Clinical trial NCT02700815
Conditions: Acute Pain
Sponsor: Boehringer Ingelheim
Start date: 2016-05-09; Completion date: 2017-07-21
Enrollment: 746 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomised, controlled multi-centre parallel group trial will assess the efficacy and tolerability of a topical formulation gel of the combination of diclofenac and capsaicin in comparison to gels with diclofenac alone, capsaicin alone, and placebo for the treatment of acute back pain or neck pain

Detailed description:

Arms: arm 1: Fixed dose combination arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: Diclofenac intervention 2: Capsaicin intervention 3: Placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_001.pdf: 
001-MCS-40-106-RD-03 (11.0) / Saved on: 24 Jul 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c03317678-02
EudraCT No.:
2015-000404-25
BI Trial No.:
1358.1
BI Investigational 
Products:
Diclofenac + Capsaicin
Title:
A randomized, controlled multi-centre parallel group study to 
assess the efficacy and safety of multiple doses of a topically 
applied combination containing diclofenac 2% + capsaicin
0.075% (2 g formulation per application; 2-times daily for 
5 days) compared to placebo, as well as to diclofenac 2% and 
capsaicin 0.075% in patients with acute back or neck pain
Brief Title:
Capsaicin/diclofenac gel in acute back pain or neck pain
Clinical Phase:
III
Trial Clinical 
Monitor:
Phone: 
, Fax: 
Coordinating 
Investigator:
Phone: 
, Fax: 
Status:
Final Protocol
Version and Date:
Version: 2.0
Date: 21 Jun 2016
Page 1 of 69
Proprietary confidential information.
2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim
Name of finished product:
Name of active ingredient:
Diclofenac + Capsaicin
Protocol date:
09-Dec-2015
Trial number:
1358.1
Revision date:
21-Jun-2016
Title of trial:
A randomized, controlled multi-centre parallel group study to assess the 
efficacy and safety of multiple doses of a topically applied combination 
containing diclofenac 2% + capsaicin 0.075% (2 g formulation per application; 
2-times daily for 5 days) compared to placebo, as well as to diclofenac 2% and 
capsaicin 0.075% in patients with acute back or neck pain
Coordinating
Investigator:
Phone: 
, Fax: 
Trial site(s):
Multi-centre trial, conducted in 2 countries
Clinical phase:
III
Objective(s):
To assess the efficacy and tolerability of a topical formulation gel of the 
combination of diclofenac and capsaicin in comparison to gels with diclofenac 
alone, capsaicin alone, and placebo for the treatment of acute back pain or neck 
pain.
The primary objective of this trial is to demonstrate superior efficacy of a 
formulation containing a combination of 2% diclofenac and 0.075% capsaicin 
over placebo and over formulations containing 2% diclofenac alone and 
0.075% capsaicin alone for the treatment of acute back or neck pain.
A secondary objective is to assess the safety and tolerability of the combination 
of diclofenac and capsaicin in comparison to gels with diclofenac alone, 
capsaicin alone.
Methodology:
Randomized, double-blind, placebo- and active-controlled, multi-centre 4-arm 
parallel group study, conducted in 2 countries
No. of patients: 
total entered:
Approximately 800 to achieve 700 patients eligible for the assessment of the 
primary endpoint
each treatment:
Diclofenac and capsaicin:
240
Diclofenac:
240
Capsaicin:
240
Placebo:
  80
Diagnosis :
Acute back pain or neck pain


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Name of company:
Boehringer Ingelheim
Name of finished product:
Name of active ingredient:
Diclofenac + Capsaicin
Protocol date:
09-Dec-2015
Trial number:
1358.1
Revision date:
21-Jun-2016
Main criteria
for inclusion:
Male or female patients ≥18 years with current diagnosis of acute back pain or 
of neck pain.
Acute back pain or acute neck pain resulting in pain on movement (POM) 
≥50 mm (VAS 0-100) for at least one POM procedure out of 5 standardized 
procedures.
Sensitivity to algometric pressure on the painful trigger point ≤ 25 N/cm²
Test product:
Capsaicin + diclofenac gel
dose:
0.075% Capsaicin, 2% diclofenac sodium, 2 g formulation (40 mg diclofenac 
sodium, 1.5 mg capsaicin) twice daily
mode of 
administration:
Topical
Comparator product 1:
Capsaicin gel
dose:
0.075% Capsaicin, 2 g formulation (1.5 mg capsaicin) twice daily
mode of 
administration:
Topical
Comparator product 2:
Diclofenac gel
dose:
2% Diclofenac sodium, 2 g formulation (40 mg diclofenac) twice daily
mode of 
administration:
Topical
Comparator product 3:
Placebo gel
dose:
Not applicable, 2 g formulation twice daily
mode of 
administration:
Topical
Duration of treatment:
Screening and start of treatment at the same visit (Visit 1)
5 day treatment period
2 day follow-up period
Endpoints
Primary endpoint:

Change in POMWP (for the worst procedure, i.e. the procedure leading 
to maximum pain) between baseline and Day 2 evening, 1 hour after 
drug application
Key secondary endpoints

POMWPAUC72 (Area under the curve of POMWP assessed until Day 4
morning, i.e. 72 hours after start of treatment)

POMWPAUC120 (Area under the curve of POMWP assessed until Day 6
morning, i.e. 120 hours after start of treatment)
Other secondary endpoints:

Number of patients with a decrease in POMWP of at least 30% from 
baseline on Day 2 evening, 1 hour after drug application 


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Name of company:
Boehringer Ingelheim
Name of finished product:
Name of active ingredient:
Diclofenac + Capsaicin
Protocol date:
09-Dec-2015
Trial number:
1358.1
Revision date:
21-Jun-2016

Number of patients with a decrease in POMWP of at least 50% from 
baseline on Day 2 evening, 1 hour after drug application 

Change in POMWP between baseline and the morning of Day 6 

Change in Pressure Algometry (PA) between baseline and Day 2 
evening, before drug application

Change in PA between baseline and the morning of Day 6 
Safety criteria:
Skin check, incidence of adverse events, physical examination, vital signs, 
safety laboratory parameters, patient and investigator assessment of tolerability
Statistical methods:
For the primary endpoint 

Change in POMWP between baseline and Day 2 evening, 1 hour after 
drug application
and the secondary endpoints 

Change in POMWP between baseline and the morning of Day 6 

Change in PA between baseline and Day 2 evening, before drug 
application

Change in PA between baseline and the morning of Day 6, 
restricted maximum likelihood estimation based on a mixed-effect model for 
repeated measures analysis will be used to obtain adjusted means for the 
treatment effects. This model will include treatment, time, the stratification 
factors country and application site (back/neck) as discrete fixed effects, 
baseline POMWP as a continuous fixed effect, and interaction between time and 
treatment as well as baseline POMWP and time. The primary treatment 
comparison will be the contrast between treatments at the endpoint time, 
respectively.
The key-secondary endpoints POMWPAUC72 and POMWPAUC120 will be 
analysed using analysis of covariance including treatment, country and 
application site (back/neck) as fixed effects and the baseline POMWP as a 
continuous covariate.
The number of patients with a decrease in POMWP of at least 30% or 50%, 
respectively, from baseline until Day 2 evening, 1hour after drug application,
will be analysed by a logistic regression model, including the factor treatment 
and the categorical stratification factors country and application site 
(back/neck).


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FLOW CHART
VisitK
1
Hm
2
3
4
Hm
5
Hm
Hm
6
7T
Fllw 
up
Day
1
2
3
4
5D
6D
8D
Time window for visits
±0
±0
±0
±0
±0
-1/+2
-1/+4
Approximate day timeB
M
E
MC
EC
M
E
M
E
M
E
M
Timing rel. to applicationH
Pre
Apl
Post
Apl
Pre
Apl
Post
Pre
Apl
Post
Pre
Apl
Post
Apl
Pre
Apl
Post
Apl
Apl
Apl
Patient information and 
informed consent
X
Demographics
X
Medical history
X
Previous therapies
X
Concomitant therapies
X
X
X
X
X
X
X
Vital signs
X
X
Physical examination
X
Pain On Movement (POM)L
X
XI
XI
X
XI
XI
XI
X
Pressure Algometry (PA)
X
X
X
X
X
X
Urine pregnancy testE
X
Safety laboratory tests
X
X
X
XG
X
XN
X
XN
X
XN
X
XN
XM
X
X
XF
XF
XF
XF
XF
Review of in-/exclusion 
criteria
X
Randomization via 
Interactive Response 
Technology (IRT)
X
Weighing of trial medication/ 
drug accountability
X
X
Dispense of trial drug and 
gloves; Instructions on use
X
Application of trial drug
X
X
X
X
X
X
X
X
X
X
Dispense rescue medication;
Instructions on use
X
XJ


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VisitK
1
Hm
2
3
4
Hm
5
Hm
Hm
6
7T
Fllw 
up
Day
1
2
3
4
5D
6D
8D
Time window for visits
±0
±0
±0
±0
±0
-1/+2
-1/+4
Approximate day timeB
M
E
MC
EC
M
E
M
E
M
E
M
Timing rel. to applicationH
Pre
Apl
Post
Apl
Pre
Apl
Post
Pre
Apl
Post
Pre
Apl
Post
Apl
Pre
Apl
Post
Apl
Apl
Apl
Hand-out of patient diary; 
Instructions on use
X
X
X
X
X
Assessment of skin reactions 
XN
XN
XN
XN
XN
X
XG
XG
XF
XF
XF
XF
XF
XG
Patient diary: Use of 
rescue/other medication
Continuously
Transfer of patient diary 
entries to electronic Case 
Report Form (eCRF)
X
X
X
X
X
Return of patient diary
X
X
X
X
X
Overall 
 and 
tolerability assessment by 
patient and by investigator
X
Return of trial drug and 
rescue medication
X
Adverse events
X
X
X
X
X
X
X
Completion of patient 
participation
XA
XA
A
Completion of patient participation also needs to be completed if the patient withdraws prematurely following randomization (see Section 3.3.3)
B
M = Morning; E = Evening; Morning visits should generally be performed between 7:00 am and 11:00 am.
C
Visits 2 and 3 need to be planned so that the evening application of the trial medication can be administered 12 hours (±4 hours) after the morning application.
D
Date of Visit 6 has to be agreed based on patient’s availability and severity of pain. Standard treatment duration is 5 days (Day 1-5) with Visit 6 on Day 6. Treatment could be shortened to 
4 days (with Visit 6 on Day 5) or extended to 6 days (with Visit 6 on Day 7; home procedures indicated in the Flow Chart for Day 5 to be repeated on Day 6) or 7 days (with Visit 6 on 
Day 8; home procedures indicated in the Flow Chart for Day 5 to be repeated on Day 6 and 7). Visit 7T should be performed at least 2 days and no later than 4 days after Visit 6. 
E
For women of childbearing potential only


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G
Parameters to be assessed by the patient 0.5 (±5 min), 1 (±10 min but before POM assessments), 3 (±15 min) and 6 (±15 min) hours after the morning application of the trial drug. Results 
will be entered into the patient diary.
H
Pre = before application; Apl = Application; Post = after application. The application time at each visit is to be documented in the eCRF. 
I
Assessment 1 hour (±10 min) after application of trial medication
J
Optional second dispense of rescue medication
K
Hm = Home procedure; Fllw up = Follow up
L
All five POM assessments need to be performed at Visit 1 before application. Once POMWP is determined, only POMWP and the other POM procedures related to the same stratum (either 
back or neck pain) as POMWP need to be performed at subsequent assessments (see Section 5.2.1)
M
To be assessed by the patient at home directly before and 1 hour (±10 min) after the morning application of the trial drug
N
To be assessed 1 hour (±10 min) after application of the trial drug and before POM assessments


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................8
ABBREVIATIONS................................................................................................................11
1.
INTRODUCTION...............................................................................................13
MEDICAL BACKGROUND.............................................................................13
1.1
DRUG PROFILE................................................................................................14
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....15
RATIONALE FOR PERFORMING THE TRIAL.........................................15
2.1
TRIAL OBJECTIVES........................................................................................15
2.2
BENEFIT - RISK ASSESSMENT.....................................................................15
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................17
OVERALL TRIAL DESIGN AND PLAN .......................................................17
3.1
3.1.1
Administrative structure of the trial .................................................................18
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)......................................................................................19
SELECTION OF TRIAL POPULATION .......................................................19
3.3
3.3.1
Main diagnosis for trial entry ............................................................................20
3.3.2
Inclusion criteria .................................................................................................20
3.3.3
Exclusion criteria ................................................................................................21
3.3.4
Removal of patients from therapy or assessments...........................................22
Removal of individual patients .............................................................................22
3.3.4.1
Discontinuation of the trial by the sponsor...........................................................23
3.3.4.2
4.
TREATMENTS...................................................................................................24
TREATMENTS TO BE ADMINISTERED.....................................................24
4.1
4.1.1
Identity of BI investigational product and comparator products ..................24
4.1.2
Method of assigning patients to treatment groups...........................................26
4.1.3
Selection of doses in the trial..............................................................................27
4.1.4
Drug assignment and administration of doses for each patient......................27
4.1.5
Blinding and procedures for unblinding...........................................................27
Blinding.................................................................................................................27
4.1.5.1
Unblinding and breaking the code ........................................................................28
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................28
4.1.7
Storage conditions...............................................................................................28
4.1.8
Drug accountability.............................................................................................28
Patient treatment compliance................................................................................29
4.1.8.1
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
4.2
TREATMENT.....................................................................................................29


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4.2.1
Rescue medication, emergency procedures, and additional treatment(s) .....29
4.2.2
Restrictions ..........................................................................................................30
Restrictions regarding concomitant treatment ......................................................30
4.2.2.1
Restrictions on diet and life style..........................................................................30
4.2.2.2
Restrictions regarding women of childbearing potential ......................................30
4.2.2.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................31
TRIAL ENDPOINTS..........................................................................................31
5.1
5.1.1
Primary Endpoint(s)...........................................................................................31
5.1.2
Key Secondary Endpoints ..................................................................................31
5.1.3
Other Secondary Endpoints...............................................................................31
...............................................................................................31
ASSESSMENT OF EFFICACY........................................................................32
5.2
5.2.1
Pain On Movement .............................................................................................32
5.2.2
Pressure algometry .............................................................................................35
........................................................................35
........................................................................35
........................................................................35
........................................................................35
........................................................................36
........................................................................36
ASSESSMENT OF SAFETY.............................................................................36
5.3
5.3.1
Assessment of skin reactions..............................................................................36
5.3.2
Overall assessment of tolerabilty.......................................................................37
5.3.3
Physical examination ..........................................................................................37
5.3.4
Vital Signs............................................................................................................37
5.3.5
Safety laboratory parameters ............................................................................38
5.3.6
Assessment of adverse events.............................................................................38
Definitions of AEs ................................................................................................38
5.3.6.1
5.3.7
Adverse event collection and reporting.............................................................41
APPROPRIATENESS OF MEASUREMENTS..............................................43
5.4
6.
INVESTIGATIONAL PLAN.............................................................................44
VISIT SCHEDULE.............................................................................................44
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................44
6.2
6.2.1
Screening..............................................................................................................44
6.2.2
Treatment period ................................................................................................45
6.2.3
Follow Up Period and Trial Completion...........................................................45
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................46
STATISTICAL DESIGN - MODEL.................................................................46
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................46
7.2
PLANNED ANALYSES.....................................................................................47
7.3
7.3.1
Primary endpoint analyses.................................................................................48
7.3.2
Secondary endpoint analyses .............................................................................49


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7.3.4
Safety analyses.....................................................................................................52
INTERIM ANALYSES ......................................................................................52
7.4
HANDLING OF MISSING DATA ...................................................................53
7.5
RANDOMISATION ...........................................................................................53
7.6
DETERMINATION OF SAMPLE SIZE .........................................................53
7.7
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........55
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT ...........................................................................................................55
DATA QUALITY ASSURANCE ......................................................................55
8.2
RECORDS...........................................................................................................56
8.3
8.3.1
Source documents ...............................................................................................56
8.3.2
Direct access to source data and documents.....................................................56
8.3.3
Storage period of records ...................................................................................56
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS56
8.4
8.4.1
Listedness.............................................................................................................56
8.4.2
Expedited reporting to health authorities and IEC / IRB...............................57
STATEMENT OF CONFIDENTIALITY........................................................57
8.5
END OF TRIAL..................................................................................................57
8.6
9.
REFERENCES....................................................................................................58
PUBLISHED REFERENCES............................................................................58
9.1
UNPUBLISHED REFERENCES......................................................................60
9.2
10.
APPENDICES.....................................................................................................61
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................62


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine transaminase
ASS
Acetyl salicylic acid
AST
Aspartate transaminase
BI
Boehringer Ingelheim
BP
Blood Pressure
CA
Competent Authority
CHMP
Committee for Medicinal Products for Human Use
CI
Confidence Interval
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organization
CTMF
Clinical Trial Master File
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBP
Diastolic blood pressure
DEDP
Drug Exposure During Pregnancy
DILI
Drug Induced Liver Injury
eCRF
Electronic Case Report Form
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
GCP
Good Clinical Practice
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
MedDRA
Medical Dictionary for Drug Regulatory Activities
NRS
Numerical Rating Scale
NSAID
Non-Steroidal Anti-Inflammatory Drug
OTC
Over The Counter
PA
Pressure Algometry
p.o.
per os (oral)
POM
Pain On Movement
POMWP
Pain On Movement of worst procedure (leading to maximum pain at 
baseline)
POMWPAUC72
Area under the curve of POMWP assessed until Day 4 morning, i.e. 72 
hours after start of treatment
POMWPAUC120
Area under the curve of POMWP assessed until Day 6 morning, i.e. 120
hours after start of treatment


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RDC
Remote Data Capture
REML
Restricted Maximum Likelihood
REP
Residual Effect Period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
SAE
Serious Adverse Event
SBP
Systolic Blood Pressure
SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
SUSAR
Suspected Unsuspected Serious Adverse Events
TCM
Trial Clinical Monitor
TENS
Transcutaneous Electrical Nerve Stimulation
TRPV1
Transient Receptor Potential Vanilloid 1
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
VAS
Visual Analogue Scale
VRS
Visual Response Scale


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1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
Back pain is a very common disorder with a point prevalence of approximately 35% in 
Germany [P11-08387]. In most cases specific causes cannot be identified (i.e. “unspecific 
low back pain”). Usually, low back pain is a self-limiting disorder, and approximately 90% of 
patients experience remission within 6 weeks. Musculoskeletal pain in the back area is 
worsened through a vicious circle of excessive muscle (force) load inducing pain (by minor 
muscle injury and local muscle ischaemia) that causes non-physiological posture, which in 
turn causes further pain.
Neck pain is becoming increasingly common throughout the world. The point prevalence of 
neck pain ranges from 0.4% to 41.5% (mean: 14.4%); and 1 year prevalence ranges from 
4.8% to 79.5% (mean: 25.8%). Prevalence is generally higher in women, higher in high-
income countries compared with low- and middle-income countries and higher in urban areas 
compared with rural areas [R12-4817]. Much neck pain is not attributable to a specific 
disease or disorder and is labelled as “soft-tissue” rheumatism or muscular/ mechanical/
postural neck pain [R15-2389].
Acute back/ neck pain is often treated with over the counter (OTC) analgesics, such as 
paracetamol, ibuprofen, or naproxen. Other treatment options are local heat [P11-08754] and 
hyperaemisation inducing agents [R11-2672]. Local heat and hyperaemisation inducing 
treatment were shown to augment blood flow and haemoglobin oxygenation in the skin and 
in the muscles [R11-2636, P11-05079]. Thus, such treatments can be assumed to be 
beneficial in the treatment of such musculoskeletal conditions.
Remedies against acute back/ neck pain, especially in an OTC environment, are required to 
reduce back discomfort fast and effectively while being tolerated well.
NSAIDs have been used since decades for the treatment of back and neck pain. A systematic 
review concluded that NSAIDs are effective for short-term symptomatic relief in patients 
with acute and chronic low back pain without sciatica. However, effect sizes are small [P08-
09510]. In a recent review [P15-04711] topical options for the treatment of back/neck pain 
has been discussed. In a clinical trial a hyperaemisation inducing agent has been shown to 
reduce back/neck pain with low incidence of side effects [P11-00252]. 
Topically applied remedies seem to have a low potential for systemic side effects and 
interactions with other (including systemic) medications.


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DRUG PROFILE
1.2
Diclofenac
Diclofenac is a non-steroidal drug with anti-inflammatory and analgesic activity. It inhibits 
the enzyme cyclooxygenase, and so directly inhibits the biosynthesis of prostaglandins and 
thromboxanes from arachidonic acid.
The topical usage of diclofenac in acute pain conditions is considered well established and is 
associated with an improved safety profile due the low systemic plasma concentrations [P13-
15601, P08-12601].
Capsaicin
Capsaicin is a highly selective and potent exogenous agonist for the transient receptor 
potential vanilloid 1 (TRPV1) receptor. When activated TRPV1 opens transiently and 
initiates a depolarization mediated by influx of sodium and calcium ions. In the nociceptive 
(mostly C- and some Aδ-fibers) nerve endings which selectively express TRPV1, capsaicin-
mediated depolarization results in action potentials, which are transmitted to the spinal cord 
and brain and usually reported as warming, burning, stinging or itching sensations.
Capsaicin causes an initial excitation of the neurons and a short period of hypersensitivity. 
This is followed by a refractory period with reduced sensitivity and, after repeated 
applications, persistent desensitization and decreased sensitivity to pain. There is also 
evidence that capsaicin treatment may interfere with substance P synthesis [P13-09858].
Combination rationale
Capsaicin has been shown to act as a penetration enhancer (e.g. for indomethacin [R10-
0978], naproxen [R14-1637] and thus, might improve the penetration rate and absorption of 
diclofenac. In addition, both substances have different pharmacodynamics properties and 
complementary mechanisms of action.
By combining both actives in a topical formulation, the new combination product will lead to 
an increased pain relief compared to the respective mono products.
For a more detailed description of the drug profile refer to the current Investigator’s Brochure 
(IB, [c03404356]) which is included in the Investigator Site File (ISF).


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
Diclofenac and capsaicin ointments/gels have been used for decades to treat complaints of the 
musculoskeletal system. However, no clinical trials have been performed to demonstrate 
analgesic effects for the combination of diclofenac and capsaicin in treatment of back or neck 
pain.
The aim of this study is to assess the efficacy and tolerability of diclofenac/capsaicin gel in 
comparison to diclofenac, capsaicin, and placebo gels for the treatment of acute back or neck 
pain to obtain market authorizations for this indication.
TRIAL OBJECTIVES
2.2
The objective of this pivotal study is to assess the efficacy and tolerability of a topical 
formulation gel of the combination of diclofenac and capsaicin in comparison to gels with 
diclofenac alone, capsaicin alone, and placebo for the treatment of acute back pain or neck 
pain.
The primary objective of this trial is to demonstrate superior efficacy of a formulation
containing a combination of 2% diclofenac and 0.075% capsaicin over placebo and over 
formulations containing 2% diclofenac alone and 0.075% capsaicin alone for the treatment of 
acute back or neck pain.
A secondary objective is to assess the safety and tolerability of the combination of diclofenac 
and capsaicin in comparison to gels with diclofenac alone, capsaicin alone.
BENEFIT - RISK ASSESSMENT
2.3
Topical application forms containing either diclofenac or capsaicin have been in clinical use 
for a long time and the available safety and tolerability data show that both are well tolerated 
and safe. Data from post marketing surveillance show that most of the reported unwanted 
effects of capsaicin gels are in line with the mechanism of action, e.g. skin burning sensation, 
erythema and pruritus for capsaicin gels. The most common side effects of diclofenac are 
application site reactions, including erythema, itching, burning sensation and rash. A 
combination of both safety profiles is expected for the combination of diclofenac and 
capsaicin.
Overall, the long term clinical experience with diclofenac or capsaicin gels and the 
aforementioned safety profiles of both present a favourable benefit risk assessment which 
would support proceeding with this trial.
Although very rare in topical administration, a potential for drug-induced liver injury is under 
constant surveillance by sponsors and regulators. Therefore, this trial requires timely 


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detection, evaluation, and follow-up of laboratory alterations in selected liver laboratory 
parameters to ensure patients’ safety, see also Section 5.3.6.1.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This trial is a prospective, randomised, double-blind, parallel group, multi-centre trial to show 
superiority in terms of reduction of Pain on Movement (POM) of a topical combination 
containing diclofenac 2% and capsaicin 0.075% compared to placebo, as well as to 
diclofenac 2% and capsaicin 0.075% when applied twice daily over 4 to 7 days to patients 
with acute back pain or neck pain. A total of approximately 800 patients will be randomised 
to the treatment groups diclofenac + capsaicin, diclofenac, capsaicin and placebo in a 3:3:3:1 
ratio in order to achieve 700 patients eligible for the assessment of the primary endpoint. 
After a screening evaluation (Visit 1), eligible patients will be randomised into the double-
blind treatment phase of the trial. After administration of the first treatment, the patients will 
administer the second application of the trial medication in the evening at home. They will 
return to the trial site for four more visits (Visits 2 to 5) in the morning and in the evening of 
the following day (Day 2) and in the morning of Days 3 and 4 and thereby be dosed while at 
the site. Evening applications on Day 3 and Day 4 will be administered by the patients at 
home. Thereafter, the treatment will be administered at home for one more day (Day 5). The 
patients will then return to the trial site for final assessments (Visit 6) in the morning of 
Day 6. The trial participation will be concluded by a telephone call (Visit 7T) for follow-up 
on adverse events (AEs) on Day 8.
Depending on the severity of a patient’s condition and on a patient’s availability, the 
treatment-period at home (Day 5) could be skipped or extended by one or two days. Visit 6
should then be performed on the day immediately following to that shortened or extended 
period.
The interval between two applications of the trial medication should be 12 hours. This 
interval could be shortened or extended by 4 hours as long as no more and no less than two 
applications are administered on each treatment day.
Patients who discontinue the application of the trial medication prematurely, should be 
encouraged to contact the site immediately so that Visits 6 and 7T could be performed on the 
day immediately after discontinuation.
The study will be conducted at approximately 20 study centres in Germany and Russia. The 
trial will end with completion of the last follow-up call (Visit 7T) with the last patient.
For a graphical representation of the trial, see Figure 3.1: 1.


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Figure 3.1: 1 Trial design, R = randomisation
3.1.1
Administrative structure of the trial
Boehringer Ingelheim (BI), the sponsor of this trial, has appointed a Trial Clinical Monitor, 
responsible for coordinating all required activities, in order to 

manage the trial in accordance with applicable regulations and internal SOPs,

direct the clinical trial team in the preparation, conduct, and reporting of the trial,

order the materials as needed for the trial, 

ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and Investigators of participating countries.
The sponsor will designate appropriately qualified personnel to advice on trial-related topics.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
A list of responsible persons and relevant local information (as protocol reference, if 
applicable) can be found in the ISF and the Clinical Trial Master File (CTMF).
A Coordinating Investigator will be nominated and will be responsible to coordinate 
Investigators at different centres participating in this multicentre trial. Tasks and 
responsibilities will be defined in a contract. Relevant documentation on the participating 
(Principal) Investigators and other important participants, including their curricula vitae, will 
be filed in CTMF.
A central laboratory service and an IRT vendor will be used in this trial. Details will be 
provided in IRT Manual and Central Laboratory Manual, available in the ISF.


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DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)
The study design of this trial is based on the Guideline on Clinical Development of Fixed 
Combination Medicinal Products of the EMA’s Committee for Medicinal Products for 
Human Use (CHMP) [R09-2704]. The design is suited to assess the effect of a gel containing 
diclofenac and capsaicin on acute back or neck pain compared with gels containing the 
individual components, diclofenac or capsaicin, or placebo. Comparison with the individual 
components is necessary to confirm a clinically meaningful effect of the combination in 
terms of pain relief. Comparison with placebo is necessary to assess the overall relative effect 
of the combination of diclofenac and capsaicin.
Assessment of pain at rest provides important information on patients comfort during 
treatment [P08-09626]. However, for measurement of pain at rest patients tend to move into a 
relieving posture which limits the value of the measurement to reflect patient’s restriction in 
performing daily activities. Other than at rest, functional limitations become obvious during 
movement. Functional improvement can be detected by standardized movements [R14-1467]. 
Thus, POM was selected as the primary variable for assessment of pain relief. For back and 
neck pain standardized movements have been established [R14-1467, R12-4427].
For the assessment of the primary endpoint, POMWP 1 hour after the evening application on 
Day 2 will be compared to POMWP at baseline. Typically a treatment effect of topical 
treatments can be observed after 1 to 3 days. The chosen time frame for assessment of the 
primary endpoint allows sufficient time for the trial treatment to become effective. On the 
other hand it is sufficiently short to avoid diminishing differences by the self-limiting 
properties of acute back or neck pain. Similar time frames were chosen in comparable clinical 
trials [R14-1467, R12-4427].
SELECTION OF TRIAL POPULATION
3.3
A sufficient number of patients with acute back or neck pain will be screened. It is assumed 
that approximately 800 patients will need to be randomized at around 20 trial sites to achieve 
700 patients who are evaluable with regard to the primary endpoint.
It is expected that around 40 patients will be randomised at each trial site. If enrolment is 
delayed, additional sites may be recruited. Permission to randomise more than 80 patients per 
site must be obtained from the Trial Clinical Monitor (TCM) at BI. This will only be allowed 
after a careful review of the enrolment status and of the site.
Screening of patients for this trial is competitive across all countries and sites within the trial, 
i.e. screening for the trial will stop at all sites when it is anticipated that a sufficient number 
of patients have been screened to yield the desired number of patients randomised to trial 
treatment. Investigators will be notified when sufficient patients have been screened and 
when screening is complete, and will not be allowed to recruit additional patients for the 
study.


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A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for trial entry
Only patients with acute neck or back pain will be screened for suitability for the study.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Signed and dated written informed consent at Visit 1 in accordance with Good 
Clinical Practice (GCP) and local legislation.
2. Male or female patients ≥18 years with current diagnosis of acute back pain or of 
neck pain for at least 24 hours, but less than 21 days.
3. Acute back pain or acute neck pain resulting in pain on movement (POM) ≥50 mm 
(VAS 0-100) for at least one POM procedure out of 5 standardized procedures.
The POM measurement with the highest pain response will determine if the patient 
has back or neck pain (see Section 5.2.1 for further details).
4. Sensitivity to algometric pressure on the painful trigger point ≤25 N/cm² (see 
Section 5.2.2).
5. Women of childbearing potential* must be ready and able to use highly effective 
methods of birth control per ICH M3(R2) that result in a low failure rate of less than 
1% per year when used consistently and correctly. A list of contraception methods 
meeting these criteria is provided in the patient information.
*Women of childbearing potential are defined as:
Any female who has experienced menarche and does not meet the criteria for 
"women not of childbearing potential" as described below.
Women not of childbearing potential are defined as:
Women who are postmenopausal (12 months with no menses without an alternative 
medical cause) or who are permanently sterilized (e.g. tubal occlusion, hysterectomy, 
bilateral oophorectomy or bilateral salpingectomy).


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3.3.3
Exclusion criteria
1. History of 3 or more episodes of back or neck pain in the last 6 months excluding the 
current episode
2. Surgery due to back or neck pain or rehabilitation due to back or neck pain in the last 
12 months.
3. Back or neck pain that is attributable to any specific identifiable cause (e.g. disc 
prolapse, spondylolisthesis, osteomalacia, inflammatory arthritis, metabolic, 
neurological diseases or tumour).
4. Trauma or strains of the back or neck muscles within the last 3 months.
5. Prior use within the last 3 days before Visit 1 or concomitant use of any anti-
inflammatory drugs, heparinoids, muscle relaxants or analgesics (including but not 
limited to short-acting glucocorticoids, non-steroidal anti-inflammatory drugs 
[NSAIDs], herbal preparations).
Long-acting glucocorticoids must have been discontinued 10 days before study entry.
Spinal injections should have been discontinued in due time (investigator’s 
judgement) before patient enrolment to allow complete wash-out of the active 
ingredient based on investigator’s judgment.
Exceptions: Acetyl salicylic acid (ASS) up to 100 mg/day for cardiovascular therapy, 
antidepressants or antipsychotics on stable dose for at least 2 weeks prior to Visit 1.
Use of inhaled glucocorticoids (e.g. for asthma or chronic obstructive pulmonary 
disease) is acceptable.
6. Non-pharmacological treatment (physiotherapy, heat treatment (e.g. heat patch, hot 
water bottle), or massage, acupuncture, transcutaneous electrical nerve stimulation 
[TENS]) or locally applied pharmacological product to the back or neck area 24 
hours prior study entry and during the study period.
7. Known severe hepatocellular insufficiency, severe renal insufficiency or Gilbert’s
syndrome (Morbus Meulengracht)
8. Any other medical condition that would interfere with efficacy and safety 
assessments based on investigator’s judgement or any on-going clinical condition that 
would jeopardize patient’s or site personnel’s safety or study compliance based on 
investigator judgement.


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9. Known intolerance or hypersensitivity to the active ingredients or any excipient(s).
10. Patients in whom attacks of asthma, bronchospasm, rhinitis or urticaria were
precipitated by the intake of ASS or other NSAIDs
11. Irritated skin (based on investigator’s judgement), skin wounds, eczema or open
injuries at application site (the trial medication should only be applied to intact, non-
diseased skin)
12. Negative experience in the past with heat treatments for muscle complaints (e.g. heat
pads, hyperaemisations inducing topical creams, gels, ointments, patches)
13. Patient not able to understand and comply with trial requirements based on
investigators judgement
14. Alcohol or drug abuse within 3 months prior to Visit 1 that would interfere with trial
participation based on investigator’s opinion.
15. Participation in a clinical trial within the previous 30 days before enrolment in the
trial, participation in this study before or simultaneous participation in another
clinical trial.
16. Women who are pregnant, nursing, or who plan to become pregnant while in the trial
(see also Section 4.2.2.3).
3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
An individual patient is to be withdrawn from trial treatment if:

The patient withdraws consent for study treatment or study participation, without the
need to justify the decision.

The patient needs to take concomitant drugs that interfere with the investigational
product (see Section 3.3.3) or other trial medication. See Section 4.2.2 for further
details.

The patient can no longer be treated with trial medication or rescue medication for
other medical reasons (such as surgery, adverse events, other diseases, or pregnancy)
If a patient becomes pregnant during the trial the study medication will be stopped, the 
patient will be discontinued from the trial and the patient will be followed up until birth or 
otherwise termination of the pregnancy.


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A patient can be discontinued after discussion between Sponsor and Investigator if eligibility 
criteria are being violated, or if the patient fails to comply with the protocol (e.g. non-
attendance at study assessments).
Patients who drop out during the screening prior to randomisation will be considered 
screening failures. They will be recorded as screening failures in the eCRF and no further 
follow-up is required. The data will be included in the trial database and will be reported.
Patients who discontinue or withdraw from the study after randomisation will be considered 
as “early discontinuations” and the reason for this premature discontinuation must be 
recorded in the eCRF. The Investigator must inform the sponsor within 24 hours via IRT (see 
Section 4.1) about any premature discontinuation of a subject. The data will be included in 
the trial database and will be reported. Given the patient’s agreement, the patient will undergo 
the procedures for early treatment discontinuation and follow up (Visits 6 and 7T) as outlined 
in the Flow Chart and Section 6.2.3.
For all patients the reason for withdrawal (e.g. adverse events) must be recorded in the eCRF. 
These data will be included in the trial database and reported.
Discontinuation of the trial by the sponsor
3.3.4.2
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the Clinical Trial Protocol (CTP), or the contract disturbing the 
appropriate conduct of the trial
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
TREATMENTS TO BE ADMINISTERED
4.1
The study medication will be provided by BI.
4.1.1
Identity of BI investigational product and comparator products
The characteristics of the test and comparator products are as shown in Tables 4.1.1: 1, 4.1.1: 
2, 4.1.1: 3 and 4.1.1: 4.
Table 4.1.1: 1
Test product: capsaicin + diclofenac gel
Substance:
Capsaicin
Diclofenac sodium
Pharmaceutical formulation:
Gel
Source:
C.P.M. ContractPharma GmbH & Co. KG
Arzneimittelherstellung und Verpackung
Unit strength:
0.075% capsaicin
2% diclofenac sodium
50g tubes
Posology
The single dose of the combination product 
(diclofenac sodium 2% and capsaicin 0.075%) is 
2 g formulation (40 mg diclofenac sodium, 1.5 mg 
capsaicin) to be applied on the skin. A twice daily 
application is proposed resulting in maximum 
daily dose of 4 g formulation (80 mg diclofenac 
sodium, 3.0 mg capsaicin).
Route of administration:
Topical


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Table 4.1.1: 2
Comparator product 1: diclofenac gel
Substance:
Diclofenac sodium
Pharmaceutical formulation:
Gel
Source:
C.P.M. ContractPharma GmbH & Co. KG
Arzneimittelherstellung und Verpackung
Unit strength:
2% diclofenac sodium
50g tube
Posology
The single dose of the diclofenac gel (diclofenac 
sodium 2%) is 2 g formulation (40 mg diclofenac 
sodium) to be applied on the skin. A twice daily 
application is proposed resulting in maximum 
daily dose of 4 g formulation (80 mg diclofenac 
sodium).
Route of administration:
Topical
Table 4.1.1: 3
Comparator product 2: capsaicin gel
Substance:
Capsaicin
Pharmaceutical formulation:
Gel
Source:
C.P.M. ContractPharma GmbH & Co. KG
Arzneimittelherstellung und Verpackung 
Unit strength:
0.075% capsaicin
50g tube
Posology
The single dose of the capsaicin gel (capsaicin 
0.075%) is 2 g formulation (1.5 mg capsaicin) to 
be applied on the skin. A twice daily application 
is proposed resulting in maximum daily dose of 
4 g formulation (3.0 mg capsaicin).
Route of administration:
Topical


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Table 4.1.1: 4
Comparator product 3: placebo gel
Substance:
N/A
Pharmaceutical formulation:
Gel
Source:
C.P.M. ContractPharma GmbH & Co. KG
Arzneimittelherstellung und Verpackung
Unit strength:
Not applicable
Posology
The single dose of the placebo gel is 2 g 
formulation to be applied on the skin. A twice 
daily application is proposed resulting in 
maximum daily dose of 4 g formulation.
Route of administration:
Topical
4.1.2
Method of assigning patients to treatment groups
When a patient is qualified for randomisation, treatment assignment will be by means of a 
third-party randomisation system at Visit 1. This will involve the use of IRT, which will take 
into consideration the relevant stratification factors (for further details see Section 7.6). To 
facilitate the use of IRT, the Investigator will receive all necessary instructions and/or 
documents for using the IRT.
Patients will be randomly assigned, in a 3:3:3:1 ratio, to either:
(i)
diclofenac and capsaicin
(ii)
diclofenac 
(iii) capsaicin 
(iv) placebo
For further details refer to Section 7.6. Entry into the application site stratum “back pain” will 
be capped as soon as 60% of the total trial population have been allocated to this stratum. 
Vice versa, the application site stratum “neck pain” will be capped as soon as 60% of the total 
trial population have been allocated to this stratum.
Patient assignment to the treatment groups will be determined by a computer generated 
random sequence. Access to the randomisation code will be controlled and documented. For 
further details please refer to Sections 4.1.5.1 and 4.1.5.2.
A single trial medication kit corresponding to the assigned medication number should be 
given to the patient and the number of the kit that was/were dispensed will be entered in the 
eCRF. Using this procedure, relevant parties will be blinded to the treatment group
assignment.


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4.1.3
Selection of doses in the trial
Both, capsaicin and diclofenac are contained as single active compounds in marketed 
products. The doses of the active ingredients in this trial correspond to standard doses of such 
products. For reference see e.g. the Summaries of Product Characteristics (SmPCs) of ABC 
Lokale Schmerz-Therapie Wärme-Creme 750 µg/g and Voltarol® 12 Hour Emulgel®.
4.1.4
Drug assignment and administration of doses for each patient
Patients should be equipped with disposable gloves and instructed to wear them whenever 
applying the trial medication.
The gel will be applied to the region on the patient’s back or neck where he/she feels the 
pain. If possible, the application should always be done by the patient himself/herself. An 
area of approximately 20 cm x 20 cm (corresponding to approximately two hand sizes) will 
be treated, covering the region on the patient’s back or neck where he/she feels the most 
pronounced pain as identified by POM assessment (Section 5.2). A gel drop of approximately
the size of a hazelnut will applied to the patient’s gloved hand and quickly massaged into the 
POMWP area. Following applications should be administered approximately 12 hours 
(±4 hours) from each other but not more and not less than twice daily up until the evening 
before Visit 6. The minimum treatment duration is 4 days, the maximum is 7 days.
If an application of the trial medication is missed, that application should be skipped and the 
next application should be taken as scheduled.
Patients should be instructed not to apply their trial medication in the morning before Visits 2 
and in the evening before Visit 3 as the medication will be applied at the site. They should 
also be instructed that the medication is to be applied lastly in the evening before Visit 6. The 
actual date and time of administration of the medication at the trial visit will be recorded in 
the eCRF.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
Patients, Investigators and everyone involved in trial conduct or analysis or with any other
interest in this double-blind trial will remain blinded with regard to the randomized treatment 
assignments until after database lock. The randomization code will be kept secret by Clinical 
Trial Support up to database lock.
The incidence of unblinding due to a warming effect of nonivamide can be considered very 
low, since a previous study investigating nonivamide [U13-2315-01] revealed a marked 
proportion of patients, who  perceived some warming although not treated with nonivamide, 
and as well, revealed a marked proportion of patients, who perceived no warming although 
treated with nonivamide. Blinding will further be supported by applying the study medication 
with gloves.


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Unblinding and breaking the code
4.1.5.2
Emergency unblinding will be available to the Investigator / pharmacist / investigational drug 
storage manager via IRT. It must only be used in an emergency situation when the identity of 
the trial drug must be known to the Investigator in order to provide appropriate medical 
treatment or otherwise assure safety of trial participants. The reason for unblinding must be 
documented in the source documents and/or appropriate Case Report Form (CRF) page along 
with the date and the initials of the person who broke the code.
4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by BI or a designated CRO. They will be 
packaged and labelled in accordance with the principles of Good Manufacturing Practice 
(GMP). Re-supply to the sites will be managed via an IRT system, which will also monitor 
expiry dates of supplies available at the sites.
Each medication kit will consist of one tube of 50 g gel in an outer carton. For details of 
packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
The trial medication must be kept in its tightly closed original packaging under the
recommended storage conditions indicated on the label. A temperature log must be
maintained by the Investigator/Pharmacist/investigational drug storage manager to make
certain that the medication is stored at the correct temperature. If storage conditions are found 
to be outside the specified range, the process outlined in the ISF should be followed.
Trial medication must be stored securely at the study sites, out of reach of children and be
protected from moisture and direct sunlight, e.g. in a locked cupboard or at a Pharmacy. It
may only be dispensed to trial patients fulfilling the inclusion and exclusion criteria by
authorised study personnel as documented in the ISF. Receipt, usage and return of the trial
medication must also be documented on the respective forms in the ISF.
All unused medication including all packaging, empty or filled, must be either returned to the
Sponsor, or, following written authorisation from the Sponsor, may be destroyed at site. 
Receipt, usage and return must be documented on the respective forms. Account must be
given for any discrepancies.
4.1.8
Drug accountability
The Investigator/ pharmacist/ investigational drug storage manager will receive the 
investigational drugs delivered by the Sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the Institutional Review Board (IRB) / Independent 
IEC Committee (IEC), 

Availability of a signed and dated clinical trial contract between the Sponsor and the 
head of the investigational site,

Approval/notification of the regulatory authority, e.g. competent authority (CA),


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
Availability of the curriculum vitae of the principal Investigator,

Availability of a signed and dated clinical trial protocol

Availability of the proof of a medical license for the principal Investigator (if 
applicable)
The Investigator/ pharmacist/ investigational drug storage manager must maintain records of 
the product’s delivery to the trial site, the inventory at the site, the use by each patient, and 
the return to the Sponsor or alternative disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
Investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the Sponsor. At the time of return to the 
Sponsor or appointed Clinical Research Organisation (CRO), the Investigator/ pharmacist/ 
investigational drug storage manager must verify that all unused or partially used drug 
supplies have been returned by the clinical trial patient and that no remaining supplies are in
the Investigator’s possession.
Patient treatment compliance
4.1.8.1
Records will be kept regarding when and how much of each study medication is dispensed to, 
and used by each individual patient in the study. This will be done by measuring the weight 
of the medication tubes (with cap, without the outer packaging) prior to dispense at Visit 1
and upon return by the patient at Visit 6. Both values will be recorded in the CRF. 
Appropriate scales should be used which display the tube weight with at least 1 decimal place 
(0.1 g). Tube weights should always be determined with the same device.
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
4.2
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
Paracetamol tablets (500 mg tablets) will serve as rescue medication as it is recommended as 
first line treatment in guidelines for the treatment of acute back or neck pain, e.g. the German 
National care guideline: low back pain [P11-08387]. Following the first application of study 
medication, patients may use paracetamol (one to two tablets of 500 mg per os (p.o.), up to 
twice daily; i.e. up to 4 tablets/ 2 g per day at maximum) for treating intolerable back or neck 
pain. Similar rescue concept were used in comparable clinical trials [R14-1467, R15-2151,
R12-4428, R15-2150].
The patient must always record the number of tablets and the day and time a dose is taken in 
his/her diary.


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Patients should be strongly encouraged not to take any rescue medication until Visit 3. 
Patients are advised to seek medical advice if the pain persists or the patient’s condition 
worsens, and/or if the rescue medication is used up.
There are no special emergency procedures to be followed.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
The following concomitant treatments are not permitted during the trial for the trial indication 
or other indications as they would interfere with the efficacy assessments in this trial: any
anti-inflammatory drugs, heparinoids, muscle relaxants or analgesics (including but not 
limited to long- and short-acting glucocorticoids, non-steroidal anti-inflammatory drugs 
[NSAIDs], herbal preparations), spinal injections, muscle relaxants, other topical 
pharmaceutical products at the back or neck area, antidepressants, antipsychotics, and other 
treatments for back or neck pain, such as physiotherapy, heat treatment (e.g. heat patch, hot 
water bottle), or massage, acupuncture, transcutaneous electrical nerve stimulation (TENS).
Exceptions are paracetamol as rescue medication, ASS up to 100 mg/day for cardiovascular 
therapy, antidepressants or antipsychotics on stable dose as from at least 2 weeks before 
randomisation are permitted.
Restrictions on diet and life style
4.2.2.2
No restrictions on diet are required. Patients should be informed that during treatment they 
might experience an increased sensitivity towards heat (e.g. during sun exposure, hot showers 
etc).
Restrictions regarding women of childbearing potential 
4.2.2.3
Topical application of diclofenac (Voltarol® 12 Hour Emulgel®) is contraindicated in the 
3rd trimester of pregnancy. A strict indication is required in 1st and 2nd trimester. The safety of 
capsaicin has not been established in either humans or animals. Women of child-bearing 
potential must therefore continue to practice a highly effective method of birth control (in 
accordance with the trial inclusion criteria Section 3.3.2) throughout the duration of the study.


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5.
VARIABLES AND THEIR ASSESSMENT 
TRIAL ENDPOINTS
5.1
5.1.1
Primary Endpoint(s)
The primary endpoint is the change in pain on movement (POM) between baseline and Day 2 
evening, 1 hour after drug application (Visit 3) with regard to the POM of the procedure
which gave the highest score at baseline (“POM of worst procedure”, POMWP).
Throughout the protocol the term ‘baseline’ refers to the assessment in the morning before 
the first drug application on Day 1.
POM is assessed by the patient on one standardized movement by using a Visual Analogue
Scale (VAS) ranging from 0 mm = ‘no pain’ to 100 mm = ‘worst pain possible for this 
condition’. 
5.1.2
Key Secondary Endpoints

POMWPAUC72. AUC will be calculated as area under the curve from zero to 72 hours 
using the trapezoidal rule divided by the observation time. Application date/times will be 
the basis for the calculation of respective time intervals. 

POMWPAUC120. AUC will be calculated as area under the curve from zero to 120 hours 
using the trapezoidal rule divided by the observation time. Application date/times will be 
the basis for the calculation of respective time intervals.
5.1.3
Other Secondary Endpoints

Number of patients with a decrease in POMWP of at least 30% from baseline on Day 2 
evening, 1 hour after drug application (Visit 3)

Number of patients with a decrease in POMWP of at least 50% from baseline on Day 2 
evening, 1 hour after drug application (Visit 3)

Change in POMWP between baseline and the morning of Day 6 (Visit 6)

Change in Pressure Algometry (PA) between baseline and Day 2 evening, before drug 
application (Visit 3)

Change in PA between baseline and the morning of Day 6 (Visit 6)


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ASSESSMENT OF EFFICACY
5.2
5.2.1
Pain On Movement
POM will be assessed by the patient at the performance of one standardized, muscle group 
specific movement and is measured by a Visual Analogue Scale (VAS) ranging from 0 mm = 
‘no pain’ to 100 mm = ‘worst pain possible for this condition’. The change in POM will be 
calculated as POM at baseline subtracted by the POM at a given time point.
POM assessment must always be supported by the same adequately trained person (according 
to trial-specific certification process) in an individual patient.
Baseline POM will be assessed using the following standard procedures [R12-4427, R14-
1467]:


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1. Musculus trapezius (upper part)
Position: the patient sits on a chair and the examiner 
stands behind him/her and fixes his/her shoulders. The 
examiner determines which shoulder the patient pulled 
his/her head towards (Figure 5.2.1: 1). 
Test: The patient pulls his/her head sideways towards the 
left or the right shoulder as appropriate without lifting up 
the shoulder at the same time.
Figure 5.2.1: 1
2. Musculus erector spinae (upper part)
Position: The patient sits on a chair and the examiner
stands behind him/her and fixes his/her shoulders with his 
hands. The patient’s back leans against the back of the 
chair (Figure 5.2.1: 2).
Test: The patient tries to place his/her chin onto the chest 
without lifting up the shoulders at the same time and 
without losing contact with the back of the chair.
Figure 5.2.1: 2
3. Musculus levator scapulae
Position: The patient sits on a chair with hanging arms 
and the examiner stands behind and fixes his/her 
shoulders with his hands (Figure 5.2.1: 3).
Test: The patient tries to lift the arms over the side 
upwards against the gentle resistance of the examiner’s
hands.
Figure 5.2.1: 3


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4. Musculus erector spinae (lower part)
Position: The patient lies with his/her front on a 
examination bed. The hips do not lie on the examination 
bed. With his/her hands, the patient holds on to the right 
and left edges of the examination bed (Figure 5.2.1: 4).
Test: The patient bends his/her legs to reach a square 
angle, lifts his/her thighs up towards the horizontal line.
Figure 5.2.1: 4
5. Musculus rectus abdominis
Position: The patient lies on the back, legs extended, arms 
crossed behind his/her head. Both legs are stretched and 
lifted up to reach a right angle to the surface the patient is 
lying on. The spine has full contact to the surface (Figure 
5.2.1: 5).
Test: The patient slowly lowers down the stretched legs to
the surface.
Figure 5.2.1: 5
Procedures 1-3 indicate neck pain, procedures 4-5 indicate back pain.
Before randomization, the patients will be provided at the site with 5 separate paper forms 
each with one horizontal 0-100 mm VAS each. For each procedure performed, the patient 
will draw a vertical line on the VAS, respectively. The form will collected after each 
assessment, so that the patient will not see his previous POM assessment. The same ruler 
should be used for reading the POM value, i.e. by measuring the distance between the 0 mm 
mark on the VAS and the patient’s mark. Assessment forms will be stored with the patient 
file, results will be entered into the CRF.
The procedure which results in highest POM at baseline and all other procedures related to 
the same stratum (i.e. all other procedures indicating either neck or back pain, respectively) 
will be repeated for an individual patient after the first application of trial medication at the 
time points indicated in the Flow Chart. If two or more procedures give the same highest 
POM, the patient should be asked which of the procedures giving highest POMs he/she 


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considers most unpleasant. This specific procedure and all other procedures related to the 
same stratum should then be reapplied in the course of the patient’s trial participation.
5.2.2
Pressure algometry
Pressure algometry (PA) is determined by the investigator at time points indicated in the 
Flow Chart as the pressure value (N/cm2) at a defined trigger point which is located in the 
area of POMWP. The measurement is performed by using a Somedic Algometer (Somedic 
AB, Sweden) or an equivalent calibrated and certified device. The pain reaction is determined 
by placing the algometer on the trigger point, i.e. an area of 1 cm² for which the patient 
indicates most painful tenderness. The pressure is constantly increased until the patient asks 
not to increase the pressure anymore. Upon this pain reaction, the corresponding pressure
value will be documented in the CRF. The trigger point should be marked with a ball pen so 
that the assessment could always be done at the same position.


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ASSESSMENT OF SAFETY
5.3
5.3.1
Assessment of skin reactions
Skin reactions at the application site will be examined and graded approximately 1 hour after 
each application of the study medication at the site. This assessment will be done by using the
numerical Dermal Response Score (DRS) outline in Table 5.3.1: 1 which is based on the 
DRS described in the “Guideline on the pharmacokinetic and clinical evaluation 4 of 
modified release dosage forms” (EMA/CPMP/EWP/280/96 Corr1 [R15-1313]).
Clinically relevant dermal reactions should be documented as an AE at investigator’s 
discretion.


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Table 5.3.1: 1 
Dermal Response Score for assessment of skin reactions
Dermal Response Score
Score
Score definition
0
No evidence of irritation 
1
Minimal erythema, barely perceptible 
2
Definite erythema, readily visible
3
Minimal edema or minimal papular response
4
Erythema and papules 
5
Erythema, edema, and papules 
6
Vesicular eruption 
7
Strong reaction spreading beyond test site 
Based on the Dermal Response Score, skin reactions will be categorised as positive for scores 
≥3 and negative for scores <3.
5.3.2
Overall assessment of tolerability
The patient will assess the overall tolerability of the trial treatment on a 4-point verbal rating 
scale by answering the question: “How would you rate the overall tolerability of the study
medication?” (0 = poor; 1 = fair; 2 = good; 3 = very good). The investigator should make the 
corresponding assessment at about the same time as the patient. Assessments should be made 
independently from each other, i.e. without knowing the other’s assessment result when 
making the assessment.
5.3.3
Physical examination
A physical examination will be performed by the Investigator or designated site-personnel at 
the time point indicated in the Flow Chart. Documentation of, and findings from the physical 
examination, must be part of the source documents available at the site.
5.3.4
Vital Signs
Systolic and diastolic blood pressure (SBP, DBP) as well as pulse rate (electronically or by 
palpation, count for 1 minute) will be measured after 5 minutes of rest in the seated position 
at time points indicated in the Flow Chart. The BP measurements should always be 
performed before drawing blood for lab samples on the non-dominant arm and preferably by 
the same person and with the same device.
BP measurements should be recorded in the eCRF to the nearest 1 mmHg.


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5.3.5
Safety laboratory parameters
A total amount of 11 ml of blood will be taken per patient during the course of the trial for 
assessment of the laboratory parameters listed in Table 5.3.5: 1. This amount might be 
exceeded if unscheduled (additional) monitoring is warranted (e.g. in case of suspected 
DILI).
The laboratory tests will be performed at a central laboratory. Details on collection, labelling, 
handling, storage and shipping of samples will be provided in a laboratory instruction 
manual.
Table 5.3.5: 1
Safety laboratory tests
Haematology

Haematocrit

Haemoglobin

Red blood cells (RBC)/erythrocytes

White blood cells (WBC)/leukocytes

Platelet count/thrombocytes

Differential automatic (relative and 
absolute count):
o
neutrophils, eosinophils, basophils, 
monocytes, lymphocytes
Clinical chemistry

Sodium

Potassium

Creatinine

Total Bilirubin

AST (SGOT)

ALT(SGPT)

Alkaline Phosphatase

Gamma GT

Uric Acid

Lipase
Pregnancy testing (urine) will be performed in female patients at time points indicated in the 
Flow Chart. Further testings might be performed if deemed necessary by the investigator.
5.3.6
Assessment of adverse events
Definitions of AEs 
5.3.6.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment.


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An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and
unintended. Response in this context means that a causal relationship between a medicinal
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise
from use of the product within or outside the terms of the marketing authorisation or from
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening, this refers to an event in which the patient was at risk of death at
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity,

is a congenital anomaly/birth defect,
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Medical and scientific judgement 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 hospitalisation but might jeopardise the
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or
development of dependency or abuse. Any suspected transmission via a medicinal product of
an infectious agent is also considered a serious adverse reaction.
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
In accordance with the European Medicines Agency initiative on Important Medical Events,
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be


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considered to be “serious” even though they may not have met the criteria of an SAE as given
above.
The latest list of “Always Serious AEs” can be found in the RDC system. These events 
should always be reported as SAEs as described above
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, see Section 5.3.7.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

an elevation of AST and/or ALT >3 fold ULN combined with an elevation of total 
bilirubin >2 fold ULN measured in the same blood draw sample, and/or

Marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided via the 
RDC-system.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities”
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal
relationship between a suspected medicinal product and an adverse event. An adverse
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship
between a medicinal product and an occurrence is suspected.


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Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks
of drug administration; an allergic reaction weeks after discontinuation of the drug
concerned)

Continuation of the event despite the withdrawal of the medication, taking into
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g.
situations where other drugs or underlying diseases appear to provide a more likely
explanation for the observed event than the drug concerned).

Disappearance of the event even though the study drug treatment continues or remains
unchanged.
5.3.7
Adverse event collection and reporting
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their patient files.
The following must be collected and documented on the appropriate eCRF by the 
Investigator (see also Figure 5.3.7: 1):
From signing the informed consent onwards through the Residual Effect period (REP), all 
AEs (serious and non-serious), and AESIs must be reported. However, if an individual patient 
discontinues trial medication prematurely but stays in the trial (i.e. if further visits including


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telephone visits, or vital status assessments are planned) from then on and until the individual 
patient’s end of the trial the Investigator must report related SAEs and related AESIs.
Figure 5.3.7: 1 Graphical depiction of the requirements for AE collection
The REP is defined as 48 hours after the last trial medication application. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as on 
treatment please see Section 7.3.4. Events which occurred after the REP will be considered as 
post treatment events.
After the last per protocol contact the Investigator does not need to actively monitor patients 
for AEs. However, if the Investigator becomes aware of SAEs or AESIs that occurred after 
the last per protocol contact, the SAEs and AESIs should be reported by the Investigator to 
the Sponsor if considered relevant by the Investigator.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
Sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the Sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be
provided. For follow-up information the same rules and timeline apply as for initial
information.
Information required
For each AE, the Investigator should provide the information requested on the appropriate


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CRF pages and the BI SAE form. The Investigator should determine the causal relationship
to the trial medication and any possible interactions between the investigational drugs and a 
Non-Investigational Medicinal Product (NIMP) / Auxiliary Medicinal Product (AMP).
The following should also be recorded as an (S)AE in the (e)CRF and SAE form (if 
applicable):

Worsening of the underlying disease or of other pre-existing conditions

Changes in vital signs, ECG (if done outside the trial, not part of the trial 
assessments), physical examination and laboratory test results, if they are judged 
clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as 
baseline conditions.
All (S)AEs, including those persisting after trial completion must be followed up until they 
have resolved, have been sufficiently characterized, or no further information can be 
obtained.
Pregnancy
In the rare case that a female subject participating in this clinical trial becomes pregnant after 
having taken trial medication, the Investigator must report immediately (within 24 hours) the 
drug exposure during pregnancy (DEDP) to the Sponsor’s unique entry point (country-
specific contact details will be provided in the ISF). The Pregnancy Monitoring Form for 
Clinical Trials (Part A) should be used. 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the Sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B). 
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE,
only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be 
completed. If there is an SAE associated with the pregnancy then the SAE has to be reported 
on the SAE form in addition. 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
APPROPRIATENESS OF MEASUREMENTS
5.4
The efficacy tests, instruments and scales used in this trial are widely used and considered
reliable, accurate, and relevant in trials for the indication of pain relief.


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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
This trial consists of 6 clinical visits. For the follow-up contact (Visit 7T) the investigator will 
contact the patient by phone.
If a Visit 2-5 is missed, it should not be re-scheduled. However subsequent visits should 
follow the original visit schedule. If Visit 6 or Visit 7T is missed, this visit should be re-
scheduled to the closest opportunity.
All trial visits except for Visit 3 should take place in the morning, i.e. ideally be started and 
completed between 7:00 a.m. and 11:00 a.m. Patients must adhere to the visit schedule as 
specified in the Flow Chart. Visits 2 (Day 2 morning) and 3 (Day 2 evening) need to be 
scheduled such that the trial medication could be applied according to the required dosing 
interval of 12 hours (± 4 hours).
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
The study procedures which are to be performed at each visit are listed in the Flow Chart. 
Assessments of efficacy and safety are explained in Section 5.2 and 5.3. Assessment of POM,
PA and vital signs should preferably be done by the same qualified person for a given patient 
throughout the study period. This person has to be adequately trained regarding POM and PA 
and training documentation has to be filed in the ISF.
Additional details regarding visit procedures are provided below.
6.2.1
Screening
Screening will be done during the first part of Visit 1. If a patient’s eligibility is confirmed, 
trial treatment will be initiated. A patient’s informed consent has to be obtained prior to the 
first trial procedures. Following the informed consent process the patient will undergo 
screening assessments.
It is recommended to perform study procedures in the order as listed in the Flow Chart 
(column “Pre”). All procedures which are necessary to assess the eligibility of a patient must 
be performed before randomization. A final assessment of all in- and exclusion criteria 
should be the last step before making the randomization call in the IRT system.
Documentation of medical history and previous therapies should be restricted to those 
conditions which are relevant with regard to trial indication and the assessment of the in- and 
exclusion criteria (see Section 3.3).
All concomitant pharmaceutical and non-pharmaceutical therapies and the corresponding 
baseline conditions should be documented in the CRF. Other baseline conditions should be 


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documented if relevant with regard to trial indication and the assessment of the in- and 
exclusion criteria.
6.2.2
Treatment period
At Visit 1 (Day 1, morning), 2 (Day 2, morning), 3 (Day 2, evening), 4 (Day 3, morning) and 
5 (Day 4, morning) the trial medication should be applied at the site and, if possible, by the 
patient himself/herself. At Visit 1, all procedures indicated in the “Pre” column of the Flow 
Chart should be performed before the first application of the trial medication. Procedures 
indicated in the “Post” column should be performed afterwards at time points as indicated.
The trial medication should be weighed, dispensed and applied after randomization without 
delay. The application times of trial medication will be recorded at the site in the eCRF, 
where application is performed at the site.
The patient should be instructed

always to wear gloves when applying the trial medication

to perform home assessments (warming score, mobility score, time to perceptible/ 
meaningful pain relieve) at time points indicated in the Flow Chart

to refrain from using rescue medication before Visit 3 if possible. If this turns out not 
to be possible, another supply of rescue medication might be dispensed at visit 5

to record intake of rescue medication (date and number of tablets) in the patient’s 
diary

to apply the trial medication every 12 (± 4) hours

to record the time of last application of the trial medication (evening before Visit 6) in 
the patient’s diary

to return their patient’s diary at visit 2, visit 3, visit 4, visit 5 and visit 6

to return all unused trial and rescue medication and packaging at Visit 6
6.2.3
Follow Up Period and Trial Completion
All study procedures according to the Flow Chart should be performed.
Patients who want to discontinue the trial treatment prematurely should be asked to have 
Visit 6 in the morning after the last application of the trial medication and to have a Visit 7T 
at least 48 hours after that last application.
Patients who at the end of their trial participation still require treatment for the trial indication 
should be treated according to local standard of care.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
This is a randomized, double-blind, placebo- and active-controlled, multi-country, multi-
centre 4-arm parallel group study to investigate efficacy and tolerability of multiple doses of 
a topically applied combination containing diclofenac 2% + capsaicin 0.075% (2 g 
formulation per application; 2-times daily for 5 days (-1/+2 days) compared to placebo, as 
well as to diclofenac 2% and capsaicin 0.075% in patients with acute back or neck pain.
The patients will be randomised via IRT in blocks to the treatment groups diclofenac + 
capsaicin, diclofenac, capsaicin and placebo in a 3:3:3:1 ratio. Treatment allocation will be 
stratified by country and the application site (back or neck) of the study drug; the application 
site is classified after the POM assessments on a 0-100 mm VAS, following the 5 standard 
procedures, before application at Visit 1 as that site, where the worst pain is identified, and 
the corresponding POM is then denoted as POMWP. Post-dose POMWP and POM assessments 
for the other procedures within the corresponding stratum (back or neck) will be captured 
each with the same scale and the same standard procedure, respectively. For further details of 
POM assessments see Section 5.2.1.
Based upon these design considerations, the trial will be analysed using general linear models 
which will include terms for treatment, country (Germany or Russia), application site (back 
or neck) and the baseline POMWP as continuous covariate.
NULL AND ALTERNATIVE HYPOTHESES
7.2
The primary objective of this trial is to demonstrate efficacy of the combination 
2% diclofenac + 0.075% capsaicin when compared to both single components (2% diclofenac
and 0.075% capsaicin) and placebo for the treatment of acute back or neck pain. This will be 
primarily evaluated by comparing the change in POMWP between baseline (before application
at Visit 1) and Visit 3 (Day 2 evening, 1 hour after application) of the combination treatment 
against the treatment with the single components and placebo, using two-sided tests and a 
0.05 level of significance. To this purpose the following statements are hypothesised:
Null hypothesis:
There is no difference between patients treated with the combination diclofenac + capsaicin
and the patients treated with diclofenac or capsaicin alone or placebo.
Alternative hypothesis:
There is a difference between patients treated with the combination diclofenac + capsaicin
and the patients treated with diclofenac, patients treated with capsaicin alone and patients 
treated with placebo.


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The set of hypotheses can be written as:
H0: H0,1: μdiclo+caps = μdiclo or H0,2: μdiclo+caps = μcaps or H0,3: μdiclo+caps = μplacebo
versus 
H1: H1,1: μdiclo+caps ≠μdiclo and H1,2: μdiclo+caps ≠μcaps and H1,3: μdiclo+caps ≠μplacebo
where, μdiclo+caps, μdiclo , μcaps and μplacebo is the adjusted (for country and application site effect, 
and baseline POMWP) mean change in POMWP between baseline (before application at Visit 
1) and Visit 3 (Day 2 evening, 1 hour after application) for patients treated with the 
combination diclofenac + capsaicin, diclofenac, capsaicin or placebo, respectively.
Since all partial hypotheses H0,1, H0,2 and H0,3 are to be rejected in order to reject the null 
hypothesis H0, no adjustment for multiplicity issues will be made and thus all statistical 
testing will be performed using a two-sided, alpha = 0.05 level of significance.
The key secondary endpoints as outlined in Section 5.1.2 will be analysed hierarchically 
(POMWPAUC72 first) in a confirmatory way only, if statistical significance was achieved for 
the primary endpoint. Therefore, no alpha-adjustment for multiple endpoint testing will be 
applied. 
All other secondary endpoints as outlined in Section 5.1.3 will be considered as supportive 
only.
PLANNED ANALYSES
7.3
Three analysis datasets will be defined for the purpose of summarizing and analysing the trial 
data.
Treated set (TS): All randomised patients who used at least one dose of study medication will 
be included in the treated set. Patients having received the wrong treatment will be analysed 
within the planned (randomised) treatment group in the efficacy analysis and within the 
actual treatment group in the safety analysis.
Full analysis set (FAS): All patients included in the treated set, which provide a baseline 
value before application for POMWP at Visit 1 and at least one POMWP value during the 
assessment times Visit 1 (Day 1 morning, 1 hour after application), Visit 2 (Day 2, morning, 
1 hour after application, Visit 3 (Day 2 evening, before application), Visit 3 (Day 2 evening, 
1 hour after application), will constitute the full analysis set.


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7.3.1
Primary endpoint analyses
The primary endpoint ‘Change in POMWP between baseline (before application at Visit 1) 
and Visit 3 (Day 2 evening, 1 hour after application)’ will be analysed utilising a restricted 
maximum likelihood (REML) based repeated measures approach, using all available 
longitudinal POMWP observations at the assessment times T1 = Visit 1 (Day 1 morning, 
1 hour after application), T3 = Visit 2 (Day 2, morning, 1 hour after application,  T4 = Visit 3 
(Day 2 evening, before application) and T5 = Visit 3 (Day 2 evening, 1 hour after 
application). The statistical model will be applied to the analysis of change from baseline (T0 
= Visit 1 morning, before application) in POMWP at times T1, T3, T4 and T5. The statistical 
model will include the fixed, categorical effects of treatment, country, application site 
(back/neck), time and treatment-by-time interaction, as well as the continuous, fixed 
covariates of baseline POMWP and baseline-by-time interaction. The definition of baseline 
POMWP is given in Section 7.1. 
An unstructured covariance structure will be used to model the within-patient errors. In case 
this analysis fails to converge, other covariance structures to be employed will include 
Compound Symmetry, Autoregressive Model, AR (1) and Spatial Covariance, with the 
covariance structure converging to the best fit, as determined by Akaike’s information 
criterion, to be used for purposes of comparing treatment effects. The Kenward-Roger 
approximation will be used to estimate the denominator degrees of freedom [R11-1488].
Differences between the treatment group effects (diclofenac/capsaicin - diclofenac, 
diclofenac/capsaicin - capsaicin, diclofenac/capsaicin - placebo) with regard to the change in 
POMWP between T0 and T5, calculated as ‘POMWP at time T0 - POMWP at time T5’ (see
Section 5.1) will be estimated by reference to the adjusted least square means and the 
corresponding 95% confidence intervals (CI). All statistical testing will be performed using a 
two-sided, alpha = 0.05 level of significance.
The primary analysis will be based on the full analysis set (FAS) as defined in Section 7.3.
In addition to the primary analysis, a separate analysis will be performed to test the 
heterogeneity of the strata ‘application site’ and ‘country’, respectively. In these models the
two interaction terms treatment-by-stratum-by- time and stratum-by-time will be added to the 
primary model, respectively.


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7.3.2
Secondary endpoint analyses
The key secondary and other secondary endpoints will be analysed with the treated set as 
defined for efficacy analysis in Section 7.3.
The key secondary endpoints of POMWPAUC72 and POMWPAUC120 will be analysed using an
analysis of covariance (ANCOVA) including treatment, country and application site 
(back/neck) as fixed effects and the baseline POMWP as a continuous covariate. Treatment 
differences will be estimated by reference to the adjusted least square means and the 
corresponding 95% confidence intervals. The statistical testing will be performed using a 
two-sided, alpha = 0.05 level of significance.
The number of patients with a decrease in POMWP of at least 30% from baseline until Day 2 
evening, 1 hour after drug application, will be analysed by a logistic regression model, 
adjusting for the categorical covariates country and application site (back/neck). The 
likelihood-ratio test will be used to test for differences between treatments. Adjusted odds 
ratios together with 95% confidence intervals will be used to quantify the effect of treatment, 
comparing all treatments to the treatment of diclofenac/capsaicin as the reference treatment.
The number of patients with a decrease in POMWP of at least 50% from baseline until Day 2 
evening, 1h after drug application, will be analysed correspondingly.
The change in POMWP between baseline and the morning of Day 6 will be analysed 
analogously to the primary endpoint. The statistical model will be applied to the analysis of 
change from baseline (T0 = Visit 1 morning, before application) in POMWP at times T1, T3, 
T4, T5 and - additionally at times T7 (=Visit 4 = Day 3 morning, 1 hour after application), T9 
(= Visit 5 = Day 4 morning, 1 hour after application) and T12 (= Visit 6 = morning of Day 6).
The change in PA between baseline and Day 2 evening, before drug application (Visit 3) will 
be analysed analogously to the primary endpoint using all available longitudinal PA
observations at the assessment times T2 = Visit 2 (Day 2 morning, before application) and T4
= Visit 3 (Day 2, evening, before application). The statistical model will be applied to the 
analysis of change from baseline (T0 = Visit 1 morning, before application) in PA at times T2 
and T4.
The change in PA between baseline and the morning of Day 6 will be analysed analogously 
to the primary endpoint. The statistical model will be applied to the analysis of change from 


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baseline (T0 = Visit 1 morning, before application) in PA at times T2, T4, T6, T8 and -
additionally - T12 (= Visit 6 = morning of Day 6).


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7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. All 
adverse events with an onset between start of treatment and end of the REP, a period of 
48 hours after the last application of trial medication, will be assigned to the treatment period 
for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Safety analyses will be done by the actual treatment as defined for safety analysis in Section 
7.3.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and end 
of the residual effect period will be considered ‘treatment-emergent’. The residual effect 
period is defined as a period of 2 days (48 hours) after the last application of trial medication. 
Adverse events that start before first drug intake and deteriorate under treatment will also be 
considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA).
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 
listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
The final overall patient / investigator assessment of tolerability will be analysed analogously 
to 
The assessment of skin reactions will be analysed descriptively.
INTERIM ANALYSES
7.4
No interim analysis is planned.


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HANDLING OF MISSING DATA
7.5
Every effort should be made to collect the complete data at the planned time points for this 
trial.
For the analyses utilising a likelihood-based repeated measures model as described in 
Section 7.3, no imputation of missing values will be performed.
Missing entries for the assessment of efficacy will be assigned the least favourable category if 
missing was the result of discontinuation due to lack of efficacy. Missing entries for the 
assessment of tolerability will be assigned the least favourable category if missing was the 
result of discontinuation due to drug-related adverse events.
Missing patient assessments of efficacy or tolerability resulting from early discontinuation 
that was clearly unconnected to treatment will be not imputed.
RANDOMISATION
7.6
Patients will be randomized in blocks to double-blind treatment arms diclofenac + capsaicin, 
diclofenac, capsaicin and placebo in a ratio 3:3:3:1. The randomization allocation will be 
stratified by country (Russia, Germany) and application site (back/neck). At least 40% of the 
randomised total population are aimed to be patients with neck/back pain, respectively. For 
further details on the stratified randomisation see Section 4.1.2.
BI will arrange for the randomization and the packaging and labelling of trial medication. 
The randomization list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the Clinical Trial Report (CTR). Access to
the codes will be controlled and documented.
DETERMINATION OF SAMPLE SIZE
7.7
The sample size calculation is based on the assumption of superiority of the combination 
diclofenac + capsaicin versus diclofenac, capsaicin and placebo with regard to the primary 
efficacy variable ‘Change in POMWP between baseline (before application at Visit 1) and 
Visit 3 (Day 2 evening, 1 hour after application)’, which reflects a pain relief on a 0-100 mm 
VAS about 36 h after baseline.
In a previous study investigating diclofenac in comparison to placebo in patients with acute 
neck pain, the true treatment difference in POM 48 h after baseline was assumed to be 12 mm 
[R14-1467] In another study comparing the effects of a combination of comfrey root extract 
with methyl nicotinate in patients with acute back pain, the standardized difference between 
the combination and a single ingredient was assumed to be 0.4 [R12-4427]. 
The sample size for this study is based on an anticipated treatment difference of 12 mm on a 
0-100 mm VAS and a common standard deviation of 30 mm, yielding a standardized 
treatment difference of 0.4 concerning the primary endpoint. The allocation ratio to the 


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treatment groups diclofenac + capsaicin, diclofenac, capsaicin and placebo is planned to be 
3:3:3:1.
A total sample size of 700 patients (210 patients with diclofenac + capsaicin, diclofenac and 
capsaicin, respectively and 70 patients with placebo will have 98% power to detect a 
difference of 12 mm on a 0-100 mm VAS for the primary endpoint between treatment effects 
of diclofenac + capsaicin versus diclofenac and capsaicin, respectively (3:3 allocation ratio) 
and 82% power to detect the same difference between diclofenac + capsaicin and placebo 
(3:1 allocation ratio), assuming a common standard deviation of 30 mm and using a 0.05 two-
sided significance level. 
The total sample size of 700 patients will reach statistical significance with 95% confidence 
in the 3:3 comparisons (diclofenac + capsaicin versus diclofenac and capsaicin, respectively), 
when the observed treatment difference is at least 5.7 mm, and in the 3:1 comparison 
(diclofenac + capsaicin versus placebo), when the observed treatment difference is at least 
8.1 mm.
 
 
About 800 patients will be randomised to ensure that 700 patients are evaluable for the 
primary endpoint; as soon as 700 patients in total are evaluable for the primary analysis, the 
randomisation will be stopped. To ensure that each application site stratum “back pain” or 
“neck pain” is represented by at least 40% of the randomised patients, randomisation into a 
respective stratum will be capped as soon as 60% of the total trial population have been 
allocated to the respective stratum.
Calculations were performed using nQuery Advisor® 6.1 statistical package by Statistical 
Solutions Ltd.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for GCP, relevant BI SOPs, and relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP.
The rights of the Investigator and of the Sponsor with regard to publication of the results of 
this trial are described in the Investigator contract. As a rule, no trial results should be 
published prior to finalization of the Clinical Trial Report.
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB/ IEC and CA according to national and international 
regulations. The same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the Investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.”
Re-consenting may become necessary when new relevant information becomes available and
should be conducted according to the Sponsor’s instructions.
DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the Sponsor, Sponsor’s 
designees, or by IRB/ IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.


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RECORDS
8.3
eCRFs for individual patients will be provided by the Sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained. The Investigator may need to request previous medical records or transfer 
records, depending on the trial; current medical records must also be available.
For eCRF all data need to be derived from source documents.
8.3.2
Direct access to source data and documents
The Investigator/ institution will permit trial-related monitoring, audits, IRB/ IEC review and 
regulatory inspection, providing direct access to all related source data / documents. eCRF 
and all source documents, including progress notes and copies of laboratory and medical test 
results must be available at all times for review by the Sponsor’s clinical trial monitor, 
auditor and inspection by health authorities (e.g. FDA). The CRA/ on site monitor and 
auditor may review all eCRFs, and written informed consents. The accuracy of the data will 
be verified by reviewing the documents described in Section 8.3.1.
8.3.3
Storage period of records
Trial sites:
The trial site(s) must retain the source and essential documents (including ISF) according to 
the national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the Sponsor evaluates 
whether a particular adverse event is “listed”, i.e. is a known side effect of the drug or not. 
Therefore, a unique reference document for the evaluation of listedness needs to be provided. 
For capsaicin/diclofenac gel, and active comparators containing the individual components 
this is the current version of the Investigator’s Brochure [c03404356].
For paracetamol the reference document is the SmPC of Panadol Original Tablets®.


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The current versions of these reference documents are provided in the ISF. No AE are 
classified as listed for matching placebo, trial design, or invasive procedures.
8.4.2
Expedited reporting to health authorities and IEC / IRB
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSAR) to health authorities and IRBs/IECs, will be done according to local 
regulatory requirements.
STATEMENT OF CONFIDENTIALITY
8.5
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the Sponsor’s 
representatives, by the IRBs/ IECs and the regulatory authorities.
END OF TRIAL
8.6
The end of the trial is defined as last patient last follow-up visit (Visit 7T).
The IEC/ CA in each participating EU member state needs to be notified about the end of the 
trial or early termination of the trial.


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9.
REFERENCES
PUBLISHED REFERENCES
9.1
P08-09510
Roelofs PDDM, Deyo RA, Koes BW, Scholten RJPM, Tulder MW van. 
Non-steroidal anti-inflammatory drugs for low back pain (review).
Cochrane Database Syst Rev (1), CD000396 (2008)
P08-09626
Breivik H, Borchgrevink PC, Allen SM, Rosseland LA, Romundstad L, 
Breivik Hals EK, Kvarstein G, Stubhaug. A Assessment of pain. Br J 
Anaesth 101 (1), 17 - 24 (2008)
P08-12601
Zacher J, Altman R, Bellamy N, Bruehlmann P, Silva J da, Huskisson E, 
Taylor RS. Topical diclofenac and its role in pain and inflammation: an 
evidence-based review. Curr Med Res Opin 24 (4), 925 - 950 (2008)
P11-00252
Chrubasik S, Weiser T, Beime B. Effectiveness and Safety of Topical 
Capsaicin Cream in the Treatment of Chronic Soft Tissue Pain. Phytother 
Res 24 (12), 1877 - 1885 (2010)
P11-05079
Warnecke JM, Wendt T, Schak M, Schiffer T, Bloch W, Weiser T, Kohl-
Bareis M. Evaluation of haemoglobin changes of skin and muscle tissue of 
the calf induced by topical application of a nonivamide/nicoboxil cream.
77th Ann Mtg of the German Society for Experimental and Clinical 
Pharmacology and Toxicology, Frankfurt, 30 Mar - 1 Apr 2011. Naunyn 
Schmiedebergs Arch Pharmacol 383 (Suppl 1), 73, Abstr P312 (2011)
P11-08387
Bundesaerztekammer (BAEK), Kassenaerztliche Bundesvereinigung 
(KBV), Arbeitsgemeinschaft der Wissenschaflichen Medizinischen 
Fachgesellschaften (AWMF) National care guideline: low back pain - long 
version, version 1.0, 30 November 2010. Nationale Versorgungs Leitlinie
Kreuzschmerz - Langfassung, Version 1.0, 30. November 2010.
http://www.versorgungsleitlinien.de/themen/kreuzschmerz;
http://www.bptk.de/fileadmin/user_upload/Themen/Leitlinien/20101130_n
vl_kreuzsch merz_lang.pdf (access date: 12 July 2011) (2010)
P11-08754
French SD, Cameron M, Walker BF, Reggars JW, Esterman AJ. Superficial 
heat or cold for low back pain (review). Cochrane Database Syst Rev (1),, 
CD004750 (2006)
P13-09858
O'Neill J, Brock C, Olesen AE, Andresen T, Nilsson M, Dickenson AH. 
Unravelling the mystery of capsaicin: a tool to understand and treat pain.
Pharmacol Rev 64 (4), 939 - 971 (2012)


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P13-15601
Derry S, Moore RA. Topical capsaicin (low concentration) for chronic 
neuropathic pain in adults (review). Cochrane Database Syst Rev (9),, 
CD010111 (2012)
P15-04711
McCarberg B, D'Arcy Y. Options in topical therapies in the management of 
patients with acute pain. Postgrad Med 125 (4) (Suppl), 19 - 24 (2013)
R09-2704
European Medicines Agency (EMEA) Committee for medicinal products 
for human use (CHMP): guideline on clinical development of fixed 
combination medicinal products (London, 19 February 2009, doc. ref. 
CHMP/EWP/240/95 rev. 1). http://www.emea.europa.eu (2009)
R10-0978
Fang JY, Fang CL, Hong CT, Chen HY, Lin TY, Wei HM. Capsaicin and 
nonivamide as novel skin permeation enhancers for indomethacin. Eur J 
Pharm Sci 12, 195 - 203 (2001)
R11-1488
Kenward, M. G. and Roger, J. H. Small Sample Inference for Fixed Effects 
from Restricted Maximum Likelihood. Biometrics, 53, 983 - 997 (1997)
R11-2636
Okada K, Yamaguchi T, Minowa K, Inoue N. The influence of hot pack 
therapy on the blood flow in masseter muscles. J Oral Rehabil 32, 480 - 486 
(2005)
R11-2672
Higashi Y, Kiuchi T, Furuta K. Efficacy and safety profile of a topical 
methyl salicylate and menthol patch in adult patients with mild to moderate 
muscle strain: a randomized, double-blind, parallel-group, placebo-
controlled, multicenter study. Clin Ther 32 (1), 34 - 43 (2010)
R12-4427
Pabst H, Schaefer A, Staiger C, Junker-Samek M, Predel HG. Combination 
of comfrey root extract plus methyl nicotinate in patients with conditions of 
acute upper or low back pain: a multicentre randomised controlled trial.
Phytother Res 27, 811 - 817 (2013)
R12-4428
Predel HG, Hamelsky S, Gold M, Giannetti B.Efficacy and safety of 
diclofenac diethylamine 2.32% gel in acute ankle sprain.Med Sci Sports 
Exerc 44 (9), 1629 - 1636 (2012)
R12-4817
Hoy DG, Protani M, De R, Buchbinder R. The epidemiology of neck pain.
Baillieres Best Pract Res Clin Rheumatol 24, 783 - 792 (2010)
R14-1467
Predel HG, Giannetti B, Pabst H, Schaefer A, Hug AM, Burnett I. Efficacy 
and safety of diclofenac diethylamine 1.16 % gel in acute neck pain: a 
randomized, double-blind, placebo-controlled study. BMC Musculoskeletal 
Disord 14, 250 (2013)


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R14-1637
Degim IT, Uslu A, Hadgraft J, Atay T, Akay C, Cevheroglu S. The effects 
of Azone and capsaicin on the permeation of naproxen through human skin.
Int J Pharm 179, 21 - 25 (1999)
R15-1313
European Medines Agency (EMA). Committee for Medicinal Products for 
Human Use (CHMP): guideline on the pharmacokinetic and clinical 
evaluation of modified release dosage forms (EMA/CPMP/EWP/280/96 
corr1) (draft XXIII) (London, 21 February 2013, EMA/CHMP/EWP/280/96 
rev1). 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guidel
ine/2013/0 3/WC500140482.pdf (access date: 18 March 2015) ; London: 
European Medines Agency (EMA) (2013)
R15-2150
Niethard FU, Gold MS, Solomon GS, Liu JM, Unkauf M, Albrecht HH, 
Elkik F. Efficacy of topical diclofenac diethylamine gel in osteoarthritis of 
the knee. J Rheumatol 32 (12), 2384 - 2392 (2005)
R15-2151
Li C, Frangione V, Rovati S, Zheng Q. Diclofenac epolamine medicated 
plaster in the treatment of minor soft tissue injuries: a multicenter 
randomized controlled trial. Curr Med Res Opin 29 (9), 1137 - 1146 (2013)
R15-2389
Ferrari R, Russell AS. Neck pain. Baillieres Best Pract Res Clin Rheumatol 
17 (1), 57 - 70 (2003)
UNPUBLISHED REFERENCES
9.2
c03404356
Investigator’s Brochure, Diclofenac and capsaicin
U13-2315-01
A multi-centre, double-blind, 
randomised, parallel group study to assess the efficacy and safety of 
multiple doses of topically applied hyperemisation-inducing ointment (2 cm 
ointment line per application; up to 3 times daily for up to 4 days) 
containing 2.5% Nicoboxil/ 0.4% Nonivamide versus 2.5% Nicoboxil, 
0.4% Nonivamide and placebo in patients 18 to 65 years of age with acute 
low back pain. 69.52 Clinical Trial Report, 01-October-2013


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10.
APPENDICES
Not applicable


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
21-Jun-2016
EudraCT number
2015-000404-25
BI Trial number
1358.1
BI Investigational Product(s)
Diclofenac + Capsaicin
Title of protocol
A randomized, controlled multi-centre parallel 
group study to assess the efficacy and safety of 
multiple doses of a topically applied combination 
containing diclofenac 2% + capsaicin 0.075% (2 
g formulation per application; 2-times daily for 5 
days) compared to placebo, as well as to 
diclofenac 2% and capsaicin 0.075% in patients 
with acute back or neck pain
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Title page
Description of change
Phone: 
Fax:
Has been changed to:


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Phone: 
 Fax:
Rationale for change
Change of responsibility
Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS –
Main criteria for inclusion
Description of change
Sensitivity to algometric pressure on the painful 
trigger point ≤ 2.5 N/cm²
Has been changed to: 
Sensitivity to algometric pressure on the painful 
trigger point ≤ 25 N/cm²
Rationale for change
An upper limit of 2.5 N/cm² has turned out to be 
too low and would only allow the inclusion of 
patients with extremely high algometric pressure. 
This upper limit had been taken from Pabst et al. 
(2013), Phytother. Res. 27: 811–817. However, 
personal communication was received from 
 
(co-author of the 
publication and coordinating investigator of this 
trial) that actually and upper limit of 2.5 kp/cm² 
had been applied in the published study. 2.5 
kp/cm² correspond to 24.5 N/ cm².
Section to be changed
Flowchart
Description of change
Approximate day time of Visit 7T which was 
formerly given as “E” (evening) was removed.
Rationale for change
Visit 7T does not need to be performed at a 
specific day time
Section to be changed
Flowchart
Description of change
Hand-out of patient diary; Instructions on use: X 
at visit 1 
Has been changed to: 
Return of patient diary: X at visit1, visit 2, visit 
3, visit 4, visit 5
Rationale for change
The patients get a new diary at each visit 1-5 and 
are supposed to return that diary at the very next 
visit  
Section to be changed
Flowchart


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Description of change
Return of patient diary: X at visit 6 
Has been changed to: 
Return of patient diary: X at visit 2, visit 3, visit 
4, visit 5 and visit 6 
Rationale for change
The patients get a new diary at each visit 1-5 and 
are supposed to return that diary at the very next 
visit  
Section to be changed
Flowchart
Description of change
Completion of patient participation (*)
Has been changed to: 
Completion of patient participation 
Rationale for change
Correction of typo  
Section to be changed
3.3.2 Inclusion criteria
Description of change
4.
Sensitivity to algometric pressure on the 
painful trigger point ≤ 2.5 N/cm² (see Section 
5.2.2).
Has been changed to: 
4.
Sensitivity to algometric pressure on the 
painful trigger point ≤ 25 N/cm² (see Section 
5.2.2).
Rationale for change
An upper limit of 2.5 N/cm² has turned out to be 
too low and would only allow the inclusion of 
patients with extremely high algometric pressure. 
This upper limit had been taken from Pabst et al. 
(2013), Phytother. Res. 27: 811–817. However, 
personal communication was received from 
 
(co-author of the 
dinating investigator of this 
trial) that actually and upper limit of 2.5 kp/cm² 
had been applied in the published study. 2.5 
kp/cm² correspond to 24.5 N/ cm².
Section to be changed
3.3.4.1 Removal of individual patients
Description of change
Patients who discontinue or withdraw from the 
study after randomisation will be considered as 
“early discontinuations” and the reason for this 
premature discontinuation must be recorded in 


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the eCRF. The Investigator must inform the 
sponsor within 24 hours via IRT (see Section 
4.1) about any discontinuation of a subject.
Has been changed to: 
Patients who discontinue or withdraw from the 
study after randomisation will be considered as 
“early discontinuations” and the reason for this 
premature discontinuation must be recorded in 
the eCRF. The Investigator must inform the 
sponsor within 24 hours (see Section 4.1) about 
any premature discontinuation of a subject.
Rationale for change
The IRT system does not require to register the 
termination of a patient’s trial participation   
Section to be changed
Table 4.1.1: 1, table 4.1.1: 2, table 4.1.1: 3, table 
4.1.1: 4
Description of change
Semi solid formulation 
Has been changed to: 
Gel
Rationale for change
Correction  
Section to be changed


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Section to be changed
Figure 5.2.1:5
Description of change
A downward showing arrow was added to the 
image 
Rationale for change
Added for clarification
Section to be changed
5.3.3
Physical examination
Description of change
A physical examinations will be performed by 
the Investigator or designated site-personnel at 
the time point indicated in the Flow Chart.
Has been changed to:
A physical examination will be performed by the 
Investigator or designated site-personnel at the 
time point indicated in the Flow Chart.
Rationale for change
Correction of typo
Section to be changed
Table 5.3.5: 1 Safety laboratory tests
Description of change
baso-phils
Has been changed to:
basophils
Rationale for change
Correction of typo
Section to be changed
5.3.7 Adverse event collection and reporting
Description of change
From signing the informed consent onwards 
through the Residual Effect period (REP), all 


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AEs (serious and non-serious), and AESIs.
Has been changed to:
From signing the informed consent onwards 
through the Residual Effect period (REP), all 
AEs (serious and non-serious), and AESIs must 
be reported.
Rationale for change
Correction of typo
Section to be changed
6.2.2 Treatment period
Description of change
The 3rd bullet point under “The patient should be 
instructed” was changed from
to refrain from using rescue medication before 
Visit 3 if possible. If this turns out not to be 
possible, another supply of rescue medication 
might be dispensed at visit 3
to
to refrain from using rescue medication before 
Visit 3 if possible. If this turns out not to be 
possible, another supply of rescue medication 
might be dispensed at visit 5
Rationale for change
Correction of typo
Section to be changed
6.2.2 Treatment period
Description of change
The 7th bullet point under “The patient should be 
instructed” was splitted from
•
to return their patient’s diary as well as 
all unused trial and rescue medication and 
packaging at Visit 6
to
•
to return their patient’s diary at visit 2, 
visit 3, visit 4, visit 5 and visit 6
•
to return all unused trial and rescue 
medication and packaging at Visit 6
Rationale for change
The patients get a new diary at each visit 1-5 and 
are supposed to return that diary at the very next 
visit
Section to be changed
6.2.3 Follow Up Period and Trial Completion


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Description of change
All study procedures according to the Flow Chart 
should be performed. Patients who complete the 
treatment period should be registered as 
completed in the IRT system.
Has been changed to:
All study procedures according to the Flow Chart 
should be performed.
Rationale for change
The IRT system does not require to register the 
termination of a patient’s trial participation   
Section to be changed
6.2.3 Follow Up Period and Trial Completion
Description of change
Patient who want to discontinue the trial 
treatment prematurely should be asked to have 
Visit 6 in the morning after the last application of 
the trial medication and to have a Visit 7T at 
least 48 hours after that last application.
Has been changed to:
Patients who want to discontinue the trial 
treatment prematurely should be asked to have 
Visit 6 in the morning after the last application of 
the trial medication and to have a Visit 7T at 
least 48 hours after that last application.
Rationale for change
Correction of typo
Section to be changed
 endpoint 
 
 
Section to be changed
Description of change


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Rationale for change


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03317678
2.0
clinical-trial-protocol-version-2
A randomized, controlled multi-centre parallel group study to assess the efficacy and
safety of multiple doses of a topically applied combination containing diclofenac 2%
+ capsaicin 0.075% (2 g formulation per application; 2-times daily for 5 days)
compared to placebo, as well as to diclofenac 2% and capsaicin 0.075% in patients
with acute back or neck pain
Author-Trial Clinical Monitor
21 Jun 2016 16:06 CEST
Author-Trial Statistician
21 Jun 2016 16:09 CEST
Approval-Therapeutic Area 
22 Jun 2016 09:58 CEST
Author-Team Member Medicine
23 Jun 2016 09:18 CEST
Author-Trial Clinical Monitor
24 Jun 2016 15:46 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03317678
2.0

SAP_000.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c09625501-02
BI Trial No.:
1358.1
Title:
A randomized, controlled multi-centre parallel group study to
assess the efficacy and safety of multiple doses of a topically
applied combination containing diclofenac 2% + capsaicin
0.075% (2 g formulation per application; 2-times daily for 5
days) compared to placebo, as well as to diclofenac 2% and
capsaicin 0.075% in patients with acute back or neck pain
Including Protocol Amendment 1 [c03317678-02]
Test Substance:
Diclofenac + Capsaicin
Responsible trial 
statistician:
Phone
Fax
Date of statistical 
analysis plan:
06 October 2017 REVISED
Version:
Revised
Page 1 of 36
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2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
1.
TABLE OF CONTENTS ......................................................................2
LIST OF TABLES ..............................................................................................4
2.
LIST OF ABBREVIATIONS ...............................................................5
3.
INTRODUCTION..................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......8
5.
ENDPOINTS ........................................................................................11
5.1
PRIMARY ENDPOINT ....................................................................................11
5.2
SECONDARY ENDPOINTS............................................................................11
5.2.1
Key secondary endpoints..............................................................................11
5.2.2
Other secondary endpoints...........................................................................13
5.4
OTHER VARIABLES.......................................................................................14
6.
GENERAL ANALYSIS DEFINITIONS...........................................16
6.1
TREATMENTS..................................................................................................16
6.3
PATIENT SETS ANALYSED..........................................................................21
6.5
POOLING OF CENTRES ................................................................................23
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................23
6.6.1
Missing or partial dates ................................................................................23
6.6.2
Missing efficacy data.....................................................................................23
6.6.3
Safety ..............................................................................................................24
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................24
7.
PLANNED ANALYSIS.......................................................................25
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........25
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................26
7.3
TREATMENT COMPLIANCE .......................................................................26
7.4
PRIMARY ENDPOINTS..................................................................................27
7.4.1
Primary analysis............................................................................................27
7.5
SECONDARY ENDPOINTS............................................................................28
7.5.1
Key secondary endpoints..............................................................................28
7.5.2
Other secondary endpoints...........................................................................28
7.5.2.1
Endpoints from POMWP...........................................................................28
7.5.2.2
Endpoints from pressure algometry .......................................................29


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7.7
EXTENT OF EXPOSURE................................................................................30
7.8
SAFETY ANALYSIS.........................................................................................31
7.8.1
Adverse events ...............................................................................................31
7.8.2
Laboratory data.............................................................................................32
7.8.3
Vital signs.......................................................................................................32
7.8.4
Others .............................................................................................................32
7.8.4.1
Assessment of skin reactions....................................................................32
7.8.4.2
Assessment of tolerability ........................................................................32
8.
REFERENCES.....................................................................................33
10.
HISTORY TABLE...............................................................................36


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LIST OF TABLES
Table 6.1: 1
Planned treatments ..........................................................................................16
Table 6.1: 2
Study periods of interest..................................................................................16
Table 6.2: 1 
Important protocol violations..........................................................................18
Table 6.3: 1
Patient sets for planned analyses.....................................................................22
Table 10:1
History table ....................................................................................................36


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
AESI
Adverse Event
Adverse Events of Special Interest 
ANCOVA
Analysis of Covariance
ASS
Acetyl salicylic acid
AUC
Area Under the Curve
BI
Boehringer Ingelheim
BMI
Body Mass Index
BRPM
Blinded Review Planning Meeting
CI
Confidence Interval
cm
Centimetre
CRA
Clinical Research Assistant/Associate
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBLM
Database Lock Meeting
DBP
Diastolic Blood Pressure
eCRF
Electronic Case Report Form
EoT
End of Text
FAS
Full Analysis Set
g
Gram
GCP
Good Clinical Practice
ICH
International Conference on Harmonisation
IDEA
International Document Management and Electronic Archiving 
System
IMP
Investigational Medicinal Product
IPV
Important Protocol Violation
kg
Kilogram
MedDRA
Medical Dictionary for Regulatory Activities


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Term
Definition / description
MMRM
Mixed Model Repeated Measures
MQRM
Medical Quality Review Meeting
N
Newtons
NSAID
Non-steroidal Anti-Inflammatory Drug
PA
Pressure Algometry
POM
Pain on movement
POMWP
Pain on movement of worst procedure
POMWPAUC72
Area Under the Curve of POMWP assessed until Day 4 morning 
POMWPAUC120
Area Under the Curve of POMWP assessed until Day 6 morning 
PR
Pulse Rate
PT
Preferred Term
PV
Protocol Violation
Q1
Lower Quartile
Q3
Upper Quartile
REML
Restricted Maximum Likelihood
REP
Residual Effect Period
SAE
Serious Adverse Event
SAS
Statistical Analysis System
SBP
Systolic Blood Pressure
SD
Standard Deviation
PDL
Patient Data Listing
SOC
System Organ Class
TMM
Trial Member Medicine
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
VAS
Visual Analog Scale
WHO-DD
World Health Organization-Drug Dictionary


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3.
INTRODUCTION
As per ICH E9 [1], the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomisation.
SAS® Version 9.4, or a later version, will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
The following changes to CTP v1 were made and approved in CTP v2, dated 21-Jun-2016
Global Amendment 1:
1. The two endpoints, number of patients with a decrease in POMWP from baseline of at 
least 30% and 50% respectively were planned to be analysed at the timepoint, before 
drug application in the morning of day 2 (Visit 2), however no such analysis will be 
performed as there is no POM assessment scheduled at this timepoint. 
In addition, the following changes are made in the TSAP

Contrary to the protocol, all analyses pertaining to change from baseline were 
programmed as 
Change in endpoint = Endpoint at time x – endpoint at baseline
rather than 
Change in endpoint = Endpoint at baseline - Endpoint at time x
To minimize the risk of error by re-programming it was decided not to reverse the 
calculation. Additionally it was felt that, for the POM assessments in particular, it would 
be intuitively preferable to show any decrease from baseline as a negative value thus 
providing an indication of treatment effect.


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
The initial TSAP stated the planned treatment application date/time for Day 6 was to be 
included in the calculation of the time intervals used in the derivation of the key 
secondary endpoint, POMWPAUC120. However as there is no treatment application 
scheduled at Day 6, the POM assessment time for Day 6 will be imputed as the actual 
treatment application date/time for Day 5 evening + 12 hours or alternatively, Day 5 
morning + 24 hours if the former is missing.

Some sites in Germany, during the conduct of the trial, did not have sufficient POM 
booklets in stock which led to photocopies of the VAS scale being used in the POM 
assessments. Unfortunately some of these copied VAS scales were not exactly 10cm in 
length. Similarly for Russian sites, the VAS scale displayed in the POM booklets, printed 
in Russia, were not always exactly 10cm. As a consequence, 
o
all POM measurements will be normalised, prior to analysis, to a 10cm scale.
o
 
 


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary efficacy endpoint is the change in pain on movement (POM) between baseline 
and day 2 evening, 1 hour after drug application (Visit 3), with regard to the POM of the 
procedure which gave the highest score at baseline (“POM of worst procedure”, POMWP).
ℎ	 
  = ,      −,"
POM is assessed by the patient on one standardized movement by using a Visual Analog
Scale (VAS) ranging from 0 mm = ‘no pain’ to 100 mm = ‘worst pain possible for this
condition’.
For definition of study baseline please refer to section 6.7. 
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints 

POMWPAUC72 and POMWPAUC120
AUC will be calculated as area under the curve from zero to approximately 72 hours 
(corresponding to POMWP, day 4 morning post application) or to approximately 120 hours 
(corresponding to POMWP, day 6 morning) using the trapezoidal rule divided by the 
observation time. 
#$% = 1
'(
) 1
2 ((',-) + (')) ∗(' −',-)
(
1-
#$-2 = 1
'%
) 1
2 ((',-) + (')) ∗(' −',-)
%
1-


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Study drug application date/times will be the basis for the calculation of respective 
time intervals. 
t0 = 0, 
for i=1 to 6,
ti = ([actual date of application of POMWP assessment i+1] – [actual date of 
first application (visit 1)]) * 24 + [actual time of application of POMWP
assessment i+1] – [actual time of first application (visit 1)] + 1post-value. 
t7 = ([actual date of application on Day 5 evening] – [actual date of first 
application (visit 1)]) * 24 + [actual time of application on Day 5 evening –
actual time of first application (visit 1)] + 12. 
where 
1,3 = 4 0, 
6 78	 −779
:'
;  <9=	
1, 
6 7;>' −779
:'
;  <9=	
Planned assessment times are:
Assessment
ti
1 (Baseline)
t0 = 0
2 (Day 1 morning, 1 hour after application)
t1 = 1
3 (Day 2, morning, 1 hour after application)
t2 = 25
4 (Day 2 evening, before application)
t3 = 36
5 (Day 2 evening, 1 hour after application)
t4 = 37
6 (Day 3, morning, 1 hour after application)
t5 = 49
7 (Day 4, morning, 1 hour after application)
t6 = 73
8 (Day 6, morning)
t7 = 120
For AUC calculation, one or more missing assessments in between POM assessments will be 
imputed using the planned assessment time and a linear interpolation of the last available 
assessment before (including baseline, if applicable) and the first available assessment after 
the missing assessment. If there is no evaluable assessment after the planned time of the 
missing assessment, planned assessment time and LOCF will be used to impute the value.
For example, if assessment 3 is missing but assessments 2 and 4 are available, 
imputation will use the planned assessment time of 25 hours and linear interpolation 
using the data from assessments 2 and 4. If assessment 4 was also missing but 
assessment 5 was available that would be used instead. 


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5.2.2
Other secondary endpoints

Number of patients with a decrease in POMWP of at least 30% from baseline on day 2 
evening, 1 hour after drug application (Visit 3)

Number of patients with a decrease in POMWP of at least 50% from baseline on day 2 
evening, 1 hour after drug application (Visit 3)

Change in POMWP between baseline and the morning of day 6 (Visit 6)

Change in Pressure Algometry (PA) [N/cm] between baseline and day 2 evening, 
before drug application (Visit 3)

Change in PA [N/cm] between baseline and the morning of day 6 (Visit 6)


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5.4 OTHER VARIABLES

Assessment of skin reactions as assessed by Dermal Response Score (DRS) at visits 1, 
2, 3, 4, 5 and 6.
o
Observed values
The DRS is a scale ranging from 0 (no evidence of irritation) to 7 (strong 
reaction spreading beyond test site). 


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o
Responders
A responder analysis will be performed; the categorisation of changes will be 
as follows: 
Positive is defined as any score ≥3
Negative is defined as any score <3

Overall assessment of tolerability at visit 6
o
Overall tolerability as assessed by the patient
Tolerability is assessed on a scale ranging from 0 (poor) to 3 (very good). 
o
Overall tolerability as assessed by the investigator

Physical examination

Vital signs
o
Systolic blood pressure (SBP)
o
Diastolic blood pressure (DBP)
o
Pulse rate (PR)

Safety laboratory parameters

Adverse events


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
Table 6.1: 1 shows the treatments which are planned to be investigated and the treatment 
order to be displayed in the tabulations: 
Table 6.1: 1
Planned treatments
Treatment 
Order
Treatment
Short label
Administration 
timing
1
Placebo gel administered 
twice daily
Placebo
Morning and evening
2
Capsaicin 0.075% gel 
administered twice daily
Capsaicin
Morning and evening
3
Diclofenac 2% gel 
administered twice daily
Diclofenac
Morning and evening
4
Diclofenac 2% + Capsaicin 
0.075% gel administered 
twice daily
Diclofenac + 
capsaicin
Morning and evening
If a patient receives the wrong treatment the patient will be analysed within the planned 
(randomised) treatment group in the efficacy analysis and within the actual treatment group 
in the safety analysis.
The study periods of interest are displayed in Table 6.1: 2. 
Table 6.1: 2
Study periods of interest
Study period
Definition
Screening
From screening until informed consent is obtained
On-treatment
From first application of trial drug until last application of trial drug
plus 2 days (inclusive). 
Post-treatment
From date of last application of trial drug plus 2 days until trial 
termination date
Post-study
Post-trial termination date


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6.3
PATIENT SETS ANALYSED
The patient sets of treated set (TS), full analysis set (FAS) 
 as 
defined in the CTP will be used
 


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The randomised set is defined as all randomised patients, whether treated or not. 
Patients having received the wrong treatment will be analysed within the planned 
(randomised) treatment group in the efficacy analysis (TS as randomized) and within the 
actual treatment group in the safety analysis (TS as treated).
Patients who are incorrectly randomised into the stratum not containing the POMWP will be 
included in the patient set TS as randomised but will be allotted to the stratum with the 
POMWP for efficacy analyses.
Table 6.3: 1 shows which analysis set is used for each class of endpoint.
Table 6.3: 1
Patient sets for planned analyses
Planned analysis
Patient set
Disposition
Enrolled patients
Analysis sets
Randomised set
IPVs, demographic and other baseline 
characteristics, concomitant therapies and
treatment compliance
TS (as randomised)
Efficacy analysis: primary, secondary 
 
TS (as randomized)
FAS (primary endpoint only)
Safety analysis
TS (as treated)
Note that the number of patients with available data may differ between endpoints. For 
details, see Section 6.6 “Handling of missing data”.


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6.5
POOLING OF CENTRES
Country will be included in the statistical models therefore no pooling of centres is planned. 
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Every effort should be made to collect complete data for each time point at each test day. 
6.6.1
Missing or partial dates
According to the guideline, if only the year of birth is known, the day and month of birth will 
be imputed as 01 January. For other incomplete date information, the midpoint of the possible 
interval will be used. If only the year is present, the day and month will be imputed as 01 
July; if year and month are present, the day will be imputed as 15. If the year is missing, the 
date will be considered missing.
For partial start and stop dates for background medication, concomitant therapies, and 
additional treatments, the following derivations will be used to impute “worst case” values:

If the day of the end date is missing, then the end date is set to last day of the month.

If the day and month of the end date are missing, then the end date is set to 31st
December of the year.

If the day of the start date is missing, then start date is set to first day of the month.

If the day and month of the start date are missing, then the start date is set to 1st
January of the year.
All other cases need to be assessed by the trial team on an individual basis, using the above
points as guidance.
6.6.2
Missing efficacy data
Every effort should be made to collect complete data for each time point at each test day, 
independent whether it is related to POMWP endpoint data or any other endpoint data. 
For missing baseline data, no imputation will be implemented. 
For the analyses utilising a likelihood-based repeated measures model, no imputation of 
missing values will be performed. 
For details on the handling of missing data for the AUC calculation see section 5.2.1. 
Missing patient assessments of 
 resulting from early 
discontinuation that was clearly unconnected to treatment will not be imputed. 


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6.6.3
Safety
With regard to the safety analysis, no imputation of safety data is foreseen (observed case 
analysis) except for missing or incomplete adverse event (AE) dates. Missing or incomplete 
AE dates are imputed according to BI standards ( “Handling of missing and incomplete AE 
dates”) [2].
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Definition of baseline
Baseline values are defined as the last morning assessment prior to randomization and the 
first drug application on day 1 (Visit 1).
Time windows
Time windows for visits are shown in the Flow Chart in the CTP. Visits 1-5 must be carried 
out on the specified days, for Visit 6 there is a time window of -1/+2 days, for Visit 7T there 
is a time window of +4 days. 
Calculated visits
Visits which occur outside of the defined visit window are flagged as PVs. 
If a single scheduled visit is completed outside of the visit window, as defined in the CTP, 
that visit will be assigned to the scheduled visit. For example, if a patient completes a visit in 
the afternoon of day 3, the visit would be assigned to visit number 4. 
If two consecutive scheduled visits are missed, but a single visit completed between the visit 
for both scheduled (but missed) visits, the completed visit will be assigned to the closest 
scheduled visit. However, the final assignment of the visit should be agreed at a medical 
quality review meeting (MQRM) or BRPM. 
Unscheduled visits are not expected for this study. However, should unscheduled visits occur 
between non-missed scheduled visits, they are assigned separate visit numbers according to 
BI convention, but will not be included in the summary statistics and will not be used in any 
inferential analysis. 


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7.
PLANNED ANALYSIS
For End-of-Text (EoT) tables, for continuous variables, the set of summary statistics is: 
Number of patients with non-missing values / Mean / standard deviation (SD) / Minimum / 
Q1 (lower quartile) / Median / Q3 (upper quartile) / Maximum. 
Tabulations of frequencies for categorical and ordinal data will include all possible categories 
and will display the number of observations in a category as well as the percentage (%) 
relative to the respective treatment group (unless otherwise specified, all patients in the 
respective patient set whether they have non-missing values or not). Percentages will be 
rounded to one decimal place. The category missing will be displayed only if there are 
actually missing values.
Patient sets for the planned analyses are displayed in Table 6.3: 1. Patient data listings 
(PDLs) will be based on the randomised set. If any AEs/SAEs are reported for screening 
failures, these will be summarised in the AE listing “Adverse event overall summary” and 
described in the Clinical Trial Report (CTR) if considered related to the screening 
procedures.
For all efficacy analyses pertinent to application site and applicable only to the FAS and 
 any patient who is incorrectly randomised into the stratum not containing the POMWP
will be included in the stratum with the POMWP.
As detailed in Section 4 all analyses pertaining to POM will be performed on the normalised 
POM scores derived as:
Normalised POM score (cm) =
POM score
x 10
VAS scale length
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Descriptive statistics will be presented for the treated set for the following demographic and 
baseline characteristics, by treatment group and all patients combined:
Demographic data

Age [years]

Age class (≥18 to <65, ≥65 years)

Age class (≥18 to <65, 65 to <85, ≥85 years)
(required only for the ‘Disposition of patients for data disclosure by age groups’ table)

Sex (Male, Female)

Race (American Indian/Alaska Native, Asian, Black/African American, 
Hawaiian/Pacific Islander, White)


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
Ethnicity (Not Hispanic/Latino, Hispanic/Latino)
Baseline disease characteristics

Time since onset of acute pain (days)

POM (each assessment and POMWP)

PA [N/cm2]

Pain intensity at rest

Average pain intensity
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive analysis is planned for this section of the report, using the treated set.
Concomitant medication taken in the 4 weeks before the treatment period and at baseline or 
during the treatment period will be summarised by World Health Organization-Drug 
Dictionary (WHO-DD) name and preferred term (PT), and presented by treatment group and 
all patients combined. Concomitant analgesic medication taken at baseline or during the 
treatment period will be summarized separately from both rescue medication and from all 
other concomitant medication. 
Baseline conditions / concomitant diagnoses will be summarised by Medical Dictionary for
Regulatory Activities (MedDRA) system organ class (SOC) and PT, and presented by 
treatment group and the total of all subjects.
7.3
TREATMENT COMPLIANCE
Treatment compliance will be assessed by calculating the weight difference of the tubes after 
being returned at Visit 6 from the pre-dose weight at Visit 1. In addition, the mean weight per 
gel application will be calculated based on the total number of gel applications. Descriptive 
statistics will be calculated for these parameters. 
Weight difference will be calculated by:
WeightDiff [g] = WeightPre [g] – WeightPost [g]
The mean weight per gel application will be calculated by:
Mean weight per gel application = WeightDiff [g] / total number of gel applications
Compliance will be presented by treatment group and in total, using the treated set. 


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7.4
PRIMARY ENDPOINTS
7.4.1
Primary analysis
The primary endpoint will be analysed as described in the CTP, using the FAS. 
Differences between the combination treatment (diclofenac and capsaicin) and individual 
treatments or placebo will be estimated at visit 3 (day 2 evening, 1 h after application), 
differences should be calculated as the combination treatment minus the individual treatment
or placebo, meaning negative differences favour the combination treatment. Adjusted least 
squares means (with standard errors) as well as treatment contrasts and their 95% confidence 
intervals (CIs) and two-sided (α=0.05) p-values will be presented. 
The SAS code to be used for this analysis is given in section 9.1. 
In addition, the primary endpoint will be summarized by treatment group using descriptive 
statistics. 


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7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
The key secondary endpoints will be analysed using the treated set. 
POMWPAUC72 and POMWPAUC120 will be analysed using an ANCOVA model as described 
in the CTP. Adjusted means (with standard errors) as well as treatment contrasts will be 
presented together with 95% confidence intervals. The analysis will be performed using the 
treated set. 
In addition POMWPAUC72 and POMWPAUC120 will be summarised by treatment group using 
descriptive statistics. 
7.5.2
Other secondary endpoints
All other secondary endpoints will be analysed using the treated set. 
7.5.2.1
Endpoints from POMWP
The number of patients with a decrease in POMWP of at least 30% from baseline until day 2 
evening, 1h after drug application, will be analysed using a logistic regression model as 
described in the CTP. Treatment differences will be analysed using adjusted odds ratios 
which will be presented together with 95% confidence intervals, the combination treatment 
(diclofenac and capsaicin) will be used as the reference treatment. Odds ratios will be 


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calculated as combination treatment/individual treatments or placebo, meaning an odds ratio 
>1 would indicate better responses for the combination treatment. 
The number of patients with a decrease in POMWP of at least 50% from baseline until day 2 
evening, 1h after drug application, will be analysed similarly. 
Change in POMWP between baseline and the morning of day 6 will be analysed analogously 
to the primary endpoint, using all available data points as described in CTP section 7.3.2.
7.5.2.2
Endpoints from pressure algometry
Change in PA between baseline and day 2 evening before drug application and change in PA 
between baseline and the morning of day 6 will all be analysed analogously to the primary 
endpoint, using all available data points as described in CTP section 7.3.2. 


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7.7
EXTENT OF EXPOSURE
Duration of treatment exposure will be determined for each patient during the randomised 
treatment period. The basis for the treatment exposure will be the duration of exposure 
counted in days on treatment. 
Duration of treatment exposure will be calculated as: 
Number of days on treatment = treatment discontinuation date – treatment start date + 1
Extent of exposure will be summarised using descriptive statistics. A frequency table 
showing the number of gel applications, per day and in total, as recorded in the patient diary, 
will be presented. Descriptive statistics will be calculated and displayed by treatment group 
as well as all patients combined. 


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the Treated set (as treated). 
7.8.1
Adverse events
Adverse events will be coded using the most recent version of MedDRA.
AE data will be handled according to the current version of the BI AE guideline [2]. 
The analyses of adverse events will be descriptive in nature. All analyses of AEs will be 
based on the number of patients with AEs and not the number of AEs. For this purpose, AE 
data will be combined in a 2-step procedure into AE records:
In the first step, AE occurrences, i.e. AE entries on the eCRF, will be collapsed into AE 
episodes provided that all of the following apply:

The same MedDRA lowest level term was reported for the occurrences

The occurrences were time-overlapping or time-adjacent (time-adjacency of 2 
occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence)
In the second step, AE episodes will be condensed into AE records provided that the episodes 
were reported with the same term on the respective MedDRA level. For further details on 
summarisation of AE data, please refer to the guideline 'Handling and summarization of 
adverse event data for clinical trial reports and integrated summaries' [3].
Other significant AEs will be reported and summarized according to ICH E3 criterion.
Thus, AEs classified as ‘other significant’ will include those non-serious adverse events with:
(i) ‘action taken = discontinued from study’, or
(ii) marked hematological and other lab abnormalities, or lead to significant 
concomitant therapy as identified by the Clinical Monitor / Investigator at a MQRM 
or a BRPM.
An overall summary of adverse events will be presented by treatment group.
The frequency of patients with adverse events will be summarised by treatment group,
primary SOC and PT. Separate tables will be provided for patients with other significant 
adverse events, for patients with adverse events of special interest (AESI), for patients with 
serious adverse events, for patients with AEs leading to discontinuation,  for patients with 
drug-related AEs and for patients with drug-related serious adverse events.
The SOCs will be sorted alphabetically; PTs will be sorted by frequency (within SOC).


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7.8.2
Laboratory data
Laboratory data will be analysed and summarised as described in the CTP.
Clinically significant findings will appear under “Baseline condition” or “Adverse events” 
and will be analysed accordingly. 
Where repeat measurements are taken for a patient, the worst value according to BI standards
will be presented.
7.8.3
Vital signs
Vital signs (systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse rate 
(PR)) will be summarised by treatment group using descriptive statistics for observed values 
and changes from baseline. 
7.8.4
Others
7.8.4.1
Assessment of skin reactions
Assessment of skin reactions will be analysed descriptively only. 
Two tables will be presented, by treatment group and in total. The first table will be a 
frequency count of the individual dermal response scores (range 0-7) and the second a 
responder analysis table, categorised as positive for scores ≥3 and negative for scores <3. 
7.8.4.2
Assessment of tolerability
Final overall patient assessment of tolerability and final overall investigator assessment of 
tolerability will be analysed 


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8.
REFERENCES
[1]
CPMP/ICH/363/96: “Statistical Principles for Clinical Trials”, ICH Guideline 
Topic E9; Note For Guidance on Statistical Principles for Clinical Trials, current 
version.
[2]
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
[3]
001-MCG-156: "Handling and summarisation of adverse event data for clinical 
trial reports and integrated summaries", version 5.0; IDEA for CON.


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10.
HISTORY TABLE
This is a revised TSAP including the following modifications to the final TSAP.
Table 10:1
History table
Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
Final
29-Jun-17
None
This is the final TSAP without any 
modification
Revised
06-Oct-17
Refer to 
Section 4
Refer to Section 4