Conditions: Post-herpetic Neuralgia
Keywords: post-herpetic neuralgia neuropathic pain angiotensin II type 2 receptor antagonist dose ranging
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 130
Healthy volunteers: no

Brief summary:
This study was designed to characterize dose response, and evaluate safety and efficacy of three different doses of EMA401 compared to placebo in patients with post-herpetic neuralgia (PHN).

Detailed description:
This was an interventional, randomized, parallel, placebo-controlled, dose ranging, double-blind treatment study consisting of 3 periods i.e. Screening, Treatment, and Treatment withdrawal. The study was planned in two cohorts. The initial cohort had three treatment arms i.e. Placebo b.i.d., EMA401 25 mg b.i.d., or EMA401 100 mg b.i.d. Following an unblinded safety review by an independent DMC, the second cohort was to have been initiated with an additional treatment arm i.e. EMA401 300 mg b.i.d.. Due to the premature study termination, the second cohort was not initiated. At the end of treatment period the 25mg BID and 100mg BID arms were 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: Ema401 25 mg was administered orally twice a day arm 2: Ema401 100 mg was administered orally twice a day arm 3: Matching placebo capsules administered orally twice a day

Interventions: intervention 1: EMA401 intervention 2: Placebo
Intervention descriptions: intervention 1: EMA401 intervention 2: Placebo

Protocol document:
Prot_000.pdf: 
Global Clinical Development - General Medicine 
EMA401/ Olodanrigan
Clinical Trial Protocol CEMA401A2201 / NCT03094195
A double-blind, placebo-controlled, randomized dose 
ranging trial to determine the safety and efficacy of three 
dose levels of EMA401 in reducing 24-hour average pain 
intensity score in patients with post-herpetic neuralgia 
(EMPHENE)
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)
Document type:
Amended Protocol Version 
EUDRACT number
2016-000280-16
Version number
v01 (Clean)
Development phase
II
Release date:
14-May-2018


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Protocol No. CEMA401A2201
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Amendment 1 ....................................................................................................................11
Summary of previous amendments ..........................................................................................16
Protocol summary..............................................................................................................17
1
Introduction .......................................................................................................................20
1.1
Background............................................................................................................20
1.2
Purpose ..................................................................................................................21
2
Study objectives and endpoints .........................................................................................21
2.1
Objectives and related endpoints...........................................................................21
3
Investigational plan ...........................................................................................................23
3.1
Study design...........................................................................................................23
3.2
Rationale for study design .....................................................................................25
3.3
Rationale for dose/regimen, route of administration and duration of treatment....26
3.3.1
Efficacy .................................................................................................26
3.3.2
Pharmacokinetics ..................................................................................27
3.3.3
Non-Clinical Safety...............................................................................27
3.3.4
Clinical Safety.......................................................................................28
3.4
Rationale for choice of comparator .......................................................................28
3.5
Purpose and timing of interim analyses/design adaptations..................................28
3.6
Risks and benefits..................................................................................................28
4
Population..........................................................................................................................29
4.1
Inclusion criteria ....................................................................................................29
4.2
Exclusion criteria...................................................................................................30
5
Treatment...........................................................................................................................32
5.1
Study treatment......................................................................................................32
5.1.1
Investigational and control drugs..........................................................32
5.2
Treatment arms......................................................................................................32
5.3
Treatment assignment and randomization.............................................................33
5.4
Treatment blinding.................................................................................................34
5.5
Treating the patient................................................................................................34
5.5.1
Patient numbering .................................................................................34


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5.5.2
Dispensing the study drug.....................................................................35
5.5.3
Handling of study and additional treatment..........................................35
5.5.4
Instructions for prescribing and taking study treatment........................36
5.5.5
Permitted dose adjustments and interruptions of study treatment ........36
5.5.6
Rescue medication ................................................................................36
5.5.7
Concomitant medication .......................................................................36
5.5.8
Prohibited medication ...........................................................................37
5.5.9
Emergency breaking of assigned treatment code..................................39
5.6
Study completion and discontinuation...................................................................40
5.6.1
Study completion and post-study treatment..........................................40
5.6.2
Discontinuation of study treatment .......................................................40
5.6.3
Withdrawal of informed consent...........................................................41
5.6.4
Loss to follow-up ..................................................................................42
5.6.5
Early study termination by the sponsor.................................................42
6
Visit schedule and assessments .........................................................................................42
6.1
Information to be collected on screening failures..................................................48
6.2
Patient demographics/other baseline characteristics .............................................48
6.3
Treatment exposure and compliance .....................................................................48
6.4
Efficacy..................................................................................................................48
6.4.1
11-point Numeric Rating Scale (NRS) .................................................49
6.4.2
Verbal Rating Scale (VRS) pain intensity ............................................49
6.4.3
Brief Pain Inventory- Short Form (BPI-SF)..........................................50
6.4.4
Patient Global Impression of Change (PGIC).......................................50
6.4.5
Neuropathic Pain Symptom Inventory (NPSI) .....................................50
6.4.6
Insomnia Severity Index (ISI)...............................................................50
51
51
51
6.4.10
Appropriateness of efficacy assessments..............................................52
6.5
Safety.....................................................................................................................52
6.5.1
Physical examination ............................................................................52
6.5.2
Vital signs..............................................................................................52
6.5.3
Height and weight .................................................................................53
6.5.4
Laboratory evaluations..........................................................................53
6.5.5
Electrocardiogram (ECG) .....................................................................54
6.5.6
Pregnancy and assessments of fertility .................................................54


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6.5.7
Appropriateness of safety measurements..............................................55
6.6
Other assessments..................................................................................................55
55
55
6.6.3
Resource utilization...............................................................................55
6.6.4
Pharmacokinetics ..................................................................................55
56
6.6.6
Other biomarkers...................................................................................56
7
Safety monitoring..............................................................................................................56
7.1
Adverse events.......................................................................................................56
7.2
Serious adverse events...........................................................................................58
7.2.1
Definition of SAE .................................................................................58
7.2.2
SAE reporting........................................................................................59
7.3
Liver safety monitoring .........................................................................................59
7.4
Renal safety monitoring.........................................................................................60
7.5
Reporting of study treatment errors including misuse/abuse ................................61
7.6
Pregnancy reporting...............................................................................................61
62
8
Data review and database management.............................................................................62
8.1
Site monitoring ......................................................................................................62
8.2
Data collection.......................................................................................................63
8.3
Database management and quality control............................................................63
8.4
Data Monitoring Committee..................................................................................64
8.5
Adjudication Committee........................................................................................65
9
Data analysis......................................................................................................................65
9.1
Analysis sets ..........................................................................................................65
9.2
Patient demographics and other baseline characteristics.......................................65
9.3
Treatments .............................................................................................................66
9.4
Analysis of the primary variable(s) .......................................................................66
9.4.1
Primary Variable(s)...............................................................................66
9.4.2
Statistical model, hypothesis, and method of analysis..........................66
9.4.3
Handling of missing values/censoring/discontinuations.......................68
9.4.4
Supplementary Analyses.......................................................................68
9.4.5
Sensitivity analyses ...............................................................................69
9.5
Analysis of secondary variables ............................................................................69
9.5.1
Efficacy variables..................................................................................69


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9.5.2
Safety variables .....................................................................................70
9.5.3
Resource utilization...............................................................................72
9.5.4
Pharmacokinetics ..................................................................................72
72
9.5.6
Biomarkers............................................................................................73
9.5.7
PK/PD ...................................................................................................73
9.6
Analysis of exploratory variables ..........................................................................73
9.7
Interim analyses.....................................................................................................75
9.8
Sample size calculation..........................................................................................75
10 Ethical considerations........................................................................................................76
10.1
Regulatory and ethical compliance........................................................................76
10.2
Informed consent procedures.................................................................................76
10.3
Responsibilities of the investigator and IRB/IEC..................................................76
10.4
Publication of study protocol and results...............................................................77
10.5
Quality Control and Quality Assurance.................................................................77
11 Protocol adherence ............................................................................................................77
11.1
Protocol amendments.............................................................................................77
12 References .........................................................................................................................78
13 Appendix 1: Clinically notable laboratory values and vital signs.....................................80
14 Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.....................................................................................................................81
15 Appendix 3: Specific Renal Alert Criteria and Actions....................................................84
16 Appendix 4: Proprietary screening algorithm for assessing eligibility .............................85
17 Appendix 5: PK sample log - Time schedule for blood sampling for PK assessments ....86
18 Appendix 6: Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
(DSM-V) diagnostic criteria for Major Depressive Disorder............................................87
19 Appendix 7: Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
(DSM-V) diagnostic criteria for Substance Use Disorders ...............................................89
List of tables
Table 2-1
Objectives and related endpoints ..........................................................21
Table 5-1
Randomization scheme .........................................................................33
Table 5-2
Prohibited medication ...........................................................................37
Table 6-1
Assessment schedule.............................................................................44
Table 6-2
Abbreviated schedule of assessments for patients with data 
collected after study treatment discontinuation.....................................47


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Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................61
Table 13-1
Clinically notable values for vital signs and weight changes ...............80
Table 14-1
Liver Event and Laboratory Trigger Definitions ..................................81
Table 14-2
Follow Up Requirements for Liver Events and Laboratory Triggers...81
Table 15-1
Specific Renal Alert Criteria and Actions.............................................84
Table 17-1
Time schedule for blood sampling for PK assessments (all patients)...86
Table 17-2
Time schedule for blood sampling for PK assessments (additional 
sampling for patients taking pregabalin or gabapentin)........................86
List of figures
Figure 3-1
Study design..........................................................................................24


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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 receptor
ATC
Anatomic Therapeutic Chemical classification
AUC
Area under the Curve
AV Block 
Atrioventricular block 
b.i.d.
twice a day
BL
Baseline
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
CL/F
Apparent total clearance of the drug from plasma after oral administration
Cmax
Maximum concentration
CNS
Central Nervous System
CPO
Country Pharma Organization
CRA
Clinical Research Associate
CRF
Case Report/Record Form (paper or electronic)
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
DDI
Drug-Drug Interactions
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
DSM-V
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
EC
Ethics Committee
 
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ED50
The dose at which half of the maximum effect is reached


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EDC
Electronic Data Capture
eDiary
EFD
Electronic diary
Embryo-Fetal Development
eGFR
Estimated Glomerular Filtration Rate
EMA
European Medicines Agency
Emax
The maximum effect attributable to the drug
EoT
End of Trial
ePRO
Electronic Patient Reported Outcome
FAS
Full Analysis Set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
γ-GT
gamma-glutamyltransferase
HBV
Hepatitis B Virus
HCV
Hepatitis C vírus
HIV
Human Immunodeficiency Virus
HR
Heart Rate
IB
Investigator’s Brochure 
ICH
ICF
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
Informed Consent Form
IEC
Independent Ethics Committee
IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISI
Insomnia Severity Index 
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
MCP-Mod
Multiple Comparison Procedure – Modelling
MCV
Mean Corpuscular Volume
MDE
Major Depressive Episode
MDRD
Modification of Diet in Renal Disease


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MedDRA
Medical dictionary for regulatory activities 
MTD
Maximum Tolerated Dose
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
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
RoW
Rest of World
SAD
Single Ascending Dose
SAE
Serious Adverse Event
SAF
Safety population
SOP
Standard Operating Procedure
SSRI
Selective Serotonin Reuptake Inhibitor
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
Total bilirubin
TD
Study Treatment Discontinuation
TENS
Transcutaneous Electrical Nerve Stimulation
TEAE
Treatment-Emergent Adverse Events
UGT
Uridine Diphosphate Glycosyltransferase
ULN
Upper limit of Normal
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.”
Patient/subject ID 
A unique number assigned to each patient upon signing the informed 
consent 
Personal data
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples
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 study 
consent (WoC)
Withdrawal of consent from the study occurs only when a subject does 
not want to participate in the study any longer, and does not allow any 
further collection of personal data.


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Amendment 1
Amendment rationale
This is the first global protocol amendment after protocol v00. The protocol is amended to:

Update Inclusion criteria list
o
Criterion No. 4: The words electronic Patient Reported Outcome (ePRO) 
website of this criterion are replaced with electronic tablet. The patient eligibility 
is to be confirmed on electronic tablet and not ePRO website. This is now #4a.
o
Criterion No 5: The wording of this criterion related to inadequate treatment 
response to at least two different therapies of post herpetic neuralgia (PHN) has 
been modified, for more clarity. PHN patients are often treated by general 
practitioners or other physicians and are referred to tertiary care at later stage. 
Two previous therapies with inadequate treatment response also include 
analgesics prescribed for the treatment of PHN by general practitioners and other 
treating physicians. This is now #5a.
o
Criterion No 6: Study patients willingness to complete electronic Diary (eDiary) 
is now included as an inclusion criterion. This change is to better explain this 
criterion which was previously covered as an exclusion criterion.

Update Exclusion criteria list
o
Criterion No. 3 Editorial changes and text clarification has been done to this 
criterion on comorbid Electrocardiogram (ECG) abnormalities. This is now #3a.
o
Criterion No 6: As per Novartis standard text embedded in clinical trial 
protocols, the patients considered for interventional clinical trials have to be 
cleared of any medical 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 
recurrences or metastases. This standard text is included to reduce probability of 
recurrence of the prior cancer in long term studies but does not consider studies 
with shorter duration. The total study duration is only 13 weeks in this protocol 
and therefore medical history of malignancy of any organ system in the past 2 
years before screening are to be considered sufficient for the CEMA401A2201 
study. This is now #6a.
o
Criterion No. 10: Criterion on Women of Child Bearing Potential (WOCBP) 
has been updated based on the latest toxicity data available since protocol V00 
release. This is now #10a.
o
Criteria No. 11: Criterion on sexually active males who must use a condom 
during intercourse (the same applying to vasectomized men) has been deleted 
based on data from genotoxic studies, as well as from the recently completed 
reproductive toxicity studies detailed in Investigator Brochure edition #11 


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Sections 4.3.5/4.3.7. Text has been added to clarify that this criterion has been 
removed in this amendment.
o
Criterion No.14: Criterion about positive urine drug screen at Screening has 
been updated to refer to Section 6.5.4.5. This is now #14a. 
o
Criterion No. 15: Criterion has been updated to make it clearer that patients 
with only active gallbladder or bile duct disease are not considered for the study.
This is now #15a.
o
Criterion No. 18: Editorial changes and text clarification has been done to 
criteria regarding other pain conditions. This is now #18a with sub-bullets.
o
Criterion No. 20: Text from this criterion “ongoing Social Security Disability, 
Workman’s Compensation claim and/or” has been updated for better 
understanding. This is now #20a.
o
Criterion No 21: This criterion has been removed to consider for enrolment 
patients who have previously taken herpes zoster vaccine (HZV). The previous 
history of vaccination is not considered to have an impact on the response to 
study drug. Hence the exclusion criterion with regards to the previous use of 
herpes zoster vaccine (HZV) is now removed which will allow patients that 
suffer from moderate to severe PHN pain even after vaccination in the study to 
potentially participate to the study. Text has been added to clarify that this 
criterion has been removed in this amendment.
o
Criterion No 22: The criterion related to exclude patients unwilling to complete 
eDiary has been removed and replaced by addition of inclusion criteria no.6 for 
better understanding of the protocol language. Text has been added to clarify 
that this criterion has been removed in this amendment.
 
 

Update on study Design:
o
The study screening period editorial update to clarify the 5 week screening 
period. In the previous version it was 5 weeks (35 days) however at certain 
places in the study design figure and text it was mentioned as “up to 4weeks (35 
days)”.
o
Patients will now be allowed to stop prohibited concomitant medication during 
the screening period after V1.
o
The patients who need to come off the prohibited concomitant medication after 
screening visit will need to take last dose of prohibited concomitant medication 
at least 2 weeks (14 days) prior to V101 (i.e. baseline visit)
o
Text has been modified to explain that patients will need to complete baseline 
24-hour pain intensity scores daily from day of screening till the day they will 
return to the study site at Visit 101 (i.e. Baseline). 


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
Update on concomitant medication:
o
Text added to explain allowed concomitant medication can be initiated for 
patients during the screening period. 

Update on prohibited medication: 
o
The prohibited medication criteria modified to consider the tapering of certain 
medications after screening and prior to randomization. Addition of antifungal 
medications (e.g Azoles) made to prohibited medication list with potential DDIs 
(Drug Drug Interactions) and a footnote added to allow the  Investigators to refer 
to Section 5.1.5.2 of the Investigators Brochure Edition 11 for details of DDIs 
(Drug Drug Interactions) 
o
It is also clarified in the table that any change in allowed concomitant medication 
post randomization will be considered as prohibited medication.

Addition of a third supplementary analysis: this analysis is not of primary interest in 
this study, but it may help comparing the results of this trial with future trials that may 
target the treatment-policy estimand.

Update on Study Treatment: 
o
Capsule appearance description updated. 
o
The criteria of patient re-screening updated to allow patients that fail due to 
“screening algorithm”.

Update on rescue medication:
o
The requirement of eDiary update for rescue medication taken for pain due to 
PHN clarified. It has been further explained that rescue medication taken for any 
other type of pain to be recorded in electronic Case Report Form (eCRF) as 
“other rescue medication”.

Update Visit Assessment Schedule :
o
Visit window proposed for encouraging adherence to protocol visit schedule. 
Explained the need to strictly follow the V199 and V201 dates as planned to 
avoid a patient’s over-exposure to EMA401 beyond 13weeks.
o
Serum pregnancy has been added to V101 and deleted from V1 visit.
o
Urine pregnancy added at V1, V104, 106 and V201 visits in the assessment 
schedule.
o
Clarification text added for ease of understanding of the baseline visit and 
management of background concomitant medication of the patient.

Updated Discontinuation of Study Treatment:
o
The independent consultation by dermatologist may not needed if the 
investigator is a dermatologist or for minor rash e.g. insect bite etc. This has been 
already updated in the Japan local protocol amendment. These changes are 
helpful for patient visit management.


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
Withdrawal of informed consent: 
o
The criteria of withdrawal of consent updated.
o
Text clarifying the use of data by Novartis as per applicable laws in the 
geographies added. 
 
 
 
Changes to the protocol

Section 1.1 Background: Updated information that safety data is based now on 8 phase 
1 studies.
 

Section 3.1 and Figure 3-1 Study design: clarification about the duration of the 
screening epoch, allowance of tapering of prohibited medication to allow stoppage 
during screening period, clarifications with principles of the blinded screening algorithm.

Section 3.3.3: Non-Clinical safety: Minor text update to reflect latest information.

Section 3.3.4: Clinical Safety: Updated an overview of the total numbers of 
subjects/patients enrolled in the EMA401 clinical program as well as numbers of 
subjects/patients having received EMA401 or placebo till a certain cut-off date.

Section 4.2: Inclusion criteria:
o
Criterion No. 4, text modified. This is now #4a.
o
Criterion No. 5, text modified. This is now #5a.
o
Criterion No 6 added: Patients must be willing to complete daily eDiary.

Section 4.1: Exclusion criteria:
o
Criterion No 3, No.18 and No 20 editorial changes and text clarification. These are 
now #3a, #18a (with sub-bullet points) and #20a.
o
Criterion No 6: The malignancy case history timeline criteria has been modified from 
5 years to 2 years. This is now #6a.
o
Criterion No. 10: WOCBP criteria text has been updated. This is now #10a.
o
Criterion No. 14: Urine drug screen at Screening been updated to refer to Section 
6.5.4.5. This is now #14a.
o
Criterion No. 15: Bullet point about known gallbladder or bile duct disease updated. 
This is now #15a.
o
Criterion No. 11, 21 and 22 deleted.


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
Section 5.1.1: Investigational and control drugs: Description of capsule appearance 
updated.

Section 5.5.1: Patient numbering: Updated patient identification and numbering 
detailed text; Patient re-screening allowed once.

Sections 5.5.6: Rescue medications: Rescue medication recording explained.

Section 5.5.7: Concomitant medication: Text updated to explain start of concomitant 
medication during screening period.

Section 5.5.8 and Table 5.2: Prohibited medications: Text updated to consider the 
tapering of certain prohibited medications after screening and prior to randomization; 
Table of prohibited medications updated considering the different metabolic pathways 
of EMA401

Section 5.6.2: Discontinuation of study treatment

Section 5.6.3: Withdrawal of informed consent: Text added to clarify the withdrawal 
criteria’s and the use of data for patients that withdraw from the study based on 
applicable laws.

Table 6-1: Visit schedule and assessments/Assessment Schedule: The assessment 
schedule updated to add/modify the assessments. (e.g Urine pregnancy testing added)

Section 6.5.4.2: Clinical chemistry: Serum pregnancy testing schedule updated.

Section 6.5.4.3: Urinalysis: Albumin testing removed.

Section 6.5.4.5: Urine drug screen: Clarification that prescribed medications could 
be consumed abusively resulting in positive test. The testing could be repeated once 
during the screening period.

Section 6.5.6: Pregnancy and assessments of fertility: Clarification that pre-
menopausal women will have pregnancy testing as per the visit assessment schedule.
 
 
 

Section 9: Data analysis: Added a third planned supplementary analysis, align with the 
rest of the protocol amendment items.
 
 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
Upon finalization of this protocol the recruitment in the study is ongoing. Thirty eight (38) 
patients have been randomized by Czech Republic, Denmark, France, Germany, Hungary, 
Japan, Norway, Slovakia, Portugal, Austria, Belgium and United Kingdom.


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IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent.  Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
Summary of previous amendments
Local amendment (For Japan ONLY)
Amendment rationale
The purpose of this amendment was to take into consideration the clinical practice about the 
management of patients suffering from Post-Herpetic Neuralgia (PHN) in Japan. Numerous 
dermatology clinics only have one qualified clinician specialized in dermatology. These 
qualified dermatologists are able to examine and treat patients on their own and would be the 
treating physician of the eligible patients in the EMA401A2201 study in Japan.
In case an event like a skin rash or other dermatologic event would occur while being on study 
treatment, the investigators who are dermatologists by education and practice medicine in 
dermatology clinics would be able to take their own decisions about the potential 
interruption/discontinuation of study treatment in the context of a suspicion of allergic 
dermatitis and ultimately be the ones to judge whether or not the study treatment could be re-
started and thus making the consultation by an independent dermatologist as non-essential.
Changes to the protocol
Section 5.6.2
Text corrected to remove the reference to the consultation with an independent dermatologist 
as the investigators/study doctors will be qualified to examine and treat patients in case of a 
skin rash or a dermatologic event that would occur while patients being on study treatment.


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Protocol summary
Protocol number
CEMA401A2201
Full Title
A double-blind, placebo-controlled, randomized dose ranging trial to 
determine the safety and efficacy of three dose levels of EMA401 in 
reducing 24-hour average pain intensity score in patients with post-
herpetic neuralgia (EMPHENE)
Brief title
Dose response study of EMA401 in patients with post-herpetic neuralgia
(PHN)
Sponsor and Clinical 
Phase
Novartis
Phase 2
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of this study is to characterize dose response, and evaluate 
safety and efficacy of three different doses of EMA401 compared to 
placebo in patients with post-herpetic neuralgia (PHN). Data from this 
study will be used to inform the selection of EMA401 doses for future 
Phase 3 clinical trials.
Primary Objective(s) 
To characterize dose-response for change in the weekly mean of 24-hour 
average pain intensity scores at Week 12 
Secondary Objectives

Objective 1: 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 at least one 
active dose of EMA401 vs. placebo

Objective 2: 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 3: 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 4: To evaluate the efficacy of EMA401 compared to 
placebo, on the Patient Global Impression of Change (PGIC) at Week 
12

Objective 5: 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 6: To evaluate the effect of EMA401 compared to placebo 
on the Insomnia Severity Index (ISI) at Week 12

Objective 7: To evaluate the effect of EMA401 compared to placebo 
on the Neuropathic Pain Symptom Inventory (NPSI) at Week 12

Objective 8: To evaluate the safety and tolerability of EMA401 
compared to placebo in PHN 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 9: To evaluate the pharmacokinetics (PK) of EMA401 and 
exposure-response (decrease in pain intensity) relationship for 
EMA401 throughout the study


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Study design
The study is interventional, randomized, parallel, placebo-controlled,
dose ranging, double-blind treatment.
Population
The study population will consist of approximately 360 randomized male 
and female patients (≥18 years old) with PHN 
Key Inclusion criteria

At the time of Screening, have documented diagnosis of PHN (ICD-
10 code B02.29), defined as pain in the region of the rash persisting 
for more than 6 months after onset of herpes zoster rash.

Be assessed as suffering from moderate to severe neuropathic pain 
across the Screening epoch (NRS ≥ 4).

Patients must have documented past and/or ongoing inadequate 
treatment response (having insufficient pain relief with treatment or 
inability to tolerate) to at least 2 different prescribed 
therapies/analgesics commonly used to treat and considered 
effective for the treatment of PHN.

Patients must be willing to complete daily electronic Diary (eDiary)
Key Exclusion criteria

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.

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 study medication. Highly effective contraceptive 
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 Informed 
Consent Form (ICF)

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.


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
Patients who have a known diagnosis of diabetes and are stable on 
medication with a hemoglobin A1C > 8%. Those who do not have a 
known diagnosis of diabetes with a hemoglobin A1c > 7%.
Study treatment
EMA401 and placebo
Efficacy assessments

11-point Numeric Rating Scale (NRS)

Brief Pain Inventory-Short Form (BPI-SF)

Patient Global Impression of Change (PGIC) 

Insomnia Severity Index (ISI)

Neuropathic Pain Symptom Inventory (NPSI)
Key safety 
assessments

Adverse event monitoring

Physical examinations and vital signs

Monitoring of laboratory markers in blood and urine

ECGs
Other assessments

Pharmacokinetics (PK)
 

Intake of rescue medication
Data analysis
The primary objective will be to characterize dose-response for change in 
the weekly mean of 24-hour average pain intensity scores at Week 12. 
The primary estimation method is based on an Analysis of covariance
( ANCOVA) model including region (e.g. US, EU), treatment, sex, use of 
concomitant pain medication for PHN (yes/no) as factors and baseline 
(mean pain intensity) score and age as covariates.  The analysis will
account for different post-randomization events, such as changes in 
doses of concomitant medication for PHN, 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.
Dose-response estimation will be performed based on the ANCOVA least 
square estimates using Multiple Comparison Procedure – Modelling 
(MCP-Mod).
Key words
Post-herpetic neuralgia, neuropathic pain, angiotensin II type 2 receptor 
antagonist, dose ranging


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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).
Post-herpetic neuralgia (PHN) is clinically defined as a persistent neuropathic pain following 
the appearance of the skin rash and is thought to be caused by scarring of the dorsal root 
ganglion and atrophy of the dorsal horn in areas affected by the zoster outbreak (Cunningham 
and Dworkin 2000). PHN manifests as an assortment of symptoms, including spontaneous 
aching or burning pain, continuous or the sudden onset of shooting pains, allodynia and 
hyperalgesia (Cunningham and Dworkin 2000). 
Recent recommendations of Neuropathic Pain Special Interest Group (NeuPSIG) for the 
pharmacotherapy of neuropathic pain include use of tricyclic antidepressants, serotonin-
noradrenaline reuptake inhibitors, 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 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 dropout 
rates and thus may substantially limit the utility of such combinations (Chaparro et al 2012). 
Given the prevalence and severity of PHN, 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 eight 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 


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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 characterize dose response, and evaluate safety and efficacy of 
three different doses of EMA401 (25 mg b.i.d. (i.e. 50 mg/day), 100 mg b.i.d. (i.e. 200 mg/day), 
300 mg b.i.d. (i.e. 600 mg/day)) compared to placebo in patients with post-herpetic neuralgia 
(PHN). Data from this study will be used to inform the selection of EMA401 doses for future 
Phase 3 clinical trials.
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 characterize dose-response for 
change in the weekly mean of 24-hour 
average pain intensity scores at 
Week 12 
Endpoint(s) for primary objective(s) 

Dose-response in change in weekly 
mean of the 24-hour average pain 
score, using an 11-point Numeric 
Rating Scale (NRS), from Baseline to 
Week 12
Secondary 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 at least one 
active dose of EMA401 vs. placebo

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
Endpoint(s) for secondary objective(s)

Change in weekly mean 24-hour 
average pain score (using the 11 point 
NRS) from Baseline to Week 12

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 Week 12


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Objective(s)
Endpoint(s)

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 effect of EMA401 
compared to placebo on the 
Neuropathic Pain Symptom Inventory 
(NPSI) at Week 12

To evaluate the safety and tolerability of 
EMA401 compared to placebo in PHN 
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

Proportion of patients meeting 
responder criteria from Baseline to 
Week 12

Change in ISI from Baseline to Week 
12

Change in NPSI 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
Exploratory Objective(s) 

To evaluate the proportion of patients 
who need rescue medication and the 
time to first intake of rescue medication
Endpoint(s) for exploratory objective(s)

Proportion of patients who need rescue 
medication and the time to first intake 
of rescue medication


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Objective(s)
Endpoint(s)
3
Investigational plan
3.1
Study design
The study is interventional, randomized, parallel, placebo-controlled, dose ranging, double-
blind treatment.
The study will consist of a Screening epoch (up to 5 weeks), a double-blind Treatment epoch 
(12 weeks), and a double-blind Treatment withdrawal epoch (1 week). 

In the initial cohort, patients will be randomized in a 1:1:1 ratio to treatment with placebo, 
EMA401 25 mg b.i.d., or EMA401 100 mg b.i.d. (approximately 135 patients). 
Randomization of patients to the high dose arm (EMA401 300 mg b.i.d.) in study 
CEMA401A2201 will only be initiated following an unblinded safety review by an 
independent Data Monitoring Committee (DMC) after exposure of 50 patients treated 
with EMA401 up to 100 mg b.i.d. for at least 8 weeks (i.e. 25 patients on 25 mg b.i.d. and 
25 patients on 100 mg b.i.d.). 

Future patients will then be randomized in the second cohort in a 1:1:1:2 ratio to 
treatment with placebo, EMA401 25 mg b.i.d., EMA401 100 mg b.i.d., or EMA401 300 
mg b.i.d. (approximately 225 patients).  
Overall approximately 360 patients will be enrolled in the study (i.e. approximately 90 patients 
will be enrolled in each treatment arm). In the event that the EMA401 300 mg b.i.d. treatment 
arm is not initiated, the original 1:1:1 randomization ratio will remain and overall approximately 
270 patients will be enrolled in the study (i.e. approximately 90 patients will be enrolled in each 
of the treatment arms of placebo, EMA401 25 mg b.i.d., and EMA401 100 mg b.i.d.). End of 
Trial (EoT) will occur when the last patient completes last visit (LPLV).
Figure 3-1 presents an overview of the study design.


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Figure 3-1
Study design
Screening epoch (Up to 5 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, 
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. 
Patients who pass preliminary Screening assessments will receive their electronic patient 
reported outcome (ePRO) electronic diary (eDiary) device.
Washout of any prohibited concomitant medications (see Table 5-2) should be initiated from 
day of screening. The last dose of the prohibited medication should be taken minimum 2 weeks 
(14 days) prior to baseline visit.
Patients are required to complete their baseline 24-hour pain intensity scores daily from the day 
of screening till the day they return to the study site at Visit 101 (i.e. Baseline).
The patient’s final eligibility will be based on an assessment of their 24-hour average pain 
intensity scores recorded in the eDiary device using a proprietary screening algorithm
(Appendix 4) prior to randomization. 


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General principles of the algorithm will 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. 
Designated investigator 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. Patients will visit the study site for assessments that are outlined in the 
visit assessment schedule (Table 6-1). At each scheduled visit the designated investigator 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, 
and retrain the patient’s 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 the designated investigator site staff can assess patient’s compliance with the 
dosing regimen. Patients should bring their pregabalin /gabapentin medication (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)
At the end of the 12-week double-blind 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 either stop 
treatment abruptly (i.e. receive placebo) or to continue the active treatment assigned during the 
double-blind Treatment epoch. 
3.2
Rationale for study design
The study is intended to provide information on the minimum effective dose and the optimal 
dose range for therapeutic doses of EMA401. It will evaluate the safety and efficacy of three 
dose levels of EMA401 in the treatment of PHN. 
For each dose, 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 treatment 


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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 establishing evidence of a dose response 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. The staggered approach to randomizing patients to 
the EMA401 300 mg b.i.d. arm following DMC unblinded review of safety data, together with 
clinical assessments every two weeks will ensure patient safety.
The study will evaluate the potential for a rebound effect of EMA401 in both safety and efficacy 
after study drug discontinuation during a treatment withdrawal period designed to minimize 
bias.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment 
The dose range planned to be studied includes: 25 mg b.i.d., 100 mg b.i.d., and 300 mg b.i.d.
Guidelines on the clinical development of medicinal products intended for the treatment of pain 
state that dose response studies should evaluate ceiling effects for efficacy (EMA Guideline 
2015, FDA Guideline 2014).
It is recommended that dose ranging studies should be designed for estimating dose response 
characteristics across a 10 fold range (e.g. 0.1 – 1.0 of the maximum tolerated dose-MTD) 
and adapting to the reality of the specific drug and disease (EMA Report from Dose Finding 
Workshop, 2015). 
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). 
Doses selected will allow clear differentiation and characterization of pharmacodynamic dose 
response over 12 fold dose dynamic range.
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
Non-clinical safety pharmacology and toxicology studies with EMA401 have been conducted 
in dogs (up to 4-week duration), rats and monkeys (up to 13-week duration) to support clinical 
trials of up to 13-week in duration and embryo-fetal development (EFD) toxicity studies in rats 
(definitive) and rabbits (preliminary) have been conducted. In the 13-week toxicity study in rats, 
mortality and excessive toxicity were noted at doses ≥ 1000/500 mg/kg/day. Oral administration 
of EMA401 resulted in various pathological changes in the gastrointestinal tract (especially the 
nonglandular stomach) and nasal turbinate at doses ≥ 150 mg/kg/day. In the 13-week toxicity 
study in monkeys, oral administration of EMA401 caused abnormal feces and vomitus/emesis 
at doses ≥ 100 mg/kg/day. Those effects were not adverse because they were transient, did not 
decrease body weight/body weight gain and thus did not affect the overall health of the animals. 
The non-clinical studies completed to date support the use of EMA401 up to dose of 300 mg 


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b.i.d. for up to 13 weeks including in Women of child bearing potential. A summary of 
completed non-clinical studies and their results can be found in the Investigator’s Brochure.
3.3.4
Clinical Safety
Eight studies in healthy subjects and two in patients have been completed for EMA401. Three 
hundred seventy three unique subjects (250 healthy subjects, 92 patients with PHN, and 31 
patients with Chemotherapy Induced Neuropathic Pain (CINP)) have received EMA401, and 
183 subjects (92 healthy subjects and 91 patients with PHN) have received placebo in the 
clinical program till date. 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.
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.
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 


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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: 
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 gabapentin) and other comorbid 
diseases at stable doses is therefore allowed, no safety concerns are foreseen.
4
Population
The study population will consist of male and female patients (≥18 years old) with post-herpetic 
neuralgia (PHN). The goal is to randomize a total of approximately 360 patients in 
approximately 100-120 centers worldwide. Since a 40% screening failure rate is expected, 
approximately 600 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.
3. At the time of Screening, have documented diagnosis of PHN (ICD-10 code B02.29), 
defined as pain in the region of the rash persisting for more than 6 months after onset of 
herpes zoster rash.
4a. 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 designated 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.
5a. Patients must have documented past and/or ongoing inadequate treatment response 
(having insufficient pain relief with treatment or inability to tolerate) to at least 2 different 
prescribed therapies / analgesics commonly used to treat and considered effective for the 
treatment of PHN.
6. Patient must be willing to complete daily eDiary


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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.
3a. 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. Skin conditions in the affected dermatome that in the Investigator’s opinion could alter 
sensation or active herpes zoster upon physical examination at Screening.
6a. 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  2 years, regardless 
of whether there is evidence of local recurrence or metastases.
7. 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).
 
 
 
9. Pregnant or nursing (lactating) women.
10a. 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 
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
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 Informed Consent Form (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.
11. This criterion has been removed in this amendment.
12. 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).
13. 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).
14a.
Positive urine drug screen at Screening. (See section 6.5.4.5).
15a.
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.

Active gallbladder or bile duct disease.

Acute or chronic pancreatitis.
16. 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.
17. Patients who have a known diagnosis of diabetes and are stable on medication with a
hemoglobin A1c > 8%. Those who do not have a known diagnosis of diabetes with a
hemoglobin A1c > 7%.
18a.
Other conditions :

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.

Had a clinically significant illness or operative procedure within four weeks of 
Screening (e.g., influenza, myocardial infarction).


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
Have, any other pain in the region of the herpes zoster rash or any other moderate to 
severe pain that can be confused with the patient’s PHN, or other chronic pain 
conditions including osteoarthritis, that may confound evaluation of treatment 
response.
19. Have undergone neurolytic or neurosurgical therapy or use a neuro stimulating device for 
PHN within 3 months of Screening or are using/ plan to use Transcutaneous Electrical 
Nerve Stimulation (TENS).
20a. Subjects with an ongoing litigation related to their pain disorder.
21. This criterion has been removed in this amendment
22. This criterion has been removed in this amendment.
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:

12.5 mg

50 mg

150 mg
All dosage strengths of EMA401 and placebo will be identical in appearance. Additional 
treatment
No additional treatment beyond investigational drug and control drug are included in this trial.
5.2
Treatment arms 
In the initial cohort, patients will be assigned at Baseline (Visit 101) to one of the following 3 
treatment arms in the ratio of 1:1:1.

Placebo b.i.d.

EMA401 25 mg b.i.d.

EMA401 100 mg b.i.d.
After unblinded safety review by an independent DMC, future patients will then be assigned in 
the second cohort at Baseline (Visit 101) to one of the following 4 treatment arms in the ratio 
of 1:1:1:2.

Placebo b.i.d.

EMA401 25 mg b.i.d.

EMA401 100 mg b.i.d.

EMA401 300 mg b.i.d.
In the event that the EMA401 300 mg b.i.d. treatment arm is not initiated, patients will continue 
to be randomized according to the original 1:1:1 ratio to placebo, EMA401 25 mg b.i.d., or 


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EMA401 100 mg b.i.d. until the planned enrollment in each dose arm is completed (i.e. 90 
patients).
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 
(initial cohort)
Randomization ratio
(second cohort)
Placebo
Placebo
2
2
EMA401 25 mg
EMA401 25 mg 
1
1
EMA401 25 mg
Placebo
1
1
EMA401 100 mg
EMA401 100 mg
1
1
EMA401 100 mg
Placebo
1
1
EMA401 300 mg
EMA401 300 mg
0
2
EMA401 300 mg
Placebo
0
2
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 PHN (yes/no) in order to achieve balance of treatment allocation within the 
stratification factors. 


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For the primary analysis at Week 12, the overall study randomization ratio will be 1:1:1:1 for 
the treatment arms placebo, EMA401 25 mg b.i.d., EMA401 100 mg b.i.d., or EMA401 300 mg 
b.i.d. (refer to Section 9.8). In the event that the EMA401 300 mg b.i.d. treatment arm is not 
initiated, patients will continue to be randomized according to the original 1:1:1 ratio to placebo, 
EMA401 25 mg b.i.d., or EMA401 100 mg b.i.d. until the planned enrollment in each dose arm 
is completed (i.e. 90 patients).  
The randomization scheme for patients will be reviewed and approved by a member of the 
Randomization Office.
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 
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 data base 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 


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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.
Re-screening for patients will only be allowed once.
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 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.


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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 
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 pregabalin/gabapentin if applicable) prior to arriving at the site and 
completing the necessary assessments. Patients should bring their pregabalin/gabapentin 
(if applicable) with them to the study visits where PK is collected so it may be administered 
after the PK 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 3 or 4 times/day) for unacceptable pain due to any reason during the study. 
Acetaminophen/paracetamol will not be provided by Novartis. 
The patients will be instructed to complete the pain scores in eDiary before intake of 
acetaminophen/paracetamol when taken due to unacceptable pain due to PHN. 
The intake of acetaminophen/paracetamol in eDiary is to be recorded by the patient only when 
taken for unacceptable pain due to PHN. 
The intake of acetaminophen/paracetamol if taken, for unacceptable pain due to any other 
reason, should be recorded in the eCRF as “other rescue medication” by the designated 
investigator staff.
5.5.7
Concomitant medication 
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All 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.


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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.
Allowed concomitant medications can be initiated for patients if deemed necessary by the 
investigator, however they should be on stable dose at least 2 weeks  (14 days) prior to V101 
(i.e. Baseline visit).
1. Patients will be allowed to take only one of the following prescribed medications for 
managing their PHN, provided the dose level has been stable for at least 2 weeks prior to
the Randomization Visit (Visit 101 i.e Baseline visit) and must remain at stable doses 
throughout the study (PRN (as needed) use is not allowed):

Pregabalin

Gabapentin 
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.

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 gabapentin) must be stable for at least 2 weeks prior to Randomization, and must remain 
stable throughout the study. 
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 Randomization and throughout study
High dose capsaicin patch (8%)
3 months prior to 
Randomization and after 
Randomization.
Discontinue study treatment 
Prohibited 2 weeks prior to Randomization and throughout the study
Any skeletal muscle relaxant 
(e.g. baclofen, orphenadrine, 
methocarbamol)
2 weeks prior to 
Randomization and after 
Randomization
None


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Medication
Prohibition period
Action taken for study 
treatment
Mexiletine
2 weeks prior to 
Randomization and after 
Randomization
None
Dextromethorphan
2 weeks prior to 
Randomization d after 
Randomization 
None
Memantine
2 weeks prior to 
Randomization and after 
Randomization
None
Alpha-lipoic acid
2 weeks prior to 
Randomization and after 
Randomization
None
Other anti-epileptic drugs (e.g. 
valproic acid, carbamazepine*, 
phenytoin)
2 weeks prior to 
Randomization and after 
Randomization
Discontinue study treatment 
upon 2nd episode of 
medication use
Oral or injectable steroids
2 weeks prior to 
Randomization and after 
Randomization 
Discontinue study treatment 
upon 2nd episode of 
medication use
Monoamine oxidase inhibitors or 
any other antidepressants (except 
stable dosage of SSRI)
2 weeks prior to 
Randomization and after 
Randomization 
Discontinue study treatment 
upon 2nd episode of 
medication use
Antipsychotic or neuroleptic 
medications
2 weeks prior to 
Randomization and after 
Randomization 
Discontinue study treatment 
upon 2nd episode of 
medication use
Cannabinoids (e.g. marijuana)
2 weeks prior to 
Randomization and after 
Randomization 
Discontinue study treatment 
upon 2nd episode of 
medication use
Prescribed opioids, including 
codeine
2 weeks prior to 
Randomization and after 
Randomization 
Discontinue study treatment 
upon 2nd episode of 
medication use
Any prescription systemic pain 
medication, or topical treatment for 
PHN, including lidocaine plaster 
2 weeks prior to 
Randomization and after 
Randomization
Discontinue study treatment 
upon 2nd episode of 
medication use
Nonsteroidal Anti-inflammatory 
Drugs (NSAIDs) or any other over-
the-counter pain medications
2 weeks prior to 
Randomization and after 
Randomization 
None


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Medication
Prohibition period
Action taken for study 
treatment
Any non-drug therapies that could 
modulate the perception of pain 
either directly or indirectly (i.e. 
transcutaneous electrical nerve 
simulation (TENS) or surgery)
2 weeks prior to 
Randomization and after 
Randomization 
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) , Antiviral 
medications (e.g. valacyclovir, 
acyclovir, amantadine, anti-HIV), 
Antifungals (e.g Azoles)
2 weeks prior to 
Randomization and after 
Randomization 
None
Prohibited after Randomization and throughout study   
Any change to a different 
standard of care medication from 
baseline (e.g. switch from 
pregabalin to gabapentin) will be 
treated as prohibited medication
After randomization
Discontinue study 
treatment
(*Prohibited due to potential Drug-Drug Interactions (DDIs), please refer to Investigator Brochure Ed 
11, Section 5.1.5.2 for details)
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 place 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


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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 
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 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 7.6)

Use of prohibited treatment as described in Section 5.5.8

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: 


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
Skin rash – Interrupt study treatment until consultation by a dermatologist (and 
documented in patient’s source). Identified common dermatologic conditions 
symptoms, including rash that are clearly attributable to non-study drug related causes 
(i.e. insect bites, poison ivy etc.) can be evaluated and treated per standard of care by 
investigator. In cases of suspected allergic dermatitis, body temperature and blood 
chemistry (including Liver Function Tests (LFTs) and Complete Blood Cell Count 
(CBC)) will be obtained. Study treatment can be started again following 
recommendation of the dermatologist and investigator. Study treatment must be 
permanently discontinued thereafter if rash 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 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 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.
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
and

Does not allow further collection of personal data


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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.
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form. 
For EU and Rest of world (RoW): All biological samples not yet analyzed at the time of 
withdrawal will no longer be used, unless permitted by applicable law. They will be stored 
according to applicable legal requirements.
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
Novartis may terminate the trial for reasons related to the benefit risk assessment of treatment 
for participants in the study, or for regulatory or medical reasons (including slow enrollment).
In the event that the study is terminated early, the Institutional Review Boards (IRBs)/Ethics 
Committees (ECs) will be informed and will be asked to approve the process to prematurely 
withdraw the participants. In general, the participant should be seen as soon as possible and 
assessed as a prematurely withdrawn participant from the study. The withdrawal process may 
include additional procedures to be followed, in order to ensure that adequate consideration is 
given to the protection of the participant’s interests.
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.


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Patients must be seen for all visits on the designated date or as close to it as possible. (Suggested 
window is +/- 3 days with the exception of V199 and V201 which must be performed no later 
than 13-week after the Baseline visit.)
For V199 and V201, the scheduled dates should be strictly adhered to avoid treatment exposure 
of more than 13 weeks after baseline visit. 
The scheduled visit date should be calculated based on V101 (BL) for all visits from V101 
(week 0) till V201 (week 13). 
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 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, 2
X
X
X
Urine pregnancy test
X
X
X
X
Hematology/Blood chemistry
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
Dispense ePRO eDiary device
S
Complete pain diary 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
TD = Study Treatment Discontinuation visit
X = assessment to be recorded on clinical data base; S = assessment to be recorded on source documentation only
1Collected as part of the blood chemistry.
2Required for all pre-menopausal women who are not surgically sterile.
3Urine dipstick to be performed at the site. If abnormalities are present, urine sample should be sent to the central laboratory for microscopy analysis.


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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
 
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 & pre-dose single ECG Vital signs Pre-dose PK & 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 pregabalin or gabapentin according to the schedule detailed in Table 17-2. Patients should be instructed not to take 
their morning dose of pregabalin/gabapentin prior to arriving at the site and completing the necessary assessments. Patients should bring their pregabalin/gabapentin (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 diary daily (NRS)
X
X
X
X
X
X
X
BPI-SF, NPSI
X
X
X
PGIC
X
Treatment epoch disposition
X
X = assessment to be recorded on clinical data base; S = assessment to be recorded on source documentation only
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. 
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 must 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 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 respondent, 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 
electronic device or an electronic tablet. Detailed training on use of the device 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.
Designated Investigator 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 as per 
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
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.


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At Baseline, the designated investigator 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.
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
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 NPSI will be completed by patients using the electronic tablet at the site at the specified 
visits.
6.4.6
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.


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6.4.10
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, 
 tools are recommended 
for assessing the patient’s perception of the impact of disease and treatment on daily life 
physical, psychological and social functioning and well-being. Therefore BPI-SF, 
 
 are included. 
Co-morbid anxiety and depression are common in chronic pain patients. Mood changes, anxiety 
and 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 the comorbid conditions. Global Impression of Change 
reported by the patient is a useful supportive indicator of the overall perceived benefit of 
treatment in chronic pain trials. 
NPSI is a multidimensional tool to evaluate treatment response on sensory and affective 
qualities of pain. 
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, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed.
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 using an automated validated device, e.g. OMRON, with an appropriately 
sized cuff. The repeat supine measurements will be made at approximately 1 to 2 minute 
intervals and the mean of the three measurements will be used. In case the cuff sizes available 
are not large enough for the patient's arm circumference, a sphygmomanometer with an 
appropriately sized cuff may be used. After the patient has been standing for 3 minutes, systolic 
and diastolic blood pressure will be again measured using the above procedure. 


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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.
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.
Serum pregnancy will be performed in accordance with Table 6-1
6.5.4.3
Urinalysis
Dipstick measurements for specific gravity, 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.
 
 


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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 for a prescribed medications that could be 
consumed abusively the site may perform a repeat urine drug screen within the screening period.
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 and this patient 
cannot be re-screened in the future. A second repeat is not admissible. No repeat drug screen 
will be permitted for recreational drugs.
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 Fridericia QT 
correction formula (QTcF) should be used for clinical decisions.
Single 12 lead ECGs are collected with ECG machines supplied by the core laboratory at the 
visits indicated in Table 6-1. The original ECGs, appropriately signed, must be collected and 
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. 
If needed clinically significant ECG findings at randomization (pre-dose) may 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.


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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. 
 
6.6
Other assessments 
6.6.1
Patient Reported Outcomes (PRO)
Please refer to Section 6.4 for details on all Patient Reported Outcomes (PRO).
6.6.3
Resource utilization 
Not applicable.
6.6.4
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 


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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). 
For those patients who are also taking pregabalin or gabapentin, an additional pre-dose PK 
sample will be collected at Baseline, Week 8, and Week 12 before the patient takes their 
morning dose of pregabalin or gabapentin.
PK sample should also be collected if abnormal ECG result (see Section 6.5.5).
6.6.6
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 
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Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

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 with 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.


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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 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 


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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 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.
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. 


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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.
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:


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
confirmed (after ≥24h) 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 DAR (dose administration record) 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 
(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 
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.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 


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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.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the female partner.
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.
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, 


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serious adverse events (SAEs), discontinuations due to adverse events and cases of interest 
(allergic dermatitis, and clinically significant abnormal hepatic and hematology values).
Unblinded safety review by the independent DMC will be implemented to stagger patient 
exposure to the study drug. Randomization of patients to the high dose arm (EMA401 300 mg 
b.i.d.) in study CEMA401A2201 will only be initiated following an unblinded safety review by 
the independent DMC after exposure of 50 patients treated with EMA401 up to 100 mg b.i.d. 
for at least 8 weeks (i.e. 25 patients on 25 mg b.i.d. and 25 patients on 100 mg b.i.d.). 
Furthermore, another unblinded safety review will be conducted after the completion of 
12 weeks exposure of 30 patients in the EMA401 300 mg b.i.d. treatment arm to determine if 
300 mg b.i.d. dosing can be continued as planned.
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) will include all patients randomized.

The Safety population (SAF) will include all patients who took at least one dose of study 
medication and who had at least one post-baseline safety assessment.
The primary efficacy analysis will be 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). 


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Relevant medical history/current medical conditions will be summarized by system organ class 
and preferred term of the MedDRA dictionary.  
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 PHN will also be summarized by treatment.
The analyses will be based on the SAF and FAS populations.
9.4
Analysis of the primary variable(s)
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 will record 
his/her daily pain intensity score across the preceding 24 hours at a single time point. The daily 
pain intensity score will then be averaged over 7 days to obtain the mean pain intensity score 
for a week. 
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 are detailed in an Estimand Charter. 
The primary estimation method is based on an Analysis of Covariance (ANCOVA) model
including region (e.g. US, EU), treatment, sex, use of concomitant pain medication for PHN 
(yes/no) as factors and baseline (mean pain intensity) score and age as covariates. The analysis
will account for different post-randomization events as follows:

Changes in doses of concomitant medication for PHN: Efficacy observations collected 
during the period of changes in doses of concomitant medication for PHN (compared to 


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baseline) and the 2-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 
multiply imputed 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 multiply
imputed 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, 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 arms, missing at random assumption for placebo arm (Carpenter, Roger, and 
Kenward 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 multiply imputed
using the MAR assumption. 
The multiple imputations will be carried out on the weekly mean pain score.
The primary objective will be achieved if the null hypothesis of flat dose-response curve (where 
all dose means are equal to the placebo mean) at Week 12 is rejected using alpha=0.025 one-
sided. The null hypothesis of a flat dose-response curve will be tested using Multiple 
Comparison Procedure – Modelling (MCP-Mod) with three Emax and 2 sigmoidal-Emax dose 
response models as the candidate shapes. The following ED50 (the dose at which half of the 
maximum effect is reached) values will be used for the Emax models: 17, 80, and 200. The 
parameters of the sigmoidal Emax models (ED50, h) will be as follows: (77, 3) and (175, 1.5), 
where h is the Hill parameter that determines the steepness of the dose-response shape. The 
MCP-Mod dose response test will be performed at each post-baseline visit. No multiplicity 
adjustment by visit will be carried out.
Dose-response estimation will be performed based on the ANCOVA least square estimates 
using MCP-Mod as described in Pinheiro et al (2014). The same candidate models as above 
will be used in a model averaging approach to obtain an estimate of the dose-response curve.
The same ANCOVA model will be applied at the visits prior to Week 12.


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Summary statistics by treatment and visit will be provided for the primary efficacy variable.
In the event the EMA401 300 mg b.i.d. dose cannot be initiated, then the dose response 
characterization will not be performed. In that case, the first secondary objective will be 
evaluated to compare the efficacy of the remaining doses of EMA401 over placebo in 24-hour 
average pain intensity score at Week 12, using an 11 point Numeric Rating Scale (NRS). This 
comparison will be done by testing the null hypothesis of superiority of at least one active dose 
of EMA401 over placebo, while adjusting for multiplicity. The estimation of the treatment 
difference and missing data handling will be performed using the method of analysis mentioned 
for the primary analysis. Multiplicity adjustment for the pairwise comparisons will be 
performed using the Hochberg procedure.    
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.
For all analyses, imputation of intermittent missing observations before treatment 
discontinuation will be carried out following a MAR mechanism for all treatment arms.
9.4.4
Supplementary Analyses  
The supplementary analyses to the primary analysis will be performed on the FAS population.
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 arms will 
be multiply imputed 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 


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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 PHN 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 will be performed corresponding to the primary and 
supplementary estimands.
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 three supplementary analyses, 
respectively. Missing data after discontinuation will in a first step be imputed in the same way 
as for the primary and three supplementary analyses, respectively. For the EMA401 arms these 
imputed values will further be worsened in subsequent steps via the application of increasingly 
large penalties (tipping point analysis, Permute 2015).
9.5
Analysis of secondary variables
9.5.1
Efficacy variables 
The following secondary efficacy variables will be evaluated:
1. To compare the efficacy of EMA401 over placebo in 24-hour average pain intensity score 
at Week 12, using an 11 point Numeric Rating Scale (NRS). This comparison will be done 
by testing the null hypothesis of superiority of at least one active dose of EMA401 over 
placebo while adjusting for multiplicity. The estimation of the treatment difference and 
missing data handling will be performed using the method of analysis mentioned for the 
primary analysis. Multiplicity adjustment for the pairwise comparisons will be performed 
using the closed MCP-Mod procedure. The closed MCP-Mod approach works by applying 
the maximum contrast test associated with standard MCP-Mod to all intersection 
hypotheses in a closed testing strategy. As known from standard MCP-Mod the maximum 
contrast test controls the type I error across multiple dose-response shapes, so it is a valid 
level alpha test for all intersection hypotheses, and can thus be applied in the context of 
the closed testing principle.
2. 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 
patients who prematurely discontinue study treatment, the responder status will be 
calculated after missing data are multiply imputed according to the approaches specified 
for the primary and three 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 


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concomitant medications for PHN, 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.
3. 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. 
4. 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.
5. PGIC at Week 12. The proportional odds model with the same factors as the ANCOVA 
model for the primary variable will be used.
6. Change from baseline to Week 12 in NPSI. The total score NPSI (sum of 10 descriptor 
items) variable will be analyzed according to the same ANCOVA model as the one used 
for the primary variable. The temporal items will be summarized descriptively.
7. 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.  
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.
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.


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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 (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.
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 and expected events 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.
Laboratory data will be summarized by presenting summary statistics of raw data and change 
from baseline values, and by presenting shift tables using clinically notable ranges (baseline to 
most extreme post-baseline value). Laboratory data, and specifically liver enzymes, will also 
be summarized by maximum change from baseline. 
For liver enzymes, the number of subjects with newly occurring liver enzymes abnormalities 
will be summarized by treatment group. Plots related to analysis of laboratory data will be 
specified in the statistical analysis plan.
Urine pregnancy test results will also be summarized.
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.


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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
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. 
Pregabalin and gabapentin 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.


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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.
9.6
Analysis of exploratory variables 
The following exploratory analysis will be performed:


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4. The proportion of patients who need rescue medication (at each visit and at least once 
during the study) will be evaluated. 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.
5. The time to first rescue medication intake 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. The Kaplan-Meier estimates of the proportion of 
patients with rescue medication intake, along with the associated 95% confidence 
intervals using the Greenwood’s formula will be provided.


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9.7
Interim analyses
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. 
The DMC is responsible for unblinded safety review to stagger patient exposure to the study 
drug. Randomization of patients to the high dose arm (EMA401 300 mg b.i.d.) in study 
CEMA401A2201 will only be initiated following an unblinded safety review by an independent 
DMC after exposure of 50 patients treated with EMA401 up to 100 mg b.i.d. for at least 8 weeks 
(i.e. 25 patients on 25 mg b.i.d. and 25 patients on 100 mg b.i.d.). Furthermore, another 
unblinded safety review will be conducted after the completion of 12 weeks exposure of 30
patients in the EMA401 300 mg b.i.d. treatment arm and will determine if 300 mg b.i.d. dosing 
can be continued as planned.
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. 
Since no efficacy evaluation will be performed by DMC, no multiplicity adjustment for the 
primary efficacy objective is required. 
9.8
Sample size calculation
With the planned sample size of N=(90, 90, 90, 90) for placebo, 25 mg b.i.d., 100 mg b.i.d. and 
300 mg b.i.d., the power of the dose-response trend test [to reject the null hypothesis of a flat 
dose-response curve where all dose means of EMA401 (EMA401 25 mg b.i.d., EMA401 
100 mg b.i.d., EMA401 300 mg b.i.d.) are equal to the placebo mean] for the primary variable 
is at least 77% under the candidate models using the MCP-Mod methodology (see Section 9.4.2) 
using alpha=0.025 one-sided.
The power calculation is based on the following assumptions:

The assumed true dose-response curves for power calculation are the 5 candidate shapes 
(see Section 9.4.2) with the model parameter chosen so that the maximum effect in the 
dose-range is 1.0 attained with the 300 mg b.i.d. dose. 

The standard deviation is 2.6 points (based on data from pregabalin historical trials –
see FDA Approval Package Medical Review, 2004). In Study EMA401-003, 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.
The planned sample size allows to estimate the placebo-corrected response (the treatment 
difference between the active EMA401 doses and placebo) with a root mean squared error of 
0.34 averaged over the three active doses and taking the maximum over the 5 candidate 
models.


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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.
10.2
Informed consent procedures 
Eligible patients may only be included in the study after providing written (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. In cases 
where the patient’s representative gives consent, the patient must be informed about the study 
to the extent possible given his/her understanding. If the patient is capable of doing so, he/she 
must indicate assent by personally signing and dating the written informed consent document 
or a separate assent form. 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.
 
 
 
 
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.


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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 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 should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
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.
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.
Cunningham AL, Dworkin RH (2000) The management of post-herpetic neuralgia. Br Med J;
321(7264):778–9.
Dworkin RH, Turk DC, Peirce-Sandner S, et al (2010) Research design considerations for 
confirmatory chronic pain clinical trials: IMMPACT recommendations. Pain;149: 177-193.
European Medicines Agency (2015) Report from Dose Finding Workshop. 
EMA/117491/2015 (Internet) Available from: 
<http://www.ema.europa.eu/docs/en_GB/document_library/Report/2015/04/WC500185864.p
df> (Accessed 25 Jan 2017).
European Medicines Agency, Committee for Medicinal Products for Human Use (2015) 
Guideline on the clinical development of medicinal products intended for the treatment of 
pain. EMA/CHMP/970057/2011, Corr. 1 (Internet) Available from:                                         
<http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/12/WC
500199242.pdf> (Accessed 12 Dec 2016).
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 (2014) Guidance 
for Industry Analgesic Indications: Developing Drug and Biological Products, Draft guidance 
(Internet) Available from:
<http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/
ucm384691.pdf> (Accessed 12 Dec 2016).
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).
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;
371:1526–1533.
Kravit A, Kuranz S (2015) Neuropathic Pain. Decision Resources Group. 2015 DR/Decision 
Resources, LLC.


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Mixcoatl-Zecuatl T, Calcutt NA (2013) Biology and Pathophysiology of Painful Diabetic 
Neuropathy. in: E. Lawson, M. 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.
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. 
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.
 
 


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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)
 
 


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Criteria
Actions required
Follow-up monitoring
> 5 to ≤ 8 × ULN

Repeat LFT within 48 hours

If elevation persists, continue follow-up 
monitoring

If elevation persists for more than 2 
weeks, discontinue the study drug

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
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
Investigator discretion


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Criteria
Actions required
Follow-up monitoring

Establish causality

Complete liver CRF
collected at the time of event, after 48 
hours, after 96 hours if 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 of health authorities and IRB/IECs.


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


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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: 
o
Requiring a markedly increased dose of the substance to achieve the desired 
effect 
o
A markedly reduced effect when the usual dose is consumed. 
11. Withdrawal, as manifested by either of the following:
o
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. 
o
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_001.pdf: 
Clinical Development
EMA401
CEMA401A2201 / NCT03094195
A double-blind, placebo-controlled, randomized dose 
ranging trial to determine the safety and efficacy of three 
dose levels of EMA401 in reducing 24-hour average pain 
intensity score in patients with post-herpetic neuralgia 
(EMPHENE)
Statistical Analysis Plan (SAP)
Author:
 (CRO), 
Document type:
SAP Documentation
Document status:
Amendment 1 Final
Release date:
07-Jun-2019
Number of pages:
35
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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SAP
CEMA401A2201
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
23-
Jun-
2017
Prior 
to 
FPFV
Creation 
of 
final version
N/A – First version
NA
07-
Jun-
2019
Before 
DB 
lock
Creation 
of 
amendment 1

Tables 
added 
as 
required 
for 
ClinicalTrials.gov and EudraCT 

Clarification of the definition of newly 
occurring or worsening

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

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

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

Plot for liver function test have been removed  
2.8.1 Adverse events 
2.8.3 Laboratoy data 
2.8.4 Other safety data
1.1, Study design, 
 
  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)
2.13 Other Exploratory 
analyses
2.8.1
Adverse  
events (AEs)
2.8.1.2 Liver events
2.8.3
Laboratory 
data


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SAP
CEMA401A2201
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)

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
2.8.4
Other safety 
data
 
 
5.1.5 
Prohibited 
medication for PDS


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SAP
CEMA401A2201
Table of contents
Table of contents .................................................................................................................4
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................9
1.1
Study design.............................................................................................................9
1.2
Study objectives and endpoints .............................................................................10
2
Statistical methods.............................................................................................................11
2.1
Data analysis general information .........................................................................11
2.1.1
General definitions................................................................................12
2.2
Analysis sets ..........................................................................................................14
14
2.3
Patient disposition, demographics and other baseline characteristics ...................14
2.3.1
Patient disposition.................................................................................15
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................15
2.4.1
Study treatment / compliance................................................................15
2.4.2
Prior, concomitant and post therapies...................................................15
2.5
Analysis of the primary objective..........................................................................16
2.5.1
Primary endpoint...................................................................................16
2.5.2
Statistical hypothesis, model, and method of analysis..........................16
2.5.3
Handling of missing values/censoring/discontinuations.......................20
2.5.4
Supportive analyses...............................................................................20
2.6
Analysis of the key secondary objective ...............................................................21
2.7
Analysis of secondary efficacy objective(s)..........................................................21
2.7.1
Testing of superiority with regard to NRS at Week 12.........................21
2.7.2
Responder Analysis...............................................................................21
2.7.3
Other secondary efficacy objectives .....................................................22
2.8
Safety analyses.......................................................................................................22
2.8.1
Adverse events (AEs)............................................................................22
2.8.2
Deaths....................................................................................................24
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
2.11
Patient-reported outcomes .....................................................................................26
2.12
Biomarkers.............................................................................................................26
2.13
Other Exploratory analyses....................................................................................26


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CEMA401A2201
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 PHN .................................................................................29
5.1.3
AE date imputation ...............................................................................29
5.1.4
Concomitant medication date imputation .............................................29
5.1.5
Prohibited medication for PHN.............................................................29
5.2
AEs coding/grading ...............................................................................................29
5.3
Laboratory parameters derivations ........................................................................29
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 ............................................30
5.4.3
Brief Pain Inventory- Short Form (BPI-SF)..........................................30
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)...............................................................31
31
32
32
32
32
5.5
Statistical models...................................................................................................34
5.5.1
Primary analysis....................................................................................34
5.5.2
Secondary analysis................................................................................34
5.5.3
Exploratory analysis..............................................................................34
5.6
Rule of exclusion criteria of analysis sets..............................................................34
6
References .........................................................................................................................35


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CEMA401A2201
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
BL
Baseline
BPI-SF
Brief Pain Inventory-Short Form
CRO
Contract Research Organization
 
CSR
Clinical Study Report 
DAR
Dose Administration Record
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ED50
The dose at which half of the maximum effect is reached
eGFR
Estimated Glomerular Filtration Rate
Emax
The maximum effect attributable to the drug
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 
LFT
Liver function test 
LoE
Lack of efficacy
MAR
Missing at random
mFAS
Modified Full Analysis Set
MCP-Mod
Multiple Comparison Procedure – Modelling
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical dictionary for regulatory activities 
NPSI
Neuropathic Pain Symptom Inventory 
NRS
Numeric Rating Scale
NSAID
Nonsteroidal Anti-inflammatory Drugs
PCR
Protein-Creatinine Ratio


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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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CEMA401A2201
Amendment 1
This amendment of the statistical analysis plan (SAP) is largely based on changes induced  due 
to the early termination of  the CEMA401A2201 study.  129 patients out of 360 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.
Due to the considerably reduced number of patients who completed the study, only 
descriptive subgroup analyses will be provided. Moreover, most of the secondary 
 
 endpoints will also be summarized descriptively only. 
 
 


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1
Introduction
This statistical analysis plan (SAP) describes all planned analyses for the Clinical Study Report 
(CSR) of study CEMA401A2201, a Phase 2, double-blind, placebo-controlled, randomized 
dose ranging trial to determine the safety and efficacy of three dose levels of EMA401 in 
reducing 24-hour average pain intensity score in patients with post-herpetic neuralgia. 
The content of this SAP is based on the final version of protocol CEMA401A2201 Amendment 
1 (release date 14-May-2018). 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, dose ranging, double-
blind treatment.
The study will consist of a Screening epoch (up to 5 weeks), a double-blind Treatment epoch 
(12 weeks), and a double-blind Treatment withdrawal epoch (1 week).

In the initial cohort, patients will be randomized in a 1:1:1 ratio to treatment with placebo, 
EMA401 25 mg b.i.d., or EMA401 100 mg b.i.d. (approximately 135 patients). 
Randomization of patients to the high dose arm (EMA401 300 mg b.i.d.) will only be 
initiated following an unblinded safety review by an independent Data Monitoring 
Committee (DMC) after exposure of 50 patients treated with EMA401 up to 100 mg b.i.d. 
for at least 8 weeks (i.e. 25 patients on 25 mg b.i.d. and 25 patients on 100 mg b.i.d.).

Future patients will then be randomized in the second cohort in a 1:1:1:2 ratio to treatment 
with placebo, EMA401 25 mg b.i.d., EMA401 100 mg b.i.d., or EMA401 300 mg b.i.d. 
(approximately 225 patients).
Overall approximately 360 patients 
were estimated to be enrolled in the study (i.e. 
approximately 90 patients were planned to be enrolled in each treatment arm). Due to the early 
termination in the scope of USM the EMA401 300 mg b.i.d. treatment arm was not initiated as 
planned. The original 1:1:1 randomization ratio has been applied to treatment with placebo, 
EMA401 25 mg b.i.d., or EMA401 100 mg b.i.d 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 (e.g. America, Europe and Australia, Asia) and use 
of concomitant pain medication for PHN (yes/no) in order to achieve balance of treatment 
allocation within the stratification factors.
Primary objective of this study is to characterize dose-response for change in the weekly mean 
of 24-hour average pain intensity scores at Week 12.


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CEMA401A2201
1.2
Study objectives and endpoints
Table 1-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)

To characterize dose-response for 
change in the weekly mean of 24-hour 
average pain intensity scores at 
Week 12 
Endpoint(s) for primary objective(s) 

Dose-response in change in weekly 
mean of the 24-hour average pain 
score, using an 11-point Numeric 
Rating Scale (NRS), from Baseline to 
Week 12
Secondary 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 at least one 
active dose of EMA401 vs. placebo

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 effect of EMA401 
compared to placebo on the 
Neuropathic Pain Symptom Inventory 
(NPSI) at Week 12

To evaluate the safety and tolerability of 
EMA401 compared to placebo in PHN 
patients, as measured by treatment 
emergent adverse events (TEAEs), 
adverse events (AEs) leading to study 
Endpoint(s) for secondary objective(s)

Change in weekly mean 24-hour 
average pain score (using the 11 point 
NRS) from Baseline to Week 12

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 Week 12

Proportion of patients meeting 
responder criteria from Baseline to 
Week 12

Change in ISI from Baseline to Week 
12

Change in NPSI 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.


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Objective(s)
Endpoint(s)
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

Plasma pharmacokinetics of EMA401 
will be characterized by population 
non-linear mixed effects modeling 
techniques
Exploratory Objective(s) 

To evaluate the proportion of patients 
who need rescue medication and the 
time to first intake of rescue medication
Endpoint(s) for exploratory objective(s)

Proportion of patients who need rescue 
medication and the time to first intake 
of rescue medication24-hour average 
NRS pain score by subgroup
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.


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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: 12.5 mg, 50 mg.
All dosage strengths of 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:
•
Placebo b.i.d.
•
EMA401 25 mg 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 25 mg b.i.d. -> EMA401 25 mg b.i.d.
•
EMA401 25 mg 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:


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
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:
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 5 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 
 
 
he 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.


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These visit windows need not to be exactly the same as the formal visit windows what the sites 
have to follow for their scheduling.
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) will include all patients randomized. 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 and who had at least one post-baseline safety assessment.
The primary efficacy analysis will be the FAS.
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, QTc using Fridericia's correction, 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 PHN into < 1 year, > 1 - 5 years, > 5 - 10 years, > 10 - 15 years, > 15 - 20 
years, and > 20 years; 
Demographic and background information will be summarized for 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.


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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 reason 
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. 
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).The PHN medications recorded on the Screening PHN 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.


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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 and treatment withdrawal period separately. Visit mapping will be done 
according to the visit window strategy document. 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 
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 are detailed in the Estimand Charter. 
The primary estimation method is based on an Analysis of Covariance (ANCOVA) model
including region (America orEurope and Australia, Asia), treatment, sex, use of concomitant 
pain medication for PHN (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 PHN: Efficacy observations collected 
during the period of changes in doses of concomitant medication for PHN (compared to 
baseline) and the 2-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 
multiply imputed using the Missing at random (MAR) assumption.

Intake of rescue medication: Efficacy data collected during intake of rescue medication 
will be used for analysis. 


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
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 
 
 
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 multiply imputed 
using the MAR assumption.
Table 2-1
Prohibited medication
Medication
Prohibition period
Action taken for study 
treatment
Prohibited prior to Randomization and throughout study
High dose capsaicin patch (8%)
3 months prior to 
Randomization and after 
Randomization
Discontinue study treatment 
Prohibited 2 week prior to Randomization and throughout the study
Any skeletal muscle relaxant (e.g. 
baclofen, orphenadrine, 
methocarbamol)
2 weeks prior to 
Randomization and after 
Randomization
None
Mexiletine
2 weeks prior to 
Randomization and after 
Randomization
None
Dextromethorphan
2 weeks prior to 
Randomization and after 
Randomization
None
Memantine
2 weeks prior to 
Randomization and after 
Randomization
None
Alpha-lipoic acid
2 weeks prior to 
Randomization and after 
Randomization
None
Other anti-epileptic drugs (e.g. valproic 
acid, carbamazepine, phenytoin)
2 weeks prior to 
Randomization and after 
Randomization
Discontinue study treatment 
upon 2nd episode of 
medication use
Oral or injectable steroids
2 weeks prior to 
Randomization and after 
Randomization
Discontinue study treatment 
upon 2nd episode of 
medication use
Monoamine oxidase inhibitors or any 
other antidepressants (except stable 
dosage of SSRI)
2 weeks prior to 
Randomization and after 
Randomization
Discontinue study treatment 
upon 2nd episode of 
medication use


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Medication
Prohibition period
Action taken for study 
treatment
Antipsychotic or neuroleptic 
medications
2 weeks prior to 
Randomization and after 
Randomization
Discontinue study treatment 
upon 2nd episode of 
medication use
Cannabinoids (e.g. marijuana)
2 weeks prior to 
Randomization and after 
Randomization
Discontinue study treatment 
upon 2nd episode of 
medication use
Prescribed opioids, including codeine
2 weeks prior to 
Randomization and after 
Randomization
Discontinue study treatment 
upon 2nd episode of 
medication use
Any prescription systemic pain 
medication, or topical treatment for 
PHN, including lidocaine plaster 
2 weeks prior to 
Randomization and after 
Randomization
Discontinue study treatment 
upon 2nd episode of 
medication use
Nonsteroidal Anti-inflammatory Drugs 
(NSAIDs) or any other over-the-counter 
pain medications
2 weeks prior to 
Randomization and after 
Randomization
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)
2 weeks prior to 
Randomization and after 
Randomization
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) , Antiviral 
medications (e.g. valacyclovir, 
acyclovir, amantadine, anti-HIV), 
Antifungals (e.g Azoles)
2 weeks prior to 
Randomization and after 
Randomization
None
Prohibited after Randomization and throughout study
Any change to a different
standard of care medication from
baseline (e.g. switch from
pregabalin to gabapentin) will be
treated as prohibited medication
After randomization
Discontinue study
treatment
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 


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will be multiply imputed based on placebo arm data, i.e. “jump to reference” (J2R) 
assumption for the EMA401 arms, missing at random assumption for placebo arm 
(Carpenter, Roger, and Kenward 2013). If no RDO data was collected after study 
treatment  permanent discontinuation, missing data will be multiply imputed based on the 
J2R  assumption for the EMA arms and under the MAR assumption for placebo arm. 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 multiply imputed 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.
If the 300 mg b.i.d dose would have been initiated: The primary objective would have been 
achieved if the null hypothesis of flat dose-response curve (where all dose means are equal to 
the placebo mean) at Week 12 is rejected using alpha=0.025 one-sided. The null hypothesis of 
a flat dose-response curve will be tested using Multiple Comparison Procedure – Modelling 
(MCP-Mod) with three Emax and two sigmoidal-Emax dose response models as the candidate 
shapes. The following ED50 (the dose at which half of the maximum effect is reached) values 
will be used for the Emax models: 17, 80, and 200. The parameters of the sigmoidal Emax models 
(ED50, h) will be as follows: (77, 3) and (175, 1.5), where h is the Hill parameter that determines 
the steepness of the dose-response shape. The MCP-Mod dose response test will be performed 
at each post-baseline visit. No multiplicity adjustment by visit will be carried out.
Dose-response estimation will be performed based on the ANCOVA least square estimates 
using MCP-Mod as described in Pinheiro et al (2014). The same candidate models as above 
will be used in a model averaging approach to obtain an estimate of the dose-response curve. 
The final estimate of the dose-response curve is the median of the dose-response curves 
obtained. 
The same ANCOVA model will be applied at the visits prior to Week 12.
Summary statistics for absolute values and change from baseline by treatment and visit will be 
provided for the original measurements (i.e. 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. 
 
 
In the event the EMA401 300 mg b.i.d. dose cannot be initiated, the trend tests deduced from 
the set of candidate models will be performed but the dose response estimation will not be 
performed. In that case, the first secondary objective will be evaluated to compare the efficacy 
of the remaining doses of EMA401 over placebo in 24-hour average pain intensity score at 
Week 12, using an 11 point Numeric Rating Scale (NRS). This comparison will be done by


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testing the null hypotheses of superiority of EMA401 25 mg b.i.d. over placebo and of EMA401 
100 mg b.i.d. over placebo, while adjusting for multiplicity. The estimation of the treatment 
difference and missing data handling will be performed using the method of analysis mentioned 
for the primary analysis. Multiplicity adjustment for the pairwise comparisons will be 
performed using the Hochberg procedure. 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. 
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 (i.e. collected prior to study treatment 
discontinuation), the mean will be calculated based on those on-treatment values. If all seven 
values in one week are off-treatment because collected after study treatment discontinuation 
(RDO), the resulting weekly average will be regarded as an RDO value for analysis.
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.
2.5.4
Supportive analyses
2.5.4.1
Supplementary analysis
The following supplementary analysis to the primary analysis 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 in both treatment arms will be imputed using 
the MAR assumption. 
2.5.4.2
Sensitivity analysis
A sensitivity analysis will be performed on the mFAS population using the same ANCOVA 
model and the same rules for handling intercurrent events as for the primary analysis.


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2.6
Analysis of the key secondary objective
Not applicable.
2.7
Analysis of secondary efficacy objective(s)
The following secondary efficacy variables will be evaluated for the FAS:
2.7.1
Testing of superiority with regard to NRS at Week 12
To compare the efficacy of EMA401 over placebo in 24-hour average pain intensity score at 
Week 12, using an 11 point Numeric Rating Scale (NRS). This comparison will be done by 
testing the null hypotheses of superiority of EMA401 25 mg or  over placebo and of EMA401 
100 mg over placebo while adjusting for multiplicity. Multiplicity adjustment for the pairwise 
comparisons will be performed using the Hochberg procedure. Based on the set of candidate 
models as specified in Section 2.5.2 trend tests will be performed to evaluate the existence of a 
dose-response effect using MCP-mod. 
2.7.2
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 analyses 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 estimands 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 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 PHN 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.


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The responder analyses will be performed for each visit, with the obvious modification in the 
definition for the week of interest. 
2.7.3
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.
3. Number of patients in each level of PGIC at Week 12 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. Change from baseline to Week 4, Week 8 and Week 12 in NPSI. The total score NPSI 
(sum of 10 descriptor items) variable will be analyzed according to the same ANCOVA 
model as the one used for the primary variable. NPSI total score will also be summarized 
descriptively by treatment and visit. The same supplementary analysis as for the primary 
endpoint will be performed. Multiple imputation will be carried out in a similar fashion as 
for the primary analysis of the NRS pain score. The 5 dimensions of pain (burning pain, 
deep/pressing pain, paroxysmal pain, evoked pain, paraesthesia/dysesthesia) will be 
summarized descriptively by treatment and visit in the double-blind treatment epoch.
5. Insomnia Severity Index (ISI) will be summarized descriptively by treatment and visit. 
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 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. 
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. 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. 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 epochSeverity 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 


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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 TEAES with onset date before 25-Feb-2019
For rash adverse events, following details will be listed:

Laterality and location of rash

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 Sheet. 
The most recent Compound Case Retrieval Strategy (eCRS) at the time of database lock will 
be used to determine the MedDRA search criteria to identify events of special interests.


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2.8.2
Deaths
The primary reason for death will be summarized by system organ class and preferred term. All 
deaths will be listed. Deaths for screen failures will be listed separately.
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. The 
same approach as for notable laboratory values will be used to define newly occurring notable 
vital sign values. 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.
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.
2.13
Other Exploratory analyses
The following exploratory analysis will be performed:
1. The proportion of patients who need rescue medication (at each visit and at least once 
during the study) will be evaluated. 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.
2. The Kaplan-Meier estimates of the proportion of patients with rescue medication intake, 
along with the associated 95% confidence intervals using the Greenwood’s formula will 
be provided.
3. The proportion of EMA401 patients achieving a 30%, 50% reduction in the weekly 
mean of the 24-hour average NRS pain score compared to placebo at Week 4 and at 
Week 12 will be evaluated after multiple imputation is done on the primary variable. 
The corresponding responder variables will be derived and analyzed based on a logistic 


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regression model with the same factors as the ANCOVA model for the primary analysis. 
Cumulative responder plots will be displayed. 
2.14
Interim analysis - Safety
The DMC is responsible for unblinded safety review to stagger patient exposure to the study 
drug. Randomization of patients to the high dose arm (EMA401 300 mg b.i.d.) will only be 
initiated following an unblinded safety review by an independent DMC after exposure of 50 
patients treated with EMA401 up to 100 mg b.i.d. for at least 8 weeks (i.e. 25 patients on 25 mg 
b.i.d. and 25 patients on 100 mg b.i.d.). Furthermore, another unblinded safety review was 
planned after the completion of 12 weeks exposure of 30 patients in the EMA401 300 mg b.i.d. 
treatment arm to determine if 300 mg b.i.d. dosing can be continued as planned. Due to the 
early termination in the scope of USM the EMA401 300 mg b.i.d. treatment arm was not 
initiated as planned. 
The DMC reviews 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 had been specified in a separate DMC analysis 
plan and not repeated here in detail. 
3
Sample size calculation
With the planned sample size of N=(90, 90, 90, 90) for placebo, 25 mg b.i.d., 100 mg b.i.d. and 
300 mg b.i.d., the power of the dose-response trend test [to reject the null hypothesis of a flat 
dose-response curve where all dose means of EMA401 (EMA401 25 mg b.i.d., EMA401 
100 mg b.i.d., EMA401 300 mg b.i.d.) are equal to the placebo mean] for the primary variable 
is at least 77% under the candidate models using the MCP-Mod methodology using 
alpha=0.025 one-sided.
The power calculation is based on the following assumptions:

The assumed true dose-response curves for power calculation are the 5 candidate shapes 
(see Section 2.5) with the model parameter chosen so that the maximum effect in the 
dose-range is 1.0 attained with the 300 mg b.i.d. dose. 

The standard deviation is 2.6 points (based on data from pregabalin historical trials –
see FDA Approval Package Medical Review, 2004). In Study EMA401-003, 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.
The planned sample size allows to estimate the placebo-corrected response (the treatment 
difference between the active EMA401 doses and placebo) with a root mean squared error of 
0.34 averaged over the three active doses and taking the maximum over the 5 candidate 
models.


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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
- 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 
- time to "sustained" pain reduction
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.


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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 PHN
Rules for imputing date of first diagnosis of PHN 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 PHN
Exclusion period of values in case of changed PHN medication or intake of prohibited 
medication will be derived as follows:

Programming Dataset Specification (PDS) will describe how to identify dose changes of 
concomitant PHN 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
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 covered under the adverse events analysis, safety topics of interest ):

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)


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
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 note to file at 
 path 
 
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. 
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.


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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
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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5.5
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 + region + treatment + sex + age + PHNmed (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 + region + treatment + sex + age + PHNmed (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.
5.5.3
Exploratory analysis
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
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.
CEMA401A2201 Handling of missing items in the derivation of total scores for efficacy 
measures (last version available before DB lock is used)
CEMA401A2201 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)
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