgia. J Rheumatol.
1999;26(3):674-682.
Posner K. 2007. State of the Science: Measurement of Suicidal Adverse Events and The 
Columbia Suicide Severity Rating Scale. NCDEU:  Boca Raton FL.
Russell IJ, Mease PJ, Smith TR, Kajdasz DK, Wohlreich MM, Detke MJ, Walker DJ, Chappell 
AS, Arnold LM. Efficacy and safety of duloxetine for the treatment of fibromyalgia in patients 
with or without major depressive disorder:  results from a 6-month, randomized, double-blind, 
placebo-controlled, fixed-dose trial. Pain. 2008;136(3):432-444.
Sardini S, Ghirardini M, Betelemme L, Arpino C, Fatti F, Zanini F. Epidemiological study of 
primary fibromyalgia in a pediatric age. Minerva Pediatr. 1996;48(12):543-550.

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Siegel DM, Janeway D, Baum J. Fibromyalgia syndrome in children and adolescents: Clinical 
features at presentation and status at follow-up. Pediatrics. 1998;101(3):377-382.
Varni JW, Thompson KL, Hanson V. The Varni/Thompson Pediatric Pain Questionnaire. I. 
Chronic musculoskeletal pain in juvenile rheumatoid arthritis. Pain. 1987;28(1):27-38.
Varni JW, Seid M, Smith Knight T, Burwinkle T, Brown J, Szer IS. The PedsQL in pediatric 
rheumatology:  reliability, validity, and responsiveness of the Pediatric Quality of Life 
Inventory Generic Core Scales and Rheumatology Module. Arthritis Rheum. 2002;46(3):714-
725.
Walker LS, Greene JW. The functional disability inventory:  measuring a neglected dimension of 
child health status. J Pediatr Psychol. 1991;16(1):39-58.
Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell P, 
Campbell SM, Abeles M, Clark P, Fam AG, Farber SJ, Fiechtner JJ, Franklin CM, Gatter RA, 
Hamaty D, Lessard J, Lichtbroun AS, Masi AT, McCain GA, Reynolds WJ, Romano TJ, 
Russell IJ, Sheon RP. The American College of Rheumatology 1990 criteria for the 
classification of fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum.
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Yunus MB, Masi AT. Juvenile primary fibromyalgia syndrome. A clinical study of thirty-three 
patients and matched normal controls. Arthritis Rheum. 1985;28(2):138-145.

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Attachment 1.Protocol HMGW Study Schedule

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F1J-MC-HMGW Clinical Protocol
Page 58
Study Schedule, Protocol F1J-MC-HMGW
Study Period
I
II
III
IVa
Unschldb
ET/
DSC
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
301
Unschld
ET/
DSC
Week of Treatment
–1
0
1
2
4
7
10
13
14
16
19
23
28
33
39
40
n/a
n/a
Days from Visit 2
-9 
to
-5
n/a
5 
to 
9
12 
to 
16
26 
to 
30
47 
to 
51
68 
to 
72
89 
to 
93
96 
to 
100
110 
to 
114
131 
to 
135
157
to 
165
192
to 
200
227
to 
235
269
to 
277
278
to
282
n/a
n/a
Informed Consent/assent
X
Clinical Assessments
Demographics
X
Psychiatric, medical, drug, 
and family history
X
Previous treatment for 
fibromyalgia
X
Psychotherapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Habits
X
X
X
X
Physical Exam
X
Date of first menses
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient Summary/Disposition
X
X
X
X
Diagnostic Measurements
MINI-Kid
X
Yunus and Masi
X
X
X
X
ACR Criteria
X
X
X
X

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Study Schedule for F1J-MC-HMGW (continued)
Study Period
I
II
III
IVa
Unschldb
ET/
DSC
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
301
Unschld
ET/
DSC
Week of Treatment
–1
0
1
2
4
7
10
13
14
16
19
23
28
33
39
40
n/a
n/a
Days from Visit 2
-9 
to
-5
n/a
5 
to 
9
12 
to 
16
26 
to 
30
47 
to 
51
68 
to 
72
89 
to 
93
96 
to 
100
110 
to 
114
131 
to 
135
157
to 
165
192
to 
200
227
to 
235
269
to 
277
278
to
282
n/a
n/a
Investigational Product
Call IVRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense investigational 
product
X
X
X
X
X
X
X
X
X
X
X
X
X
Xd
Xc
Xd
Drug return/accountability
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Date of first dose
X
Date of last dose
X
X
Efficacy Measures
BPI: Adolescent Version
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CGI-Severity:  Overall
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CGI-Severity: Mental Illness
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pediatric Pain Questionnaire
X
X
X
X
X
Functional Disability 
Inventory-Child
X
X
X
X
X
Functional Disability 
Inventory-Parent
X
X
X
X
X
Children’s Depression 
Inventory
X
X
X
X
X
X
X
Multidimensional Anxiety 
Scale for Children
X
X
X
X
X
X
X

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Study Schedule for F1J-MC-HMGW (continued)
Study Period
I
II
III
IVa
Unschldb
ET/
DSC
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
301
Unschld
ET/
DSC
Week of Treatment
–1
0
1
2
4
7
10
13
14
16
19
23
28
33
39
40
n/a
n/a
Days from Visit 2
-9 
to
-5
n/a
5 
to 
9
12 
to 
16
26 
to 
30
47 
to 
51
68 
to 
72
89 
to 
93
96 
to 
100
110 
to 
114
131 
to 
135
157
to 
165
192
to 
200
227
to 
235
269
to 
277
278
to
282
n/a
n/a
Laboratory Tests
Pregnancy teste
X
TSH
X
Chemistry panel, non-fastingf
X
X
X
X
X
X
X
HbA1c
X
X
X
X
Hematology
X
X
X
X
X
X
X
UDSe
X
Urinalysis
X
X
X
X
Pharmacogenomic sampleg
X
Safety
Vital signs (Sitting HR and 
BP) h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogrami
X
X
X
X
X
C-SSRS/ Self Harm 
Supplement
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Self Harm Follow-up Formj
Height
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events/ Pre-existing 
Conditions
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Study Schedule for F1J-MC-HMGW (concluded)
Abbreviations:  ACR = American College of Rheumatology; AE = adverse event; BP = Blood Pressure; BPI = Brief Pain Inventory; CGI-Severity = Clinical 
Global Impressions of Severity; C-SSRS = Columbia-Suicide Severity Rating Scale; DSC = discontinuation; ET = Early Termination; HR = Heart Rate; 
IVRS = Interactive Voice Response System; MINI = Mini International Neuropsychiatric Interview; n/a= not applicable; TSH = Thyroid-Stimulating 
hormone; UDS = Urine Drug Screen; Unschld - Unscheduled
a
Drug taper period should be completed for patients discontinuing at or after Visit 4 in Study Period II.  Patients discontinuing the study between Visits 9-15 
on duloxetine 30 mg QD do not need to enter the drug taper period.
b
Unscheduled visits can occur anytime.  Patients must come in the office for an unscheduled visit and be assessed by the primary investigator.
c
Investigational product dispensed only if a dose decrease occurs at an unscheduled visit during Study Period II, but not dispensed during Study Period III.
d
Investigational product dispensed only if patient entering drug taper period. Patients discontinuing the study between Visits 9-15 on duloxetine 30 mg QD do 
not need to enter the drug taper period.
e
May be repeated at the investigator’s discretion throughout trial.
f
Hepatic serologies collected at baseline for hepatitis endemic countries and may also be collected for hepatic monitoring follow-up.
g
Pharmacogenomic sample may be collected at with blood draws scheduled at a later Visit if necessary. 
h
Blood pressure and pulse will be collected in triplicate at each visit. Readings should be taken approximately 3 minutes apart.
i
Three ECGs will be collected approximately 1 minute apart at these visits.
j
The Self-Harm Follow-up Form will be completed at any visit when a suicidal or non-suicidal self-injurious behavior is identified.

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Attachment 2.Protocol HMGW Clinical Laboratory Tests

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Clinical Laboratory Tests, Non-Fasting
Hematology:
Clinical Chemistry:
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Mean cell volume (MCV)
Bicarbonate
Mean cell hemoglobin (MCH)
Chloride
Mean cell hemoglobin concentration (MCHC)
Total bilirubin
Leukocytes (WBC)
Direct bilirubin
Neutrophils, segmented
Albumin
Neutrophils, juvenile (bands)
Alkaline phosphatase
Lymphocytes
Gamma-glutamyl transferase (GGT)
Monocytes
Alanine aminotransaminase (ALT/SGPT)
Eosinophils
Aspartate transaminase (AST/SGOT)
Basophils
Blood urea nitrogen (BUN)
Platelets
Serum Creatinine
Cell morphology
Uric acid
Phosphorus
Urinalysis:
Calcium
Color
Glucose, non-fasting
Specific gravity
Total Protein
pH
Albumin
Protein
Total Cholesterol
Glucose
Triglycerides
Ketones
Creatine kinase (CK)
Blood
Nitrate
Thyroid Function Test:
Urine leukocyte esterase
Thyroid stimulating hormone (TSH)a
Serum Pregnancy Test (females only) 
Urine Drug Screenb
HgbA1C
Serologies as appropriatec,d
Prothrombin Time (PT) as appropriatee
a
If TSH level is outside normal range, patient is excluded.  Patients previously diagnosed with hyperthyroidism or 
hypothyroidism that have taken a stable dose of thyroid supplement for at least the past 3 months, have medically 
appropriate TSH concentrations, and are clinically euthyroid will be permitted to enroll in the study.  One retest 
is allowed at the investigator’s discretion.
b
UDS may be repeated at investigator discretion throughout the trial
c
Serologies collected at baseline for hepatitis endemic regions: Hepatitis B surface antigen, Hepatitis C antibody.
d
Serologies collected with hepatic follow-up:  Hepatitis B surface antigen (HBsAg); Hepatitis B core antibody 
(HBcAb); Hepatitis B core IgM antibody [HBV-Ab (IgM)]; Hepatitis C antibody (HCV-Ab); Hepatitis A IgM 
antibody [HAV-Ab (IgM)]; Hepatitis E virus IgM antibody is collected with hepatic alert for endemic areas.
e
Prothrombin time (PT) collected with hepatic follow up as appropriate

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Attachment 3.Protocol HMGW Sampling Summary
This table summarizes the maximum number of samples by venipuncture and blood volumes for
all sampling (screening, standard laboratory, pharmacogenetic) and tests during the study.  Fewer
samples may actually be taken, but this will not require a protocol amendment.
Protocol F1J-MC-HMGW Sampling Summary
Purpose
Sample 
Type
Maximum Amount 
per Sample
Maximum 
Number 
Samples
Maximum 
Total Amount
Screening testsa
Blood
5 mL
2b
10 mLb
Standard laboratory testsa
Blood
5 mL
6
30 mL
Pharmacogenetic sample
Blood
10 mL
1
10 mL
Total Blood
20 mL
50 mL
a
Additional samples may be drawn if needed for safety purposes.
b
An additional sample is required for hepatitis endemic regions.  The maximum total amount would then be 
15mL.