Clinical trial NCT03297294
Conditions: Painful Diabetic Neuropathy
Keywords: Painful diabetic neuropathy Neuropathic pain Angiotensin II type 2 receptor antagonist adult EMA401 diabetic neuropathy
Sponsor: Novartis Pharmaceuticals
Start date: 2018-03-14; Completion date: 2019-03-25
Enrollment: 142 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate safety and efficacy of EMA401 compared to placebo in patients with painful diabetic neuropathy (PDN).

Detailed description:
This was an interventional, randomized, parallel, placebo-controlled, double-blind treatment study consisting of 3 periods i.e. Screening, Treatment, and Treatment withdrawal. Patients were planned to be randomized in a 1:1 ratio to Placebo b.i.d. or EMA401 100 mg b.i.d.. Concomitant use of pregabalin or duloxetine at stable doses was allowed. Based on historical data, it was planned that the study would enroll approximately 50% of patients who were on stable doses of concomitant pregabalin or duloxetine in the study. At the end of treatment period the 100mg b.i.d. arm was re-randomized (1:1) to the same treatment or placebo. Placebo arm stayed on placebo. The planned duration of treatment period was 12 weeks and 1 week of treatment withdrawal at the end of treatment period.

The study was terminated early due to pre-clinical toxicity data that became available after start of trial. Novartis implemented a Urgent Safety Measure (USM) which instructed sites to discontinue study treatment immediately and to have all patients return for additional laboratory assessments (full hematology including coagulation and clinical chemistry panel). Safety data from the USM was presented as a separate outcome measure table and not included in the Adverse Event section

Arms: arm 1: During the treatment epoch, patients will receive EMA401 for 12 weeks. During the treatment withdrawal epoch, patients will receive EMA401 or matching placebo for 1 week. arm 2: Participants will receive matching placebo to EMA401 during both the treatment and treatment withdrawal epochs for a total of 13 weeks.
Interventions: intervention 1: EMA401 intervention 2: Placebo
Intervention descriptions: intervention 1: capsules, oral intervention 2: Placebo to EMA401 capsules, oral

Protocol documents:
Prot_001.pdf: 
Global Clinical Development - General Medicine 
EMA401
Clinical Trial Protocol CEMA401A2202 / NCT03297294
A double-blind, placebo-controlled, randomized trial to 
determine the safety and efficacy of EMA401 100 mg b.i.d. 
in reducing 24-hour average pain intensity score in patients 
with painful diabetic neuropathy (EMPADINE)
Document type:
Clinical Trial Protocol
EUDRACT number:
2016-000281-39
Version number:
00 (Original Protocol)
Clinical trial phase:
II
Release date:
15-Sep-2017
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.2 (July 2016)


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Protocol summary..............................................................................................................11
1
Introduction .......................................................................................................................14
1.1
Background............................................................................................................14
1.2
Purpose ..................................................................................................................15
2
Study objectives and endpoints .........................................................................................15
2.1
Objectives and related endpoints...........................................................................15
3
Investigational plan ...........................................................................................................17
3.1
Study design...........................................................................................................17
3.2
Rationale for study design .....................................................................................19
3.3
Rationale for dose/regimen, route of administration and duration of treatment....19
3.3.1
Efficacy .................................................................................................19
20
3.3.3
Non-Clinical Safety...............................................................................20
3.3.4
Clinical Safety.......................................................................................21
3.4
Rationale for choice of comparator .......................................................................22
3.5
Purpose and timing of interim analyses/design adaptations..................................22
3.6
Risks and benefits..................................................................................................22
4
Population..........................................................................................................................22
4.1
Inclusion criteria ....................................................................................................22
4.2
Exclusion criteria...................................................................................................23
5
Treatment...........................................................................................................................25
5.1
Study treatment......................................................................................................25
5.1.1
Investigational and control drugs..........................................................25
5.1.2
Additional treatment..............................................................................25
5.2
Treatment arms ......................................................................................................25
5.3
Treatment assignment and randomization.............................................................26
5.4
Treatment blinding.................................................................................................26
5.5
Treating the patient................................................................................................27
5.5.1
Patient numbering .................................................................................27
5.5.2
Dispensing the study drug.....................................................................28


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5.5.3
Handling of study and additional treatment..........................................28
5.5.4
Instructions for prescribing and taking study treatment........................28
5.5.5
Permitted dose adjustments and interruptions of study treatment ........29
5.5.6
Rescue medication ................................................................................29
5.5.7
Concomitant medication .......................................................................29
5.5.8
Prohibited medication ...........................................................................30
5.5.9
Emergency breaking of assigned treatment code..................................31
5.6
Study completion and discontinuation...................................................................32
5.6.1
Study completion and post-study treatment..........................................32
5.6.2
Discontinuation of study treatment .......................................................32
5.6.3
Withdrawal of informed consent...........................................................33
5.6.4
Loss to follow-up ..................................................................................34
5.6.5
Early study termination by the sponsor.................................................34
6
Visit schedule and assessments .........................................................................................34
6.1
Information to be collected on screening failures..................................................40
6.2
Patient demographics/other baseline characteristics .............................................40
6.3
Treatment exposure and compliance .....................................................................40
6.4
Efficacy..................................................................................................................40
6.4.1
11-point Numeric Rating Scale (NRS) .................................................41
6.4.2
Neuropathic Pain Symptom Inventory (NPSI) .....................................41
6.4.3
Brief Pain Inventory-Short Form (BPI-SF)...........................................42
6.4.4
Patient Global Impression of Change (PGIC).......................................42
6.4.5
Insomnia Severity Index (ISI)...............................................................42
6.4.6
Appropriateness of efficacy assessments..............................................42
6.5
Safety.....................................................................................................................43
6.5.1
Physical examination ............................................................................43
6.5.2
Vital signs..............................................................................................43
6.5.3
Height and weight .................................................................................43
6.5.4
Laboratory evaluations..........................................................................43
6.5.5
Electrocardiogram (ECG) .....................................................................45
6.5.6
Pregnancy and assessments of fertility .................................................45
6.5.7
Appropriateness of safety measurements..............................................45
6.6
Other assessments..................................................................................................46
6.6.1
Clinical Outcome Assessments (COAs) ...............................................46
6.6.2
Resource utilization...............................................................................48
6.6.3
Pharmacokinetics ..................................................................................48


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6.6.5
Other biomarkers...................................................................................49
7
Safety monitoring ..............................................................................................................49
7.1
Adverse events.......................................................................................................49
7.2
Serious adverse events...........................................................................................51
7.2.1
Definition of SAE .................................................................................51
7.2.2
SAE reporting........................................................................................52
7.3
Liver safety monitoring .........................................................................................53
7.4
Renal safety monitoring.........................................................................................54
7.5
Reporting of study treatment errors including misuse/abuse ................................54
7.6
Pregnancy reporting...............................................................................................54
55
8
Data review and database management.............................................................................55
8.1
Site monitoring ......................................................................................................55
8.2
Data collection.......................................................................................................56
8.3
Database management and quality control............................................................56
8.4
Data Monitoring Committee..................................................................................57
8.5
Adjudication Committee........................................................................................58
9
Data analysis......................................................................................................................58
9.1
Analysis sets ..........................................................................................................58
9.2
Patient demographics and other baseline characteristics.......................................58
9.3
Treatments .............................................................................................................59
9.4
Analysis of the primary variable and key secondary variable...............................59
9.4.1
Primary variable(s)................................................................................59
9.4.2
Statistical model, hypothesis, and method of analysis..........................59
9.4.3
Handling of missing values/censoring/discontinuations.......................61
9.4.4
Supplementary analyses ........................................................................62
9.4.5
Sensitivity analyses ...............................................................................62
9.5
Analysis of secondary variables ............................................................................62
9.5.1
Efficacy variables..................................................................................62
9.5.2
Safety variables .....................................................................................64
9.5.3
Resource utilization...............................................................................65
9.5.4
Pharmacokinetics ..................................................................................66
66
9.5.6
Biomarkers ............................................................................................66
9.5.7
PK/PD ...................................................................................................66


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66
67
68
9.7
Interim analyses .....................................................................................................68
9.8
Sample size calculation..........................................................................................68
10 Ethical considerations........................................................................................................69
10.1
Regulatory and ethical compliance........................................................................69
10.2
Informed consent procedures.................................................................................70
10.3
Responsibilities of the investigator and IRB/IEC..................................................70
10.4
Publication of study protocol and results...............................................................70
10.5
Quality Control and Quality Assurance.................................................................71
11 Protocol adherence ............................................................................................................71
11.1
Protocol amendments.............................................................................................71
12 References .........................................................................................................................72
13 Appendix 1: Clinically notable laboratory values and vital signs.....................................74
14 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.....................................................................................................................75
15 Appendix 3: Specific Renal Alert Criteria and Actions ....................................................78
16 Appendix 4: Proprietary screening algorithm for assessing eligibility .............................79
17 Appendix 5: PK sample log - Time schedule for blood sampling for PK assessments ....80
18 Appendix 6: Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
(DSM-V) diagnostic criteria for Major Depressive Disorder............................................81
19 Appendix 7: Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
(DSM-V) diagnostic criteria for Substance Use Disorders ...............................................83
List of tables
Table 2-1
Objectives and related endpoints ..........................................................15
Table 5-1
Randomization scheme .........................................................................26
Table 5-2
Prohibited medication ...........................................................................30
Table 6-1
Assessment schedule.............................................................................36
Table 6-2
Abbreviated schedule of assessments for patients with data 
collected after study treatment discontinuation.....................................39
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................54
Table 13-1
Clinically notable values for vital signs and weight changes ...............74
Table 14-1
Liver Event and Laboratory Trigger Definitions ..................................75
Table 14-2
Follow Up Requirements for Liver Events and Laboratory Triggers ...75


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Table 15-1
Specific Renal Alert Criteria and Actions.............................................78
Table 17-1
Time schedule for blood sampling for PK assessments (all patients)...80
Table 17-2
Time schedule for blood sampling for PK assessments (additional 
sampling for patients taking duloxetine)...............................................80
List of figures
Figure 3-1
Study design..........................................................................................17
Figure 9-1
Sequentially rejective, weighted Bonferroni-type test using the 
graphical approach ................................................................................61


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List of abbreviations
ACR
Albumin-Creatinine Ratio
AE
Adverse Event
AIDS
Acquired immunodeficiency syndrome
ALP
Alkaline Phosphate 
ALT
Alanine Aminotransferase
ANCOVA
Analysis of covariance
aPTT
activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
AT2
Angiotensin II type 2
ATC
Anatomic Therapeutic Chemical classification
AUC
Area under the Curve
AV Block 
Atrioventricular block 
b.i.d.
twice a day
BPI-SF
Brief Pain Inventory-Short Form
CBC
Complete Blood Cell count 
CFR
US Code of Federal Regulations 
CINP
Chemotherapy Induced Neuropathic Pain
CK
Creatine kinase
Cmax
Maximum concentration
CNS
Central Nervous System
COA
Clinical Outcome Assessment
CPO
Country Pharma Organization
CRA
Clinical Research Associate
CRF
Case Report/Record Form 
CRO
Contract Research Organization
 
CSR
Clinical Study Report 
CTCAE
Common Terminology Criteria for Adverse Events
CYP2C9
Cytochrome P450 2C9
CYP3A4
Cytochrome P450 3A4
DAR
Dose Administration Record
DM
Diabetes Mellitus
DMC
Data Monitoring Committee
DN4
Douleur Neuropathique en 4 Questions
DSM-V
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
EC
Ethics Committee
 
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture


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eDiary
Electronic diary
eGFR
Estimated Glomerular Filtration Rate
EMA
European Medicines Agency
EoT
End of Trial
ePRO
Electronic Patient Reported Outcome
EU
European Union
FAS
Full Analysis Set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
γ-GT
gamma-glutamyltransferase
HbA1c
Glycated hemoglobin
HBV
Hepatitis B Virus
HCV
Hepatitis C virus
HIV
Human Immunodeficiency Virus
HR
Heart Rate
IB
Investigator’s Brochure 
ICH
International Conference for Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISI
Insomnia Severity Index 
J2R
Jump to reference
LFT
Liver function test 
LoE
Lack of efficacy
LPLV
Last patient last visit
MAD
Multiple Ascending Dose
MAR
Missing at random
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCSFR1
Macrophage colony-stimulating factor 1 receptor
MCV
Mean Corpuscular Volume
MDE
Major Depressive Episode
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical dictionary for regulatory activities 
MTD
Maximum Tolerated Dose


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NeuPSIG
Neuropathic Pain Special Interest Group
NPSI
Neuropathic Pain Symptom Inventory 
NRS
Numeric Rating Scale
NSAID
Nonsteroidal Anti-inflammatory Drugs
OATP1B1
Organic Anion Transporter Protein 1B1
OATP1B3
Organic Anion Transporter Protein 1B3
OC/RDC
Oracle Clinical/Remote Data Capture 
OCT2
Organic Cation Transporter 2
PCR
Protein-Creatinine Ratio
PDN
Painful Diabetic Neuropathy
PerfO
Performance Outcomes
PHN
Post-Herpetic Neuralgia
PK
Pharmacokinetics
PGIC
Patient Global Impression of Change
PRO
Patient Reported Outcome
PRN
pro re nata (as needed)
PT
Prothrombin Time
QM
Quality Management
 
QTc
Corrected QT interval
QTcF
Fridericia QT correction formula
SAD
Single Ascending Dose
SAE
Serious Adverse Event
SAF
Safety set
SOP
Standard Operating Procedure
SSRI
Selective Serotonin Reuptake Inhibitor
SUSAR
Suspected Unexpected Serious Adverse Reactions
TD
Study Treatment Discontinuation
TENS
Transcutaneous Electrical Nerve Stimulation
TEAE
Treatment-Emergent Adverse Events
UGT
Uridine Diphosphate Glycosyltransferase
ULN
Upper limit of Normal
US
United States
VRS
Verbal Rating Scale
WHO
World Health Organization 
WoC
Withdrawal of Consent


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Glossary of terms
Cohort/arm
A specific group of patients/subjects fulfilling certain criteria
Control drug
Drugs(s) used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug
Dosage
Dose of the study treatment given to the patient in a time unit (e.g. 
100 mg once a day, 75 mg twice a day)
Electronic Data Capture 
(EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces.
EDC includes the use of Electronic Case Report Forms (eCRFs) which 
are used to capture data transcribed from paper source forms used at 
the point of care.
Enrollment
Point/time of patient entry into the study at which informed consent must 
be obtained (e.g. prior to starting any of the procedures described in the 
protocol)
Epoch
A portion of the study which serves a specific purpose. Epochs in this 
study are: screening, treatment, and treatment withdrawal
Investigational drug
The drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.”
Medication pack number
A unique identifier on the label of each investigational drug package
Patient/subject ID 
A unique number assigned to each patient upon signing the informed 
consent 
Randomization number
A unique identifier assigned to each randomized patient, corresponding 
to a specific treatment arm assignment
Source Data/Document
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, 
a spreadsheet or even hard-coded data, such as paper or eSource.
Study drug/treatment
Any single drug or combination of drugs administered to the patient as 
part of the required study procedures; includes investigational drug (s), 
placebo/comparator active drug run-ins or background therapy
Study Treatment 
Discontinuation (TD)
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study
Withdrawal of consent 
(WoC)
Withdrawal of consent from the study is defined as when a patient does 
not want to participate in the study any longer, and does not want any 
further visits or assessments, and does not want any further study 
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Protocol summary
Protocol number
CEMA401A2202
Full Title
A double-blind, placebo-controlled, randomized trial to determine the safety 
and efficacy of EMA401 100 mg b.i.d. in reducing 24-hour average pain 
intensity score in patients with painful diabetic neuropathy (EMPADINE)
Brief title
Safety and efficacy of EMA401 in patients with painful diabetic neuropathy 
(PDN)
Sponsor and Clinical 
Phase
Novartis
Phase 2
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of this study is to evaluate safety and efficacy of EMA401 100 
mg b.i.d. compared to placebo in patients with painful diabetic neuropathy 
(PDN).
Primary Objective(s) 
To compare the efficacy of EMA401 vs. placebo in 24-hour average pain 
intensity score at Week 12, using an 11 point Numeric Rating Scale (NRS) 
by testing the superiority of EMA401 100 mg b.i.d vs. placebo
Key secondary 
Objective
To compare the efficacy of EMA401 vs. placebo in Neuropathic Pain 
Symptom Inventory (NPSI) total score by testing the superiority of EMA401
100 mg b.i.d vs. placebo
Secondary Objectives

Objective 1: To evaluate the efficacy of EMA401 compared to placebo, 
as measured by the Brief Pain Inventory-Short Form (BPI-SF) 
interference total score at Week 12

Objective 2: To evaluate the efficacy of EMA401 compared to placebo, 
as measured by the weekly mean of the 24-hour worst pain intensity 
score, using an 11-point Numeric Rating Scale (NRS) at Week 12

Objective 3: To evaluate the efficacy of EMA401 compared to placebo, 
on the Patient Global Impression of Change (PGIC) at Week 12

Objective 4: To evaluate the proportion of EMA401 patients achieving a 
≥ 30% and a ≥ 50% reduction in weekly mean 24-hour average pain 
intensity score using the NRS compared to placebo (i.e., responder 
rates) at Week 12

Objective 5: To evaluate the effect of EMA401 compared to placebo on 
the Insomnia Severity Index (ISI) at Week 12

Objective 6: To evaluate the safety and tolerability of EMA401 
compared to placebo in PDN patients, as measured by treatment-
emergent adverse events (TEAEs), adverse events (AEs) leading to 
study drug discontinuation and serious adverse events (SAEs) 
throughout the study

Objective 7: To evaluate the pharmacokinetics (PK) of EMA401 and 
exposure-response (decrease in pain intensity) relationship for 
EMA401 throughout the study

Objective 8: To evaluate the proportion of patients who need rescue 
medication separately for the double blind treatment epoch and 
treatment withdrawal epoch and the time to first intake of rescue 
medication during the double blind treatment epoch.
Study design
The study is interventional, randomized, parallel, placebo-controlled,


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double-blind treatment.
Population
The study population will consist of approximately 400 randomized male 
and female patients (≥18 years old) with PDN
Key Inclusion criteria

At the time of Screening, have documented diagnosis of Type I OR 
Type II diabetes mellitus (DM) with painful distal symmetrical 
sensorimotor neuropathy (for example ICD-10 code G63.2) of more 
than 6 months duration with any one or more of the following: 

Neuropathic symptoms (e.g. numbness, non-painful paresthesias 
or tingling, non-painful sensory distortions or misinterpretations, 
etc.)

Decreased distal sensation (e.g. decreased vibration, pinprick 
sensation, light touch, etc.)

Be assessed as suffering from moderate to severe neuropathic pain 
across the Screening epoch (NRS ≥ 4)

A score of ≥4 on the Douleur Neuropathique en 4 Questions (DN4) 
questionnaire at Screening
Key Exclusion criteria

History or current diagnosis of electrocardiogram (ECG) abnormalities 
indicating significant risk of safety for patients participating in the study 

Major depressive episode within 6 months prior to Screening and/or a 
history of diagnosed recurrent major depressive disorder according to 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
(DSM-V) diagnostic criteria

Have evidence of significant renal insufficiency or pre-existing liver 
condition

Have platelets ≤100 x 109/L, or neutrophil count < 1.2 x 109/L (or 
equivalent), hemoglobin ≤100 g/L for women or hemoglobin ≤110 g/L 
for men

Participants whose glycemic control has been unstable within 3 months 
immediately prior to screening (e.g., ketoacidosis requiring 
hospitalization, any recent episode of hypoglycemia requiring 
assistance through medical intervention, uncontrolled hyperglycemia)

Patients with any differential diagnosis of PDN including but not limited 
to other neuropathies (e.g. Vitamin B12 deficiency, Chronic 
Inflammatory Demyelinating Polyneuropathy), polyradiculopathies, 
central disorders (e.g. demyelinating disease), or rheumatological 
disease (e.g., foot arthritis, plantar fasciitis)

Patient is unwilling or unable to complete daily eDiary
Study treatment
EMA401 and placebo
Efficacy assessments

11-point Numeric Rating Scale (NRS)

Neuropathic Pain Symptom Inventory (NPSI)

Brief Pain Inventory-Short Form (BPI-SF)

Patient Global Impression of Change (PGIC) 

Insomnia Severity Index (ISI)
Key safety 
assessments

Adverse event monitoring

Physical examinations and vital signs

Monitoring of laboratory markers in blood and urine

ECGs


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
Withdrawal and rebound effect
Other assessments

Pharmacokinetics (PK)
 
Data analysis
The primary objective of the study will be achieved if the active dose
(EMA401 100 mg b.i.d.) is statistically significant versus placebo in terms of 
24-hour average pain intensity score at Week 12, using an 11 point 
Numeric Rating Scale (NRS).
Similarly, key secondary objective of the study will be achieved if the active 
dose (EMA401 100 mg b.i.d.) is statistically significant versus placebo in 
terms of Neuropathic Pain Symptom Inventory (NPSI) total score.
While comparing EMA401 100 mg b.i.d. versus placebo, for the primary 
and key secondary endpoints the statistical testing will be carried out using 
the graphical testing procedure to preserve the family-wise error rate at 
the 2.5% level. 
The estimation of the treatment effect will be performed based on an 
Analysis of Covariance (ANCOVA) model including region (e.g. US, EU), 
treatment, sex, use of concomitant pain medication for PDN (yes/no) as 
factors and baseline score and age as covariates. The analysis will
account for different post-randomization events, such as changes in doses 
of concomitant medication for PDN, intake of rescue medication, intake of
prohibited medications that have a potential confounding effect on efficacy 
of the investigational drug, and discontinuations of study treatment due to
different reasons.
Key words
Painful diabetic neuropathy, neuropathic pain, angiotensin II type 2 
receptor antagonist


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1
Introduction
1.1
Background 
Neuropathic pain is recognized as having one of the most significant unmet needs of all the 
various forms of chronic pain. Painful diabetic neuropathy (PDN) is the most prevalent type 
of neuropathic pain, affecting up to 50% of diabetic patients (Mixcoatl-Zecuatl and Calcutt 
2013). It is estimated that there will be over 8 million prevalent cases of PDN in US and
Europe by the end of 2016, with 2.5% annual growth rate to reach 10 million cases by 2024 
(Kravit and Kuranz 2015). The next most prevalent forms of neuropathic pain are HIV/AIDS-
related neuropathy, neuropathic cancer pain and post-herpetic neuralgia (PHN). The latter two 
affect over 0.5 million patients each and the proportion of patients is expecting to grow at 1.4% 
annual growth rate till 2024. About 20% of patients with herpes zoster report some pain at 
3 months after the onset of symptoms, and 15% report pain at 2 years (Johnson and Rice 
2014). Neuropathic cancer pain is experienced by 29% of people living with inoperable 
cancer (Kravit and Kuranz 2015).
Diabetic neuropathy is a common and disabling complication of diabetes mellitus (DM) and 
has been recognized as a leading cause of non-traumatic amputations secondary to foot 
ulceration (Vinik et al 2000; Mahmood et al 2009). The typical diabetic neuropathy is a 
chronic, symmetrical, length-dependent sensory-motor polyneuropathy. Though the precise 
etiology of diabetic neuropathy remains to be elucidated, it develops on a background of long-
standing metabolic dysfunction associated with diabetes 
(including polyol flux, 
hyperglycemia, accumulation of advanced glycation end products, oxidative stress, and lipid 
alterations among other metabolic abnormalities) and cardiovascular risk factors (Dyck et al 
1999; Tesfaye et al 2005; Dyck et al 2006). The neuropathy in diabetes can affect the 
peripheral (painful diabetic neuropathy; PDN) nervous system or the autonomic nervous 
system (diabetic autonomic neuropathy); the current study focuses exclusively on the former.
Pain is a common complication of diabetic neuropathy and the condition, PDN, has few 
validated treatments. The patient complains of pain which is distal, symmetrical, often 
associated with nocturnal exacerbations, and commonly described as prickling, deep aching, 
sharp, like an electric shock, or burning with hyperalgesia and frequently allodynia upon 
examination (Apfel et al 2001; Boulton et al 2004).
Recent recommendations of Neuropathic Pain Special Interest Group (NeuPSIG) for the 
pharmacotherapy of neuropathic pain include use of tricyclic antidepressants, serotonin-
noradrenaline reuptake inhibitors (i.e. duloxetine), pregabalin, and gabapentin as first line 
agents (Finnerup et al 2015). Recommended second line therapy includes lidocaine patches, 
capsaicin high-concentration patches, and tramadol. These treatments however work in a 
subset of the patient population; significant proportion of patients get < 50% pain reduction 
and are accompanied by side effects that limit their utility (Hempenstall et al 2005). High-
dose monotherapy or combination of existing therapies is often used in patients with 
inadequate pain control in clinical practice. However, the benefit of the combination of 
currently available first or second line agents is limited due to additional tolerability issues ,
and disadvantages of combinations often outweigh the benefits. The majority of combinations 


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evaluated to date involve drugs which share some element of central nervous system (CNS) 
depression (e.g. sedation, cognitive dysfunction). This aspect of side effect overlap between 
combinations results in high treatment discontinuation rates and thus may substantially limit 
the utility of such combinations (Chaparro et al 2012). Given the prevalence and severity of 
PDN, a clear need exists for better treatments to reduce the condition's burden on patients and 
society.
EMA401 is an angiotensin II type 2 (AT2) receptor antagonist that has been shown to be 
active in established animal and clinical neuropathic pain models (Rice et al 2014; Smith and 
Muralidharan 2015). Initial safety data for EMA401 has been generated in seven Phase 1 
studies and one open label Phase 2 study in Chemotherapy Induced Neuropathic Pain (CINP).
Additionally, a randomized, placebo-controlled, multi-centric, proof of concept Phase 2 
efficacy study in PHN patients was completed, in which patients on EMA401 (100 mg b.i.d.) 
reported significant improvement in pain intensity compared to placebo following four weeks 
of treatment (Rice et al 2014). EMA401 was well-tolerated and demonstrates a positive 
benefit risk profile based on all evidence generated to date. 
1.2
Purpose 
The purpose of this study is to evaluate safety and efficacy of EMA401 100 mg b.i.d. (i.e. 200 
mg/day) compared to placebo in patients with painful diabetic neuropathy (PDN).
2
Study objectives and endpoints
2.1
Objectives and related endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)

To compare the efficacy of EMA401 vs. 
placebo in 24-hour average pain intensity 
score at Week 12, using an 11 point 
Numeric Rating Scale (NRS) by testing 
the superiority of EMA401 100 mg b.i.d.
vs. placebo
Endpoint(s) for primary objective(s) 

Change in weekly mean 24-hour average 
pain score (using the 11 point NRS) from 
Baseline to Week 12
Key Secondary Objective(s)

To compare the efficacy of EMA401 vs. 
placebo in Neuropathic Pain Symptom 
Inventory (NPSI) total score by testing the 
superiority of EMA401 100 mg b.i.d. vs. 
placebo
Endpoint(s) for key secondary objective(s) 

Change in Neuropathic Pain Symptom 
Inventory (NPSI) total score from 
Baseline to Week 12
Secondary Objective(s)

To evaluate the efficacy of EMA401 
compared to placebo, as measured by 
the Brief Pain Inventory-Short Form (BPI-
SF) interference total score at Week 12
Endpoint(s) for secondary objective(s)

Change in BPI-SF interference total 
score from Baseline to Week 12

To evaluate the efficacy of EMA401 
compared to placebo, as measured by 

Change in weekly mean of the 24-hour 
worst pain score, using an 11-point NRS, 


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Objective(s)
Endpoint(s)
the weekly mean of the 24-hour worst 
pain intensity score, using an 11-point
Numeric Rating Scale (NRS) at Week 12
from Baseline to Week 12

To evaluate the efficacy of EMA401 
compared to placebo, on the Patient 
Global Impression of Change (PGIC) at 
Week 12

PGIC at Week 12

To evaluate the proportion of EMA401 
patients achieving a ≥ 30% and a ≥ 50% 
reduction in weekly mean 24-hour 
average pain intensity score using the 
NRS compared to placebo (i.e., 
responder rates) at Week 12

Proportion of patients meeting responder 
criteria from Baseline to Week 12

To evaluate the effect of EMA401 
compared to placebo on the Insomnia 
Severity Index (ISI) at Week 12

Change in ISI from Baseline to Week 12

To evaluate the safety and tolerability of 
EMA401 compared to placebo in PDN 
patients, as measured by treatment-
emergent adverse events (TEAEs), 
adverse events (AEs) leading to study 
drug discontinuation and serious adverse 
events (SAEs) throughout the study

Number and severity of treatment-
emergent adverse events and the 
frequency of adverse events leading to 
discontinuation. Number of serious 
adverse events.

To evaluate the pharmacokinetics (PK) of 
EMA401 and exposure-response 
(decrease in pain intensity) relationship 
for EMA401 throughout the study

Plasma pharmacokinetics of EMA401 will 
be characterized by population non-linear 
mixed effects modeling techniques

To evaluate the proportion of patients 
who need rescue medication separately 
for the double blind treatment epoch and 
treatment withdrawal epoch and the time 
to first intake of rescue medication during 
the double blind treatment epoch.

Proportion of patients who need rescue 
medication separately for the double 
blind treatment epoch and treatment 
withdrawal epoch, the time to first intake 
of rescue medication during the double 
blind treatment epoch


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3
Investigational plan
3.1
Study design
The study is interventional, randomized, parallel, placebo-controlled, double-blind treatment.
The study will consist of a Screening epoch (up to 4 weeks), a double-blind Treatment epoch 
(12 weeks), and a double-blind Treatment withdrawal epoch (1 week). Concomitant use of 
pregabalin or duloxetine at stable doses is allowed (Section 5.5.7). Based on historical data
study will enroll approximately 50% of patients on concomitant pregabalin or duloxetine.

Patients will be randomized in a 1:1 ratio to treatment with placebo or EMA401 100 mg 
b.i.d.
Overall approximately 400 patients will be enrolled in the study (i.e. approximately 
200 patients will be enrolled in each treatment arm). End of Trial (EoT) will occur when the 
last patient completes last visit (LPLV).
Figure 3-1 presents an overview of the study design.
Figure 3-1
Study design
Screening epoch (Up to 4 weeks)
Potential participants will be required to provide written informed consent prior to any 
study-specific Screening procedures being performed. Once informed consent is obtained, 
Screening 
(Up to 4 wks)
Treatment 
(12 wks)
Treatment 
Withdrawal (1 wk)
Placebo b.i.d. 
Placebo b.i.d.
EMA401 100 mg b.i.d.
EMA401 100 mg or Placebo b.i.d.
Randomization
(1:1) 
Randomization 
(1:1)


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patients will be evaluated for eligibility based on the inclusion and exclusion criteria (see 
Section 4), which will require review of medical history and concomitant medications, vital 
signs, physical examination, assessment of patients’ current pain scores using the NRS, 12-
lead electrocardiogram (ECG), and clinical laboratory evaluations. 
During Screening, site staff must ensure that the patient is not taking any prohibited 
concomitant medications or combination therapy for neuropathic pain treatment. Patients who 
pass preliminary Screening assessments will receive their electronic patient reported outcome 
(ePRO) diary (eDiary) device. Patients completing their 7 day baseline 24-hour pain intensity 
scores will return to the study site at Visit 101 (i.e. Baseline).
The patient’s final eligibility will be based on an assessment of their average pain intensity 
scores using a proprietary screening algorithm (Appendix 4) prior to randomization. 
General principles of the algorithm include:
Exclusion of patients with scores below the minimum mean baseline pain intensity of “4”
using the NRS scale; and patients who: 

Were not compliant in completing the required data
OR

Did not record accurate pain scores
OR

Who had unacceptable variability in their baseline intensity. 
Site staff will need to check the electronic tablet to see if the patient meets these criteria to 
continue in the study and document the outcome in the patient’s source document.
Treatment epoch (12 weeks)
Patients completing all Screening assessments will then be randomized into a 12-week 
double-blind Treatment epoch at the Baseline visit (V101). Patients will visit the study site for 
assessments that are outlined in the visit assessment schedule (Table 6-1). At each scheduled 
visit Investigators/site staff will perform various assessments outlined in the visit assessment 
schedule and will review the patient’s weekly pain eDiary scores from the prior week(s) for 
compliance and entry errors, retraining the patient on eDiary entry as needed. Patients will be 
required to bring their eDiary device to every site visit. Patients will be instructed to continue 
recording their 24-hour average and worst pain intensity scores each day for the remainder of 
the study. Patients will be required to bring their previously dispensed supply of study 
medication to each scheduled visit in order that site staff can assess patient’s compliance with 
the dosing regimen. Patients should bring their duloxetine (if applicable) with them to the 
study visits where PK is collected so it may be administered after the PK assessment, as 
required.
Treatment withdrawal epoch (1 week)
For patients who complete the 12 week Treatment Epoch, there will be a 1-week, double-
blind Treatment withdrawal epoch. Patients receiving placebo treatment during the 12-week 
double-blind Treatment epoch will remain on placebo during the double-blind Treatment
withdrawal epoch. Patients receiving active treatment will be randomized in a 1:1 ratio to 


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either stop treatment (i.e. receive placebo) or to continue the active treatment assigned during 
the double-blind Treatment epoch. 
3.2
Rationale for study design
This study will evaluate the safety and efficacy of EMA401 100 mg b.i.d. in the treatment of 
PDN.
The aim is to estimate the treatment effect of the investigational drug (EMA401 100 mg b.i.d.) 
compared to placebo, for the target population on the primary pain parameter. The treatment 
effect of interest accounts for post-randomization events in a way that reflects their possible 
relationship to the investigational treatment. In particular, the treatment effect of interest:

shall not be confounded by events which are deemed non informative on the effect of the 
study medication, even if they may have the potential to confound it (e.g. some changes 
in concomitant medications), and 

shall account for events reflecting the unfavorable outcome when patients are unable to 
continue taking the study medication or unable to benefit from it (such as study treatment 
discontinuations for specific reasons). 
Further details are provided in Section 9.4.2.
The standard methodology for the purpose of evaluating safety and efficacy based on the 
above treatment effect is to conduct a double-blind, placebo-controlled, randomized, parallel 
group study. Twelve weeks of exposure is required for assessment of treatment response and 
registration in chronic pain conditions, as indicated in Food and Drug Administration (FDA) 
and European Medicines Agency (EMA) guidelines. The quarterly unblinded DMC review of 
safety data, together with clinical assessments every two weeks will ensure patient safety, 
according to the DMC Charter.
The study will evaluate the potential for a rebound effect of EMA401 in efficacy and 
withdrawal effect in safety after study drug discontinuation during a treatment withdrawal 
period designed to minimize bias via a randomized withdrawal design.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
In healthy volunteers, maximum tolerated dose (MTD) levels of EMA401 for single and 
multiple (for 7 days) dosing have been established at 2000 mg and 800 mg b.i.d. (1600 
mg/day) respectively (Study EMA401-008). 
The dose planned to be studied in this study is EMA401 100 mg b.i.d. (i.e. 200 mg per day).
3.3.1
Efficacy
In randomized, double-blind Study EMA401-003 (n=183), PHN patients on EMA401 at 
100 mg b.i.d. reported significant reduction in pain compared to placebo (mean reductions in 
pain scores −2.29 vs. −1.60) following four weeks of treatment (p=0.0066). 


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3.3.3
Non-Clinical Safety
The non-clinical program of EMA401 include safety pharmacology studies, toxicology 
studies in three species (dogs up to 4-week duration, rats and monkeys up to 13-week 
duration), mechanistic studies and preliminary embryo-fetal toxicity studies in two species 
(rat and rabbit). Together, these non-clinical studies support the conduct of clinical trials of up 
to 13-week in duration up to the highest daily clinical dose of 600 mg (300 mg b.i.d.) 
including in women of child-bearing potential. In the 13-week rat toxicity study, mortality and 
excessive toxicity was noted at doses ≥ 500 mg/kg/day (≥ 250 mg/kg b.i.d.). The various 
inflammatory changes gastrointestinal tract and nasal turbinate) noted at doses ≥ 150 
mg/kg/day (75 mg/kg b.i.d) and hepatocyte lipid vacuolation noted at doses ≥ 30 mg/kg/day 
(15 mg/kg b.i.d) were demonstrated to be clinically-irrelevant. In the 13-week toxicity study 


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in monkeys, oral administration of EMA401 sporadically resulted in abnormal feces and/or 
post-dose emesis and vomitus at doses ≥ 100 mg/kg/day (50 mg/kg b.i.d). Those clinical signs 
were not adverse because they were transient, did not result in decreased body weight/body 
weight gain and did not affect the overall health of the animals. There were no target organ of 
toxicity. A summary of completed non-clinical studies and their results can be found in the 
Investigator’s Brochure.
3.3.4
Clinical Safety
As of 05-Aug-2017, a total of 556 subjects (342 subjects from clinical pharmacology studies 
and 214 patients) have been enrolled into the EMA401 clinical program (inclusive of Phase 1 
and Phase 2), of which 373 subjects (250 healthy subjects, 92 patients with PHN, and 31 
patients with CINP) have received EMA401 and 183 subjects (92 healthy subjects and 91 
patients with PHN) have received placebo. Maximum doses tested were up to 2000 mg in 
single ascending dose (SAD), 800 mg b.i.d. (1600 mg/d) for 7 days in multiple ascending 
dose (MAD), and 100 mg b.i.d. (200 mg/d) in Phase 2 for 28 days. 
No deaths or SAEs have been attributed to EMA401 at the time of protocol finalization.
Study EMA401-008 determined maximum tolerated doses (MTDs) for EMA401 in healthy 
volunteers. Gastrointestinal AEs (particularly nausea and diarrhea) were the most significant 
dose-related AEs in subjects who received EMA401. All reported TEAEs were mild to 
moderate in severity in both single and multiple ascending cohorts. There was an apparent 
dose-related trend in gastrointestinal events in both the SAD and MAD components with 
highest incidence in single dose of 2000 mg or 800 mg b.i.d. multiple dose cohorts. As a 
result, these two dose levels have been determined to be the single and short-term repeat 
maximum tolerated doses (MTDs) for EMA401, respectively. 
In PHN patients (Study EMA401-003), EMA401 demonstrated an acceptable safety profile 
and was well-tolerated. Overall, 32 patients reported 56 treatment-emergent adverse events 
(TEAEs) in the EMA401 group compared to 29 patients reporting 45 TEAEs in the placebo 
group. TEAEs of headache, allergic dermatitis and pharyngitis were observed more frequently 
with EMA401 treatment compared to placebo. All reported TEAEs events were mild to 
moderate in severity. Patients were allowed to use concomitant medications for PHN,
including pregabalin and gabapentin, and other comorbid conditions (e.g. insomnia, 
depression). No safety concerns were identified with use of EMA401 and concomitant 
medications over 4 weeks.
The Ethnic Sensitivity Study (EMA401A1101) with the new formulation has recently been 
conducted to characterize pharmacokinetics, safety and tolerability of EMA401 after single 
ascending oral doses administered in Japanese (N=40) and Caucasian healthy adult subjects 
(N=20) and multiple oral doses administered in Japanese healthy elderly subjects (N=12). The 
safety part of the EMA401A1101 study is already analyzed. 
Single and multiple oral doses of EMA401 were safe and well-tolerated in Caucasian healthy 
subjects as well as in Japanese healthy adult and elderly subjects enrolled in EMA401A1101 
study. There were no deaths, no SAEs, and no discontinuation due to AEs. Gastrointestinal 
AEs (e.g. diarrhea) were the most significant AEs in subjects who received EMA401 in the 


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seven complete phase 1 studies. Overall AE profile is consistent with previous experience in 
EMA401 studies in healthy subjects.
3.4
Rationale for choice of comparator
In accordance with the Food and Drug Administration (FDA) and European Medicines 
Agency (EMA) guidelines, a placebo-control design was considered essential for this study as 
placebo-associated improvements are prominent in studies in chronic pain (Dworkin et al 
2010). 
3.5
Purpose and timing of interim analyses/design adaptations
Not applicable.
3.6
Risks and benefits 
The available safety information, combined with the potential of EMA401 to effectively treat 
neuropathic pain symptoms in patients, suggests a favorable risk-benefit ratio for exposure up 
to 13 weeks (see Section 3.3). Appropriate exclusion criteria are defined to ensure patient 
safety and allow estimation of treatment response with minimal factors that confound 
assessment of neuropathic pain. The risk to patients in this trial will be minimized by 
compliance with the eligibility criteria and study procedures, close clinical monitoring, 
monitoring for treatment-emergent adverse events, and discontinuation of study treatment due 
to adverse events or based on judgment of the investigator (Section 5.6.2). In addition, the 
DMC will conduct quarterly full unblinded safety reviews. The DMC will review cumulative 
safety data, as well as patient narratives for deaths, serious adverse events (SAEs), 
discontinuations due to adverse events and cases of interest (allergic dermatitis, and clinically 
significant abnormal hepatic and hematology values). Novartis will also report the following 
events to the DMC on a “real time” basis: Suspected Unexpected Serious Adverse Reactions
(SUSARs), Death/outcome leading to death, and cases of interest as noted above.
Study population includes patients suffering from moderate to severe pain, which is often 
associated with comorbid conditions (e.g. anxiety, depression and sleep disturbances).
Concomitant use of medications for pain (pregabalin or duloxetine) and other comorbid 
diseases at stable doses is therefore allowed, as no safety concerns are foreseen.
4
Population
The study population will consist of male and female patients (≥18 years old) with painful 
diabetic neuropathy (PDN). The goal is to randomize a total of approximately 400 patients in 
approximately 100 centers worldwide. Since a 40% screening failure rate is expected, 
approximately 675 patients will be screened.
4.1
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed. 
2. Males and females, 18 years and older.


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3. At the time of Screening, have documented diagnosis of Type I OR Type II diabetes 
mellitus (DM) with painful distal symmetrical sensorimotor neuropathy (for example 
ICD-10 code G63.2) of more than 6 months duration with any one or more of the 
following: 
a) Neuropathic symptoms (e.g. numbness, non-painful paresthesias or tingling, non-
painful sensory distortions or misinterpretations, etc.)
b) Decreased distal sensation (e.g. decreased vibration, pinprick sensation, light touch, 
etc.)
4. Be assessed as suffering from moderate to severe neuropathic pain across the Screening 
epoch (NRS ≥ 4). The assessment of moderate and severe pain will be made using a 
proprietary screening algorithm (as described in Section 3.1). The Investigator/site staff 
will be informed immediately as to whether the patient is eligible or ineligible on the 
electronic tablet based on the patient entering all relevant pain scores in the eDiary device.
5. A score of ≥4 on the Douleur Neuropathique en 4 Questions (DN4) questionnaire at 
Screening.
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the Investigator, in order to ensure that the study 
population will be representative of all eligible patients.
1. Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days, 
whichever is longer.
2. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes.
3. History or current diagnosis of electrocardiogram (ECG) abnormalities indicating 
significant risk of safety for patients participating in the study such as:

Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular 
tachycardia, and clinically significant second or third degree Atrioventricular block 
(AV block) without a pacemaker

History of familial long QT syndrome or known family history of Torsades de Pointes.
4. Patients taking medications prohibited by the protocol (see Section 5.5.8, 
Table 5-2).
5. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless 
of whether there is evidence of local recurrence or metastases.
6. Major depressive episode within 6 months prior to Screening and/or a history of diagnosed 
recurrent major depressive disorder according to Diagnostic and Statistical Manual of 
Mental Disorders, 5th Edition (DSM-V) diagnostic criteria (see Appendix 6).
 
 
 


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8. Pregnant or nursing (lactating) women.
9. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 3 days after stopping of study medication. Highly effective 
contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment.

Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject.

Placement of an intrauterine device (IUD) or intrauterine system (IUS).
In case local regulations deviate from the contraception methods listed above, local 
regulations apply and will be described in the ICF.
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow-up hormone level assessment is she considered 
not of child bearing potential.
10. Have evidence of significant renal insufficiency, indicated by an estimated glomerular 
filtration rate (eGFR) using the modification of diet in renal disease (MDRD) equation of 
< 40 mL/min/1.73 m2 at Screening (as calculated by the central laboratory).
11. Alcohol Use Disorder or other Substance-use disorders (other than nicotine or caffeine) in 
accordance with DSM-V criteria within 12 months of screening (see Appendix 7).
12. Positive urine drug screen at Screening.
13. Evidence of pre-existing liver condition as defined as any of the following:

Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 1.5 x ULN 
(upper limit of normal), or total bilirubin or alkaline phosphatase >ULN for the 
central laboratory at Screening 

Known history of or active hepatitis B virus (HBV), hepatitis C virus (HCV), or 
human immunodeficiency virus (HIV)

Hepatitis A or B vaccination within 3 months of Screening

Known gallbladder or bile duct disease

Acute or chronic pancreatitis
14. Have platelets ≤100 x 109/L, or neutrophil count < 1.2 x 109/L (or equivalent), or 
hemoglobin ≤100 g/L for women or hemoglobin ≤110 g/L for men at Screening.


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15. Participants whose glycemic control has been unstable within 3 months immediately prior 
to screening (e.g., ketoacidosis requiring hospitalization, any recent episode of 
hypoglycemia requiring assistance through medical intervention, uncontrolled 
hyperglycemia).
16. Patients with any differential diagnosis of PDN including but not limited to other 
neuropathies (e.g. Vitamin B12 deficiency, Chronic Inflammatory Demyelinating 
Polyneuropathy), polyradiculopathies, central disorders (e.g. demyelinating disease), or 
rheumatological disease (e.g., foot arthritis, plantar fasciitis).
17. Other than pain as a result of PDN: 

Have an active, uncontrolled medical condition (e.g., neurological, gastrointestinal, 
renal, hepatic, cardiovascular, pulmonary, metabolic, endocrine, hematological, 
genitourinary or other major disorder), psychotic disorder or any other uncontrolled 
psychiatric illness (patients who are not stable on medication for at least two months 
prior are excluded), or any other significant clinical disorder or laboratory finding, 
other chronic pain conditions (e.g. osteoarthritis, fibromyalgia), that in the opinion of 
the Investigator, precludes participation in the study or may interfere with the study 
objectives and assessment of change in neuropathic pain

Had a clinically significant illness or operative procedure within four weeks of 
Screening (e.g., influenza, myocardial infarction)
18. Have undergone neurolytic or neurosurgical therapy or use a neuro stimulating device for 
PDN within 3 months of Screening or are using/ plan to use Transcutaneous Electrical 
Nerve Stimulation (TENS).
19. Patient is unwilling or unable to complete daily eDiary.
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
The investigational drug, EMA401, will be provided as capsules. The following oral dosage 
strengths will be used:

50 mg
EMA401 and placebo will be identical in appearance. 
5.1.2
Additional treatment
No additional treatment beyond investigational drug and control drug are included in this trial.
5.2
Treatment arms
Patients will be assigned at Baseline (Visit 101) to one of the following 2 treatment arms in 
the ratio of 1:1.

Placebo b.i.d.

EMA401 100 mg b.i.d.


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5.3
Treatment assignment and randomization 
At Baseline (Visit 101), all eligible patients will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms in the double-blind Treatment epoch and to 
one of the treatment arms in the double-blind Treatment withdrawal epoch. Logistically, the 
randomization into all epochs will be pre-specified according to the following randomization 
scheme.
Table 5-1
Randomization scheme
Treatment epoch 
(treatment arms)
Treatment 
withdrawal epoch 
(treatment arms)
Randomization ratio
Placebo b.i.d.
Placebo b.i.d.
2
EMA401 100 mg b.i.d.
EMA401 100 mg b.i.d.
1
EMA401 100 mg b.i.d.
Placebo b.i.d.
1
The investigator or his/her delegate will contact the IRT after confirming that the patient 
fulfills all the inclusion/exclusion criteria. The IRT will assign a randomization number to the 
patient, and will specify a unique medication number for the first package of study drug to be 
dispensed to the patient. The randomization number will not be communicated to the caller.
At Week 12 (Visit 199), all patients who completed the 12-week double-blind Treatment 
epoch will enter the 1-week double-blind Treatment withdrawal epoch. The IRT system will 
indicate the unique medication number for the package of study drug to be dispensed to the 
patient during the double-blind Treatment withdrawal epoch. This medication number will 
correspond to the blinded withdrawal regimen assigned at Baseline. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to packs containing the investigational drug(s).
Randomization will be stratified by region (e.g. US, EU) and use of concomitant pain 
medication for PDN (yes/no) in order to achieve balance of treatment allocation within the 
stratification factors. 
For the primary analysis at Week 12, the overall study randomization ratio will be 1:1 for the 
treatment arms placebo and EMA401 100 mg b.i.d. (refer to Section 9.8).
The randomization scheme for patients will be reviewed and approved by a member of the 
Randomization Group.
5.4
Treatment blinding 
Patients, investigator staff, persons performing the assessments, and data analysts will remain 
blind to the identity of the treatment from the time of randomization until database lock, using 


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the following methods: (1) Randomization data are kept strictly confidential until the time of 
unblinding, and will not be accessible by anyone else involved in the study with the following 
exceptions: Drug Supply Management, PK analyst and the IRT staff. (2) The identity of the 
treatments will be concealed by the use of study drug that are all identical in packaging, 
labeling, schedule of administration, and appearance.
The randomization codes associated with patients from whom PK samples are taken will be 
disclosed to PK analysts who will keep PK results confidential until database lock.
Unblinding will only occur in the case of patient emergencies (see Section 5.5.9) and at the 
conclusion of the study. The external DMC and independent Contract Research Organization 
(CRO) will have access to unblinded data, as further described in Section 8.4.
5.5
Treating the patient 
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
5.5.1
Patient numbering
Each patient is uniquely identified by a Subject Number which is composed of the site 
number and a sequential number. Once assigned to a patient, the Subject Number will not be 
reused. 
Upon signing the informed consent form, the patient is assigned the next sequential number. 
The investigator or his/her staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. The site must select the Case Report 
Form (CRF) book with a matching Subject Number from the Electronic Data Capture (EDC)
system to enter data. 
If the patient fails to be randomized for any reason, the IRT must be notified within 2 days 
that the patient was not treated. The reason for not being treated will be entered on the 
Screening Disposition CRF.
A patient may fail the Screening epoch one time; Investigators may re-screen a patient if there 
is reasonable certainty that reasons for screen failure will be resolved prior to or during a 
repeat screening attempt. Some examples of re-screening reasons are listed below. If needed, 
questions regarding re-screen eligibility may be discussed with Novartis. Should this occur, 
the site should re-consent the patient and assign a new subject identification number. Once 
randomized, the subject identification number must remain constant throughout the entire 
clinical study.

Laboratory value(s) out of range due to sampling error or that might be within range after 
medically-appropriate supplementation. (Note: Before screen failing and then re-screening 
the subject, efforts should be made to repeat the laboratory assessment(s) during the 
original initial screening phase.)

The patient has a medical condition that can be stabilized or resolved prior to the repeat 
screening attempt.


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Patients may NOT be re-screened if the reason for screen failure was due to not meeting the 
requirements of the proprietary screening algorithm based on assessment of their 24-hour 
average pain intensity scores recorded in the eDiary device. 
5.5.2
Dispensing the study drug 
Each study site will be supplied with study drug in packaging of identical appearance.
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the treatment arms and a specific dose. 
Investigator staff will identify the study drug package(s) to dispense to the patient by 
contacting the IRT and obtaining the medication number(s). Immediately before dispensing 
the package to the patient, investigator staff will detach the outer part of the label from the 
packaging and affix it to the source document (Drug Label Form) for that patient’s unique 
subject number. 
5.5.3
Handling of study and additional treatment 
5.5.3.1
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designees have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels. Clinical supplies are to be dispensed only in accordance 
with the protocol. Technical complaints are to be reported to the respective Novartis Country 
Pharma Organization (CPO) Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the study treatment but no information 
about the patient except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Patients will be asked 
to return all unused study treatment and packaging at every study visit and at the end of the 
study or at the time of discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
5.5.3.2
Handling of additional treatment 
Not applicable.
5.5.4
Instructions for prescribing and taking study treatment 
For all treatment groups, each dose will be self-administered orally as two capsules with a full 
glass of non-carbonated water twice daily, consisting of a morning dose and an evening dose.
The study medication should be taken on an empty stomach at least one hour before a meal or 


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at least two hours after a meal. At the scheduled study visits where PK is collected (refer to 
Table 6-1), patients should be instructed not to take their morning dose of study 
medication (and duloxetine if applicable) prior to arriving at the site and completing the 
necessary assessments. Patients should bring their duloxetine (if applicable) with them to the 
study visits where PK is collected so it may be administered after the PK assessment, as 
required.
All kits of study treatment assigned by the IRT will be recorded/databased in the IRT.
The investigator must promote compliance by instructing the patient to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the patient’s 
safety and the validity of the study. The patient must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed.
5.5.5
Permitted dose adjustments and interruptions of study treatment 
Investigational or other treatment dose adjustments and/or interruptions are not permitted.
5.5.6
Rescue medication
Patients will be allowed to take acetaminophen/paracetamol up to a maximum of 3 g daily 
(divided into 4 times per day) for unacceptable pain due to any reason during the study.
The patients will be instructed to fill out the electronic pain diary (eDiary) before intake of 
acetaminophen/paracetamol. Use of acetaminophen/paracetamol must be recorded in the 
eDiary.
5.5.7
Concomitant medication 
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after enrolling into the study. All medications including antidiabetic medications, 
procedures and significant non-drug therapies (including physical therapy and blood 
transfusions) administered after the patient was enrolled into the study must be recorded in the 
concomitant medications/significant non-drug therapies eCRF.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started.
1. Patients will be allowed to take only one of the following prescribed medications for 
managing their PDN, provided the dose level has been stable for at least 2 weeks prior to 
the Screening Visit (Visit 1) and must remain at stable doses throughout the study (PRN
(as needed) use is not allowed):

Pregabalin

Duloxetine
2. In addition to other medications for non-pain related co-morbid conditions, patients will 
be allowed to take throughout the study the following medications for other concomitant 
medical conditions. The dose level must be stable at Baseline and must continue at stable 
doses throughout the study (PRN (as needed) use is not allowed):

A benzodiazepine, zolpidem, diphenhydramine or related drugs for insomnia.


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
A selective serotonin reuptake inhibitor (SSRI) for depression.

Oral aspirin (≤ 325 mg/day) for cardio-protection.
5.5.8
Prohibited medication
Medications that the patient may be taking for the treatment of neuropathic pain (i.e. 
pregabalin or duloxetine) must be stable for at least 2 weeks prior to the Screening visit, and 
must remain stable throughout the study. Any change to a different standard of care 
medication from baseline (e.g. switch from pregabalin to duloxetine) will be treated as 
prohibited medication.
In addition, use of the treatments displayed in Table 5-2 is prohibited.
Table 5-2
Prohibited medication
Medication
Prohibition period
Action taken for study 
treatment
Prohibited prior to Screening Visit and throughout study
Any skeletal muscle relaxant (e.g. 
baclofen, orphenadrine, 
methocarbamol)
2 weeks prior to Screening 
and after Screening
None
Mexiletine
2 weeks prior to Screening
and after Screening
None
Dextromethorphan
2 weeks prior to Screening
and after Screening
None
Memantine
2 weeks prior to Screening
and after Screening
None
Alpha-lipoic acid
2 weeks prior to Screening
and after Screening
None
Other anti-epileptic drugs (e.g. valproic 
acid, carbamazepine, phenytoin)
2 weeks prior to Screening
and after Screening
Discontinue study treatment 
upon 2nd episode of 
medication use
Antiviral medications (e.g. valacyclovir, 
acyclovir, amantadine, anti-HIV)
2 weeks prior to Screening
and after Screening
None
High dose capsaicin patch (8%)
6 months prior to Screening
and after Screening
Discontinue study treatment 
Prohibited after Screening Visit and throughout study
Oral or injectable steroids
After Screening
Discontinue study treatment 
upon 2nd episode of 
medication use
Monoamine oxidase inhibitors or any 
other antidepressants (except stable 
dosage of SSRI)
After Screening
Discontinue study treatment 
upon 2nd episode of 
medication use
Antipsychotic or neuroleptic medications
After Screening
Discontinue study treatment 
upon 2nd episode of 
medication use
Cannabinoids (e.g. marijuana)
After Screening
Discontinue study treatment 
upon 2nd episode of 
medication use
Prescribed opioids, including codeine
After Screening
Discontinue study treatment 


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Medication
Prohibition period
Action taken for study 
treatment
upon 2nd episode of 
medication use
Prescription systemic pain medication,
or topical treatment for PDN, including 
lidocaine plaster 
After Screening
Discontinue study treatment 
upon 2nd episode of 
medication use
Nonsteroidal Anti-inflammatory Drugs 
(NSAIDs) or any other over-the-counter 
pain medications
After Screening
None
Any non-drug therapies that could 
modulate the perception of pain either 
directly or indirectly (i.e. transcutaneous 
electrical nerve simulation (TENS) or 
surgery)
After Screening
Discontinue study treatment 
Other medications that may have 
potential drug-drug interactions (e.g. 
felodipine, eplerenone, nisoldipine, 
ticagrelor, tacrolimus, avasimibe, 
rifampin, cyclosporine, gemfibrozil, 
clarithromycin, St. John’s Wort; oral, 
injected or implanted hormonal methods 
of contraception)
After Screening
None
5.5.9
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. If the IRT system 
is not available for technical reasons, the IRT help desk can facilitate emergency code break 
requests. When the investigator contacts the system to break a treatment code for a patient, 
he/she must provide the requested patient identifying information and confirm the necessity to 
break the treatment code for the patient. The investigator will then receive details of the 
investigational drug treatment for the specified patient and a fax or email confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
Study Team that the code has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in p lace to 
allow access to the IRT at any time in case of emergency. The investigator will provide:

protocol number

study drug name (if available)

patient number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-
blinding can be performed at any time. 
An assessment will be done by the appropriate site personnel and the Study Team after an 
emergency treatment code break to assess whether or not investigational treatment should be 


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discontinued for a given patient and, if applicable, whether the patient can continue into the 
next trial epoch.
5.6
Study completion and discontinuation 
5.6.1
Study completion and post-study treatment
A patient will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol. The study will be considered complete (End of Trial) when 
the last patient completes the last visit (i.e., LPLV) in the study.
Provision of study treatment after completion of this study is not planned as pre-clinical 
toxicological studies currently permit a maximum of 13 weeks of treatment administration in 
human subjects.
Continuing care should be provided by investigator and/or referring physician based on 
patient availability for follow-up. 
5.6.2
Discontinuation of study treatment
Discontinuation of study treatment for a patient occurs when study drug is stopped earlier than 
the protocol planned duration, and can be initiated by either the patient or the investigator. 
The investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of trial participation.
Study treatment must be discontinued under the following circumstances: 

Patient wish 

Pregnancy (see Section 6.5.6 and Section 7.6)

Use of prohibited treatment that requires study treatment discontinuation as described in 
Table 5-2

Positive urine drug screen

Any situation in which study participation might result in a safety risk to the patient

Unsatisfactory therapeutic effect

Patient’s condition no longer requiring study treatment

Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the patient’s overall status, prevents the patient from continuing 
participation in the study
In addition, study treatment must be interrupted/ discontinued under the following 
circumstances:

Emergence of the following adverse events: 

Skin rash – In the event a skin rash occurs while on study medication, initial 
evaluation by a qualified clinician is required. Identified common dermatologic 
conditions (i.e. insect bites, poison ivy etc.) can be evaluated and treated per standard 
of care by investigator. In cases of suspected allergic dermatitis does not respond to 
treatment, consultancy with an independent dermatologist for follow-up is required 


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with appropriate documentation in patient’s source. Study treatment should be 
interrupted if allergic dermatitis is suspected. The following assessments should be 
done at the time of determination and recorded in the appropriate CRF: body 
temperature, blood chemistry (including Liver Function Tests (LFTs) and Complete 
Blood Cell Count (CBC)). Study treatment can be started again following 
recommendation of the dermatologist and investigator. Study treatment must be 
permanently discontinued thereafter if allergic dermatitis appears again after re-
initiation of study treatment. All decisions should be documented in the patient’s 
medical chart.

Hepatic enzyme elevation – Refer to Appendix 2 for requirements for temporary and 
permanent discontinuation of study medication.

Abnormal hematology evaluation, defined as any of the following, requires temporary 
discontinuation of study medication and repeat testing within 48 hours (via central or 
local laboratory) and follow-up until recovery to ≤ grade 1 Common Terminology 
Criteria for Adverse Events (CTCAE). Study treatment must be permanently 
discontinued thereafter if hematology values are abnormal again (as defined below)
after re-initiation of study treatment.

Platelets <50 x 109/L

Absolute neutrophil count <1.0 x 109/L

Hemoglobin <80 g/L
If discontinuation of study treatment occurs, the patient should NOT be considered withdrawn 
from the study. The patient should return to the clinic as soon as possible, after 
discontinuation of study drug, for a study treatment discontinuation visit as detailed in 
Table 6-1. The investigator must determine the primary reason for the patient’s premature 
discontinuation of study treatment and record this information in the on the Dosage 
Administration eCRF. 
Patients who discontinue study drug should be treated according to the best standard of care 
and be encouraged to stay in the study and continue to be followed with an abbreviated 
schedule of assessments as indicated in Table 6-2.
If the patient cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person pre-designated by the patient. This 
telephone contact should preferably be done according to the abbreviated study visit schedule.
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.
If study drug discontinuation occurs because treatment code has been broken, please refer to 
Section 5.5.9.
5.6.3
Withdrawal of informed consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent from the study is defined as when a patient:

Does not want to participate in the study anymore


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and

Does not want any further visits or assessments
and

Does not want any further study related contacts
and

Does not allow analysis of already obtained biologic material
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient’s decision to withdraw his/her consent and record 
this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in Table 6-
1.
5.6.4
Loss to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of 
telephone calls, registered letters, etc. A patient cannot be considered as lost to follow-up until 
the time point of his/her scheduled end of study visit has passed.
5.6.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the 
patient must be seen as soon as possible and treated as a prematurely discontinued patient. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the patient’s interests. The 
investigator will be responsible for informing the Institutional Review Board/Independent 
Ethics Committee (IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 lists all of the assessments and indicates with an “X” or “S” when the visits are 
performed.
Patients must be seen for all visits on the designated day, or as close to it as possible. Missed 
or rescheduled visits should not lead to automatic discontinuation. Patients who prematurely 
discontinue the study treatment for any reason should be scheduled for a visit as soon as 


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possible, at which time all of the assessments listed for the Treatment Discontinuation visit 
(TD) will be performed. At this visit, all dispensed investigational product should be 
reconciled and the adverse event and concomitant medications reconciled on the CRF. If 
patients then agree to continue in the study (for further safety and efficacy data collection), 
subsequent visits will then be according to the Abbreviated schedule of assessments for 
patients with study treatment discontinuation as outlined in Table 6-2. Patients following the 
Abbreviated schedule of assessments must continue to adhere to the protocol requirements for 
changes to concomitant medications for neuropathic pain, rescue medication and prohibited 
medications.
Patients will be contacted for safety evaluations during the 30 days following the last 
administration of study treatment.


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Table 6-1
Assessment schedule
Epoch
Screening 
Treatment 
Treatment 
withdrawal 
Visit
1
101
102
103
104
105
106
107
199
201
Week
-5 to -1
0 (BL)
1
2
4
6
8
10
12 
TD 
visit
13
Day
-35 to -7
1 
8
15
29
43
57
71
85
92
Informed consent
X
Inclusion/Exclusion criteria
X
Demography
X
Disease & Medical History
X
Smoking, Alcohol, Liver History
X
Surgical and medical 
procedures/Concomitant 
Medications/Rescue Medications
X
X
X
X
X
X
X
X
X
X
X
Complete Physical exam
S
S
S
S
S
Brief Physical exam
S
S
S
S
S
S
Vital signs
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
Urine drug screen
X
X
Serum pregnancy test 1
X
X
X
X
Urine pregnancy test
X
X
X
X
Hematology/Blood chemistry2
X
X
X
X
X
X
X
X
X
X
X
Urinalysis3
X
X
X
X
X
X
X
12-lead ECG5, 6
X
X
X
X
X
X
X
Contact IRT
X
X
X
X
X
X
X
X
X
X
X
Dispense study medication
S
S
S
S
S
S
S
S7


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Epoch
Screening 
Treatment 
Treatment 
withdrawal 
Visit
1
101
102
103
104
105
106
107
199
201
Week
-5 to -1
0 (BL)
1
2
4
6
8
10
12 
TD 
visit
13
Day
-35 to -7
1 
8
15
29
43
57
71
85
92
Dosage Administration Record
X
X
X
X
X
X
X
X
X
Treatment Compliance
S
S
S
S
S
S
S
S
Adverse Events/SAEs
X
X
X
X
X
X
X
X
X
X
X
DN4 screening questionnaire
X
Dispense ePRO eDiary device
S
Complete pain eDiary daily (NRS)
X
X
X
X
X
X
X
X
X
X
X
Record VRS pain intensity
X
Check electronic tablet for eligibility
S
BPI-SF
X
X
X
X
X
PGIC
X
X
NPSI
X
X
X
X
X
X
ISI, 
X
X
X
Pharmacokinetics
X10
X9,10
X9,10
Screening disposition
X
Treatment epoch disposition
X
X
Treatment withdrawal epoch 
disposition
X
S = assessment to be recorded on source documentation only; TD = Study Treatment Discontinuation visit; X = assessment to be recorded on clinical data base


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Epoch
Screening 
Treatment 
Treatment 
withdrawal 
Visit
1
101
102
103
104
105
106
107
199
201
Week
-5 to -1
0 (BL)
1
2
4
6
8
10
12 
TD 
visit
13
Day
-35 to -7
1 
8
15
29
43
57
71
85
92
1Collected as part of the blood chemistry.
2HbA1c will be collected at Baseline and Week 12/TD
3Urine dipstick to be performed at the site. If abnormalities are present, urine sample should be sent to the central laboratory for microscopy analysis.
 
5Triplicate ECG and PK sample should also be collected if abnormal ECG result (QTcF>500 ms).
6Should blood sampling procedures, ECG and vital signs assessments be required at the same visit, the blood sampling procedures should be started after completion of 
the ECG collection and hemodynamic assessments as shown in the following sequence: 10 min resting period and pre-dose single ECG Vital signs Pre-dose PK 
and lab samples Study drug administration.
7Drug dispensation only for patients continuing into Treatment withdrawal epoch. Patients will take their last dose of “Treatment” study medication from their old bottle at 
the site visit in the morning, and will take their first dose of “Treatment withdrawal” study medication from their new bottle that evening.
9PK samples for all patients should be collected according to the schedule detailed in Table 17-1. Patients should be instructed not to take their morning dose of study 
medication prior to arriving at the site and completing the necessary assessments. PK sample should also be collected if abnormal ECG result (QTcF>500 ms).
10Additional PK sample collected for patients taking duloxetine according to the schedule detailed in Table 17-2. Patients should be instructed not to take their morning 
dose of duloxetine prior to arriving at the site and completing the necessary assessments. Patients should bring their duloxetine (if applicable) with them to the study 
visits where PK is collected so it may be administered after the PK assessment, as required.
 


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Table 6-2
Abbreviated schedule of assessments for patients with data collected after study treatment discontinuation 
Epoch
Treatment 
Visit1,2
102
103
104
105
106
107
199
Week
1
2
4
6
8
10
12
Day
8
15
29
43
57
71
85
Complete Physical exam
S
Brief Physical exam
S
S
S
S
S
S
Surgical and medical 
procedures/Concomitant Medications
X
X
X
X
X
X
X
Adverse Events/SAEs
X
X
X
X
X
X
X
Complete pain eDiary daily (NRS)
X
X
X
X
X
X
X
BPI-SF, NPSI
X
X
X
PGIC
X
Treatment epoch disposition
X
S = assessment to be recorded on source documentation only; X = assessment to be recorded on clinical data base
1The abbreviated schedule should be adopted from the visit following the study treatment discontinuation. For example, if a patient discontinues study 
drug at Week 4, the patient should be scheduled for the TD visit (Table 6-1) as soon as possible and then follow the abbreviated schedule for Week 6 
and subsequent visits (Table 6-2). At premature withdrawal from the study, or at completion of the study, the End of Study visit assessments (V199) 
should be performed instead of the next scheduled visit.
2Patients following the Abbreviated schedule of assessments must continue to adhere to the protocol requirements for changes to concomitant 
medications for neuropathic pain, rescue medication and prohibited medications.


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6.1
Information to be collected on screening failures 
All patients who have signed informed consent but not entered into the double-blind 
Treatment 
epoch
will 
have 
the 
Screening 
phase 
disposition, 
demographics, 
inclusion/exclusion, and serious adverse event (SAE) data collected. Adverse events that are 
not SAEs will be followed by the investigator and collected only in the source data.
6.2
Patient demographics/other baseline characteristics
Patient demographic and baseline characteristic data to be collected on all patients include: 
date of birth, age, sex, race, ethnicity, relevant medical history/current medical condition 
present before signing informed consent. Where possible, diagnoses, and not symptoms, will 
be recorded. In addition, previous/ongoing PDN medication(s) use will be collected (i.e. the 
latest dosing information of each medication and corresponding start/end dates).
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
6.3
Treatment exposure and compliance
Compliance will be assessed by the investigator and/or study personnel at each visit using pill 
counts and information provided by the patient. This information should be captured in the 
source document at each visit. All study treatment dispensed and returned should be recorded 
in the Drug Accountability Log.
Investigator should also check the electronic patient diaries and remind the patient of the 
importance of daily completion.
Protocol Deviations should be recorded for patients with an overall study medication 
compliance of less than 80% or patients with more than 3 full consecutive days of missed 
doses (more than 6 consecutive doses).
6.4
Efficacy
Assessments are to be collected as specified in Table 6-1. At study visits, all questionnaires 
should be completed first before any other study assessments are done.
A detailed training manual relating to the administrative procedures of the questionnaires will 
be provided to the sites.
All questionnaires will be completed in the language most familiar to the patient, at the 
scheduled study visit prior to the patient seeing the investigator for any clinical assessment or 
evaluation. The patient should be given sufficient instruction, space, time and privacy to 
complete the questionnaire. The study coordinator should check the responses to the 
questionnaire for completeness and encourage the patient to complete any missing responses.


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All patients will complete the Patient Reported Outcome (PRO) questions via a handheld 
eDiary device or an electronic tablet. Detailed training on use of the devices should be 
provided and recorded in the patient’s source document. Attempts should be made to collect 
responses to all PROs for all patients, including from those who prematurely discontinue prior 
to the study evaluation completion visit, however, if patients refuse to complete PROs, this 
should be documented in study source records.
Site staff will review eDiary compliance with the patient at each visit. Completed 
questionnaires will be reviewed and examined by the investigator, before the clinical 
examination, for responses that may indicate potential adverse events (AEs) or serious 
adverse events (SAEs), and the review should be documented in the patient’s source 
document accordingly. If AEs or SAEs are confirmed, then the physician must record the 
events according to instructions given in Section 7.1 and Section 7.2 of the protocol. 
6.4.1
11-point Numeric Rating Scale (NRS)
The Numeric Rating Scale (NRS) is an 11–point scale for patient self-reporting of pain.
24-hour Average Pain Score
The 24-hour average pain score will be assessed using the 11-point numeric rating scale (NRS) 
scale ranging from zero to ten. Patients will evaluate their average pain during the past 
24 hours in the evening prior to sleep by touching the appropriate corresponding number 
between zero ("no pain") and ten ("pain as bad as you can imagine") on the eDiary device. 
The 24-hour average pain score should be completed daily for seven consecutive days prior to 
randomization and then every day through the end of the study. Patients will be allowed to 
record their pain scores up to 1 day in the past. Any entries >1 day old will not be allowed and 
will be considered missing data.
Please note that patients will be required to bring their eDiary device in to the clinic for every
study visit, and should return the eDiary device at the end of study.
24-hour Worst Pain Score
The 24-hour worst pain score will also be assessed using the 11-point NRS scale ranging from 
zero to ten. Patients will rate their worst pain during the past 24 hours in the evening prior to 
sleep by touching the appropriate corresponding number between 0 ("no pain") and ten ("pain 
as bad as you can imagine") on the eDiary device. 
The 24-hour worst pain score should be completed daily for seven consecutive days prior to 
randomization and then every day through the end of the study. Patients will be allowed to 
record their pain scores up to 1 day in the past. Any entries >1 day old will not be allowed and 
will be considered missing data.
Please note that patients will be required to bring their eDiary device in to the clinic for every 
study visit, and should return the eDiary device at the end of study.
6.4.2
Neuropathic Pain Symptom Inventory (NPSI)
The Neuropathic Pain Symptom Inventory (NPSI) is a 12 item patient reported outcome 
measure that contains 10 descriptors representing 5 dimensions of pain (burning pain, 


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deep/pressing pain, paroxysmal pain, evoked pain and paraesthesia/dysesthesia) and 
2 temporal items designed to assess pain duration and the number of pain paroxysms.
The NPSI will be completed by patients using the electronic tablet at the site at the specified 
visits.
6.4.3
Brief Pain Inventory-Short Form (BPI-SF)
The Brief Pain Inventory-Short Form (BPI-SF) is a validated, self-administered questionnaire 
that assesses pain severity and its impact on daily functions. 
Patients will be asked to complete the 7-item pain interference scale which assesses the degree 
to which pain interferes with walking and other physical activity, work, mood, relations with 
others and sleep using a zero to ten numeric rating scale, with zero being "does not interfere" 
and ten being "completely interferes."
The 7-item pain interference scale of the BPI-SF will be completed by patients using the 
electronic tablet at the site at the specified visits.
6.4.4
Patient Global Impression of Change (PGIC)
The Patient Global Impression of Change (PGIC) is a patient-reported instrument that 
measures change in overall status on a scale ranging from one ("very much improved") to 
seven ("very much worse"). 
The PGIC is based on the validated Clinical Global Impression of Change scale.
The PGIC will be completed by patients using the electronic tablet at the site at the specified 
visit.
6.4.5
Insomnia Severity Index (ISI)
The Insomnia Severity Index (ISI) is a validated seven-item patient questionnaire used to 
quantify perceived insomnia severity. 
Patients will be asked to complete the ISI using five-point Likert-style scale as a measure of 
perceived sleep difficulties. Scores can range from zero to 28, with a cut-off score of eight 
suggesting the presence of sub-threshold insomnia. The questionnaire assesses the severity of 
insomnia, satisfaction with current sleep pattern, sleep interference, "noticeability" of sleeping 
problem to others and concern about sleeping problems.
The ISI will be completed by patients using the electronic tablet at the site at the specified 
visits.
6.4.6
Appropriateness of efficacy assessments 
Efficacy assessments used for evaluation of pain relief (NRS) are standard recommended 
primary outcome measures for neuropathic pain clinical trials, also supported by Food and 
Drug Administration (FDA) and European Medicines Agency (EMA) guidelines. As chronic 
pain interferes with daily activities, quality of life, additional patient reported outcome 
measures (PROs) of physical functioning, 
 are 
recommended for assessing the patient’s perception of the impact of disease and treatment on 


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daily life physical, psychological and social functioning and well-being. The Patient Global 
Impression of Change is a useful supportive indicator of the overall perceived benefit of 
treatment in chronic pain trials. Therefore BPI-SF and PGIC are included. 
NPSI is a multidimensional tool to evaluate treatment response on sensory and affective 
qualities of pain.
Sleep disturbance may change pain perception and might affect efficacy assessments. 
Furthermore, pharmacodynamic effects of EMA401 may influence these comorbidities. ISI 
will be used to access impact on perceived insomnia severity. 
6.5
Safety 
6.5.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes,
and extremities, vascular and neurological.
A brief physical exam, as per local practice, will include the examination of general 
appearance and will be at all visits, except where a complete physical examination is required 
(see above).
Information for all physical examinations must be included in the source documentation at the 
study site. Clinically relevant findings that are present prior to signing informed consent must 
be included in the Medical History part of the CRF. Significant findings made after signing 
informed consent which meet the definition of an Adverse Event must be recorded on the 
Adverse Event section of the CRF.
6.5.2
Vital signs 
Vital signs include blood pressure, pulse measurements, respiratory rate, and temperature. 
After the patient has been supine for five minutes, systolic and diastolic blood pressure will be 
measured three times. The repeat supine measurements will be made at approximately 1 to 
2 minute intervals and the mean of the three measurements will be used. After the patient has 
been standing for 3 minutes, systolic and diastolic blood pressure will be again measured 
using the above procedure. 
Clinically notable vital signs for blood pressure, pulse, and weight are defined in Appendix 1.
6.5.3
Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor 
clothing, but without shoes) will be measured.
6.5.4
Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are 
provided to investigators in the laboratory manual. Clinically significant abnormalities should
be recorded on the Medical History/Adverse Event CRF page as appropriate.


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Clinically notable laboratory findings are defined in Appendix 1.
6.5.4.1
Hematology
The following parameters will be collected: standard hematology with differential (red blood 
cell count, white blood cell count, platelet count, hemoglobin, hematocrit, mean corpuscular 
volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin 
concentration (MCHC), red blood cell morphology, white blood cell differential).
Measures of coagulability to be collected: activated partial thromboplastin time (aPTT), 
prothrombin time/International Normalized Ratio (PT/INR).
6.5.4.2
Clinical chemistry
The following parameters will be collected: albumin, alkaline phosphatase, amylase, 
bicarbonate, total bilirubin (direct and indirect bilirubin measured if total bilirubin >1.5 x
ULN), calcium, chloride, cholesterol, creatinine, creatine kinase (CK), gamma-
glutamyltransferase (γ-GT), glucose, lipase, lactate dehydrogenase, inorganic phosphorus, 
magnesium, 
potassium, 
total 
protein, 
aspartate 
aminotransferase
(AST), 
alanine 
aminotransferase (ALT), sodium, triglycerides, urea and uric acid.
At Screening (Visit 1) the following parameters will also be analyzed to determine a patient’s 
eligibility: HIV antibodies, hepatitis B surface antigen, hepatitis C antibodies.
At Baseline and Week 12/TD, glycated hemoglobin (HbA1c) will also be collected.
Serum pregnancy will be performed according to Table 6-1. 
6.5.4.3
Urinalysis
Dipstick measurements for specific gravity, albumin, protein, glucose and blood will be done 
at the site. If there are any abnormalities present, urine sample should be sent to the central 
laboratory for microscopy analysis.
6.5.4.5
Urine drug screen
A urine drug screen for drug abuse will include screening for cocaine, amphetamines, 
barbiturates, cannabinoids (including tetrahydrocannabinol), opiates, phencyclidine and 
methadone. If the results of the Screening urinalysis are positive, the site may perform a 


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single repeat urine drug screen within the screening period after the Screening visit. If the 
results from the repeat urine drug screen are negative, the patient may be included. If the 
repeat results are positive, the patient must be excluded from the study. A second repeat is not 
admissible. 
Urine drug screen will also be performed at Week 4 according to Table 6-1.
6.5.5
Electrocardiogram (ECG) 
ECGs must be recorded according to the ECG investigator manual. The preferred sequence of 
cardiovascular data collection during study visits is ECG collection first, followed by vital 
signs, and blood sampling. The Fridericia QT correction formula (QTcF) should be used for 
clinical decisions.
Single 12 lead ECGs are collected with ECG machines supplied by the central vendor at the 
visits indicated in Table 6-1. The original ECGs, appropriately signed, should be archived at 
the study site.
Each ECG tracing must be labeled with study number, subject initials, subject number, date 
and time, and filed in the study site source documents. If the single ECG shows a 
QTcF > 500 ms (males or females), 2 additional ECG replicates should be recorded under 
continued controlled environmental conditions (patient resting, no interfering procedures to 
ensure as much as possible stable heart rate) to confirm the safety findings and copies 
forwarded to the central ECG laboratory for assessment. Shortly after completion of the 
triplicate ECG recording, a PK sample should be drawn to allow for correlation of PK to the 
QT/QTc. 
Clinically significant ECG findings at randomization (pre-dose) must be discussed with the 
sponsor before administration of study treatment. Clinically significant abnormalities must be 
recorded on the relevant section of the Medical history/Current medical conditions/AE eCRF 
page as appropriate.
Detailed instructions concerning the ECG recording will be provided to all Investigators in a 
separate manual prior to the start of the study.
6.5.6
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements.
Serum and urine pregnancy tests will be performed according to the schedule in Table 6-1. 
6.5.7
Appropriateness of safety measurements 
The safety assessments selected are standard for this patient population. Since EMA401 is 
currently at Phase 2 of clinical development, safety evaluation including hematology and 
blood chemistry assessments are planned every 2 weeks for close patient monitoring and early 
detection of any safety signals.
 


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6.6
Other assessments
6.6.1
Clinical Outcome Assessments (COAs)
6.6.1.1
Patient Reported Outcomes (PRO)
The impact of PDN on various aspects of patient’s health status will be assessed by the 
following measures:
Douleur Neuropathique 4 (DN4)
The Douleur Neuropathique 4 (DN4) is a clinician administered questionnaire that can be 
useful in diagnosing neuropathic pain (Bouhassira et al 2005). 
The DN4 consists of 10 items. Seven items are related to pain quality (i.e. sensory and pain 
descriptors) and are based on an interview with the patient, and 3 items are based on the 
clinical examination. The clinical examination assesses whether there is reduced sensation 
(hypoesthesia) to touch or pinprick, and whether light brushing increases or causes pain 
(allodynia).
The DN4 will be administered by the clinician at Screening and recorded in the electronic 
tablet at the site.
Verbal Rating Scale (VRS) pain intensity
The Verbal Rating Scale (VRS) is a questionnaire administered by the clinician to capture the 
patient’s level of pain.
At Baseline, the clinical site staff will capture pain intensity information from each patient 
using the 4-point categorical VRS. The patient will be asked “What is your pain level at this 
time?” and the response will be recorded as 0 = none, 1 = mild, 2 = moderate, and 3 = severe. 
This will be recorded in the electronic tablet at the site.


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6.6.2
Resource utilization 
Not applicable.
6.6.3
Pharmacokinetics 
Further details on sample collection, numbering, processing and shipment can be found in the 
Laboratory Manual. The PK collection blood log is given in Appendix 5.
For all patients, PK samples will be collected at Week 8 and Week 12 according to Table 6-1
in order to measure EMA401 blood levels. The first blood sample should be collected after 
the patients have come to the clinic before taking morning study medication (i.e. 
EMA401/placebo). The second blood sample should be collected between 1-3 hours after the 
morning study medication dose (i.e. EMA401/placebo). The third blood sample should be 
collected between 4-6 hours after the morning study medication dose (i.e. EMA401/placebo). 


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For those patients who are also taking duloxetine, an additional pre-dose PK sample will be 
collected at Baseline, Week 8, and Week 12 before the patient takes their morning dose of 
duloxetine.
PK sample should also be collected if abnormal ECG results (see Section 6.5.5).
6.6.5
Other biomarkers
Not applicable.
7
Safety monitoring 
7.1
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.
The occurrence of adverse events must be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination findings, laboratory 
test findings, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:


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
they induce clinical signs or symptoms, 

they are considered clinically significant, 

they require therapy. 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1.
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information:

the severity grade

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities

its relationship to the study treatment 

Yes

No

its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported.

whether it constitutes a serious adverse event (SAE - See Section 7.2 for definition of SAE) 
and which seriousness criteria have been met.

action taken regarding investigational treatment 

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving;
recovered/resolved with sequelae; fatal; or unknown)
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 

no action taken (e.g. further observation only) 

investigational treatment interrupted/withdrawn

concomitant medication or non-drug therapy given 

non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition of 
SAE)
Once an adverse event is detected, it must be followed until its resolution or until it is judged 
to be permanent, and assessment must be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator’s Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any 


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new information regarding the safety profile of the medicinal product that is identified 
between IB updates will be communicated as appropriate, for example, via an Investigator 
Notification (IN) or an Aggregate Safety Finding. New information might require an update to 
the informed consent and has then to be discussed with the patient.
The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
7.2
Serious adverse events 
7.2.1
Definition of SAE 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)]
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the 
following criteria:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 


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bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (please refer to Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
7.2.2
SAE reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis safety within 24 hours of learning of its occurrence. Any SAEs experienced after the 
30 day period after the last study visit should only be reported to Novartis safety if the 
investigator suspects a causal relationship to study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at 
a different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to study treatment,
complete the SAE Report Form in English, and submit the completed form within 24 hours to 
Novartis. Detailed instructions regarding the submission process and requirements for 
signature are to be found in the investigator folder provided to each site. 
Follow-up information is submitted as instructed in the investigator folder. Each re-
occurrence, complication, or progression of the original event must be reported as a follow-up 
to that event regardless of when it occurs. The follow-up information should describe whether 
the event has resolved or continues, if and how it was treated, whether the blind was broken or 
not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01 or as per national regulatory 
requirements in participating countries.
Note: SAEs must be reported to Novartis within 24 hours of the investigator learning of its 
occurrence/receiving follow-up information.


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7.3
Liver safety monitoring 
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities/adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as (S)AE):

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages
Please refer to Table 14-1 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events. 
Every liver laboratory trigger or liver event as defined in Table 14-1 of Appendix 2 should be 
followed up by the investigator or designated personal at the trial site as summarized below. 
Detailed information is outlined in Table 14-2 in Appendix 2.
For the liver laboratory trigger:

Repeating the liver function test (LFT) within the next week to confirm elevation
These LFT repeats must be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory must then be performed at central laboratory as soon as possible. If 
a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event must be reported on the Liver CRF pages.

If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate.
For the liver events:

Repeating the LFT to confirm elevation as appropriate, 
 

Discontinuation of the investigational drug if appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications)

Specialist consultation at the discretion of the investigator.

An investigation of the liver event which needs to be followed until resolution. 
These investigations can include serology tests, 
, imaging and 
pathology assessments, hepatologist’s consultancy, based on investigator’s discretion. All 
follow-up information, and the procedures performed must be recorded on appropriate CRF 
pages, including the liver event overview CRF pages.


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7.4
Renal safety monitoring 
The following two categories of abnormal renal laboratory values have to be considered 
during the course of the study:

Serum event:

confirmed (after ≥24 h) increase in serum creatinine of ≥25% compared to baseline 
during normal hydration status

Urine event

new onset (≥1+) proteinuria; confirmed by doubling in the urinary albumin-creatinine 
ratio (ACR) or urinary protein-creatinine ratio (PCR) (if applicable)

new onset (≥1+), hematuria or glycosuria 
Every renal laboratory trigger or renal event as defined in Table 15-1 in Appendix 3 should be 
followed up by the investigator or designated personnel at the trial site as summarized in 
Appendix 3. Specialist consultation may be obtained at the discretion of the investigator.
7.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (European Medicines Agency definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the dose administration record (DAR) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an 
AE/SAE.
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error 
type
Document in Dose 
Administration
Record (DAR) eCRF
(Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes
Yes, even if not associated 
with a SAE
7.6
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 


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followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications for up to 12 months after birth.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
8
Data review and database management
8.1
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and Good Clinical Practice (GCP) compliance and the quality/integrity of the sites’ 
data. The field monitor will visit the site to check the completeness of patient records, the 


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accuracy of data capture/data entry, the adherence to the protocol and to Good Clinical 
Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits. Continuous remote monitoring of each 
site’s data may be performed by a centralized Novartis Clinical Research Associate (CRA)
organization. Additionally, a central analytics organization may analyze data & identify risks 
& trends for site operational parameters, and provide reports to Novartis Clinical Teams to 
assist with trial oversight.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the data capture and/or data entry. Novartis monitoring standards 
require full verification for the presence of informed consent, adherence to the 
inclusion/exclusion criteria, documentation of SAEs, and of data that will be used for all 
primary variables. Additional checks of the consistency of the source data with the CRFs are 
performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the patients will be disclosed.
8.2
Data collection 
Designated investigator staff will enter the data required by the protocol into the Oracle 
Clinical/Remote Data Capture (OC/RDC) system. Designated investigator site staff will not 
be given access to the system until they have been trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site. 
8.3
Database management and quality control 
Novartis staff review the data entered into the CRFs by investigational staff for completeness 
and accuracy and instruct the site personnel to make any required corrections or additions. 
Queries are sent to the investigational site using an electronic data query. Designated 
investigator site staff is required to respond to the query and confirm or correct the data. 
Concomitant medications entered into the database will be coded using the World Health 
Organization (WHO) Drug Reference List, which employs the Anatomical Therapeutic 
Chemical classification system. Concomitant procedures, non-drug therapies and adverse 
events will be coded using the Medical dictionary for regulatory activities (MedDRA) 
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Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
ECG readings will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Diary data will be entered into an electronic diary (eDiary) by the patient. The system will be 
supplied by a vendor(s), who will also manage the database.
Patients will fill in their PRO data in a site based electronic tablet. The systems will be 
supplied by a vendor(s), who will also manage the database. The database will be sent 
electronically to Novartis personnel (or designated CRO).
 
 
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
Development management.
8.4
Data Monitoring Committee 
An external Data Monitoring Committee (DMC) will be established with the primary goal to 
perform an ongoing review of safety data from all ongoing EMA401 patient studies. The 
DMC will consist of external experts who have experience in the management and monitoring 
of clinical trials and disease area expertise but without any direct involvement in any activities 
related to EMA401 studies. The DMC will function independently of all other individuals 
associated with the conduct of the trials, including the investigators, Novartis personnel and 
other committees overseeing the trials (e.g. ethics committee). Novartis study personnel will 
not have access to treatment codes or any unblinded data or data summaries prepared for the 
DMC. Further details will be provided in a DMC charter.


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The DMC is responsible for monitoring the safety of the trial participants, ensuring that the 
EMA401 trials are being conducted with highest scientific and ethical standards and making 
appropriate recommendations based on the data seen. DMC will conduct quarterly full 
unblinded safety reviews of cumulative safety data, as well as patient narratives for deaths, 
serious adverse events (SAEs), discontinuations due to adverse events and cases of interest 
(allergic dermatitis, and clinically significant abnormal hepatic and hematology values).
DMC could make the following recommendations:

Making recommendations regarding changes or adjustments that may be required to 
ensure patient safety and preserve the trial integrity

Suggesting modifications to the trial protocols; modifications may include, but are not 
limited to: changes in inclusion/exclusion criteria, frequency of visits or safety monitoring, 
alterations in trial procedures or trial conduct, or discontinuation of one or more trial 
treatment groups if applicable

Recommending continuation of the trials according to the protocols and any relevant 
amendments OR to discontinue the trials (with provisions for orderly discontinuation in 
accordance with good clinical practice)
8.5
Adjudication Committee 
Not required.
9
Data analysis 
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation.
9.1
Analysis sets 
The following analysis populations will be used for analysis.

The Enrolled population will include all patients who were enrolled into the study.

The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been 
assigned. Following the intent-to-treat principle, subjects will be analyzed according to the 
treatment assigned to at randomization.

The Safety Set (SAF) includes all subjects who received at least one dose of study 
medication. Subjects will be analyzed according to treatment received.
The primary efficacy analysis will be performed on the FAS. 
9.2
Patient demographics and other baseline characteristics 
Demographic and background information will be summarized for the SAF and FAS 
populations using frequency distributions (for categorical variables) and descriptive statistics 
of mean, standard deviation, minimum, median and maximum (for continuous variables). 
Relevant medical history/current medical conditions will be summarized by system organ 
class and preferred term of the MedDRA dictionary.


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9.3
Treatments 
Duration (days) of exposure to double-blind study medication will be summarized by 
treatment group. 
Frequency and percentages of patient disposition and reasons for discontinuation of study 
medication will be presented for both double-blind Treatment epoch and double-blind 
Treatment withdrawal epoch. Patients who prematurely discontinue the study medication will 
be listed along with the reason for discontinuation. 
The number and percentage of patients who used concomitant medications (coded by World
Health Organization [WHO] Anatomic Therapeutic Chemical classification [ATC]) and non-
drug therapies will be presented by treatment group. Separate tabulations will be provided for 
medications taken prior to start of study medication and while a patient is on study drug (i.e. 
between the first day on study drug and the day of last visit).
The number and percentage of patients who used rescue medication and who used prohibited 
medications for PDN will also be summarized by treatment.
The analyses will be based on the SAF and FAS populations.
9.4
Analysis of the primary variable and key secondary variable
9.4.1
Primary variable(s)
The primary efficacy variable will be the change from baseline to Week 12 in the weekly 
mean of the 24-hour average pain score, using an 11-point Numeric Rating Scale (NRS).
To calculate the weekly mean pain intensity score for a given week, each patient recorded 
his/her daily pain intensity score across the preceding 24 hours at a single time point. The 
daily pain intensity score was then averaged over 7 days to obtain the mean pain intensity 
score for a week. 
The key secondary efficacy variable will be the change from baseline to Week 12 in the 
Neuropathic Pain Symptom Inventory (NPSI) total score which is calculated as the sum of 10 
descriptors outcome measure (as defined in Section 6.4.2) out of the 12 items measured in the 
NPSI.
The primary population will be the FAS.
9.4.2
Statistical model, hypothesis, and method of analysis
The aim is to estimate the treatment effect of the investigational drug (EMA401) compared to 
placebo, for the target population on the primary pain parameter. The definition and the 
justification of the corresponding primary estimand, as well as the definition of the 
supplementary and secondary estimands for NRS are detailed in an Estimand Charter. The 
definitions of the estimands for the key secondary variable NPSI will also be detailed in an 
Estimand Charter.
Summary statistics by treatment and visit will be provided for the primary and key secondary 
efficacy variables.


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The primary estimation method for the both primary and key secondary efficacy variable 
will be based on an Analysis of Covariance (ANCOVA) model including region (e.g. US,
EU), treatment, sex, use of concomitant pain medication for PDN (yes/no) as factors and 
baseline score of the corresponding scale and age as covariate in an univariate fashion. The
analysis will account for different post-randomization events as follows:

Changes in doses of concomitant medication for PDN: Efficacy observations collected 
during the period of changes in doses of concomitant medication for PDN (compared to 
baseline) and the 3-days thereafter will be excluded, since they are considered affected by 
the concomitant medication dose change. The resulting missing data after this step will be 
imputed via multiple imputation method using the Missing at random (MAR) assumption.

Intake of rescue medication: Efficacy data collected during intake of rescue medication 
will be used for analysis.

Intake of prohibited medications with potential confounding effect prior to study 
treatment discontinuation: The prohibited medications with a potential confounding 
effect are defined as those listed in Table 5-2 requiring study treatment discontinuation. 
Efficacy observations collected during the intake period of such prohibited medications
and the 7-days thereafter will be excluded, since they are considered affected by the 
prohibited medication intake. The resulting missing data after this step will be imputed via 
multiple imputation method using the MAR assumption.
The design feature of retrieved drop-outs, considered in order to minimize the occurrence of
missing data on primary pain parameter, is exploited for the statistical analysis as follows:

Permanent discontinuation of study treatment due to AE, Lack of efficacy (LoE) and 
use of prohibited medication: If retrieved drop-out data are available, these will be used 
for analysis. If no data was retrieved after study treatment discontinuation, missing data 
will be multiply imputed based on placebo arm data, i.e. “jump to reference” (J2R) 
assumption for the EMA401 arm, missing at random assumption for placebo arm 
(Carpenter et al 2013). More details on the imputation model will be specified in the 
statistical analysis plan prior to unblinding.

Permanent discontinuation of study treatment due to other reasons than AE, LoE 
and use of prohibited medication: If efficacy data collected after study treatment 
discontinuation are available (retrieved drop-out), then the retrieved drop-out data will be 
excluded and missing data after study treatment discontinuation will be imputed via 
multiple imputation using the MAR assumption. 
The multiple imputations for the primary efficacy variable (NRS) will be carried out on the 
weekly mean pain score.
The primary objective will be achieved if the EMA401 100 mg b.i.d. dose is statistically 
significant versus placebo in terms of the primary efficacy variable after multiplicity 
adjustment.
The key secondary objective will be achieved if the EMA401 100 mg b.i.d. dose is
statistically significant versus placebo in terms of NPSI total score after multiplicity 
adjustment.


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The primary population will be the FAS. To preserve the family-wise error rate at the 2.5% 
level when comparing the EMA401 100 mg b.i.d. dose versus placebo on the two endpoints 
NRS and NPSI, statistical testing will be carried out using the following sequentially rejective, 
weighted Bonferroni-type test using the graphical approach (Bretz et al 2009) mentioned in
Figure 9-1. 
Figure 9-1
Sequentially rejective, weighted Bonferroni-type test using the 
graphical approach
In the graphical testing procedure given in Figure 9-1, H1 and H2 denote the two null 
hypotheses of no treatment difference of EMA401 100 mg b.i.d. vs. placebo for the primary 
efficacy variable NRS and key secondary efficacy variable NPSI total score. The 
corresponding alternative hypotheses will be EMA401 100 mg b.i.d. is superior to placebo for 
the NRS and NPSI respectively. In the Figure 9-1 the number in the circle represents the 
proportion of alpha level to be assigned at the initial stage among the two null hypotheses. 
The direction and the number in the arrow represent the proportion of the alpha to be 
propagated to the next hypothesis. 
Initially, H1 will be tested at the full alpha level (1 sided) 0.025. If H1 is rejected then H2 will 
be tested also at the full alpha level (1 sided) 0.025.
The same ANCOVA model will be applied at the visits prior to Week 12. Multiplicity 
adjustment at visits prior to Week 12 will not be carried out.
9.4.3
Handling of missing values/censoring/discontinuations
Handling of missing daily pain score values within a week (within-week imputation)
The 24-hour average pain score is measured daily for seven consecutive days prior to 
randomization and then every day through the end of the study (See Section 6.4.1). At each 
visit, the weekly mean of the seven 24-hour average pain assessments will be calculated. 
The weekly mean will be calculated based on the available assessments. If only one 
measurement is available, the mean will be based on that value.
Handling of missing weekly mean pain score values (weekly mean imputation)
The multiple imputation for the primary variable will be carried out on the weekly mean pain 
score. 
The imputation procedure related to primary analysis is described in Section 9.4.2 while the 
imputation procedure for the supplementary analyses is included in Section 9.4.4. The details 
of these imputation rules will be specified in an Estimand Charter and in the statistical 
analysis plan prior to unblinding.


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For all analyses, imputation of intermittent missing observations before treatment 
discontinuation will be carried out following a MAR mechanism for both treatment arms.
9.4.4
Supplementary analyses
The supplementary analyses to the primary analysis for NRS will be performed on the FAS
population. The supplementary estimands corresponding to these supplementary analyses are 
described in detail in an Estimand Charter.
The first supplementary analysis will be performed to quantify the treatment effect by
considering the discontinuation due to any reason other than the administrative reasons (e.g.
technical problems, study terminated by sponsor) and other than pregnancy as unfavorable 
outcomes (no difference to a placebo patient). The estimation method and handling of post 
randomization events will be same as for the primary analysis, except that missing data after
discontinuation due to any reason other than administrative reason in the EMA401 arm will 
be imputed via multiple imputation according to a “jump-to-reference” assumption.
The second supplementary analysis will be performed to quantify the treatment effect of 
the investigational drug compared to placebo that would have been observed had all patients 
remained on their assigned treatment for 12 weeks. The handling of post randomization events 
will be same as for the primary analysis, except that missing data after discontinuation for 
any reason will be imputed using the MAR assumption. 
The third supplementary analysis will be performed to quantify the treatment effect of the 
investigational drug compared to placebo regardless of changes in the dose of concomitant 
medications for PDN and regardless of use of prohibited medications with potential 
confounding effect. Such treatment effect corresponds to a “treatment-policy/intention-to-treat”
estimand. 
9.4.5
Sensitivity analyses
The following sensitivity analyses for NRS will be performed corresponding to each of the 
primary and supplementary analyses.
The same ANCOVA model as for the primary estimation will be adopted. Post randomization 
events will be handled in the same way as in the primary and two supplementary analyses, 
respectively. Missing data after discontinuation will in a first step be imputed in the same way 
as for the primary and two supplementary analyses, respectively. For the EMA401 arm these 
imputed values will further be worsened in subsequent steps via the application of 
increasingly large penalties (tipping point analysis, Permutt 2015).
9.5
Analysis of secondary variables
9.5.1
Efficacy variables 
The following secondary efficacy variables will be evaluated:
1. Responder analyses (based on at least a 30% or 50% improvement from baseline on NRS) 
will be performed in order to facilitate the interpretation of the results of the primary and 
supplementary analyses from a clinical relevance perspective. The responder status for 
each patient will be calculated based on the continuous weekly score measurements. For 


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patients who prematurely discontinue study treatment, the responder status will be 
calculated after missing data are imputed via multiple imputation according to the 
approaches specified for the primary and two supplementary analyses. Further analyses 
will be performed by considering patients who discontinue study treatment due to specific 
discontinuation reasons as non-responders. Additionally, to study the effect of changes in 
doses of concomitant medications for PDN, the use of prohibited medications and rescue 
medications on the responder criteria, a combined responder status of the patients will be 
calculated based on their continuous weekly score along with the use of the medications 
mentioned above. These analyses will be performed on the FAS population. The detail 
definition of the responder status and the corresponding secondary estimand and its
supplementary estimands are defined in detail in an Estimand Charter. 
From an analysis point of view, the resulting responder variables will be analyzed using a 
logistic regression model including all randomized patients and adjusting for the same 
covariates as the ANCOVA model for the primary analysis. Odds ratios will be estimated 
along with their 95% CIs.
The responder analyses will be performed for each visit, with the obvious modification in 
the definition for the week of interest.
2. Change from baseline to Week 12 in BPI-SF interference total score. This variable will be 
analyzed according to the same ANCOVA model as the one used for the primary variable. 
3. Change from baseline to Week 12 in weekly mean of the 24-hour worst NRS pain score, 
using an 11-point Numeric Rating Scale (NRS). This variable will be analyzed according 
to the same ANCOVA model as the one used for the primary variable.
4. PGIC at Week 12. The proportional odds model with the same factors as the ANCOVA 
model for the primary variable will be used.
5. The temporal items of NPSI will be summarized descriptively.
6. Change from baseline to Week 12 in ISI. This variable will be analyzed according to the 
same ANCOVA model as the one used for the primary variable.
7. The proportion of patients who need rescue medication (at each visit and at least once 
during the study) will be evaluated separately for the double blind treatment epoch and 
treatment withdrawal epoch. The corresponding binary variables will be derived and 
analyzed based on a logistic regression model with the same factors as the ANCOVA 
model for the primary analysis.
8. The Kaplan-Meier estimates of the proportion of patients with rescue medication intake
during the double blind treatment epoch, along with the associated 95% confidence 
intervals using the Greenwood’s formula will be provided The time to first rescue 
medication intake during the double blind treatment epoch will be compared between each 
dose of EMA401 and placebo via a Cox proportional hazard regression model with the 
same set of covariates used for the primary analysis. The corresponding hazard ratio with 
the 95% confidence interval will be reported.
Multiple imputation for the secondary variables will be carried out in a similar fashion as for 
the primary analysis of the NRS pain score. However, for PGIC no imputation will be 
performed because it is collected only at one post-baseline visit (Week 12 or Treatment 
Discontinuation visit). Thus the analysis for PGIC will be performed only on the observed 
cases. No multiplicity adjustment will be carried out for the secondary variables.


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Summary statistics by treatment and visit will be provided for the secondary efficacy 
variables.
9.5.2
Safety variables
Safety analyses will be conducted using the safety (SAF) dataset. Patients will be grouped by 
the actual treatment received.
The assessment of safety will be primarily based on the frequency of adverse events 
(including death and non-fatal serious adverse events). Additional safety assessments include 
laboratory tests, physical examination (including examination of skin), vital sign measures 
and ECG evaluations. Clinically significant findings in these additional safety assessments 
will be reported as adverse events and analyzed as such. In addition all safety assessments will 
be summarized or listed as appropriate. The analyses of additional safety assessments will be 
defined in the statistical analysis plan.
9.5.2.1
Adverse events
Treatment-emergent adverse events (TEAEs) are defined as any adverse events that develops 
after initiation of study treatment or any event already present that worsens following 
exposure to the study treatment. 
TEAEs will be summarized (number of cases as a percentage of number at risk) by treatment
group. Number and percentage of patients with TEAE will be summarized by primary system 
organ class and preferred term for each treatment group during the double blind Treatment 
epoch and during the double-blind Treatment withdrawal epoch. Relationship to study 
medication will be classified as related (“probably related” and “possibly related”) and 
unrelated (“not related”). Severity will be classified as “mild”, “moderate” and “severe”. 
Serious TEAEs, drug related TEAEs, TEAEs by maximum severity and TEAEs leading to 
premature discontinuation from study drug will be presented in a similar format as adverse 
events. Additionally, a listing of patients with TEAE will be presented. Drug abuse-related 
adverse events and suicidality will be summarized during the double-blind Treatment epoch
and treatment withdrawal epoch. The search criterion for each of these events will be defined 
based on MedDRA. The drug abuse-related adverse events will be summarized for the
double-blind Treatment withdrawal epoch to assess the potential for withdrawal effect.
9.5.2.2
Potential risks and Expected events
Allergic dermatitis, elevation in hepatic enzymes and neutropenia are the potential risks 
related to EMA401. Dizziness, headache, nausea, pre syncope and upper respiratory tract 
infections are the expected events related to EMA401. The search criterion for each of these 
risks and events will be defined based on MedDRA. The incidence of potential risks and 
expected events will be summarized. The detailed analysis of potential risks, expected events 
and the events of special interest will be specified in the statistical analysis plan.
9.5.2.3
Laboratory data
The summary of laboratory evaluations will be presented for 3 groups of laboratory tests: 
Hematology, Chemistry and Urinalysis.


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Laboratory data will be summarized by presenting summary statistics of raw data and change 
from baseline values, and by presenting shift tables to compare a patient’s baseline laboratory 
evaluation relative to minimum (when applicable) and maximum values post baseline For the 
shift tables, the reference ranges provided in the laboratory manual will be used to evaluate 
whether the most-extreme post baseline laboratory test value is normal, low, or high relative 
to whether or not the baseline value is normal, low, or high. 
Incidence of newly occurring liver enzymes abnormalities and renal events will be 
summarized using number and percentage of patients by treatment group. Plots related to 
analysis of laboratory data will be specified in the statistical analysis plan.
9.5.2.4
Vital signs
Vital sign measurements and their change from baseline will be summarized with descriptive
statistics (mean, median, standard deviation, min, max) by visit. The number and percentage 
of subjects with clinically notable vital signs will be presented.
9.5.2.5
ECG evaluations
ECG intervals will be summarized by presenting summary statistics for change from baseline 
values. The (uncorrected) QT interval will be corrected according to the Bazett’s and 
Fridericia’s formulae. The incidence rates of clinically notable ECG abnormalities will be 
summarized.
9.5.2.7
Other safety evaluations
All clinically significant safety findings based on additional safety evaluations (e.g. ECG or 
physical examination including assessments of skin, lymph nodes, lung, etc.) must be reported 
as adverse events on the AE CRF. The statistical analysis of these findings will be done in the 
analysis of adverse events.
Other safety data will be summarized or listed as appropriate.
9.5.3
Resource utilization 
Not applicable.


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9.5.4
Pharmacokinetics 
EMA401 plasma concentration data will be listed by treatment, subject, and visit/sampling 
time point. A population PK model will be fitted to the data in order to investigate whether 
covariates (e.g. age, gender, weight, ethnicity, baseline laboratory values, concomitant 
medications, etc.) influence the PK of EMA401. The choice of covariates to be included in the 
final model will be guided by exploratory plots of random effects (inter-individual variability 
parameters) against covariates. Those that are judged to show evidence of a relationship with 
the random effects will be tested for entry into the model, using the likelihood-ratio test with 
p <0.05. The final covariate model will be derived using a rigorous and acceptable model 
building procedure. 
Duloxetine plasma concentration data will be listed and summarized by visit and EMA401 
treatment group. Descriptive comparisons between the baseline visit assessments and the post-
baseline visit assessments will be made.
9.5.6
Biomarkers 
Not applicable.
9.5.7
PK/PD
Evaluation of effect of EMA401 exposure on efficacy variables (e.g. change from baseline of 
pain score), via the development of a continuous descriptive Pharmacokinetics/
Pharmacodynamics (PK/PD) will be done. All population PK/PD analyses and simulations 
will be carried out using a non-linear mixed-effects modelling approach.


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9.7
Interim analyses
No interim analysis will be performed for the efficacy evaluation, therefore no multiplicity 
adjustment for the primary efficacy objective is required. An external Data Monitoring 
Committee (DMC) is established for the EMA401 program with the primary goal to perform 
an ongoing review of safety data (Section 8.4).
The details of the analysis required for DMC will be specified in a separate DMC statistical
analysis plan. 
9.8
Sample size calculation
The calculation of power for the testing procedure mentioned in Figure 9-1 is based on the 
following assumptions:

The treatment difference of 100 mg b.i.d. vs. placebo was assumed as 0.7, 0.8 and 0.9
points, for the primary efficacy variable (weekly mean of the 24-hour average pain 
score). A treatment difference of 0.7 points was observed for the 100 mg b.i.d. dose vs. 
placebo for weekly mean of the 24-hour average pain score (NRS) in the Study 
EMA401-003 during a 4-week treatment period. The standard deviation is 2.6 points 
(based on data from pregabalin historical trials – see FDA Approval Package Medical 
Review, 2004) is assumed for the primary efficacy variable. In Study EMA401-003 in 
PHN patients, a standard deviation of approximately 2.0 points was observed. A 


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slightly higher value of 2.6 has been chosen to account for a possible higher variability 
due to a higher number of centers and due to multiple imputations (as opposed to 
single imputation) in the analysis. It is also assumed that the same standard deviation 
holds for the PDN population.

Treatment differences of 5 points for Pregabalin and 10 points for Duloxetine on NPSI 
total score were observed via an indirect comparison using the results from Tesfaye 
(2013) which is an active control study (Pregabalin vs Duloxetine) and Kalliomaki 
(2013) which is a placebo controlled study (AZD2423 vs placebo). The standard 
deviation was derived as 16 points using the results from Kalliomaki (2013). A 
correlation of approximately 0.2 was observed between the baseline scores of NRS 
and NPSI total score in Freeman et al (2014). The power of the study was calculated 
assuming correlation coefficient values of 0 and 0.2. Since the power values obtained 
for correlation values of 0.2 and 0 are similar, in a conservative scenario the results 
reported herein are for correlation value of 0. 
Since the NPSI has not been studied in the EMA401-003 study, to mitigate the risk of 
uncertainty on the value of treatment difference and standard deviation, the effect size 
(treatment difference/ standard deviation) of NPSI total score has been considered for 
the calculation of power. The power of the study was calculated for different effect 
sizes ranging in 0.1, 0.5 for NPSI total score corresponding to 100 mg.
Under the assumptions of a 0.8 point treatment difference between 100 mg b.i.d. and placebo, 
a standard deviation as 2.6 for the primary efficacy variable and an effect size of 0.4 for 100 
mg b.i.d. for the key secondary variable, N=200 patients per treatment arm will provide 
approximately 85% power to show that 100 mg b.i.d. is statistically significant over placebo 
for the primary efficacy variable, using the testing procedure mentioned in Figure 9-1. The 
power of showing the statistical significance of 100 mg b.i.d. dose in terms of the key 
secondary variable will be 84% under the same scenario. If we assume the treatment 
difference of 0.7 for the NRS as observed in the 4-week PoC study and the effect size for 
NPSI as 0.35, then the power for the primary objective will be 77% and that for the key 
secondary objective will be 72%. If the treatment difference between 100 mg b.i.d. and
placebo is 0.9 for the NRS, and effect size is 0.45 for 100 mg b.i.d. for the NPSI, the power 
increases to 94% for the primary objective. The corresponding power for the key secondary 
objective increases to 93%.
10
Ethical considerations
10.1
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US CFR 21, and 
Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in 
the Declaration of Helsinki.


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10.2
Informed consent procedures 
Eligible patients/subjects may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if applicable after 
such consent has been provided by a legally acceptable representative(s) of the patient. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the patient source documents.
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of child bearing potential must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
must not be entered in the study.
 
 
 
 
 
10.3
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to patients. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
10.4
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report 


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the results of this trial will be either submitted for publication and/or posted in a publicly 
accessible database of clinical trial results.
10.5
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance, a group independent from those involved in 
conducting, monitoring or performing quality control of the clinical trial. The clinical audit 
process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal Standard Operating Procedures (SOPs), and are performed according to 
written Novartis processes.
11
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients/subjects 
should be administered as deemed necessary on a case by case basis. Under no circumstances 
including incidental collection is an investigator allowed to collect additional data or conduct 
any additional procedures for any purpose involving any investigational drugs under the 
protocol, other than the purpose of the study. If despite this interdiction, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented.
11.1
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately provided the health authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed.


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12
References
References are available upon request.
Apfel SC, Asbury AK, Bril V, et al (2001) Positive neuropathic sensory symptoms as 
endpoints in diabetic neuropathy trials. J Neurol Sci; 189(1-2):3-5.
Boulton AJ, Malik RA, Arezzo JC, et al (2004) Diabetic somatic neuropathies. Diabetes Care; 
27(6):1458–86.
Bouhassira D, Attal N, Alchaar H, et al (2005) Comparison of pain syndromes associated with 
nervous or somatic lesions and development of a new neuropathic pain diagnostic 
questionnaire (DN4). Pain; 114(1-2):29-36.
Bretz F, Maurer W, Brannath W, et al (2009) A graphical approach to sequentially rejective
multiple test procedures. Stat Med; 28(4):586-604.
Carpenter JR, Roger JH, Kenward MG (2013) Analysis of longitudinal trials with protocol 
deviation: a framework for relevant, accessible assumptions, and inference via multiple 
imputation. J Biopharm Stat; 23(6):1352-71.
Chaparro LE, Wiffen PJ, Moore RA, et al (2012) Combination pharmacotherapy for the 
treatment of neuropathic pain in adults. Cochrane Database Syst Rev; 7:CD008943.
Dworkin RH, Turk DC, Peirce-Sandner S, et al (2010) Research design considerations for 
confirmatory chronic pain clinical trials: IMMPACT recommendations. Pain; 149:177-93.
Dyck PJ, Davies JL, Wilson DM, et al (1999) Risk factors for severity of diabetic 
polyneuropathy: intensive longitudinal assessment of the Rochester Diabetic Neuropathy 
Study cohort. Diabetes Care; 22(9):1479–86.
Dyck PJ, Davies JL, Clark VM, et al (2006) Modeling chronic glycemic exposure variables as 
correlates and predictors of microvascular complications of diabetes. Diabetes Care; 
29(10):2282-88.
Finnerup NB, Attal N, Haroutounian S, et al (2015) Pharmacotherapy for neuropathic pain in 
adults: a systematic review and meta-analysis. Lancet Neurol; 14(2):162-73.
Finnerup NB, Haroutounian S, Kamerman P (2016) Neuropathic pain: An updated grading 
system for research and clinical practice. Pain; 157(8):1599-1606.
Food and Drug Administration, Center for Drug Evaluation and Research (2004) Approval 
package for application number NDA 21-273, Medical Review. (Internet) Available from: 
<http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/021723s000_LyricaCaps_medr.pd
f> (Accessed 12 Dec 2016).
Freeman R, Baron R, Bouhassira D, et al (2014) Sensory profiles of patients with neuropathic 
pain based on the neuropathic pain symptoms and signs. Pain; 155(2):367–76.
Freeman R, Durso-Decruz E, Emir B (2008) Efficacy, safety, and tolerability of pregabalin 
treatment for painful diabetic peripheral neuropathy: findings from seven randomized, 
controlled trials across a range of doses. Diabetes Care; 31(7):1448-54.


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Hempenstall K, Nurmikko TJ, Johnson RW et al (2005) Analgesic therapy in postherpetic 
neuralgia: a quantitative systematic review. PLoS Med; 2(7):628–44.
Johnson RW, Rice AS (2014) Clinical practice. Postherpetic neuralgia. N Engl J Med;
371:1526–33.
Kalliomäki J, Attal N, Jonzon B, et al (2013) A randomized, double-blind, placebo-controlled 
trial of a chemokine receptor 2 (CCR2) antagonist in posttraumatic neuralgia. Pain;
154(5):761-67.
Kravit A, Kuranz S (2015) Neuropathic Pain. Decision Resources Group. 2015 DR/Decision 
Resources, LLC.
Mahmood D, Singh BK, Akhtar M (2009) Diabetic neuropathy: therapies on the horizon. J 
Pharm Pharmacol; 61(9):1137-45.
Mixcoatl-Zecuatl T, Calcutt NA (2013) Biology and Pathophysiology of Painful Diabetic 
Neuropathy in: E. Lawson, M. “Misha” Backonja (Eds.) Painful Diabetic Polyneuropathy: A 
Comprehensive Guide for Clinicians. 1st ed. Springer-Verlag, New York:13–26.
Permutt T (2015) Sensitivity analysis for missing data in regulatory submissions. Stat Med;
35:2876-9.
Rice A, Dworkin R, McCarthy T, et al (2014) EMA401, an orally administered highly 
selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic 
neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial. Lancet; 
383(9929):1637-47.
Smith M, Muralidharan A (2015) Targeting angiotensin II type 2 receptor pathways to treat 
neuropathic pain and inflammatory pain. Expert Opin Ther Targets; 19(1):25-35.
Tesfaye S, Chaturvedi N, Eaton SE, et al (2005) Vascular risk factors and diabetic neuropathy. 
N Engl J Med; 352(4):341–50.
Tesfaye S, Wilhelm S, Lledo A, et al (2013) Duloxetine and pregabalin: High-dose 
monotherapy or their combination? The ‘‘COMBO-DN study’’– a multinational, randomized, 
double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain. Pain; 
154(12):2616–25.
Vinik AI, Park TS, Stansberry KB, et al (2000) Diabetic neuropathies. Diabetologia; 43(8): 
957-73.
 
 


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13
Appendix 1: Clinically notable laboratory values and vital 
signs
Table 13-1
Clinically notable values for vital signs and weight changes
Variable
Criterion value
Change relative to baseline
Heart rate/pulse
120 bpm
50 bpm
and an
and a
increase of ≥ 15 bpm
decrease of ≥ 15 bpm
Systolic blood pressure
180 mm Hg
90 mm Hg
and an
and a
increase of ≥ 20 mm Hg
decrease of ≥ 20 mm Hg
Diastolic blood pressure
105 mm Hg
50 mm Hg
and an
and a
increase of ≥ 15 mm Hg
decrease of ≥ 15 mm Hg
Weight
Baseline weight (kg)
and an
and a
increase of ≥ 7%
decrease of ≥ 7%
bpm= beats per minute
Clinically notable laboratory values
Notable laboratory values will be specified in the laboratory manual with specific alert values. 
Both the Novartis clinical team and the investigator will be notified for all types of alerts.


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14
Appendix 2: Liver event and Laboratory trigger Definitions 
and Follow-up Requirements
Table 14-1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
LIVER LABORATORY TRIGGERS

3 x ULN < ALT / AST 5 x ULN

1.5 x ULN < TBL 2 x ULN
LIVER EVENTS

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 2 × ULN (in the absence of known Gilbert syndrome)

ALT or AST > 3 × ULN and INR > 1.5 

Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 
TBL > 2 × ULN [mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia

Any adverse event potentially indicative of a liver toxicity*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms
TBL= total bilirubin; ULN= upper limit of normal 
Table 14-2
Follow Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law 
casea

Discontinue the study treatment 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
 
 
 
ALT or AST
> 8 × ULN

Discontinue the study treatment 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
 
 
 
> 3 × ULN and INR > 
1.5

Discontinue the study treatment 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
 
 
 
> 5 to ≤ 8 × ULN

Repeat LFT within 48 hours
ALT, AST, TBL, Alb, PT/INR, ALP and 


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Criteria
Actions required
Follow-up monitoring

If elevation persists, continue follow-up 
monitoring

If elevation persists for more than 2 
weeks, discontinue the study drug

Establish causality

Complete liver CRF
γGT until resolutionc (frequency at 
investigator discretion)
 
 
 
> 3 × ULN 
accompanied by 
symptomsb

Discontinue the study treatment 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
 
 
 
> 3 to ≤ 5 × ULN 
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks 
ALP (isolated)
> 2 × ULN (in the 
absence of known 
bone pathology)

Repeat LFT within 48 hours

If elevation persists, establish causality

Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks or at 
next visit
 
 
 
TBL (isolated)
> 2 × ULN (in the 
absence of known 
Gilbert syndrome)

Repeat LFT within 48 hours

If elevation persists, discontinue the study 
drug immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
Test for hemolysis (e.g., reticulocytes, 
haptoglobin, unconjugated [indirect] 
bilirubin)
 
 
 
> 1.5 to ≤ 2 × ULN
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient 
Investigator discretion
Monitor LFT within 1 to 4 weeks or at 
next visit
Jaundice

Discontinue the study treatment 
immediately

Hospitalize the patient

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
 
 
 
Any AE potentially 
indicative of a liver 
toxicity*

Consider study treatment interruption or 
discontinuation 

Hospitalization if clinically appropriate

Establish causality
Investigator discretion
 
 
 


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Criteria
Actions required
Follow-up monitoring

Complete liver CRF
liver enzymes are still rising, and at 
resolution
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable values at 
three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 
months, (4) liver transplantation, and (5) death.


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15
Appendix 3: Specific Renal Alert Criteria and Actions
Table 15-1
Specific Renal Alert Criteria and Actions
Serum Event
Serum creatinine increase
25 – 49% compared to baseline
Confirm 25% increase after 24-48h 
Follow up within 2-5 days
Acute Kidney Injury: Serum creatinine increase 
50% compared to baseline
Follow up within 24-48h if possible
Consider study treatment interruption 
Consider patient hospitalization /specialized treatment
Urine Event
New dipstick proteinuria ≥1+
Albumin- or Protein-creatinine ratio increase ≥2-fold
Albumin-creatinine ratio (ACR) ≥30 mg/g or ≥3 
mg/mmol;
Protein-creatinine ratio (PCR) ≥150 mg/g or >15 
mg/mmol
Confirm value after 24-48h
Perform urine microscopy
Consider study treatment interruption / or discontinuation 
New dipstick glycosuria ≥1+ not due to diabetes
Blood glucose (fasting)
Perform serum creatinine, ACR 
New dipstick hematuria ≥1+ not due to trauma
Urine sediment microscopy
Perform serum creatinine, ACR 
For all renal events:
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and additional diagnostic 
procedures performed 
Monitor patient regularly (frequency at investigator’s discretion) until either: 
Event resolution: sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline, or
Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio stabilization at a 
new level with ±50% variability over last 6 months.


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16
Appendix 4: Proprietary screening algorithm for assessing 
eligibility
Available upon request.


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17
Appendix 5: PK sample log - Time schedule for blood 
sampling for PK assessments
Table 17-1
Time schedule for blood sampling for PK assessments (all patients)
Plasma EMA401 concentration
Week
Scheduled time
Dose 
reference 
ID
Sample 
number
Blood 
volume 
8
Prior to morning study medication (i.e. 
EMA401/placebo) dose
1
101
6 mL
1-3 hours after morning study 
medication (i.e. EMA401/placebo) dose
1
102
6 mL
4-6 hours after morning study 
medication (i.e. EMA401/placebo)
1
103
6 mL
12
Prior to morning study medication (i.e. 
EMA401/placebo) dose
2
104
6 mL
1-3 hours after morning study 
medication (i.e. EMA401/placebo) dose
2
105
6 mL
4-6 hours after morning study 
medication (i.e. EMA401/placebo)
2
106
6 mL
Total amount of blood for PK assessments
36 mL
Table 17-2
Time schedule for blood sampling for PK assessments (additional 
sampling for patients taking duloxetine)
Plasma concentration of duloxetine
Week
Scheduled time
Dose 
reference 
ID
Sample 
number
Blood 
volume 
0
Prior to morning duloxetine dose
3
201
3 mL
8
Prior to morning duloxetine dose
4
202
3 mL
12
Prior to morning duloxetine dose
5
203
3 mL
Total amount of blood for PK assessments
9 mL


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18
Appendix 6: Diagnostic and Statistical Manual of Mental 
Disorders, 5th Edition (DSM-V) diagnostic criteria for Major 
Depressive Disorder
A. Five (or more) of the following symptoms have been present during the same 2-week 
period and represent a change from previous functioning; at least one of the symptoms 
is either (1) depressed mood or (2) loss of interest or pleasure.
Note: Do not include symptoms that are clearly attributable to another medical 
condition.
1. Depressed mood most of the day, nearly every day, as indicated by either 
subjective report (e.g., feels sad, empty, hopeless) or observation made by 
others (e.g., appears tearful). (Note: In children and adolescents, can be 
irritable mood.)
2. Markedly diminished interest or pleasure in all, or almost all, activities most of 
the day, nearly every day (as indicated by either subjective account or 
observation).
3. Significant weight loss when not dieting or weight gain (e.g., a change of more 
than 5% of body weight in a month), or decrease or increase in appetite nearly 
every day. (Note: In children, consider failure to make expected weight gain.)
4. Insomnia or hypersomnia nearly every day.
5. Psychomotor agitation or retardation nearly every day (observable by others, 
not merely subjective feelings of restlessness or being slowed down).
6. Fatigue or loss of energy nearly every day.
7. Feelings of worthlessness or excessive or inappropriate guilt (which may be 
delusional) nearly every day (not merely self-reproach or guilt about being 
sick).
8. Diminished ability to think or concentrate, or indecisiveness, nearly every day 
(either by subjective account or as observed by others).
9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation
without a specific plan, or a suicide attempt or a specific plan for committing 
suicide.
B. The symptoms cause clinically significant distress or impairment in social, 
occupational, or other important areas of functioning.
C. The episode is not attributable to the physiological effects of a substance or another 
medical condition.
Note: Criteria A–C represent a major depressive episode (MDE).
Note: Responses to a significant loss (e.g., bereavement, financial ruin, losses from a 
natural disaster, a serious medical illness or disability) may include the feelings of 


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intense sadness, rumination about the loss, insomnia, poor appetite, and weight loss 
noted in Criterion A, which may resemble a depressive episode. Although such 
symptoms may be understandable or considered appropriate to the loss, the presence 
of a major depressive episode in addition to the normal response to a significant loss 
should also be carefully considered. This decision inevitably requires the exercise of 
clinical judgment based on the individual’s history and the cultural norms for the 
expression of distress in the context of loss.
In distinguishing grief from a major depressive episode (MDE), it is useful to consider 
that in grief the predominant affect is feelings of emptiness and loss, while in an MDE 
it is persistent depressed mood and the inability to anticipate happiness or pleasure. 
The dysphoria in grief is likely to decrease in intensity over days to weeks and occurs 
in waves, the so-called pangs of grief. These waves tend to be associated with thoughts 
or reminders of the deceased. The depressed mood of an MDE is more persistent and 
not tied to specific thoughts or preoccupations. The pain of grief may be accompanied 
by positive emotions and humor that are uncharacteristic of the pervasive unhappiness 
and misery characteristic of an MDE. The thought content associated with grief 
generally features a preoccupation with thoughts and memories of the deceased, rather 
than the self-critical or pessimistic ruminations seen in an MDE. In grief, self-esteem 
is generally preserved, whereas in an MDE feelings of worthlessness and self-loathing 
are common. If self-derogatory ideation is present in grief, it typically involves 
perceived failings vis-à-vis the deceased (e.g., not visiting frequently enough, not 
telling the deceased how much he or she was loved). If a bereaved individual thinks 
about death and dying, such thoughts are generally focused on the deceased and 
possibly about “joining” the deceased, whereas in an MDE such thoughts are focused 
on ending one’s own life because of feeling worthless, undeserving of life, or unable 
to cope with the pain of depression.
D. The occurrence of the major depressive episode is not better explained by 
schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional 
disorder, or other specified and unspecified schizophrenia spectrum and other 
psychotic disorders.
E. There has never been a manic episode or a hypomanic episode.
Note: This exclusion does not apply if all of the manic-like or hypomanic-like episodes 
are substance-induced or are attributable to the physiological effects of another medical 
condition.


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19
Appendix 7: Diagnostic and Statistical Manual of Mental 
Disorders, 5th Edition (DSM-V) diagnostic criteria for 
Substance Use Disorders
The diagnosis of a substance use disorder can be applied to all 10 classes except caffeine 
(alcohol; cannabis; hallucinogens; inhalants; opioids; sedatives, hypnotics, and anxiolytics; 
stimulants; tobacco; and other (or unknown) substances). For certain classes some symptoms 
are less salient, and in a few instances not all symptoms apply (e.g., withdrawal symptoms are 
not specified for phencyclidine use disorder, other hallucinogen use disorder, or inhalant use 
disorder).
Diagnostic Criteria
A problematic pattern of substance use leading to clinically significant impairment or distress, 
as manifested by at least two of the following criteria, occurring within a 12-month period:
1. The individual may take the substance in larger amounts or over a longer period than 
was originally intended. 
2. The individual may express a persistent desire to cut down or regulate substance use 
and may report multiple unsuccessful efforts to decrease or discontinue use. 
3. The individual may spend a great deal of time obtaining the substance, using the 
substance, or recovering from its effects. 
4. Craving, or a strong desire or urge to use the substance.
5. Recurrent substance use may result in a failure to fulfill major role obligations at work, 
school, or home. 
6. The individual may continue substance use despite having persistent or recurrent 
social or interpersonal problems caused or exacerbated by the effects of the substance. 
7. Important social, occupational, or recreational activities may be given up or reduced 
because of substance use.
8. Recurrent substance use in situations in which it is physically hazardous. 
9. The individual may continue substance use despite knowledge of having a persistent 
or recurrent physical or psychological problem that is likely to have been caused or 
exacerbated by the substance.
10. Tolerance, as defined by either of the following: 

Requiring a markedly increased dose of the substance to achieve the desired 
effect 

A markedly reduced effect when the usual dose is consumed. 
11. Withdrawal, as manifested by either of the following:

A syndrome that occurs when blood or tissue concentrations of a substance 
decline in an individual who had maintained prolonged heavy use of the 


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substance. Withdrawal symptoms vary greatly across the classes of substances, 
and separate criteria sets for withdrawal are provided for the drug classes. 

The substance (or a closely related substance) is taken to relieve or avoid 
withdrawal symptoms
A mild substance use disorder is suggested by the presence of two to three symptoms, 
moderate by four to five symptoms, and severe by six or more symptoms.

SAP_000.pdf: 
Clinical Development
EMA401
CEMA401A2202 / NCT03297294
A double-blind, placebo-controlled, randomized trial to 
determine the safety and efficacy of EMA401 100 mg b.i.d. 
in reducing 24-hour average pain intensity score in patients 
with painful diabetic neuropathy (EMPADINE)
Statistical Analysis Plan (SAP)
Author:
 (CRO), 
Document type:
SAP Documentation
Document status:
Amendment 1 Final
Release date:
18-Jun-2019
Number of pages:
36
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


Novartis
For business use only
Page 2
SAP
CEMA401A2202
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted (Current)
16-
Feb-
2018
Prior 
to 
FPFV
Creation 
of 
final version
N/A – First version
NA
18-Jun-
2019
Prior 
to DB 
lock
Creation 
of 
amendment 1

Region names have changed.

modified FAS population has been added

vitals signs and Friderica's correction 
have been removed from demographic 
summary

analyses 
of 
prior 
and 
concomitant 
medicationshave partly been revised and 
described in more detail. Analyses 
regarding prohibited medications have 
been removed

supplementary analyses regarding the 
primary endpoint have been reduced. The 
second supplementary analysis has been 
kept

covariate region has been removed from 
the ANCOVA model

Tipping point analysis has been removed. 
A sensitivity analysis on the modified full 
analysis set has been added. 

Supplementary analyses of responders 
have been reduced. BPI-SF, PGIC, worst 
NRS, 
ISI 
 
will 
be 
summarized 
descriptively 

Temporal items of NPSI will not be 
summarized descriptively. No summaries 
of the 5 dimensions of  NPSI  during the 
treatment withdrawal period will be 
provided
1.1, Study design, 
 
, 2.5.2 
Statistical, 
hypothesis, 
model, 
and 
method 
of 
analysis
                   2.2. 
Analysis 
sets 
  
2. 2.3
Patient 
disposition, demographics 
and 
other 
baseline 
characteristics
2.4
Treatments (study 
treatment, 
rescue 
medication, 
concomitant 
therapies)
2.5
Analysis 
of 
primary objective
2.7
Analysis 
of 
secondary 
efficacy 
objective(s)
2.8.1
Adverse  events 
(AEs)


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Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted (Current)

Analyses of AEs have been reduced. No 
subgroup analyses and analyses of drug-
related AEs will be provided

Dot plots and Kaplan Meier plots of AEs 
have been removed

Section has been removed. 

    Summary 
statistics 
of 
laboratory 
parameters, vital signs and ECG intervals 
will not be presented

    Shift tables of laboratory data have 
been removed

Bazett correction has been removed

For derivation of exclusion windows PD 
date can not be used
2.8.1.2 Liver events
2.8.3
Laboratory data
2.8.4
Other safety data
5.1.5 Prohibited medication 
for PDS


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Table of contents
Table of contents .................................................................................................................4
List of abbreviations............................................................................................................6
Amendment 1 ......................................................................................................................8
1
Introduction .........................................................................................................................9
1.1
Study design.............................................................................................................9
1.2
Study objectives and endpoints ...............................................................................9
2
Statistical methods.............................................................................................................11
2.1
Data analysis general information .........................................................................11
2.1.1
General definitions................................................................................11
2.2
Analysis sets ..........................................................................................................13
13
2.3
Patient disposition, demographics and other baseline characteristics ...................14
2.3.1
Patient disposition.................................................................................14
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................14
2.4.1
Study treatment / compliance................................................................14
2.4.2
Prior, concomitant and post therapies...................................................15
2.5
Analysis of the primary objective..........................................................................15
2.5.1
Primary endpoint...................................................................................15
2.5.2
Statistical hypothesis, model, and method of analysis..........................16
2.5.3
Handling of missing values/censoring/discontinuations.......................19
2.5.4
Supportive analyses...............................................................................20
2.6
Analysis of the key secondary objective ...............................................................20
2.6.1
Key secondary endpoint........................................................................20
2.6.2
Statistical hypothesis, model and method of analysis...........................20
2.7
Analysis of secondary efficacy objective(s)..........................................................21
2.7.1
Responder Analysis...............................................................................21
2.7.2
Other secondary efficacy objectives .....................................................21
2.8
Safety analyses.......................................................................................................22
2.8.1
Adverse events (AEs)............................................................................22
2.8.2
Deaths....................................................................................................23
2.8.3
Laboratory data .....................................................................................24
2.8.4
Other safety data ...................................................................................25
2.9
Pharmacokinetic endpoints....................................................................................26
2.10
PD and PK/PD analyses.........................................................................................26


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2.11
Patient-reported outcomes .....................................................................................26
2.12
Biomarkers.............................................................................................................26
26
26
2.14
Interim analysis - Safety........................................................................................27
3
Sample size calculation .....................................................................................................27
4
Change to protocol specified analyses ..............................................................................28
5
Appendix ...........................................................................................................................29
5.1
Imputation rules.....................................................................................................29
5.1.1
Study drug.............................................................................................29
5.1.2
Diagnosis of PDN .................................................................................29
5.1.3
AE date imputation ...............................................................................29
5.1.4
Concomitant medication date imputation .............................................29
5.1.5
Prohibited medication for PDN.............................................................29
5.2
AEs coding/grading ...............................................................................................30
5.3
Laboratory parameters derivations ........................................................................30
5.4
Derivation of index values and scores...................................................................30
5.4.1
11-point Numeric Rating Scale (NRS) .................................................30
5.4.2
Verbal Rating Scale (VRS) pain intensity ............................................31
5.4.3
Brief Pain Inventory- Short Form (BPI-SF)..........................................31
5.4.4
Patient Global Impression of Change (PGIC).......................................31
5.4.5
Neuropathic Pain Symptom Inventory (NPSI) .....................................31
5.4.6
Insomnia Severity Index (ISI)...............................................................32
32
32
32
32
33
5.4.12
Douleur Neuropathique 4 (DN4) ..........................................................34
5.5
Statistical models...................................................................................................35
5.5.1
Primary analysis....................................................................................35
5.5.2
Secondary analysis................................................................................35
5.6
Rule of exclusion criteria of analysis sets..............................................................35
6
References .........................................................................................................................36


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List of abbreviations
ACR
Albumin-Creatinine Ratio
AE
Adverse Event
ALP
Alkaline Phosphate 
ALT
Alanine Aminotransferase
ANCOVA
Analysis of covariance
AST
Aspartate Aminotransferase
ATC
Anatomic Therapeutic Chemical classification
b.i.d.
twice a day
BPI-SF
Brief Pain Inventory-Short Form
CRO
Contract Research Organization
 
CSR
Clinical Study Report 
DAR
Dose Administration Record
DMC
Data Monitoring Committee
DN4
Douleur Neuropathique en 4 Questions
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
e-diary
Electronic diary
EU
European Union
FAS
Full Analysis Set
FDA
Food and Drug Administration
GGT
gamma-glutamyltransferase
HIV
Human Immunodeficiency Virus
INR
International Normalized Ratio
IRT
Interactive Response Technology
ISI
Insomnia Severity Index 
J2R
Jump to reference
LFT
Liver function test 
LoE
Lack of efficacy
MAR
Missing at random
mFAS
Modified Full Analysis Set
MedDRA
Medical dictionary for regulatory activities 
NPSI
Neuropathic Pain Symptom Inventory 
NRS
Numeric Rating Scale
NSAID
Nonsteroidal Anti-inflammatory Drugs
PCR
Protein-Creatinine Ratio
PDN
Painful Diabetic Neuropathy


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PHN
Post-Herpetic Neuralgia
PK
Pharmacokinetics
PGIC
Patient Global Impression of Change
PRO
Patient Reported Outcome
 
QTc
Corrected QT interval
QTcB
Bazett QT correction formula
QTcF
Fridericia QT correction formula
SAE
Serious Adverse Event
RDO
Retrieved drop-out
SAF
Safety population
SSRI
Selective Serotonin Reuptake Inhibitor
TBL
Total bilirubin
TD
Study Treatment Discontinuation
TEAE
Treatment-Emergent Adverse Events
ULN
Upper limit of Normal
USM
Urgent Safety Measures
VRS
Verbal Rating Scale
WHO
World Health Organization 


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Amendment 1
This amendment of the statistical analysis plan (SAP) is largely based on changes induced  
due to the early termination of  the CEMA401A2202 study. 137 patients out of 400 planned 
patients have been randomized. As the number of patients included in the study isconsiderably 
reduced, an abbreviated Clinical Study Report (CSR) that still meets all requirements for 
reporting and disclosure of the demographics, primary endpoint, secondary endpoints and 
safety results to public registries will be created. 
The primary analysis on the change from baseline to Week 12 in the weekly mean of the 24-
hour average pain score will be performed as originally planned. Besides the primary 
estimand, which is of main clinical interest, the supplementary estimand, which provides 
insight into the magnitude of improvement in efficacy that might be achieved if all patients 
were able to take EMA401 as prescribed for 12 weeks, will be analysed. The other planned 
supplementary estimands will be dropped, as they are of minor interest in the situation with 
many study treatment discontinuations due to trial termination in the scope of the Urgent 
Safety Measures (USM). 
To support the primary analysis and to get an idea about the effect that might be achieved if 
the trial had not been terminated and if all patients had the chance to complete the Week 12 
assessment, a sensitivity analysis on a modified population will be performed. The modified 
full analysis set will include all patients who had a chance to complete the study before the 
termination date, i.e who had been randomized at least 12 weeks before study termination date.
Similar considerations were made for the key-secondary endpoint. 
Due to the considerably reduced number of patients who completed the study, only 
descriptive subgroup analyses will be provided. Moreover, the secondary endpoints will also 
be summarized descriptive only. 


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1
Introduction
This statistical analysis plan (SAP) describes all planned analyses for the Clinical Study 
Report (CSR) of study CEMA401A2202, a Phase 2, double-blind, placebo-controlled, 
randomized trial to determine the safety and efficacy of EMA401 in reducing 24-hour average 
pain intensity score in patients with painful diabetic neuropathy. 
The content of this SAP is based on the final version of protocol CEMA401A2202 (release 
date 15-Sep-2017). All decisions regarding final analysis, as defined in the SAP document, 
have been made prior to database lock and unblinding of the study data.
1.1
Study design
The study is interventional, randomized, parallel, placebo-controlled, double-blind treatment.
The study will consist of a Screening epoch (up to 4 weeks), a double-blind Treatment epoch 
(12 weeks), and a double-blind Treatment withdrawal epoch (1 week).

Patients will be randomized in a 1:1 ratio to treatment with placebo or EMA401 100 mg 
b.i.d.
Overall approximately 400 patients will be enrolled in the study (i.e. approximately 200 
patients will be enrolled in each treatment arm). 
At Week 12 (Visit 199), all patients who completed the 12-week double-blind Treatment 
epoch will enter the 1-week double-blind Treatment withdrawal epoch. The IRT system will 
indicate the unique medication number for the package of study drug to be dispensed to the 
patient during the double-blind Treatment withdrawal epoch. This medication number will 
correspond to the blinded withdrawal regimen assigned at Baseline.
Randomization will be stratified by region (America, Europe and Australia) and use of 
concomitant pain medication for PDN (yes/no) in order to achieve balance of treatment 
allocation within the stratification factors.
Primary objective of this study is to compare the efficacy of EMA401 vs. placebo in 24-hour 
average pain intensity score at Week 12, using an 11 point Numeric Rating Scale (NRS) by 
testing the superiority of EMA401 100 mg b.i.d. vs. placebo. 
1.2
Study objectives and endpoints
Table 1-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)

To compare the efficacy of EMA401 vs. 
placebo in 24-hour average pain intensity 
score at Week 12, using an 11 point 
Numeric Rating Scale (NRS) by testing 
the superiority of EMA401 100 mg b.i.d. 
vs. placebo
Endpoint(s) for primary objective(s) 

Change in weekly mean 24-hour 
average pain score (using the 11 point 
NRS) from Baseline to Week 12
     Key Secondary Objective(s)
Endpoint(s) for key secondary objective(s)


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Objective(s)
Endpoint(s)

To compare the efficacy of EMA401 vs. 
placebo in Neuropathic Pain Symptom 
Inventory (NPSI) total score by testing the 
superiority of EMA401 100 mg b.i.d. vs. 
placebo
      

Change in Neuropathic Pain Symptom 
Inventory (NPSI) total score from 
Baseline to Week 12
Secondary Objective(s)

To evaluate the efficacy of EMA401 
compared to placebo, as measured by 
the Brief Pain Inventory-Short Form (BPI-
SF) interference total score at Week 12

To evaluate the efficacy of EMA401 
compared to placebo, as measured by 
the weekly mean of the 24-hour worst 
pain intensity score, using an 11-point 
Numeric Rating Scale (NRS) at Week 12

To evaluate the efficacy of EMA401 
compared to placebo, on the Patient 
Global Impression of Change (PGIC) at 
Week 12

To evaluate the proportion of EMA401 
patients achieving a ≥ 30% and a ≥ 50% 
reduction in weekly mean 24-hour 
average pain intensity score using the 
NRS compared to placebo (i.e., 
responder rates) at Week 12

To evaluate the effect of EMA401 
compared to placebo on the Insomnia 
Severity Index (ISI) at Week 12

To evaluate the safety and tolerability of 
EMA401 compared to placebo in PDN 
patients, as measured by treatment 
emergent adverse events (TEAEs), 
adverse events (AEs) leading to study 
drug discontinuation and serious adverse 
events (SAEs) throughout the study

To evaluate the pharmacokinetics (PK) of 
EMA401 and exposure-response 
(decrease in pain intensity) relationship 
for EMA401 throughout the study

To evaluate the proportion of patients 
who need rescue  medication separately 
for the double-blind Treatment epoch and 
Treatment withdrawal epoch an the time 
first intake of rescue medication during 
the double-blind Treatment epoch.
Endpoint(s) for secondary objective(s)

Change in BPI-SF interference total 
score from Baseline to Week 12

Change in weekly mean of the 24-hour 
worst pain score, using an 11-point 
NRS, from Baseline to Week 12

PGIC at end of study

Proportion of patients meeting 
responder criteria from Baseline to 
Week 12

Change in ISI from Baseline to Week 12

Number and severity of treatment 
emergent adverse events and the 
frequency of adverse events leading to 
discontinuation. Number of serious 
adverse events.

Plasma pharmacokinetics of EMA401 
will be characterized by population non-
linear mixed effects modeling 
techniques

Proportion of patients who need rescue 
medication separately for the double-
blind Treatment epoch and Treatment 
withdrawal epoch, the time to first intake 
of rescue medication during the double-
blind Treatment epoch


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2
Statistical methods
2.1
Data analysis general information
The statistical analysis of the study will be performed by 
, a designated 
Contract Research Organization (CRO).
SAS version 9.4 will be used to perform all data analyses and to generate tables, figures and 
listings.
Qualitative data (e.g., gender, race, etc.) will be summarized by means of frequency tables; a 
missing category will be included as applicable. Percentages will be calculated using the 
number of patients in the relevant population or subgroup as the denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive 
statistics, i.e., n, mean, standard deviation (SD), first quartile (Q1), median, third quartile (Q3), 
minimum, and maximum.
No interim analysis will be performed for the efficacy evaluation. An external Data 
Monitoring Committee (DMC) will be established with the primary goal to perform an 
ongoing review of safety data.
2.1.1
General definitions 
Investigational drug and study treatment
The investigational drug, EMA401, will be provided as capsules. The following oral dosage 
strengths will be used:  50 mg.
EMA401 and placebo will be identical in appearance . 
For all treatment groups, each dose will be self-administered orally as two capsules with a full 
glass of non-carbonated water twice daily, consisting of a morning dose and an evening dose.
The following abbreviated treatment groups, independently of cohort number, will be used as 
the headers in the tables for the double-blind Treatment epoch:


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•
Placebo b.i.d.
•
EMA401 100 mg b.i.d.
The following abbreviated treatment groups will be used as the headers in the tables for the 
double-blind Treatment withdrawal epoch:
•
Placebo b.i.d. -> Placebo b.i.d.
•
EMA401 100 mg b.i.d. -> EMA401 100 mg b.i.d.
•
EMA401 100 mg b.i.d. -> Placebo b.i.d.
Date of first and last administration of study drug
The date/time of first administration of study drug is defined as the first date/time of 
administration as per Dosage Administration Record eCRF. The date/time of last 
administration of study drug is defined as the last date/time when a dose is administered as per 
Dosage Administration Record eCRF. This value has to be compared to the "End of study 
treatment" as recorded on the corresponding eCRF. In case of different dates, the latest will be 
used as treatment end.
For subjects with missing first dose date, the randomization date will be considered as 
reference start date.
Study day
The study day, describes the day of the event or assessment date, relative to the reference start 
date which is the date of first administration of study drug. 
The study day is defined as:

The date of the event (visit date, onset date of an event, assessment date etc.) − reference 
start date + 1 if event is on or after the reference start date.

The date of the event (visit date, onset date of an event, assessment date etc.) − reference 
start date if event precedes the reference start date.
Baseline
For safety and efficacy evaluations, the last available assessment (either scheduled or 
unscheduled) before the first administration of study drug and after the screening visit is 
defined as “baseline” assessment. If patients have no value prior to first administration of 
study drug the baseline result will be missing.
Post-baseline
For safety and efficacy evaluations all assessments after the first administration of study drug 
are defined as “post-baseline” assessment. 
Change and percent change from baseline for continuous parameter.
Change from baseline and percent change from baseline will only be summarized for subjects 
with both baseline and post-baseline values and will be calculated as:


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change from baseline = post-baseline value – baseline value 
percent change from baseline = 100 * change from baseline / baseline value.
For summary statistics the raw values (and not imputed values) will be used.
Study periods and date of last contact
The overall observation period will be divided into three mutually exclusive segments:

A screening phase of up to 4 weeks 

A double-blind treatment phase starting with first dose of study drug at Visit 101 and 
covering 12 weeks of treatment. 

A double-blind treatment withdrawal phase for one week starting after 12 weeks of 
treatment with Visit 201.
Inferential analysis will be performed on either only treatment phase or on both treatment and 
treatment withdrawal phase separately. It is never the case that both phases will be pooled 
together.
Visit windows
Visit windows will be applied for all measurements except NRS scores. The definition of 
seamless windows can be found in the following 
 location
 
 
The most recent version of this document available 
before the database lock will be used to determine the visit windows for baseline and post 
baseline visits and treatment discontinuation visit mapping.
2.2
Analysis sets
The following analysis populations will be used for analysis.

The Enrolled population will include all patients who were enrolled into the study.

The Full Analysis Set (FAS) comprises all patientsto whom the study treatment has 
been assigned. Following the intention-to-treat principle, patientswill be analyzed 
according to the treatment assigned to at randomization. Mis-randomized patients will 
be excluded from the FAS.

The modified Full Analysis Set (mFAS) will include all patients who could have 
completed Week 12 by the study termination date. That means, all patients which were
randomized at least 12 weeks prior to 25-Feb-2019 will be included. 

The Safety population (SAF) will include all patients who took at least one dose of 
study medication. Patients will be analyzed according to treatment received. 
The primary efficacy analysis will be performed on the FAS.


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2.3
Patient disposition, demographics and other baseline 
characteristics
Patient demographic and baseline characteristic data to be collected on all patients include: 
year of birth, age, sex, race, ethnicity, relevant medical history/current medical condition 
present before signing informed consent, height, weight, body mass index (BMI), prior 
concurrent medications, NRS at screening, 
. 
In addition, the following categorizations of continuous variables will be done: 

Age into 18-64 years, 65- 84 years, >= 85 years; 

Duration of PDN into < 1 year, > 1 - 5 years, > 5 - 10 years, > 10 - 15 years, > 15 - 20 
years, and > 20 years; 
Duration of PDN is calculated from the start date of PDN as reported on the eCRF until the 
date of Visit 1.
Demographic and background information will be summarized the FAS population using 
frequency distributions (for categorical variables) and descriptive statistics of mean, standard 
deviation, minimum, median and maximum (for continuous variables). Relevant medical 
history/current medical conditions will be summarized by system organ class and preferred 
term of the MedDRA dictionary.
2.3.1
Patient disposition
For each study phase (i.e., Screening, Treatment epoch and Treatment withdrawal epoch), the 
overall number of patients who entered, completed, and discontinued that phase will be 
summarized including the reasons for discontinuation. The summary of the screening phase 
will be done for the Enrolled set, for the Treatment and Treatment withdrawal epoch. The 
analyses will be based on the FAS population.
Patients who prematurely discontinue the study medication will be listed along with the 
reasons for discontinuation.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Duration (days) of exposure to double-blind study medication will be summarized by 
treatment group and treatment phase (Treatment epoch and Treatment withdrawal epoch 
seperately). In addition, the number of subjects with exposure of at least certain time 
thresholds (any exposure, >= 1 week, >= 2 weeks, >= 4 weeks, >= 6 weeks, >= 8 weeks, >= 
10 weeks, >= 12 weeks) will be displayed. 
Compliance will be recorded as source documentation only and not analysed. 


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The analyses will be based on the SAF population.
2.4.2
Prior, concomitant and post therapies
The number and percentage of patients who used concomitant medications (coded by World 
Health Organization [WHO] Anatomic Therapeutic Chemical classification [ATC]) will be 
presented by treatment group and treatment phase (Treatment epoch and Treatment 
withdrawal epoch separately). 
Separate tabulations will be provided for medications taken prior to start of study medication 
and while a patient is on study drug (i.e. concomitant, between the first day on study drug and 
the day of last visit). In addition, the PDN medications recorded on the Screening PDN 
Medication Log will be summarized using a frequency table for each medication. The primary 
reason for treatment failure will also be tabulated.
Prior medications are defined as drugs taken and stopped prior to first dose of study treatment. 
For the Treatment epoch concomitant medications are defined as any medication given at 
least once between the day of first dose of study treatment and the end of the treatment epoch , 
including those which were started pre-baseline and continued into the treatment period. For 
the Treatment withdrawal epoch concomitant medications are any medications given at least 
once between the day of first dose of study medication in the treatment withdrawal epoch, and 
the end of the epoch, including those which were started pre-baseline or in the treatment 
period epoch, and continued into the treatment withdrawal epoch.
Non-drug therapies will be listed.
2.4.2.1
Rescue medication
The number and percentage of patients who received rescue medication (Acetaminophen/ 
Paracetamol as reported on the diary page) will also be summarized by treatment and by visit 
during the double-blind treatment and treatment withdrawal period separately. Visit mapping 
will be done according to the visit window strategy document (see Section 2.1.1). The dose 
received will be listed.
Analysis of time to first use of rescue medication will be performed using Kaplan-Meier 
curves.
Number of patients with at least one intake will also be summarized.
2.5
Analysis of the primary objective
2.5.1
Primary endpoint
The primary efficacy variable will be the change from baseline to Week 12 in the weekly 
mean of the 24-hour average pain score, using an 11-point Numeric Rating Scale (NRS).
The NRS is captured in the e-diary daily by the patient as the intensity of pain in the past 24 
hours. To calculate the weekly mean pain intensity score for a given week, the daily pain 


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intensity scores collected by the patient in the e-diary during the 7 days of that week will be 
averaged.
The primary population will be the FAS.
2.5.2
Statistical hypothesis, model, and method of analysis
The aim is to estimate the treatment effect of the investigational drug (EMA401) compared to 
placebo, for the target population on the primary pain parameter. The definition and the 
justification of the corresponding primary estimand, as well as the definition of the 
supplementary and secondary estimands for NRS are detailed in the Estimand Charter. The 
most 
recent 
version 
of 
the 
Estimand 
charter 
stored 
at 
 
available before the database lock will be used as reference.
The primary estimation method is based on an Analysis of Covariance (ANCOVA) model
including treatment, sex, use of concomitant pain medication for PDN (yes/no) as factors and 
age and baseline (mean pain intensity) score as covariate. The analysis will account for
different intercurrent events (i.e. events that occur post-randomization) as follows:

Changes in doses of concomitant medication for PDN: Efficacy observations collected 
during the period of changes in doses of concomitant medication for PDN (compared to 
baseline) and the 3-days thereafter will be excluded, since they are considered affected by 
the concomitant medication dose change. The resulting missing data after this step will be 
imputed via multiple imputation method  using the Missing at random (MAR) assumption.

Intake of rescue medication: Efficacy data collected during intake of rescue medication 
will be used for analysis. 

Intake of prohibited medications with potential confounding effect prior to study 
treatment discontinuation: The prohibited medications with a potential confounding 
effect are defined as those listed in Table 2-1 requiring study treatment discontinuation. A 
list of prohibited medications is available at the following 
 location
 
. Efficacy observations collected during the 
intake period of such prohibited medications and the 7-days thereafter will be excluded, 
since they are considered affected by the prohibited medication intake. The resulting 
missing data after this step will be imputed via multiple imputation method  using the 
MAR assumption.
Table 2-1
Prohibited medication
Medication
Prohibition period
Action taken for study 
treatment
Prohibited prior to Screening and throughout study
Any skeletal muscle relaxant (e.g. 
baclofen, orphenadrine, 
methocarbamol)
2 weeks prior to Screening 
and after Screening
None
Mexiletine
2 weeks prior to Screening 
None


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Medication
Prohibition period
Action taken for study 
treatment
and after Screening
Dextromethorphan
2 weeks prior to Screening 
and after Screening
None
Memantine
2 weeks prior to Screening 
and after Screening
None
Alpha-lipoic acid
2 weeks prior to Screening 
and after Screening
None
Other anti-epileptic drugs (e.g. valproic 
acid, carbamazepine, phenytoin)
2 weeks prior to Screening 
and after Screening
Discontinue study treatment 
upon 2nd episode of 
medication use
Antiviral medications (e.g. valacyclovir, 
acyclovir, amantadine, anti-HIV)
2 weeks prior to Screening 
and after Screening
None
High dose capsaicin patch (8%)
6 months prior to Screening 
and after Screening
Discontinue study treatment 
Prohibited after Screening and throughout study
Oral or injectable steroids
After Screening
Discontinue study treatment 
upon 2nd episode of 
medication use
Monoamine oxidase inhibitors or any 
other antidepressants (except stable 
dosage of SSRI)
After Screening
Discontinue study treatment 
upon 2nd episode of 
medication use
Antipsychotic or neuroleptic medications
After Screening
Discontinue study treatment 
upon 2nd episode of 
medication use
Cannabinoids (e.g. marijuana)
After Screening
Discontinue study treatment 
upon 2nd episode of 
medication use
Prescribed opioids, including codeine
After Screening
Discontinue study treatment 
upon 2nd episode of 
medication use
Prescription systemic pain medication,
or topical treatment for PDN, including 
lidocaine plaster 
After Screening
Discontinue study treatment 
upon 2nd episode of 
medication use
Nonsteroidal Anti-inflammatory Drugs 
(NSAIDs) or any other over-the-counter 
pain medications
After Screening
None
Any non-drug therapies that could 
modulate the perception of pain either 
directly or indirectly (i.e. transcutaneous 
electrical nerve simulation (TENS) or 
surgery)
After Screening
Discontinue study treatment 


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Medication
Prohibition period
Action taken for study 
treatment
Other medications that may have 
potential drug-drug interactions (e.g. 
felodipine, eplerenone, nisoldipine, 
ticagrelor, tacrolimus, avasimibe, 
rifampin, cyclosporine, gemfibrozil, 
clarithromycin, St. John's Wort; oral, 
injected or implanted hormonal methods 
for contraception)
After Screening
None
Retrieved drop-out (RDO) patients are defined as patients who discontinue study treatment 
and decide to remain in the study by following an abbreviated schedule of assessments.
These patients must continue to adhere to protocol requirements (see respective
protocol Table 6-2). The design feature of retrieved drop-outs, considered in order to
minimize the occurrence of missing data on primary pain parameter, is exploited for the 
statistical analysis as follows:

Permanent discontinuation of study treatment due to AE, lack of efficacy (LoE) and 
use of prohibited medication: If retrieved drop-out data are available, these will be used 
for analysis. If no data was retrieved after study treatment discontinuation, missing data 
will be multiply imputed based on placebo arm data, i.e. “jump to reference” (J2R) 
assumption for the EMA401 arm, missing at random assumption for placebo arm 
(Carpenter, Roger, and Kenward 2013). Of note,  alternatively one could build the 
imputation model based on the RDO data, however, we expect sparse RDO data which 
will likely hinder us to build an imputation model. More details on the imputation model 
are specified in Section 5.

Permanent discontinuation of study treatment due to other reasons than AE, LoE 
and use of prohibited medication (including discontinuation due to USM): If efficacy
data collected after study treatment discontinuation are available (retrieved drop-out), then 
the retrieved drop-out data will be excluded and missing data after study treatment 
discontinuation will be imputed via multiple imputation method using the MAR
assumption. 
The multiple imputations will be carried out on the weekly mean pain score. Details on 
multiple imputation can be found in Section 5 of this document.
The primary objective will be achieved if the EMA401 100 mg b.i.d. dose is statistically 
significant versus placebo in terms of the primary efficacy variable after multiplicity 
adjustment. To preserve the family-wise error rate at 2.5%  level when comparing the 
EMA401 100 mg b.i.d. dose versus placebo on the primary and key secondary endpoints (see 
Section 2.6), statistical testing will be carried out using the following sequentially rejective, 
weighted Bonferroni-type test using the graphical approach (Bretz et al 2009) mentioned in 
Figure 2-1.
Figure 2-1  Sequentially rejective, weighted Bonferroni type test using the graphical approach


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In the graphical testing procedure given in Figure 2-1, H1 and H2 denote the two null 
hypotheses of no treatment difference of EMA401 100 mg b.i.d. vs. placebo for the primary 
efficacy variable NRS and key secondary efficacy variable NPSI total score. The 
corresponding alternative hypotheses will be EMA401 100 mg b.i.d. is superior to placebo for 
the NRS and NPSI respectively. In the Figure 2-1 the number in the circle represents the 
proportion of alpha level to be assigned at the initial stage among the two null hypotheses.The 
direction and the number in the arrow represent the proportion of the alpha to be propagated 
to the next hypothesis. Initially, H1 will be tested at the full alpha level (1 sided) 0.025. If H1 
is rejected then H2 will be tested also at the full alpha level (1 sided) 0.025.
To facilitate the interpretation of the estimated treatment difference a standardized effect size
will be provided and will be calculated based on the results of the ANCOVA analysis.
The same ANCOVA model will be applied at the visits prior to Week 12. Multiplicity 
adjustment at visits prior to Week 12 will not carried out. 
Summary statistics for absolute values and change from baseline by treatment and visit will be 
provided for the original measurements (i.e. for the raw data prior to multiple imputation) of 
the primary efficacy variable. If a measurement is collected under the period of use of 
prohibited medications or the 7 days thereafter, it will be excluded from the summaries. 
 
 
2.5.3
Handling of missing values/censoring/discontinuations
Handling of missing daily pain score values within a week (within-week imputation)
The 24-hour average pain score is measured daily for seven consecutive days prior to 
randomization and then every day through the end of the study. At each week, the weekly 
mean of the seven 24-hour average pain assessments will be calculated. 
The weekly mean will be calculated based on the available assessments. If only one 
measurement is available, the mean will be based on that value. Assessments made under 
treatment will not be mixed up with RDO data. If there is at least one value among the seven 
values in one week which is on-treatment, the mean will be calculated based on that.
Handling of missing weekly mean pain score values (weekly mean imputation)
The multiple imputation for the primary variable will be carried out on the weekly mean pain 
score. 
The imputation procedure related to primary analysis is described in Section 2.5.2 while the 
imputation procedure for the supplementary analyses is included in Section 2.5.4. The details 
of these imputation rules are specified in the Estimand Charter and in Section 5.
For all analyses, imputation of intermittent missing observations before treatment 
discontinuation will be carried out following a MAR mechanism for all treatment arms.


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2.5.4
Supportive analyses
2.5.4.1
Supplementary analysis
The following supplementary analysis to the primary analysis for NRS will be performed on 
the FAS population. 
to quantify the treatment effect of the investigational drug compared to placebo, that would 
have been observed had all patients remained on their assigned treatment for 12 weeks. The 
handling of post randomization events will be same as for the primary analysis, except that
missing data after discontinuation for any reason will be imputed using the MAR assumption. 
The supplementary estimand corresponding to this supplementary analysis is described in 
detail in the Estimand Charter.
2.5.4.2
Sensitivity analysis
A sensitivity analysis will be performed on the mFAS population using the same ANCOVA 
model as for the primary analysis.
2.6
Analysis of the key secondary objective
2.6.1
Key secondary endpoint
The key secondary efficacy variable will be the change from baseline to Week 12 in the 
Neurophathic Pain Symptom Inventory (NPSI) total score which is calculated as the sum of 
10 descriptors outcome measure out of the 12 items measured in the NPSI.
The key secondary endpoint will be evaluated for the FAS.
2.6.2
Statistical hypothesis, model and method of analysis
To compare the efficacy of EMA401 over placebo in the NPSI total score the null hypothesis 
of superiority of EMA401 over placebo will be tested. The definitions of the estimands for the 
key secondary variable NPSI will also be detailed in an Estimand Charter.
The estimation of the treatment difference and missing data handling will be performed using 
the method of analyses mentioned for the primary analysis for NRS. Post randomization 
events will be handled in the same way as in the primary analysis for NRS. 
The key secondaray objective will be achieved if the EMA401 100 mg b.i.d. dose is 
statistically siginificant versus placebo in terms of NPSI total score after multiplicity 
adjustment. To preserve the family-wise error rate at the 2.5% level when comparing the 
EMA401 100 mg b.i.d. dose versus placebo on the two endpoints NRS and NPSI, statistical 
testing will be carried out using the graphical testing procedure as explained in Section 2.5.2. 
The same ANCOVA model will be applied at the visits prior to Week 12. Multiplicity 
adjustment at visits prior to Week 12 will not carried out. 
The same supplementary analysis as for the primary endpoint will be performed.
Summary statistics by treatment and visit will be provided for the key secondary endpoint.


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2.7
Analysis of secondary efficacy objective(s)
The following secondary efficacy variables will be evaluated for the FAS:
2.7.1
Responder Analysis
Responder analyses (based on at least a 30%, 50% improvement from baseline on NRS) will 
be performed in order to facilitate the interpretation of the results of the primary and 
supplementary analysis from a clinical relevance perspective. These analyses will be 
performed on the FAS population. One secondary estimand is considered, together with one 
supplementary estimand. 
The secondary estimand and the supplementary estimand to the secondary estimand differ 
from the primary and supplementary estimand in two ways:

First, the variable of interest is the responder status in NRS score, with response status 
corresponding to at least a 30% (50%) improvement in pain from baseline.

Second, the measure of intervention effect is the odds ratio of the proportions of 
responders between investigational drug and placebo.
The other features characterizing these responder analyses are exactly the same as for the 
primary and the t supplementary analysis, respectively. 
From an analysis point of view, the responder status for each patient will be calculated on the 
continuous weekly score measurements after missing data are multiply imputed based on the 
approach specified corresponding to the primary analysis and the supplementary analyses. If 
the patient is a completer but week 12 measurement is affected by the changes in doses of 
concomitant medication for PDN or the use of prohibited medication then the responder 
criteria will be defined based on the multiply imputed values by MAR. The resulting 
responder variable will be analyzed using a logistic regression model including all 
randomized patients and adjusting for the same covariates as the ANCOVA model for the 
primary analysis.
From an analysis point of view, the resulting responder variables will be analyzed using a 
logistic regression model including all randomized patients (FAS population) and adjusting 
for the same covariates as the ANCOVA model for the primary analysis. Odds ratios will be 
estimated along with their 95% CIs.
The responder analyses will be performed for each visit, with the obvious modification in the 
definition for the week of interest. 
2.7.2
Other secondary efficacy objectives
1. BPI-SF interference total score will be summarized descriptively by treatment and visit.. 
2. Weekly mean of the 24-hour worst NRS pain score, using an 11-point Numeric Rating 
Scale (NRS). This variable will be summarized descriptively by treatment and visit.


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3. Number of patients in each level of PGIC at end of study treatment will be presented by 
treatment. PGIC classification will also be combined into two categories: Either a "very 
much improved" or a "much improved" reported, and the five remaining categories.  
4. Insomnia Severity Index (ISI) will be summarized descriptively by treatment and visit. 
5. The proportion of patients who need rescue medication (at each visit and at least once 
during the study) will be evaluated separately for the double-blind Treatment epoch and 
Treatment withdrawal epoch. 
6. The Kaplan-Meier estimates of the proportion of patients with rescue medication intake 
during the double-blind Treatment epoch, along with the associated 95% confidence 
intervals using the Greenwood’s formula will be provided.
2.8
Safety analyses
Safety analyses will be conducted using the safety (SAF) population. Patients will be analysed 
by the actual treatment they received. All the safety analyses including AEs, vital signs, 
laboratory parameters, ECGs  
 will be reported for double-blind treatment period 
as well as for the treatment withdrawal period separately. 
2.8.1
Adverse events (AEs)
Treatment-emergent adverse events (TEAEs) are defined as any adverse events that develops 
after initiation of study treatment until the end of study visit or any event already present that 
worsens following exposure to the study treatment. 
If an adverse event starts at the date of week 12 visit it should be allocated to the treatment 
epoch and not to the treatment withdrawal epoch. Adverse events reported 21 days after end 
of study date in the scope of USM will not be included in the summary tables, but will be 
listed.
TEAEs will be summarized (number of cases as a percentage of number at risk) by treatment 
group separately for Treatment epoch and Treatment withdrawal epoch. Number and 
percentage of patients with TEAE will be summarized by primary system organ class and 
preferred term for each treatment group during the double-blind Treatment epoch and during 
the double-blind Treatment withdrawal epoch.Severity will be classified as “mild”, “moderate” 
and “severe”. Serious TEAEs, TEAEs by maximum severity and TEAEs leading to premature 
discontinuation from study drug will be presented in a similar format as adverse events. 
Additionally, a listing of patients with TEAE will be presented. Drug abuse-related adverse 
events (identified using a pre-specified search criterion) will be summarized during the 
double-blind Treatment epoch. To assess the potential for withdrawal effect, drug abuse-
related adverse events will be summarized for the double-blind Treatment withdrawal epoch.
The following additional analysis will be performed.

Analysis of treatment-emergent adverse events with onset date before 25-Feb-2019
For rash adverse events, following details will be listed:

Laterality and location of rash


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
Did the subject start any new topical non-pharmaceutical products within the last 14 days 
prior to the start of rash?

Topical Non-pharmaceutical Products related to the event of rash including soap, 
detergent, perfume, cologne and lotion.

Were there any additional contributing factors that may have led to the rash?

Did the dermatologist agree with the event?

Additional investigation performed to diagnose that event: yes, no
       For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on <on-
treatment/treatment emergent> adverse events which are not serious adverse events with an 
incidence greater than X% and on <on-treatment/treatment emergent> serious adverse events 
and SAE suspected to be related to study treatment will be provided by system organ class 
and preferred term on the safety set population.
       If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted otherwise.
       For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and 
SAEs irrespective of study treatment relationship will be provided by SOC and PT.
2.8.1.1
Adverse events of special interest / grouping of AEs
Allergic dermatitis, elevation in hepatic enzymes and neutropenia are the potential risks 
related to EMA401. Dizziness, headache, nausea, pre syncope and upper respiratory tract 
infections are the expected events related to EMA401. In addition suicidality and drug abuse 
related events will be adverse events of special interest. The search criterion for each of these 
risks and events will be defined based on MedDRA and on the Program Compound Case 
Retrieval 
The most recent Compound Case Retrieval Strategy (CRS) at the time of database 
lock will be used to determine the MedDRA search criteria to identify events of special 
interests. 
2.8.2
Deaths
The primary reason for death will be summarized by system organ class and preferred term. 
All deaths will be listed. 


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2.8.3
Laboratory data
The summary of laboratory evaluations will be presented for three groups of laboratory tests: 
Hematology, Chemistry and Urinalysis.
The number and percentage of patients with newly occurring or worsening laboratory 
abnormalities meeting the clinically notable criteria  at any post-baseline visit  will be 
summarized by laboratory parameter. For a patient to meet the criterion of a newly occurring 
clinically notable value, the patient needs to have a baseline value that is not clinically notable 
for that parameter. For a patient to meet the criterion of a worsening clinically notable value, 
the patient needs to have a baseline value that is clinically notable and also have a worse post-
baseline value. For patients with missing baseline value, any post-baseline notable value will 
be considered as newly occurring.
Incidence of newly occurring liver enzymes abnormalities and renal events will be 
summarized using the number and percentage of patients by treatment group. Notable 
laboratory values will be listed.
Laboratory assessements performed at the follow-up visits in the scope of the USM will not 
be included in the summaries but will be listed. That means, assessments reported 21 days 
after end of study date will not be included in the summary tables. 
Liver function tests (LFT)
To evaluate potential drug-induced liver injury, the number and percentage of patients with 
newly occurring or worsening abnormalities in liver function tests at any time post-baseline 
will be summarized by treatment. The same approach as for notable laboratory values will be 
used to define newly occurring or worsening abnormalities in liver function tests.
When a criterion contains multiple laboratory parameters, the criterion will only be 
considered to have been met when all conditions occur at the same time (i.e., within the same 
sample). A case where all criteria are met at a post-baseline time point will be considered as 
newly occurring if the criteria are not met at baseline and will be considered as worsening if 
the criteria are met at baseline and at least one component is worsening from baseline 
irrespective of whether the other(s) are better.
Listings of patients with clinically notable LFT values will be provided.
The same analysis will be repeated for the Treatment withdrawal epoch.


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2.8.4
Other safety data
2.8.4.1
ECG 
The (uncorrected) QT interval will be corrected according to Fridericia’s formulae. The 
incidence rates of newly occurring or worsening clinically notable ECG abnormalities will be 
summarized. The same approach as for notable laboratory values will be used to define a 
newly occurring notable QTc value and a worsening notable QTc value. Notable ECG values 
will be listed. 
Notable criteria are: 

QTcF > 500 msec or

increase from baseline > 60 msec 
If the single ECG shows a QTcF > 500 ms (males or females), 2 additional ECG replicates 
should be recorded to confirm the safety findings and copies forwarded to the central ECG 
laboratory for assessment. The results from those triplicate ECGs will be averaged and 
analysed as one value for summary and notable tables.
2.8.4.2
Vital signs
The number and percentage of subjects with clinically notable vital signs will be presented.
Notable vital sign values will be listed. 
Notable criteria are: 
Variable
Criterion value
Change relative to baseline
Heart rate/pulse
120 bpm
50 bpm
and an
and a
increase of ≥ 15 bpm
decrease of ≥ 15 bpm
Systolic blood pressure
180 mm Hg
90 mm Hg
and an
and a
increase of ≥ 20 mm Hg
decrease of ≥ 20 mm Hg
Diastolic blood pressure
105 mm Hg
50 mm Hg
and an
and a
increase of ≥ 15 mm Hg
decrease of ≥ 15 mm Hg
Weight
Baseline weight (kg)
and an
and a
increase of ≥ 7%
decrease of ≥ 7%
bpm= beats per minute
Data of subjects with newly occurring notable vital signs abnormalities will be listed in an 
additional listing.
2.8.4.3
Physical examination
Physical examination including examination of skin will be source documentation only.
 
 


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2.9
Pharmacokinetic endpoints 
Scatter plots of EMA401 plasma concentrations will be displayed in linear and 
semilogarithmic view in a CSR addendum or in a separate report.
2.10
PD and PK/PD analyses
Evaluation of effect of EMA401 exposure on efficacy variables (e.g. change from baseline of 
pain score), via the development of a continuous descriptive Pharmacokinetics/
Pharmacodynamics (PK/PD) was planned in the protocol. All population PK/PD analyses and 
simulations were to be carried out using a non-linear mixed-effects modelling approach. Due 
to early study termination the planned model based exposure-response analysis will not be 
performed and replaced with a graphical assessment of the exposure-response relationship.
This will be reported in a separate report.
2.11
Patient-reported outcomes
Please refer to efficacy analysis for details on all Patient Reported Outcomes (PRO).
2.12
Biomarkers
Not applicable.


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2.14
Interim analysis - Safety
The DMC will review cumulative safety data, including patient narratives for deaths, serious 
adverse events (SAEs), discontinuations due to adverse events and cases of interest (allergic 
dermatitis, and clinically significant abnormal hepatic and hematology values). 
The details of the analysis required for DMC will be specified in a separate DMC analysis 
plan and not repeated here in detail. 
3
Sample size calculation
The calculation of power for the testing procedure mentioned in Figure 2-1 is based on the 
following assumptions:

The treatment difference of 100 mg b.i.d. vs. placebo was assumed as 0.7, 0.8 and 0.9
      points, for the primary efficacy variable (weekly mean of the 24-hour average pain
score). A treatment difference of 0.7 points was observed for the 100 mg b.i.d. dose vs. 
placebo for weekly mean of the 24-hour average pain score (NRS) in the Study
EMA401-003 during a 4-week treatment period. The standard deviation is 2.6 points
            (based on data from pregabalin historical trials – see FDA Approval Package Medical
            Review, 2004) is assumed for the primary efficacy variable. In Study EMA401-003 in  
            PHN patients, a standard deviation of approximately 2.0 points was observed. A   
            slightly higher value of 2.6 has been chosen to account for a possible higher variability
            due to a higher number of centers and due to multiple imputations (as opposed to
            single imputation) in the analysis. It is also assumed that the same standard deviation
            holds for the PDN population.

Treatment differences of 5 points for Pregabalin and 10 points for Duloxetine on NPSI
total score were observed via an indirect comparison using the results from Tesfaye
(2013) which is an active control study (Pregabalin vs Duloxetine) and Kalliomäki
(2013) which is a placebo controlled study (AZD2423 vs placebo). The standard
deviation was derived as 16 points using the results from Kalliomäki (2013). A
correlation of approximately 0.2 was observed between the baseline scores of NRS
and NPSI total score in Freeman et al (2014). The power of the study was calculated
assuming correlation coefficient values of 0 and 0.2. Since the power values obtained
for correlation values of 0.2 and 0 are similar, in a conservative scenario the results
reported herein are for correlation value of 0.     
                                                                                                                                      
Since the NPSI has not been studied in the EMA401-003 study, to mitigate the risk of
uncertainty on the value of treatment difference and standard deviation, the effect size  
(treatment difference/ standard deviation) of NPSI total score has been considered for   
the calculation of power. The power of the study was calculated for different effect
            sizes ranging in 0.1, 0.5 for NPSI total score corresponding to 100 mg.
Under the assumptions of a 0.8 point treatment difference between 100 mg b.i.d. and placebo,
a standard deviation as 2.6 for the primary efficacy variable and an effect size of 0.4 for 100


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mg b.i.d. for the key secondary variable, N=200 patients per treatment arm will provide
approximately 85% power to show that 100 mg b.i.d. is statistically significant over placebo
for the primary efficacy variable, using the testing procedure mentioned in Figure 2-1. The
power of showing the statistical significance of 100 mg b.i.d. dose in terms of the key
secondary variable will be 84% under the same scenario. If we assume the treatment
difference of 0.7 for the NRS as observed in the 4-week PoC study and the effect size for
NPSI as 0.35, then the power for the primary objective will be 77% and that for the key
secondary objective will be 72%. If the treatment difference between 100 mg b.i.d. and
placebo is 0.9 for the NRS, and effect size is 0.45 for 100 mg b.i.d. for the NPSI, the power
increases to 94% for the primary objective. The corresponding power for the key secondary
objective increases to 93%.
4
Change to protocol specified analyses
An additional population, the mFAS population, has been defined.
The following analyses were specified in the protocol but will not be performed due the early 
termination of study:
- first and third supplementary analysis to the primary analysis
- tipping point analysis
- supplementary responder analyses 
- ANCOVA analyses for BPI-SF, worst NRS pain score, ISI, 
- proportional odds model for PGIC
- analyses regarding maintenance effect of EMA401 over placebo
- time to "sustained" pain reduction
- Apart from analyses of  clinical abnormalities summaries of laboratory data, vital signs and 
ECG intervals have been removed
- Shift tables of laboratory data
- No safety figures will be presented
-  Bazett correction for QTc 


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The following analyses have been added:
- sensitivity analyses on modified full analysis population
- analyses of TEAEs with onset before study termination date
The analyses of patient disposition for the treatment and treatment withdrawal epoch will be 
based on the  FAS population only
Analyses of duration of exposure to study treatment will be based on the SAF population only.
Due to the early study termination only a few patients has been included in the region 
'America'. To avoid convergence problems the covariate region has been removed from the 
ANCOVA model and from the logistic regression. 
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
Missing/partial start date or end date of study treatment will not be imputed.
5.1.2
Diagnosis of PDN
Rules for imputing date of first diagnosis of PDN will be provided in Programming Dataset 
Specification (PDS) document in details.
5.1.3
AE date imputation
Rules for imputing AE end date or start date will be provided in Programming Dataset 
Specification (PDS) document in details.
5.1.4
Concomitant medication date imputation
Rules for imputing the CM end date or start date will be provided in Programming Dataset 
Specification (PDS) document in details.
5.1.5
Prohibited medication for PDN
Exclusion period of values in case of changed PDN medication or intake of prohibited 
medication will be derived as follows:

Programming Dataset Specification (PDS) will describe how to identify dose changes of 
concomitant PDN medications and prohibited medications

deterimine exclusion period: CM end date + x days where x=3 for changes in dose and 
x=7 for intake of prohibited medications with potential confounding effect

if no medication end date available, then all values from medication start date onwards 
should be excluded


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5.2
AEs coding/grading
The MedDRA version which will be available at the time of database lock, will be used for 
the coding purpose of the adverse events.
5.3
Laboratory parameters derivations
Liver events defined by laboratory parameter abnormalities (additional non-lab criteria as 
provided in the protocol are ignored):

ALT or AST > 5 × ULN

ALP > 2 × ULN

TBL > 2 × ULN

ALT or AST > 3 × ULN and INR > 1.5

ALT or AST > 3 × ULN and TBL > 2 × ULN AND ALP ≤ 2 × ULN (Potential Hy’s Law 
cases)

ALT or AST > 3 × ULN
Renal events defined by laboratory parameter abnormalities (additional non-lab criteria as 
provided in the protocol are ignored):

Serum creatinine increase 25 – 49% compared to baseline

Serum creatinine increase ≥ 50% compared to baseline

New dipstick proteinuria ≥1+

New dipstick glycosuria ≥1+ not due to diabetes

New dipstick hematuria ≥1+ not due to trauma

Albumin- or Protein-creatinine ratio increase ≥2-fold

Albumin-creatinine ratio (ACR) ≥30 mg/g or ≥3 mg/mmol

Protein-creatinine ratio (PCR) ≥150 mg/g or >15 mg/mmol
Laboratory results will be reported in SI units. 
5.4
Derivation of index values and scores
For details on handling of missing items and derivation of scores refer to the document 
“Handling of missing items and derivation of total scores". The most recent version of this 
document stored at 
 
 available before the database lock will be used as 
reference.
5.4.1
11-point Numeric Rating Scale (NRS)
The Numeric Rating Scale (NRS) is an 11–point scale for patient self-reporting of pain. The 
averaged score will be computed for every week, regardless of visits. 
24-hour Average Pain Score
The 24-hour average pain score will be assessed using the 11-point numeric rating scale (NRS) 
scale ranging from zero to ten. 


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24-hour Worst Pain Score
The 24-hour worst pain score will also be assessed using the 11-point NRS scale ranging from 
zero to ten. 
5.4.2
Verbal Rating Scale (VRS) pain intensity
The Verbal Rating Scale (VRS) is a questionnaire administered by the clinician to capture the 
patient’s level of pain. The response will be recorded as 0 = none, 1 = mild, 2 = moderate, and 
3 = severe. The score is recorded at baseline only.
5.4.3
Brief Pain Inventory- Short Form (BPI-SF)
Patients will be asked to complete the 7-item pain interference scale which assesses the degree 
to which pain interferes with walking and other physical activity, work, mood, relations with 
others and sleep using a zero to ten numeric rating scale, with zero being "does not interfere" 
and ten being "completely interferes". The score is recorded at Visits 101, 104, 106, 199, TD 
visit.
The BPI interference total score will derived as the sum of the 7 responses for the questions 
9A-9G. The total score ranges from 0 to 70. 
5.4.4
Patient Global Impression of Change (PGIC)
The Patient Global Impression of Change (PGIC) is a patient-reported instrument that 
measures change in overall status on a scale ranging from one ("very much improved") to 
seven ("very much worse"). The score is recorded at Visit 199 and TD visit only.
5.4.5
Neuropathic Pain Symptom Inventory (NPSI)
The Neuropathic Pain Symptom Inventory (NPSI) is a 12 item patient reported outcome 
measure that contains 10 descriptors representing 5 dimensions of pain (burning pain, 
deep/pressing pain, paroxysmal pain, evoked pain and paraesthesia/dysesthesia) and 
2 temporal items designed to assess pain duration and the number of pain paroxysms. The 
score is recorded at Visits 101, 104, 106, 199, 201 and TD visit.
The sum of the responses to the 10 questions (all except qn. 4 and qn. 7) will be regarded as 
the total score and will be used for the analysis.
The dimensional score of each of the five dimensions are calculated as follows :

Burning = Q1

Pressing  = ( Q2 + Q3 ) /2

Paroxysmal = ( Q5 + Q6 ) /2

Evoked = ( Q8 + Q9 + Q10 ) /3

Paraesthesia / dysesthesia = ( Q11 + Q12)/2


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5.4.6
Insomnia Severity Index (ISI)
Patients will be asked to complete the ISI using five-point Likert-style scale as a measure of 
perceived sleep difficulties. Scores can range from zero to 28, with a cut-off score of eight 
suggesting the presence of sub-threshold insomnia. The questionnaire assesses the severity of 
insomnia, satisfaction with current sleep pattern, sleep interference, "noticeability" of sleeping 
problem to others and concern about sleeping problems. The score is recorded at Visits 101, 
199 and TD visit.
The sum of seven responses represents the total score. Each of the 7 items is scored using a 
range from 0 to 4, thus the total score values can range from zero to 28.


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5.4.12
Douleur Neuropathique 4 (DN4)
The Douleur Neuropathique 4 (DN4) is a clinician administered questionnaire that can be 
useful in diagnosing neurophatic pain (Bouhassira et al 2005). DN4 consists of 10 items. 
Seven items are related to pain quality and are based on an interview with the patient, and 3 
items are based on the clinical examination. This score is recorded at Screening only. Each of 
the 10 items has a dichotomous answer Yes (=1) or No (=0). The global score is calculated as 
the sum of the 10 items.


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5.5
Statistical models
SAS codes for all statistical methodology described in this section will be included as 
programming note in TFL Shells.
5.5.1
Primary analysis
5.5.1.1
ANCOVA
The primary analysis (and all other analyses of continuous variables) will be done using 
analysis of covariance. The model is: 
mean pain score = intercept + treatment + sex + age + PDNmed (yes/no) + baseline (mean 
pain intensity) + error. 
The SAS procedure MIXED will be used for computing p-values and 95% confidence 
intervals for LS means.
5.5.1.2
Missing data imputation 
For the purpose of missing data imputation, the following two scenarios will be considered:

Jump to reference (J2R)

Missing At Random (MAR)
The imputation will be based on all available data (i.e. from all scheduled time points) using 
all covariates as specified in the ANCOVA model. For J2R only placebo data will be used, for 
MAR data from the same treatment arm will be used for building the imputation model.
5.5.2
Secondary analysis
5.5.2.1
Logistic regression
The proportion of responders will be analyzed using a repeated measures logistic regression. 
The model is similar to the ANCOVA model: 
Response = intercept + treatment + sex + age + PDNmed (yes/no) + baseline (mean pain 
intensity) + error. 
The SAS procedure GENMOD will be used.
Odds ratios will be presented along with 95% confidence intervals and p-values for the 
treatment contrasts.
5.6
Rule of exclusion criteria of analysis sets
Rule of exclusion criteria from analysis sets due to protocol deviations will be included prior 
to database lock.


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6
References
Bouhassira D, Attal N, Alchaar H, et al (2005) Comparison of pain syndromes associated with 
nervous or somatic lesions and development of a new neuropathic pain diagnostic 
questionnaire (DN4). Pain; 114(1-2):29-36.
Bretz F, Maurer W, Brannath W, et al (2009) A graphical approach to sequentially 
rejectivemultiple test procedures. Stat Med; 28(4):586-604.
Carpenter JR, Roger JH, Kenward MG (2013) Analysis of longitudinal trials with protocol 
deviation: a framework for relevant, accessible assumptions, and inference via multiple 
imputation. J Biopharm Stat; 23(6):1352-71.
CEMA401A  Handling of missing items in the derivation of total scores for efficacy measures
(last version available before DB lock is used)
CEMA401A Estimand charter (last version available before DB lock is used)
CEMA401A Visit Windows for Baseline and Post-baseline visits and Treatment 
Discontinuation (TD) visit mapping (last version available before DB lock is used)
Freeman R, Baron R, Bouhassira D, et al (2014) Sensory profiles of patients with neuropathic 
pain based on the neuropathic pain symptoms and signs. Pain; 155(2):367–76.
Kalliomäki J, Attal N, Jonzon B, et al (2013) A randomized, double-blind, placebo-controlled 
trial of a chemokine receptor 2 (CCR2) antagonist in posttraumatic neuralgia. Pain;
154(5):761-67.
Permutt T (2015) Sensitivity analysis for missing data in regulatory submissions. Stat Med; 
35:2876-9
Pinheiro J, Bornkamp B, Glimm E, et al (2014) Model-based dose finding under model 
uncertainty using general parametric models. Statist Med; 33:1646–61. 
Markus et. al. (1976), On closed testing procedures with special reference to ordered analysis 
of variance, Biometrika (1976), 63, 3 pp 655-60