Conditions: Back Pain Neck Pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 635
Healthy volunteers: no

Brief summary:
To assess the efficacy and safety of a 400 mg ibuprofen/100 mg caffeine tablet in comparison to a 400 mg ibuprofen tablet for the treatment of acute lower back or neck pain. To assess the safety and tolerability of a 400 mg ibuprofen/100 mg caffeine tablet in comparison to a 400 mg ibuprofen tablet and a placebo tablet.

Detailed description:

Arms:
arm 1: Fixed Dose Combination arm 2: None arm 3: None

Interventions: intervention 1: ibuprofen intervention 2: caffeine intervention 3: placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_001.pdf: 
ABCD
001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
Clinical Trial Protocol
TITLE PAGE
Document Number:
c08887804-02
EudraCT No.:
EU Trial No:
2016-000902-12
BI Trial No.:
1335.5
BI Investigational 
Product(s):
Ibuprofen + Caffeine
Title:
A randomized, placebo- and active-controlled multi-country, 
multi-centre parallel group study to evaluate the efficacy and 
safety of a fixed dose combination of 400 mg ibuprofen and 
100 mg caffeine compared to ibuprofen 400 mg and placebo in 
patients with acute lower back or neck pain
Lay Title:
Ibuprofen/caffeine lower back or neck pain study
Clinical Phase:
III
Trial Clinical 
Monitor:
Phone: 
Fax: 
Coordinating 
Investigator:
Phone: 
 
Fax: 
Status:
Final Protocol
Version and Date:
Version: 2.0
Date: 05 August 2016
Page 1 of 73
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:
NA
Name of active ingredient:
Ibuprofen + Caffeine
Protocol date:
28-July-2016
Trial number:
1335.5
Revision date:
05-August-2016
Title of trial:
A randomized, placebo- and active-controlled multi-country, 
multi-centre parallel group study to evaluate the efficacy and 
safety of a fixed dose combination of 400 mg ibuprofen and 100 
mg caffeine compared to ibuprofen 400 mg and placebo in 
patients with acute lower back or neck pain
Coordinating
Investigator:
Phone: 
Fax: 
Trial site(s):
Multi-centre trial, conducted in 2 countries (Germany, Russia)
Clinical phase:
III
Objective(s):
To assess the efficacy and safety of a 400 mg ibuprofen/100 mg 
caffeine tablet in comparison to a 400 mg ibuprofen tablet for the 
treatment of acute lower back or neck pain
The primary objective of this trial is to demonstrate superior 
efficacy of the combination 400 mg ibuprofen/100 mg caffeine 
versus 400 mg ibuprofen and placebo.
A secondary objective is to assess the safety and tolerability of a
400 mg ibuprofen/100 mg caffeine tablet in comparison to a 400 
mg ibuprofen tablet, and a placebo tablet.


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Name of company:
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
Ibuprofen + Caffeine
Protocol date:
28-July-2016
Trial number:
1335.5
Revision date:
05-August-2016
Methodology:
Randomised, double-blind, placebo- and active-controlled, multi-
country, multi-centre 3-arm parallel group study
No. of patients: 
650 randomized
Total entered: 
Approximately 650 randomized to achieve 600 patients eligible 
for assessment of the primary endpoint 
Each treatment:
Ibuprofen/caffeine:
260
Ibuprofen:  
260
Placebo:
130
Diagnosis :
Acute lower back or neck pain  
Main criteria
for inclusion:
Male or female patients ≥18 years with current diagnosis of acute 
lower back or neck pain for at least 24 hours but less than 21 
days.
Acute lower back pain resulting in pain on movement (POM) ≥ 
5on a 0-10-point Numerical Rating Scale (NRS) for at least one 
POM procedure out of the 5 standardized procedures.
Sensitivity to algometric pressure on the painful trigger point ≤ 25 
N/cm²
Test product:
400 mg ibuprofen and 100 mg caffeine tablet
Dose:
One tablet three times daily with intervals of 6-8 h hours over 5
days (up to Day 6 morning)
Mode of 
administration:
p.o.


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Name of company:
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
Ibuprofen + Caffeine
Protocol date:
28-July-2016
Trial number:
1335.5
Revision date:
05-August-2016
Comparator products: 400 mg ibuprofen tablet
placebo tablet
Dose:
One tablet three times daily with intervals of 6-8 h hours over 5
days (up to Day 6 morning)
Mode of 
administration:
p.o.
Duration of treatment:
5 days
Endpoints
Primary endpoint:

Change in Pain On Movement (POM) with regard to the 
Worst Procedure (WP), i.e. the procedure with the highest 
pain score at baseline (POMWP), between baseline (Day 1 
morning pre-dosing) and Day 2 morning, 2 hours after 
drug intake.
Key Secondary endpoints:

Area Under the Curve (AUC) for POMWP between 
baseline and the morning of Day 4 (POMWPAUC72h)

AUC for POMWP between baseline and the morning of 
Day 6 (POMWPAUC120h)
Other secondary endpoints:

Change in Pressure Algometry (PA) between baseline and 
Day 2 morning, 2 hours after drug intake 

Global assessment of efficacy by the patient at the end of 
treatment (Day 6 morning)

Number of patients with a decrease in POMWP of at least 
30% between baseline and Day 2 morning, 2 hours after 
drug intake


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Name of company:
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
Ibuprofen + Caffeine
Protocol date:
28-July-2016
Trial number:
1335.5
Revision date:
05-August-2016

Number of patients with a decrease in POMWP of at least 
50% between baseline and Day 2 morning, 2 hours after 
drug intake

Time to first meaningful POMWP relief within 2 hours 
after the first dose of study medication
Safety criteria:

Incidence of adverse events (AEs) and serious AEs 
(SAEs)

Laboratory test abnormalities
 
 
Statistical methods:
Primary endpoint:
For the analysis of the change in POMWP between baseline and 
Day 2 morning, 2 hours after drug intake, 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 and the 
stratification factors country and wp-site (back/neck) as discrete 
fixed effects, baseline POMWP as a continuous fixed effect, and 
interaction between time and treatment as well as interaction 
between baseline POMWP and time. The primary treatment
comparison will be the contrast between treatments at the 
endpoint time, respectively.


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Name of company:
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
Ibuprofen + Caffeine
Protocol date:
28-July-2016
Trial number:
1335.5
Revision date:
05-August-2016
For the analysis of the primary endpoint with regard to the strata 
concerning wp-site (back / neck), separate models will be 
performed as described above, but excluding the factor wp-site, 
respectively.
Key-secondary endpoints:
POMWPAUC72h and POMWPAUC120h will be analysed using 
analysis of covariance including treatment and country and wp-
site (back/neck) as fixed categorical effects and the baseline 
POMWP as a continuous covariate.
Other secondary endpoints:
The change in PA between baseline and Day 2 morning, 2 hours 
after drug intake will be analysed using analysis of covariance 
including treatment, country and wp-site (back/neck) as fixed 
categorical effects and the baseline PA as a continuous covariate.
The global assessment of efficacy by the patient at the end of 
treatment (Day 6 morning) as well as the number of patients with 
a decrease in POMWP of at least 30% or 50%, respectively, from 
baseline until Day 2 morning, 2 hours after drug intake, will be 
analysed by a logistic regression model, including the factor 
treatment and the categorical stratification factors country and 
wp-site (back/neck).
For the time to the first meaningful POMWP relief a Kaplan-Meier 
analysis will be performed and the log-rank test stratifying for the 
categorical variables country and wp-site (back/neck) will be 
used.


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Name of company:
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
Ibuprofen + Caffeine
Protocol date:
28-July-2016
Trial number:
1335.5
Revision date:
05-August-2016
For the analysis of the key- and other secondary endpoints with 
regard to the strata concerning wp-site (back / neck), separate 
models will be performed as described above, but excluding the 
factor wp-site, respectively.


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FLOW CHART
Trial Periods
Screening 
Period
Treatment period
EOT
FU10
Visit
1
1
2
3
4
5
Days
1
15
2
4
6
8-10
Time window for visits
none
none
none
± 1 Day
± 1 Day
none
Informed consent4
X
Demographics
X
Medical history
X
Physical examination
X
X
Vital signs
X
X
Safety Laboratory Tests
X
X
12 lead-ECG
X
X
Review of in-/exclusion 
criteria
X
Randomization via
Interactive Response
Technology (IRT)13
X
Dispense trial drugs
X
Distribute Patient Diary 
and Instruct Patient
X
POMWP relief score9
X
X
X
X
Administer trial drugs1
X2
X
X
X3
Pregnancy Testing 
(Urine)14
X
X
Pain On Movement (POM)
7
X
X
X
X
X
Pressure Algometry (PA)
X
X
X
X
X
Rescue Medication8
X
X
X
X
Adverse events
X
X
X
X
X
X
Compliance check
X
X
X
Concomitant therapy
X
X
X
X
X
X
Global Assessment of 
efficacy by the patient and 
investigator
X
Collect patient Diary and 
enter data onto eCRF
X
 
 
Completion of patient 
participation 
X6


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1
Study drug administered TID with doses 6-8 hours apart
2
First dose of study drug administered in clinic by the patient in the presence of investigator
3
Last dose of study drug taken on the morning of Day 6, 1-3 hours before clinic visit starts
4
Re-consenting may become necessary when new relevant information becomes available and should be 
conducted according to the sponsor’s instructions
5
Day of Randomization / Day of first intake of randomised medication
6
Completion of patient participation also needs to be completed if the patient withdraws prematurely following 
randomization. (see Section 3.3.4)
7
The POM evaluation at each visit should be in the morning (7:00-10:00) 2 hours after intake of study drug. 
POM will be assessed by the patient using a 0-10-point Numerical Rating Scale (NRS). Baseline POM will be 
assessed using five standard procedures and the procedure which results in highest POM (Worst Procedure, 
POMWP) will be repeated for an individual patient at the subsequent visits
8
Patients will be encouraged not to take rescue medication (paracetamol) until after the primary endpoint is 
assessed on Day 2. On subsequent days of the study, patients should take only a maximum dose of 2 grams 
paracetamol over a 24 hour period and doses should be at least 4 hours apart. The patient will record the date, 
time and dosage of rescue medication in the diary
9
The procedure which results in highest POM at baseline (POMWP) will be repeated by the same site staff 
member 10, 20, 30, 60 and 120 min after the first dose of study medication. The POMWP Relief Score  will be 
assessed by the patient at each of these time points by using a 5-point Verbal Rating Scale (VRS) (0= no 
POMWP relief ; 1= a little or perceptible POMWP relief ; 2= meaningful POMWP relief ; 3= a lot of POMWP
relief ; 4=complete POMWP relief) 
10
2-4 Days after visit 4 at the follow up Visit 5(FU) an interview by telephone is conducted with the patient to 
determine REP and post treatment safety status 
 
 
 
13
During randomization patients will be stratified by country and by whether the patients have back (worst pain 
with procedure 4 or 5) or neck pain (worst pain with procedure 1, 2 or 3)
14
A urine pregnancy test must be negative in women of childbearing potential at the screening visit just prior to 
randomisation and at the last clinic visit
15
2-4 Days after visit 4 at the follow up Visit 5 (FU) an interview by telephone is conducted with the patient to 
determine whether headache was perceived after end of study treatment


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TABLE OF CONTENTS
TITLE PAGE .....................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ...............................................................2
FLOW CHART..................................................................................................................8
TABLE OF CONTENTS ................................................................................................10
ABBREVIATIONS..........................................................................................................13
1.
INTRODUCTION.........................................................................................15
MEDICAL BACKGROUND.......................................................................15
1.1
DRUG PROFILE..........................................................................................16
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT17
RATIONALE FOR PERFORMING THE TRIAL...................................17
2.1
TRIAL OBJECTIVES..................................................................................17
2.2
BENEFIT - RISK ASSESSMENT...............................................................17
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION...................19
OVERALL TRIAL DESIGN AND PLAN .................................................19
3.1
3.1.1
Administrative structure of the trial ...........................................................19
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)................................................................................20
SELECTION OF TRIAL POPULATION .................................................21
3.3
3.3.1
Main diagnosis for trial entry ......................................................................21
3.3.2
Inclusion criteria ...........................................................................................21
3.3.3
Exclusion criteria ..........................................................................................22
3.3.4
Removal of patients from therapy or assessments.....................................24
Removal of individual patients .......................................................................24
3.3.4.1
Discontinuation of the trial by the sponsor.....................................................25
3.3.4.2
4.
TREATMENTS.............................................................................................26
INVESTIGATIONAL TREATMENTS .....................................................26
4.1
4.1.1
Identity of the Investigational Medicinal Products....................................26
4.1.2
Selection of doses in the trial........................................................................27
4.1.3
Method of assigning patients to treatment groups.....................................27
4.1.4
Drug assignment and administration of doses for each patient................28
4.1.5
Blinding and procedures for un-blinding ...................................................28
Blinding...........................................................................................................28
4.1.5.1
Un-blinding and breaking the code.................................................................28
4.1.5.2
4.1.6
Packaging, labelling, and re-supply.............................................................29
4.1.7
Storage conditions.........................................................................................29
4.1.8
Drug accountability.......................................................................................30
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS ..........................................................................................30


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4.2.1
Other treatments and emergency procedures............................................30
4.2.2
Restrictions ....................................................................................................31
Restrictions regarding concomitant treatment ................................................31
4.2.2.1
Restrictions on diet and life style....................................................................31
4.2.2.2
Restrictions regarding women of childbearing potential ................................32
4.2.2.3
TREATMENT COMPLIANCE..................................................................32
4.3
5.
VARIABLES AND THEIR ASSESSMENT ..............................................33
TRIAL ENDPOINTS....................................................................................33
5.1
5.1.1
Primary Endpoint .........................................................................................33
5.1.2
Secondary Endpoints....................................................................................33
Key-secondary Endpoints ...............................................................................33
5.1.2.1
Other secondary Endpoints.............................................................................33
5.1.2.2
.........................................................................................34
ASSESSMENT OF EFFICACY..................................................................34
5.2
5.2.1
Pain On Movement .......................................................................................34
5.2.2
Pressure algometry .......................................................................................36
5.2.3
Time to first meaningful pain relief.............................................................36
5.2.5
Global assessment of efficacy by the patient/
.........................37
ASSESSMENT OF SAFETY.......................................................................38
5.3
5.3.1
Endpoints of safety........................................................................................38
5.3.7
Assessment of adverse events.......................................................................41
Definitions of AEs ..........................................................................................41
5.3.7.1
Adverse event collection and reporting ..........................................................45
5.3.7.2
 
APPROPRIATENESS OF MEASUREMENTS........................................47
5.7
6.
INVESTIGATIONAL PLAN.......................................................................48
VISIT SCHEDULE.......................................................................................48
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ...........48
6.2
6.2.1
Screening and run-in period(s)....................................................................48
6.2.2
Treatment period(s)......................................................................................49


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6.2.3
Follow Up Period and Trial Completion.....................................................49
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE................................................................................................................50
STATISTICAL DESIGN - MODEL...........................................................50
7.1
NULL AND ALTERNATIVE HYPOTHESES .........................................50
7.2
PLANNED ANALYSES...............................................................................52
7.3
7.3.1
Primary endpoint analyses...........................................................................52
7.3.2
Secondary endpoint analyses .......................................................................53
............................................................................54
7.3.4
Safety analyses...............................................................................................56
INTERIM ANALYSES ................................................................................58
7.4
HANDLING OF MISSING DATA .............................................................58
7.5
RANDOMISATION .....................................................................................58
7.6
DETERMINATION OF SAMPLE SIZE ...................................................59
7.7
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY............................................................................61
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
8.1
CONSENT .....................................................................................................61
DATA QUALITY ASSURANCE ................................................................62
8.2
RECORDS.....................................................................................................62
8.3
8.3.1
Source documents .........................................................................................62
8.3.2
Direct access to source data and documents...............................................63
8.3.3
Storage period of records .............................................................................64
EXPEDITED REPORTING OF ADVERSE EVENTS ............................64
8.4
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY..64
8.5
8.5.1
Collection, storage and future use of biological samples and 
corresponding data .......................................................................................64
TRIAL MILESTONES.................................................................................65
8.6
9.
REFERENCES..............................................................................................66
PUBLISHED REFERENCES......................................................................66
9.1
UNPUBLISHED REFERENCES................................................................68
9.2
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) ...................................73


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
AMP
Auxiliary Medical Products
ANCOVA
Analysis of Covariance
ANOVA
Analysis of Variance
AUC
Area under the Curve
b.i.d.
bis in die (twice daily dosing)
BIRDS
Boehringer Ingelheim Regulatory Documents for Submission
CCDS
Company Core Data Sheet
CI
Confidence Interval
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
EOT
End of Treatment
ePRO
Electronic Patient Reported Outcome
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FC
Flow Chart
GCP
Good Clinical Practice
HPC
Human Pharmacology Center
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
i.v.
intravenous
LoEE
List of Essential Element 
MedDRA
Medical Dictionary for Drug Regulatory Activities
MST
Medical Sub team
N/cm2
Newton/square centimetre 
NIMP
Non-Investigational Medical Products
NRS
Numerical Rating Scale
OPU
Operative Unit
PA
Pressure Algometry
PD
Pharmacodynamics


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PI
Pain Intensity
PK
Pharmacokinetics
p.o.
per os (oral)
POM
Pain on Movement
POMWP
Pain on Movement, Worst procedure
PCC
Protocol Challenge Committee
q.d.
quaque die (once a day)
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
SPC
Summary of Product Characteristics
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan
t.i.d.,TID
ter in die (3 times a day)
TMF
Trial Master File
TMW
Trial Medical Writer
TSAP
Trial Statistical Analysis Plan
VRS
Verbal Rating Scale
WP
Worst Procedure (= procedure with highest POM-value)
WP-site
Site with the worst procedure (site = neck for procedures 1-3; site = back 
for procedures 4 and 5)


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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. Remedies 
against acute back/ neck pain, especially in an OTC environment, are required to reduce 
back discomfort fast and effectively while being well tolerated.
Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) that is one of the most 
widely used over-the-counter (OTC) medications around the world. Orally administered 
ibuprofen was initially approved as an OTC analgesic in the United States in 1984. The 
favourable efficacy and safety profile of OTC ibuprofen has been well established over its 
more than 28 year history of usage. Studies have shown that 400 mg of ibuprofen is a very 
effective analgesic, more effective than acetaminophen 1000 mg and aspirin 1000 mg 
(P02-05388, P90-0404, P05-00433, P02-05406, R99-0976, P13-03158). However, there 
are individuals who don’t get sufficient pain relief with currently available single 
ingredient analgesic products. The combination of ibuprofen 400 mg and caffeine 100 mg 
is currently being evaluated as a potentially more efficacious treatment for those 
consumers who do not experience adequate pain relief with maximum single doses of 
single ingredient analgesic products. Based on published studies, it is expected that 
caffeine will provide an adjuvant effect to ibuprofen and enhance its efficacy. Caffeine has 
been shown to potentiate analgesic activity probably through a central nervous system 
(CNS) mechanism of action (P12-12821, P11-05389).


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DRUG PROFILE
1.2
Caffeine is the most widely consumed psycho-stimulant drug. It is almost completely 
absorbed in the gastrointestinal tract. Since it is lipid soluble, it is rapidly absorbed into the 
brain, where its mild CNS effects, which include increased wakefulness, alertness, and 
endurance, begin to work in 6-8 minutes (P12-14205, P93-75428). Pre-clinical studies in 
rodents suggest that caffeine has weak analgesic effects.  These studies suggest that 
caffeine’s anti-nociceptive effects may be attributed to the blockade of adenosine 
receptors, inhibition of cyclo-oxygenase 2 enzyme synthesis, or potentially by changes in 
emotional status (P07-08407, P93-75428, P06-04171).
Because of its rapid absorption/distribution and CNS/analgesic effects, caffeine has been 
used in combination with both prescription and over-the-counter (OTC) analgesics for 
many years. These combination products have met widespread consumer acceptance. 
Studies in several pain models have demonstrated the analgesic adjuvant effect of caffeine 
when combined with a variety of analgesics (P10-10394, R98-0795). A recently completed 
Cochrane review of 19 randomised, double-blind, well controlled studies, involving 7,238 
patients, concluded that the addition of caffeine at doses 100 mg or greater to standard 
doses of commonly used analgesics provides an increase in the proportion of patients who 
experience a good level of pain relief (P12-04063). The addition of less than 65 mg of 
caffeine to analgesics is generally thought to be ineffective.
The Cochrane review included four published studies evaluating the combination of
ibuprofen and caffeine. An oral surgery study demonstrated the effectiveness of caffeine 
100 mg as an analgesic adjuvant to ibuprofen 100 mg and 200 mg (P02-05324). In that 
study, caffeine was found to increase the potency of ibuprofen by 140-180%. Similar 
results were obtained in a post-episiotomy model (P84-98710). In another oral surgery 
study, caffeine (50 mg, 100 mg, and 200 mg) increased the analgesic effect and provided 
an earlier onset of analgesic effect of ibuprofen 200 mg (R97-2392). There were no 
differences between the three doses of caffeine in that study. In patients with tension type 
headache, ibuprofen 400 mg combined with caffeine 200 mg was shown to provide 
superior efficacy compared to each ingredient alone, and placebo (P02-05407). The 
median time to perceptible and meaningful headache improvement was faster with the 
combination product compared to ibuprofen alone and placebo.  Eighty percent of patients 
receiving the combination experienced a meaningful improvement in headache compared 
with 67% receiving ibuprofen alone.
For a more detailed description of the study drug profile please refer to the current 
Investigator’s Brochure (IB) (c02098879-06) and for Paracetamol used as rescue 
medication the reference document is the product SmPC. 
The present study is being conducted to assess the analgesic efficacy of ibuprofen 400 mg 
combined with caffeine 100 mg compared to ibuprofen 400 mg alone and placebo in the 
treatment of acute neck or back pain. In order to provide a more complete assessment, 
safety and efficacy will be assessed following multiple dose administration over a six-day 
evaluation period.


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
The combination of ibuprofen and caffeine is being evaluated as a potentially more 
efficacious analgesic for patients who do not experience adequate pain relief with a single 
ingredient analgesic product. Based on published studies, it is expected that 100 mg of 
caffeine will provide an adjuvant effect to ibuprofen 400 mg, as caffeine at doses ranging 
from 50 mg to 200 mg has been shown to provide faster and/or better pain relief than 
ibuprofen doses of 100 mg to 400 mg alone. (P02-05407, P02-05324, R97-2392, P84-
98710, U13-3353-02).
TRIAL OBJECTIVES
2.2
To assess the efficacy and safety of a 400 mg ibuprofen/100 mg caffeine tablet in 
comparison to a 400 mg ibuprofen tablet for the treatment of acute lower back or neck 
pain.
The primary objective of this trial is to demonstrate superior efficacy of a 400 mg 
ibuprofen/100 mg caffeine tablet over a 400 mg ibuprofen tablet and a placebo tablet.
A secondary objective is to assess the safety and tolerability of a 400 mg ibuprofen/100 mg 
caffeine tablet in comparison to a 400 mg ibuprofen tablet and a placebo tablet.
BENEFIT - RISK ASSESSMENT
2.3
Many patients who use currently marketed OTC pain relievers find that no single analgesic 
agent can completely relieve their moderate to severe acute pain (P12-04607). A ceiling 
effect is obtained with currently available analgesics such as ibuprofen and acetaminophen 
and increasing dosages produce little or no analgesic benefit, but increase the risk of 
adverse effects. Therefore, there is an unmet patient need for a superior OTC analgesic 
with a favourable safety profile.  Combining an analgesic such as ibuprofen with caffeine, 
a known analgesic adjuvant, is intended to provide superior efficacy to either ingredient 
alone without increasing the risk of side effects.  In addition, an analgesic with superior 
efficacy may reduce the need for additional doses of analgesics, thereby reducing the total 
amount of analgesics consumed leading to an improved benefit risk ratio.
The safety profiles of ibuprofen and caffeine have been well established over their many 
years of use. Given that combination products containing caffeine have been marketed in 
various parts of the world for many years, there are no data to suggest that the combination 
of ibuprofen and caffeine will have a safety profile unlike that of the individual 
ingredients. A summary of the potential risks and benefits of ibuprofen combined with 
caffeine, as well as with each individual ingredient is provided in the Investigator’s 


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Brochure (IB) (c02098879-06). The investigator must become familiar with all sections of 
the current IB before the start of the study.
In order to minimize the risk of adverse events (AE) and maximize the benefit of adequate 
pain relief for patients participating in this trial, all patients will undergo a physical 
examination and safety laboratory testing to ensure that they are healthy enough to 
participate in the study. In addition, females of child bearing potential will receive a urine 
pregnancy test at screening in order to ensure that the female patient is not pregnant. 
Individuals at increased risk of developing gastrointestinal (GI) adverse events associated 
with the use of NSAIDs will be excluded from the study. The safety of patients enrolled 
into the study will be monitored by study personnel during the throughout the entire study.  
Adverse and serious adverse events are being reported from the time the patient signs the 
informed consent, until the last visit of the study.
Although rare, a potential for drug-induced liver injury (DILI) is under constant 
surveillance by sponsors and regulators. Therefore, this trial requires timely detection, 
evaluation, and follow-up of laboratory alterations in selected liver laboratory parameters 
to ensure patients´ safety, see also information on DILI in section 5.3.7.1.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
3.1.1
Administrative structure of the trial
This trial is a multi-centre, double-blind, randomised, parallel-group study comparing the 
effect of the fixed dose combination of ibuprofen 400 mg and caffeine 100 mg versus 
ibuprofen 400 mg and placebo in patients of at least 18 years of age with acute neck or 
back pain. Approximately 650 patients will be randomized in a ratio of 2:2:1:
After a screening evaluation at Visit 1, eligible patients will be randomised.
Patients are initially treated at the site with the first of three doses at least 6-8 hours apart 
over the initial 24 hours with a tablet containing ibuprofen 400 mg + caffeine 100 mg, or 
ibuprofen 400 mg or placebo. The patients will be examined after the initial 24 hour period 
at visit 2 on Day 2 at the study, 1-3 hours after taking their morning dose of study drug on 
Day 2. The patients will be encouraged not to take rescue medication before the primary 
endpoint is assessed on Day 2. 
After the visit 2 assessments have been completed patients will continue to be treated with 
their assigned blinded treatment administered TID at least 6-8 hours apart over the 
remainder of the 6 day dosing period of the study.
The study will include the following visits: Screening and initial dosing visit (Visit 1 on 
Day 1) primary endpoint assessment visit (Visit 2 on Day 2), a Visit 3, Day 4 clinic visit 
and an End-of-Treatment Visit (Visit 4 on Day 6). In addition there will be a follow up by 
telephone (Visit 5), 2-4 days after the EOT Visit.
All (S)AEs, including those persisting after individual patient’s end of trial must be 
followed up until these events have resolved, have been sufficiently characterised, or no 
further information can be obtained.
The study will be a multi-center study and is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate Investigators at different centres 
participating in this multi-center trial. Tasks and responsibilities are defined in a contract. 
Relevant documentation on the participating (Principal) Investigators and other important 
participants, including their curricula vitae, will be filed in ISF.


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Boehringer Ingelheim has appointed a Trial Clinical Monitor, responsible for coordinating 
all required activities, in order to 
-
manage the trial in accordance with applicable regulations and SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitors (CML), 
Clinical Research Associates (CRAs), and Investigators of participating countries.
The organisation of the trial in the participating countries will be performed by a Contract 
Research Organisation (CRO) with which the responsibilities and tasks will have been 
agreed and a written contract filed before initiation of the clinical trial.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are
defined according to agreed-upon SOPs. A list of responsible persons and relevant local 
information can be found in the ISF.
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 ISF.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)
This trial has been designed to assess the acute effect of a fixed dose combination (FDC) 
of ibuprofen plus caffeine in patients with back or neck pain. The pain on movement
(POM) assessment has been recognized as a reliable design for showing efficacy of new 
acute pain treatments. (R14-1467).
The effects of the FDC will be compared to ibuprofen alone, and placebo to prove 
efficacy, as well as the superiority over ibuprofen alone and placebo treatments. Then, 
patients will continue to receive assigned treatment over a total of 6 days of treatment.
This design will assess the efficacy after the first day of dosing based on the current 
knowledge about the efficacy of ibuprofen for the treatment of acute pain (see Section 
1.1). Also, the tolerability and efficacy will be evaluated throughout 6 days of treatment. 
Study medication may be taken as early as every 6 hours and no later than every 8 hours, 
up to 3 times daily while awake.
The allocation to treatment will be done in a 2:2:1 ratio for ibuprofen plus caffeine, 
ibuprofen and placebo with a total sample size of 650 patients. This distribution and 
sample size should have sufficient power to demonstrate a difference of the FDC versus 
the Ibuprofen and placebo arms.


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SELECTION OF TRIAL POPULATION
3.3
Approximately 650 male or female patients of at least 18 years of age with a current 
diagnosis of acute back or neck pain for at least 24 hours. Patients with acute back or neck 
pain resulting in pain on movement (POM) ≥ 5 on a 0-10-point Numerical Rating Scale
will be randomly assigned in a 2:2:1 ratio to each of the following treatment arms:
Ibuprofen + caffeine
Ibuprofen
Placebo
A log of all patients included into the study (i.e. having given informed consent) will be 
maintained in the investigator site file (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
Otherwise healthy individuals with acute back or neck pain for at least 24 hours not due to 
a specific diagnosis are required for this 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 who are ≥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 POM ≥5 on a 0-10-point NRS for 
at least one POM procedure out of 5 standardized procedures.
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.


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*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).
6.
Reliable, cooperative, and of adequate intelligence to record the requested 
information on the analgesic questionnaires.
7.
Examined by the attending physician and medically cleared to participate in the 
study.
8. 
In good general health, with a body mass index (BMI) < 30, and have no 
contraindications to any of the study medications.
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.
Patients with pain at rest ≥9. (0-10 NRS scale).
3.
Patients with pain at rest ≥9. (0-10 NRS scale).
4.
Patient with chronic back or neck pain as defined as pain for 3 weeks or longer.
5.
Back or neck pain that is attributable to any identifiable cause (e. g. disc prolapse, 
spondylolisthesis, osteomalacia, inflammatory arthritis, metabolic, neurological 
diseases or tumour).
6.
Any strains of the back or neck muscles documented by clinical evaluation and 
anamnesis that occurred 21 days to 3 months prior to the screening visit.
7.
Surgery due to back or neck pain or rehabilitation due to back or neck pain in the last 
12 months.
8.
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) for the same indication or other indications.


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9.
Spinal injections should have been discontinued in due time (investigator’s judgment) 
before patient enrollment to allow complete wash-out of the active ingredient based on 
investigator’s judgment.
Long-acting glucocorticoids must have been discontinued 10 days before study entry.
Exception: 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.
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.
10. Known severe hepatocellular insufficiency, severe renal insufficiency or Gilbert’s 
syndrome (Morbus Meulengracht).
11. Patients taking CNS or other psychotropic drugs, or any nutritional supplement known 
to have psychotropic effects such as St. John’s Wort, Chapparal, Comfrey, 
Germander, Gin Bu Huan, Kava, Pennyroyal Skullcap, or Valerian within two months 
of taking the first dose of study medication.  Patients who have been on stable doses of 
these medications for at least two months will be allowed into the study, as long as 
they maintain this dose throughout the study, and their condition is judged stable by 
the Principal Investigator.
12. Any other medical condition that would interfere with efficacy and safety assessments 
based on investigator’s judgment or any on-going clinical condition that would 
jeopardize patient’s or site personnel’s safety or study compliance based on 
investigator judgment.
13. Known intolerance or hypersensitivity to the active ingredients or any excipient(s).
14. Patient not able to understand and comply with trial requirements based on 
investigators judgment.
15. Major surgery (major according to the investigator’s assessment) performed within 12 
weeks prior to randomization or planned within timeframe of this study.
16. Patients who must or wish to continue the intake of restricted medications (see section 
4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial.
17. Previous enrolment in this trial.
18. Currently enrolled in another investigational device or drug study, or less than 30 days 
since ending another investigational device or drug study(s), or receiving other 
investigational treatment(s).


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19. Habituation to analgesic drugs or caffeine (i.e., routine use of oral analgesics 5 or 
more times per week or ingestion of 4 or more caffeine-containing drinks daily); use 
of "high energy" drinks more than once per week.
20. History of allergic reaction (e.g., asthma, rhinitis, swelling, shock, or hives) to 
acetaminophen, ibuprofen, naproxen, aspirin, celecoxib, or any other NSAID or 
caffeine.
21. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, 
makes them an unreliable study subject or unlikely to complete the trial.
22. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
23. Prior use of any type of analgesic or NSAID within 5 half-lives of that drug before 
initial dosing in the trial.
24. Presence or history (within 2 years of enrolment) of bleeding disorder or peptic ulcer 
disease.
25. Has a clinically significant abnormal electrocardiogram (ECG) at screening as 
determined by the investigator.
26. Has known impaired liver function, e.g., serum ALT, AST, alkaline phosphatase, or 
GGT greater than 2.5 times the upper limit of normal, or BUN, creatinine, or bilirubin 
greater than 1.5 times the upper limit of normal without a known benign explanation.
27. The patient is a member of the study site staff either directly involved with the study, 
an employee of the Sponsor, or a relative of study site personnel directly involved 
with the study or Sponsor.
3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
All patients are free to withdraw from participation in this study at any time, for any 
reason, and without prejudice.
The investigator may terminate a patient from the study at any time for lack of therapeutic 
effect that is intolerable to the patient or otherwise considered unacceptable, for intolerable 
or unacceptable AEs, inter-current illness, non-compliance with study procedures, 
administrative reasons, or in the investigator’s opinion, to protect the patient’s best 
interest.
If a patient is withdrawn before completing the study, the reason for withdrawal will be 
entered on the appropriate electronic case report form (e-CRF). Whenever possible and 


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reasonable, the evaluations which were to be conducted at the completion of the study 
should be performed at the time of premature discontinuation and at the telephone follow 
up visit.
Every effort will be made to continue safety monitoring and collection of safety data even 
if the patient chooses to discontinue from the study or is prematurely terminated from the 
study.
Discontinuation of the trial by the sponsor
3.3.4.2
Boehringer Ingelheim reserves the right to discontinue the trial at any time for the 
following reasons:
1.
Failure to meet expected enrolment goals overall or at the single centre,
2.
Emergence of any efficacy/safety information that could significantly affect 
continuation of the trial,
3.
Violation of GCP, the CTP, or the contract by the trial site or investigator, 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
INVESTIGATIONAL TREATMENTS
4.1
1.
Ibuprofen + Caffeine, 400mg/100mg film coated tablets
2.
Ibuprofen, 400mg film coated tablets
3.
Ibuprofen Placebo, film coated tablets
Through the use of ibuprofen placebo tablets, all treatments will appear identical. Patients 
will take the assigned dose three times daily, by mouth, for every 6-8 hours
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test products are as shown in Tables 4.1.1: 1 to 3. 
Table 4.1.1: 1
Ibuprofen-caffeine
Substance
Ibuprofen + Caffeine
Pharmaceutical formulation
Tablet
Source
Boehringer Ingelheim Pharma GmbH & Co. 
KG
Unit strength
400 mg ibuprofen + 100 mg caffeine
Posology
3 times daily 6-8 hours apart
Route of administration
Per os
Table 4.1.1: 2
Ibuprofen
Substance
Ibuprofen
Pharmaceutical formulation
Tablet
Source
Boehringer Ingelheim Pharma GmbH & Co. 
KG
Unit strength
400 mg ibuprofen
Posology
3 times daily 6-8 hours apart
Route of administration
Per os


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Table 4.1.1.3
Ibuprofen Placebo
Substance
Placebo
Pharmaceutical formulation
Tablet
Source
Boehringer Ingelheim Pharma GmbH & Co. 
KG
Unit strength
0 mg
Posology
3 times daily 6-8 hours apart
Route of administration
Per os
4.1.2
Selection of doses in the trial
Ibuprofen 400 mg is the maximum single dose of ibuprofen approved without a 
prescription in many countries throughout the world. Caffeine 100 mg was chosen to be 
combined with ibuprofen 100 mg since published studies have suggested that it is an
analgesic adjuvant to ibuprofen 400 mg.
4.1.3
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 such as whether the patient was in 
Russia or Germany and whether the patient had back pain (worst pain with procedure 4 or 
5) or neck pain (worst pain with procedure 1, 2 or 3). 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 2:2:1 ratio, to either:
(i) 
ibuprofen + caffeine
(ii) 
ibuprofen
(iii) 
placebo
For further details refer to Section 7.6. Entry into the application site stratum . tructions 
and/randomized use of IRT, which will takeny countries throughout the world.  Caffeine 
100 mg was chosen to be combined with ibuprofen 100 mg since published studies have 
suggested that it soon as 58% (about 350 patients) of the total trial population has 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.


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A single trial medication kit corresponding to the assigned medication number will be
given to the patient and the number of the kit that was dispensed will be entered in the
eCRF. Using this procedure, relevant parties will be blinded to the treatment group
assignment.
4.1.4
Drug assignment and administration of doses for each patient
At time of randomization at Visit 1, one medication kit containing blisters with all tablets 
to be administered during the treatment period over 6 days will be dispensed to the patient. 
The blister packs will be labelled with the medication number assigned by IRT.
Patients will take one tablet every 6-8 hours over each 24 hour period from Day 1 after 
randomization until the morning of Day 6.
Administration of the initial dose of study drug at Day 1 (Visit 1) will be under supervision 
of the investigating physician or a designee at the study centre.
4.1.5
Blinding and procedures for un-blinding
Blinding
4.1.5.1
Patients, investigator and everyone involved in analysing or with an interest in this double-
blind study will remain blinded with regard to the randomised treatment assignments until 
after database lock. The randomisation code will be kept secret by Clinical Trial Support 
up to database lock.
Un-blinding and breaking the code
4.1.5.2
An emergency un-blinding will be available to 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 in order to provide appropriate medical treatment 
or if required to assure safety of trial participants. If the code break for a patient is opened, 
the sponsor must be informed immediately. The reason for un-blinding must be 
documented on the appropriate eCRF page along with the date and the initials of the 
person who un-blinded the patient.
The investigator /pharmacist/investigational drug storage manager may un-blind a patient.  
The blind should be broken only if knowledge of this information may affect treatment of 
the patient.  Every effort must be made to contact the sponsor prior to breaking the blind.  
Once un-blinded, a patient will be ineligible for any further drug assignments and must be 
withdrawn from the trial.


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Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from Boehringer Ingelheim’s
Pharmacovigilance group to access the randomisation code for individual patients during 
trial conduct. The access to the code will only be given to authorised Pharmacovigilance
representatives and not be shared further. 
4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by BI to a designated CRO. Investigational 
product will be packaged in blister packs 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.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies, which will be provided by the sponsor, must be kept in a secure, limited 
access storage area under the storage conditions as follows: Store at 25 °C, temporary 
excursions permitted between 15-30 °C. A temperature log will be maintained to make 
certain that the drug supplies are stored at the correct temperature.
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.


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4.1.8
Drug accountability
The investigator or pharmacist or investigational drug storage manager will receive the 
investigational drugs 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),

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 or pharmacist or 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 or pharmacist or 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 CRO, the investigator or pharmacist or 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.
The investigator or pharmacist or 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 warehouse or drug distribution centre or alternative 
disposal of unused products. If applicable, the sponsor or warehouse or drug distribution 
centre will maintain records of the disposal. 
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
Paracetamol tablets (500 mg tablets) will serve as the only 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). Paracetamol 
will be supplied by the site to the patient at Visit 1. Following the first administration of 


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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 concepts 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.
Patients should be strongly encouraged not to take any rescue medication until Visit 2 
when the primary endpoint is assessed. 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.
Another supply of rescue medication might be dispensed at another site visit, if required.
There are no special emergency procedures to be followed in this study.
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). Prior to the determination of the primary endpoint on day 2 in 
addition to other restricted concomitant medications topical analgesic agents such as ice 
will not be allowed. All concomitant medications used will be recorded in the source 
document and on the e-CRF.
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. Please also review exclusion criterion 10 
regarding patients taking CNS or other psychotropic drugs or any nutritional supplements 
knowing to have psychotropic effects.
Restrictions on diet and life style
4.2.2.2
Patients should not ingest any caffeine-containing beverages, chocolate, or alcohol 
throughout the 6 days of the study.


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Restrictions regarding women of childbearing potential 
4.2.2.3
Women of childbearing potential must use the contraception methods described in the 
patient information.
TREATMENT COMPLIANCE
4.3
Patients will be asked to return all unused study medication and empty medication 
containers, as well as their diaries when they come to the clinic for all study visits. At 
those visits, the study coordinator, or appropriate designee, will review the diary, and 
count all returned study medication to reconcile medication use. Patients will be queried if 
any discrepancies are noted.  Based on tablet counts, treatment compliance will be 
calculated as the number of tablets taken, divided by the number of tablets which should 
have been taken according to the scheduled period, multiplied by 100. Compliance will be 
verified by the on-site monitor authorised by the sponsor.
Treatment compliance (%) =
Number of tablets actually taken 100
Number of tablets which should have been taken
If the number of doses taken is not between 80-120%, site staff will explain the patient the 
importance of treatment compliance.


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5.
VARIABLES AND THEIR ASSESSMENT
TRIAL ENDPOINTS
5.1
5.1.1
Primary Endpoint
The primary endpoint is the change in Pain On Movement (POM) with regard to the Worst 
Procedure (WP), i.e. the procedure with the highest pain score at baseline (POMWP), 
between baseline (Day 1 morning pre-dosing) and Day 2 morning, 2 hours after drug 
intake.
POM is assessed by the patient on one standardized movement by using a Numerical 
Rating Scale (NRS) ranging from 0 = ‘no pain’ to 10 = ‘worst pain possible for this 
condition’.
5.1.2
Secondary Endpoints
Key-secondary Endpoints
5.1.2.1

POMWPAUC72h
The AUC will be calculated as area under the curve from zero (baseline POMWP) to 
72 hours (POMWP in the morning of Day 4) using the trapezoidal rule divided by 
the observation time. The dates and times of study drug intake related to the 
POMWP assessments will be the basis for the calculation of respective time 
intervals.

POMWPAUC120h
The AUC will be calculated as area under the curve from zero (baseline POMWP) to 
120 hours (POMWP in the morning of Day 6) using the trapezoidal rule divided by 
the observation time. The dates and times of study drug intake related to the 
POMWP assessments will be the basis for the calculation of respective time 
intervals.
Other secondary Endpoints
5.1.2.2

Change in Pressure Algometry (PA) between baseline and Day 2 morning, 2 hours 
after drug intake

Global assessment of efficacy by the patient at the end of treatment (Day 6 
morning)

Number of patients with a decrease in POMWP of at least 30% between baseline 
and Day 2 morning, 2 hours after drug intake

Number of patients with a decrease in POMWP of at least 50% between baseline 
and Day 2 morning, 2 hours after drug intake

Time to first meaningful POMWP relief within 2 hours after the first dose of study 
medication


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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 Numerical Rating Scale (NRS) ranging from 0  = 
‘no pain’ to 10 = ‘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]:
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.
Test: The patient pulls her/his head sideways 
towards the left or the right shoulder as 
appropriate without lifting up the shoulder at 
the same time.


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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.
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.
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.
Test: The patient tries to lift the arms over the 
side upwards against the gentle resistance of the
examiner’s hands.
4) Musculus erector spinae (lower part)
Position: The patient lies with his/her front on a 
small 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.
Test: The patient bends his/her legs to reach a 
square angle, lifts his/her thighs up towards the 
horizontal line.
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.
Test: The patient slowly lowers down the 
stretched legs to the surface.


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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 0-10NRS each. For each procedure performed, the patient will assess the 
pain intensity on the NRS, respectively.  The form will be collected after each assessment, 
so that the patient will not see his/her previous POM assessment. 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 (Worst Procedure, POMWP) will 
be repeated for an individual patient 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 considers most unpleasant. 
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.
5.2.3
Time to first meaningful pain relief
The procedure which results in highest POM at baseline (POMWP) will be repeated by the 
investigator 10, 20, 30, 60 and 120 min after the first dose of study medication. The 
POMWP relief Score (POMWPRS) will be assessed by the patient at each of these time 
points by using a 5-point Verbal Rating Scale (VRS) (0= no POMWP relief ; 1= a little or 
perceptible POMWP relief ; 2= meaningful POMWP relief ; 3= a lot of POMWP relief ; 
4=complete POMWP relief). 
The time to first meaningful POMWP relief will be the earliest assessment time point after 
the first application of the trial medication at which the patient reports a score of ≥ 2.
 
 
 
 
 
 


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5.2.5
Global assessment of efficacy by the patient
The patient
will assess the overall efficacy of the trial treatment on a 4-point 
verbal rating scale by answering the question: “How would you rate the overall effect of 
the study medication for relieving back or neck pain?” (0 = poor; 1 = fair; 2 = good; 3 = 
very good). 
 


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ASSESSMENT OF SAFETY
5.3
5.3.1
Endpoints of safety

Incidence of adverse events (AEs) and serious AEs (SAEs)
 
 
 
 
 
 


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5.3.7
Assessment of adverse events
Definitions of AEs 
5.3.7.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a medicinal product and which does not 
necessarily have to have a causal relationship with this treatment.
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.


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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, or

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 jeopardise the patient 
and may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definitions. 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 
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 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 RDC. 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, please see section 5.3.7.2.


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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 in the 
RDC.
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. 
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. 


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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.


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Adverse event collection and reporting
5.3.7.2
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 CRF(s) by the 
Investigator:
•
From signing the informed consent onwards, through the Residual Effect Period (REP)
of 24 hours after the last dose of study drug administered, until individual patient’s end 
of trial: 
-all AEs (serious and non-serious) and all AESIs
However, if an individual patient discontinues trial medication prematurely but stays in 
the trial (i.e. if further visits incl. 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.
•
After the individual patient’s end of trial: 
the Investigator does not need to actively monitor the patient for AEs but should only 
report relevant SAEs and relevant AESIs of which the Investigator may become aware 
of.
Figure 5.3.7.2: 1
Graphic display of Residual Effect Period (REP)
The REP is defined as 24 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.
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 


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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 
CRF pages and the BI SAE form. The investigator should determine the causal 
relationship to the trial medication and any possible interactions between investigational 
drug(s) and a Non-investigational Medicinal Product (NIMP)/Auxiliary Medicinal Product 
(AMP).
The following should also be recorded as an (S)AE in the CRF and SAE form (if 
applicable):
Worsening of the underlying disease or of other pre-existing conditions
Changes in vital signs, ECG, 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 individual patient’s end of trial must be 
followed up until they have resolved, have been sufficiently characterised, or no further 
information can be obtained.
Pregnancy
In rare cases pregnancy may occur in a clinical trial. Once a patient has been enrolled into
this clinical trial and has taken trial medication, the Investigator must report immediately 
(within 24 hours) a potential 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).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying 
SAE and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the 
SAE form is to be completed. If there is an SAE and/or AESI associated with the 
pregnancy an SAE form must be completed in addition.


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APPROPRIATENESS OF MEASUREMENTS
5.7
The scales being used to assess analgesic efficacy are standard scales used almost 
universally in controlled clinical trials of analgesic drugs. Since both ibuprofen and 
caffeine have been marketed (individually) for many years, and the combination is 
expected to have a safety profile consistent with the individual ingredients, self-reported or 
observed adverse events will be used to assess safety.


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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
This trial consists of 4 clinic visits. There will also be a follow-up by telephone where the 
investigator will contact the patient 2-4 Days after visit 4 to determine post treatment 
safety status (Follow up Visit 5).
Trial visits 1, 2, 3 and 4 should take place in the morning, i.e. ideally be started and 
concluded between 7:00 a.m. and 11:00 a.m. Patients must adhere to the visit schedule as 
specified in the Flow Chart. 
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 
 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 and run-in period(s)
Screening Period
Screening will be done during the first part of Visit 1. If a patient’s eligibility is confirmed, 
trial treatment will be initiated at the same visit. 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 Screening Period). 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 
documented if relevant with regard to trial indication and the assessment of the in- and 
exclusion criteria.


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6.2.2
Treatment period(s)
At Visit 1 (Day 1 post randomization) the first dose of trial medication should be 
administered at the site by the patient. On Days 1, 2, 3, 4, 5 and the morning of day 6, trial
medication should be taken by the patient.
The last dose of study drug taken on the 
morning of Day 6, 1-3 hours before clinic Visit 4 starts. At Visit 1, all procedures indicated 
in the “Screening Period” column of the Flow Chart should be performed before the first 
administration of the trial medication. Procedures indicated in the Flow Chart as 
“Treatment period” column should be performed afterwards at time points as indicated.
The trial medication should be dispensed and administered after randomization without 
delay. The time of the first administration of trial medication should be recorded in the 
patient’s diary and transcribed into the e-CRF.
The patient should be instructed
-
to perform home assessments (
at 
time points indicated in the Flow Chart
-
to refrain from using rescue medication before the assessments at Visit 2 if 
possible. If this turns out not to be possible, another supply of rescue medication 
might be dispensed at another clinic visit
-
to record intake of rescue medication (date, time and dose) in the patient’s diary
-
to take the trial medication TID every 6-8 hours
-
to record the time of all administrations of the trial medication in the patient’s 
diary
-
to bring the diary as well as all unused trial and rescue medication and packaging at
each visit.
6.2.3
Follow Up Period and Trial Completion
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.
Patient who want to discontinue the trial treatment prematurely should be asked to have 
Visit
4 (End of Treatment) in the morning after the last application of the trial medication and to 
have the telephone follow up Visit 5 at least 48 hours after that last application.


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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 3-arm parallel group study to investigate the efficacy and safety of a fixed dose 
combination of 400 mg ibuprofen and 100 mg caffeine compared to ibuprofen 400 mg and 
placebo in patients with acute lower back or neck pain.
The patients will be randomised via IRT in blocks to the treatment groups ibuprofen +
caffeine, ibuprofen and placebo in a 2:2:1 ratio. Treatment allocation will be stratified by 
country and the site with the worst pain (wp-site); the wp-site is classified after the POM 
assessments on a 0-10-point NRS, 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 assessments 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 country (Germany or Russia), wp-site (back or neck)
and disease severity as covariates.
NULL AND ALTERNATIVE HYPOTHESES
7.2
The primary objective of this trial is to demonstrate efficacy of the combination ibuprofen
400 mg + caffeine 100 mg, when compared to ibuprofen 400 mg and placebo for the 
treatment of lower back or neck pain. This will be evaluated by comparing the change in 
POMWP between baseline (Day 1 morning pre-dosing) and Day 2 morning, 2 hours after 
drug intake, for the combination treatment vs. the treatment with ibuprofen 400 mg and
placebo.
In order to demonstrate efficacy for the complete population (regardless of the stratum 
(back or neck pain), two-sided tests and a 0.05 level of significance will be used. To this 
purpose the following statements are hypothesized:
Null hypothesis:
There is no difference in ‘Change in POMWP between baseline and Day 2 morning, 2 hours 
after drug intake’ between patients treated with the combination ibuprofen + caffeine and 
the patients treated with ibuprofen or placebo.


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Alternative hypothesis:
There is a difference in ‘Change in POMWP between baseline and Day 2 morning, 2 hours 
after drug intake’ between patients treated with the combination ibuprofen + caffeine and 
the patients treated with ibuprofen and patients treated with placebo.
The set of hypotheses can be written as:
H0: H0,1: μibu+caf = μibu
or 
H0,2: μibu+caf = μplacebo
versus
H1: H1,1: μibu+caf ≠μibu
and
H1,2: μibu+caf ≠μplacebo
, where μibu+caf, μibu and μplacebo is the adjusted (for country and wp-site effect, and baseline 
POMWP) mean change in POMWP between baseline and the morning of Day 2, 2 hours 
after drug intake, for patients treated with the combination ibuprofen + caffeine, ibuprofen 
and placebo, respectively.
Since both partial hypotheses H0,1, and H0,2 are to be rejected in order to reject the null
hypothesis H0, no adjustment for multiplicity issues will be made and thus statistical
testing of H0 will be performed using a two-sided, alpha = 0.05 level of significance.
In case H0 can be rejected for the complete population, the same hypothesis will be tested 
with respect to the strata back and neck pain using the Hochberg procedure [P05-11198]:
Step 1:
In case all p-values (obtained without multiplicity adjustments) for the 4 treatment 
comparisons (2 comparisons per stratum) are below 0.05, superiority of the combination 
ibuprofen + caffeine versus ibuprofen and placebo can be concluded for both strata, 
otherwise the following procedure will be performed:
Step 2:
In case there is a stratum with both p-values for the 2 comparisons below alpha/2 = 0.025, 
superiority of the combination ibuprofen + caffeine versus ibuprofen and placebo can be 
concluded for the respective stratum, otherwise superiority cannot be concluded for any
stratum.  
The key secondary endpoints will be analysed for the total population hierarchically 
(POMWPAUC72h first) in a confirmatory way only, when statistical significance with the 
total population was achieved for the primary endpoint. Analysis of the key-secondary 
endpoints for the strata back and neck pain will be descriptive in nature.
All other secondary endpoints will be considered as supportive only.


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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 took 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 for POMWP at Visit 1 before drug intake and at least one POMWP value at post-
treatment assessment times Visit 1 (Day 1 morning, 2 hours after drug intake) and Visit 2 
(Day 2, morning, 2 hour after drug intake), will constitute the full analysis set.
Per protocol set (PPS): All patients included in FAS, who revealed no important protocol
violations. Important protocol violations, e.g. protocol deviations affecting the results of 
the primary endpoint, will be defined during blinded report planning meetings and before
database lock. All specifications on important protocol violations will be provided in the 
Trial
Statistical Analysis Plan (TSAP).
7.3.1
Primary endpoint analyses
The primary endpoint ‘Change in POMWP between baseline (Visit 1 pre-dosing) and Day 2 
morning, 2 hours after drug intake)’ 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, 2 hours after 
drug intake) and T2 = Visit 2 (Day 2 morning, 2 hours after drug intake. 
The statistical model will be applied to the analysis of change from baseline (T0 = Visit 1 
morning, before drug intake) in POMWP at times T1 and T2. The statistical model will 
include the fixed, categorical effects of treatment, country, wp-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, in a first step the ‘singular’ option in the model 
statement of PROC MIXED may be adjusted to singular =1E-10 (or 1E-9) instead of the 
default of approximately 1E-12. In case convergence still fails, other covariance structures 
will be employed following the order ANTE(1), ARH(1) and AR(1).
The Kenward-Roger approximation will be used to estimate the denominator degrees of 
freedom [R11-1488].


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Differences between the treatment group effects (ibuprofen + caffeine vs. ibuprofen and 
ibuprofen + caffeine vs. placebo with regard to the change in POMWP between T0 and T2, 
calculated as ‘POMWP at time T0 - POMWP at time T2’ (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.
 
 
 
 
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 POMWPAUC72h and POMWPAUC120h will be analysed 
using an analysis of covariance (ANCOVA) including treatment, country and wp-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 change in PA between baseline and Day 2 morning will be analysed analogously to 
the primary endpoint using all available longitudinal PA observations at the assessment 
times T1 = Visit 1 (Day 1 morning, 2 hours after drug intake) and T2 = Visit 2 (Day 2 
morning, 2 hours after drug intake). The statistical model will be applied to the analysis of 
change from baseline (T0 = Visit 1 morning pre-dosing) in PA at times T1 and T2.
For the multinomial endpoint ‘Global assessment of efficacy by the patient at the end of 
treatment (Day 6 morning)’ an ordinal logistic regression model adjusting for the
categorical variables country and wp-site (back/neck) will be used. The likelihood-ratio 
test will be used to test for treatment differences. Adjusted odds ratios together with 95% 
confidence intervals will be used to quantify the treatment effect, comparing all treatments 
to ibuprofen + caffeine as the reference treatment.


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The number of patients with a decrease in POMWP of at least 30% from baseline until Day 
2 morning, 2 hours after drug intake, will be analysed by a logistic regression model,
adjusting for the categorical covariates country and wp-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 ibuprofen + caffeine as the reference 
treatment.
The number of patients with a decrease in POMWP of at least 50% from baseline until Day 
2 morning, 2 hours after drug intake, will be analysed correspondingly.
For the time to the first meaningful POMWP relief, a Kaplan-Meier analysis will be 
performed and the log-rank test stratifying for the categorical variables ‘country’ and ‘wp-
site’ will be used to test the difference between treatment groups. The time intervals ‘0 -
≤10 min, ‘>10 - ≤20 min’, ‘>20 - ≤30 min’, ‘>30 - ≤60 min’, ‘>60 - ≤120 min’ and ‘> 120 
min’ will be displayed.
 
 


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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 24 hours following the day 
of the last dose 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 24 hours following the day of last administration of study drug. 
Adverse events that start before first drug intake and deteriorate under treatment will also 
be considered as ‘treatment-emergent’.


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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).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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INTERIM ANALYSES
7.4
No interim analysis is planned.
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 missing baseline data, no imputation will be implemented.
For the analyses utilising a likelihood-based repeated measures model as described in
Section 7.3, no imputation of missing values will be performed.
For the calculation of POMWPAUC72h and POMWPAUC120h, the following imputation rules 
for missing POMWP assessments will be applied:
One or more missing assessments in between assessments will be imputed using the 
planned assessment time(s) 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(s) and LOCF will be used to impute the 
POMWP value.
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 patient assessments of efficacy 
 resulting from early discontinuation
that was clearly unconnected to treatment will be not imputed.
RANDOMISATION
7.6
Patients will be randomised in blocks to the double-blind treatment arms ibuprofen +
caffeine, ibuprofen and placebo in a ratio 2:2:1. The randomization allocation will be
stratified by country (Russia, Germany) and the wp-site (back/neck). 
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 CTR. Access to the codes 
will be controlled and documented.


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DETERMINATION OF SAMPLE SIZE
7.7
The sample size calculation is based on the primary efficacy variable ‘Change in POMWP
between baseline and Day 2 morning, 2 hours after drug intake’, which reflects a pain 
relief on a 0-10 NRS about 24 hours after baseline. 
In a previous study investigating diclofenac in comparison to placebo in patients with 
acute neck pain on a 0-100 mm VAS, 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].
In a previous study investigating the effects of one tablet of ibuprofen + caffeine, 
ibuprofen, caffeine or placebo, respectively, in patients with post-operative dental pain 
[c02330821], a standardized difference between the combination and ibuprofen of 0.4 was 
achieved.
The sample size for this study is based on an anticipated treatment difference of 1.2 on a 0-
10NRS and a common standard deviation of 3, yielding a standardized treatment 
difference of 0.4 concerning the primary endpoint. The allocation ratio to the treatment 
groups ibuprofen + caffeine, ibuprofen and placebo is planned to be 2:2:1.
Since the strata concerning wp-site (back / neck) will be analysed separately following the 
Hochberg procedure, the calculation of the sample size will be based on a 0.05 two-sided
significance level in order to reject the null hypothesis for both strata.
A sample size of 300 patients per stratum concerning wp-site (back / neck) (120 patients 
with ibuprofen + caffeine, ibuprofen, respectively and 60 patients with placebo will have 
86% power to detect a difference of 1.2 on a 0-10 NRS for the primary endpoint between 
treatment effects of ibuprofen + caffeine versus ibuprofen (2:2 allocation ratio) and 71% 
power to detect the same difference between ibuprofen + caffeine and placebo (2:1 
allocation ratio), assuming a common standard deviation of 3 and using a 0.05 two-sided
significance level. This results in a total sample size of 600 evaluable patients. 
With the scenario above, the power for the test of H0 for the total population will be about 
99% for the comparison of ibuprofen + caffeine versus ibuprofen (2:2 allocation ratio) and 
94% for the comparison of ibuprofen + caffeine versus placebo (2:1 allocation ratio).
With a level of significance of 0.025 (in case Step 2 of the Hochberg procedure is 
applicable) and a sample size of 120 in each of the active treatment groups in a respective
stratum, the power to detect such treatment difference between the active treatment groups 
will be 79%.
The sample size of 300 patients per stratum will reach statistical significance in the 2:2
comparison (ibuprofen + caffeine versus ibuprofen), when the observed treatment 


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difference is at least 0.76, and in the 2:1 comparison (ibuprofen + caffeine versus placebo), 
when the observed treatment difference is at least 0.93 (with a 0.05 two-sided significance 
level and a standard deviation of 3).
In order to provide at least 80% power (on a 0.05 two-sided significance level) for strata
analyses concerning the wp-site (back/neck) in the 2:2 comparison (ibuprofen + caffeine 
versus ibuprofen), a total of 200 patients (ca 42%) of the totally planned 480 evaluable 
patients in the two active-treatment groups should qualify as either back or neck patients, 
respectively.
With a level of significance of 0.025 (in case Step 2 of the Hochberg procedure is 
applicable) and a sample size of 100 in each of the active treatment groups in a respective  
stratum, the power to detect such treatment difference between the active treatment groups 
will be 71%.
In total, about 650 patients will be randomised to ensure that 600 patients in the total 
population are evaluable for the primary endpoint; as soon as 600 patients in total are 
evaluable for the primary analysis, further recruitment of patients will be stopped. 
To ensure that each stratum “back pain” or “neck pain” is represented by at least 42% of 
the randomised patients, randomisation into a respective stratum will be capped as soon as 
58% (about 380 patients) of the total trial population have been randomised 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, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY
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 Good Clinical Practice (GCP), relevant BI Standard Operating Procedures 
(SOPs), and the EU regulation 536/2014 
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 Boehringer Ingelheim transparency and publication policy can be found on the 
following web page: trials.boehringer-ingelheim.com. 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, INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed 
and approved by the respective Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) and competent authority (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.”
The investigator must give a full explanation to trial patients based on the patient 
information form. A language understandable to the patient should be chosen, technical 
terms and expressions avoided, if possible. The patient must be given sufficient time to 
consider participation in the trial. The investigator obtains written consent of the patient’s 
own free will with the informed consent form after confirming that the patient understands 
the contents. The investigator must sign (or place a seal on) and date the informed consent 


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form. If a trial collaborator has given a supplementary explanation, the trial collaborator 
also signs (or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available 
and should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
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.
RECORDS
8.3
Case Report Forms (CRF) 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
In accordance with regulatory requirements the Investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial subject. Source data as well as 
reported data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit 
trail).
Data reported on the CRF must be consistent with the source data or the discrepancies 
must be explained.
The current medical history of the subject may not be sufficient to confirm eligibility for 
the trial and the Investigator may need to request previous medical histories and evidence 
of any diagnostic tests. In this case the Investigator must make three documented attempts 
to retrieve previous medical records. If this fails a verbal history from the patient, 
documented in their medical records, would be acceptable.
Before providing any copy of patients’ source documents to the sponsor the investigator 
must ensure that all patient identifiers (e.g. patient’s name, initials, address, phone number, 
social security number) have properly been removed or redacted to ensure patient 
confidentiality.


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If the patient is not compliant with the protocol, any corrective action e.g. re-training must 
be documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, date or year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient 
was informed)

Dates of Patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if 
available)

Serious adverse events (onset date (mandatory), and end date (if available)

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

Completion of Patient’s Participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and 
in-house data quality review. The frequency of on-site monitoring will be determined by 
assessing all characteristics of the trial, including its nature, objective, methodology and 
the degree of any deviations of the intervention from normal clinical practice.
The investigator /institution will allow on-site trial-related monitoring, audits, IRB/IEC 
review and regulatory inspections. Direct access must be provided to the CRF and all 
source documents/data, including progress notes, copies of laboratory and medical test 
results, which must be available at all times for review by the CRA, auditor and regulatory 
inspector (e.g. FDA). The CRA and auditor may review all CRFs and informed consents. 
The accuracy of the data will be verified by direct comparison with the source documents
described in section 8.3.1. The sponsor will also monitor compliance with the protocol 
and ICH GCP.


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8.3.3
Storage period of records
Trial site(s):
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.
EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
8.5
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy
will 
be 
ensured 
by 
using 
patient 
identification 
code 
numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
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 IRB/IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples
and 
corresponding data
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples from clinical trial participants and the corresponding data, 
in particular

A Quality Management System has been implemented to ensure the adherence with 
the Principles of Good Clinical Practice as outlined in 'Note For Guidance On 
Good Clinical Practice' (CPMP/ICH/13 5/95)

The BI-internal facilities storing and analysing biological samples and data from 
clinical trial participants as well as the laboratories' activities for clinical trials 
sponsored by Boehringer Ingelheim are regularly audited. The analytical groups
and the banking facility are therefore assessed to be qualified for the storage and 
use of biological samples and data collected in clinical trials.

Samples and data are used only if an appropriate informed consent is available.


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TRIAL MILESTONES
8.6
The start of the trial is defined as the date of the enrolment of the first patient in the 
whole trial.
The end of the trial is defined as the date of the last visit of the last patient in the whole 
trial (“Last Patient Out”).
The “Last Patient Drug Discontinuation” (LPDD) date is defined as the date on which 
the last patient at an individual trial site ends trial medication (as scheduled per protocol or 
prematurely). Individual Investigators will be notified of SUSARs occurring with the trial 
medication until 30 days after LPDD at their site.
Early termination of the trial is defined as the premature termination of the trial due to 
any reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health 
Authority request.
The IEC/competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).


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9.
REFERENCES
PUBLISHED REFERENCES
9.1
P84-98710
Laska EM, Sunshine A, Mueller F, Elvers WB, Siegel C, Rubin A. 
Caffeine as an analgesic adjuvant. JAMA 1984; 251(13):1711-1718
P90-0404
Cooper SA, Schachtel BP, Goldman E, Gelb S, Cohn P. Ibuprofen und 
acetaminophen in the relief of acute pain: A randomized, double-blind, 
placebo- controlled study. J Clin Pharmacol 1989;29:1026-1030.
P93-75428
Sawynok J, Yaksh TL. Caffeine as an analgesic adjuvant: A review of 
pharmacology and mechanisms of action. Pharmacol Rev 1993;45(1):43-
85.
P02-05324
Forbes JA, Beaver WT, Jones KF, Kehm CJ, Smith WK, Gongloff CM, 
Zeleznock JR, Smith JW. Effect of caffeine on ibuprofen analgesia in 
postoperative oral surgery pain. Clin Pharmacol Ther 1991;49(6):674-684
P02-05388
Cooper SA, Needle SE, Kruger GO. Comparative analgesic potency of 
aspirin and ibuprofen. J Oral Surg 1977; 35:898-903.
P02-05406
Packman B, Packman E, Doyle G, Cooper S, Ashraf E, Koronkiewicz K, 
Jayawardena S. Solubilized ibuprofen: evaluation of onset, relief, and 
safety of a novel formulation in the treatment of episodic tension-type 
headache. Headache 2000;40(7):561-567.
P02-05407
Diamond S, Balm TK, Freitag FG. Ibuprofen plus caffeine in the 
treatment of tension-type headache. Clin Pharmacol Ther. 2000 
Sep;68(3):312-9.
P05-00433
Hersh EV, Levin LM, Cooper SA, Doyle G, Waksman J, Wedell D, 
Hong D, Secreto SA. Ibuprofen liquigel for oral surgery pain. Clin 
Ther2000;22(11):1306-1318.
P05-11198
Benjamini Y, Hochberg Y. Controlling the false discovery rate: a 
practical and powerful approach to multiple teting. J R Stat Soc (B) 57 
(1), 289 – 300 (1995)
P06-04171
Zhang WY. A benefit-risk assessment of caffeine as an analgesic 
adjuvant. Drug Saf 2001;24(15):1127-1142.
P07-08407
Renner B, Clarke G, Grattan T, Beisel A, Mueller C, Werner U, Kobal G, 
Brune K. Caffeine accelerates absorption and enhances the analgesic 
effect of acetaminophen. J Clin Pharmacol 2007; 47(6):715-726.
P10-10394
Palmer H, Graham G, Williams K, Day R. A risk-benefit assessment of 
paracetamol (acetaminophen) combined with caffeine. Pain Med
2010;11(6):951-965.


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P11-05389
Sawynok J. Caffeine and pain. Pain 2011; 152(4):726-729.
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. 
Weblink://versorgungsleitlinien.de/themen/kreuzschmerz; 
weblink://bptk.de/fileadmin/user_upload/Themen/Leitlinien/20101130_n
vl_kreuzsch merz_lang.pdf (access date: 12 July 2011) (2010)
P12-04607
Derry,S,Wiffen, P.J. and Moore, R.A. Relative efficacy of oral analgesics 
after third molar extraction – a 2011 update. British Dental Journal 2011, 
211(9): 419-420.
P12-04063
Derry CJ, Derry S, Moore RA. Caffeine as an analgesic adjuvant for
acute pain in adults (review). Cochrane Database Syst Rev 2012(3) 
CD009281.
P12-12821
Sawynok J, Reid AR. Caffeine inhibits antinociception by acetaminophen 
in the formalin test by inhibiting spinal adenosine A1 receptors. Eur J
Pharmacol 2012;674:248-254.
P12-14205
Donovan JL, DeVane CL. A primer on caffeine pharmacology and its 
drug interactions in clinical psychopharmacology. Psychopharmacol Bull
2001; 35(3):30-48
P13-03158
Sunshine A, Olson NZ, Zighelboim I, De Castro A. Ketoprofen, 
acetaminophen plus oxycodone, and acetaminophen in the relief of 
postoperative pain. Clin Pharmacol Ther. 1993 Nov;54(5):546-55.
R97-2392
McQuay HJ, Angell K, Caroll D, Moore RA, Juniper RP. Ibuprofen 
compared with ibuprofen plus caffeine after third molar surgery. Pain 
1996;66:247-251.
R98-0795
Zhang WY, Li Wan Po A. Analgesic efficacy of paracetamol and its 
combination with codeine and caffeine in surgical pain - a meta -
analysis. J Clin Pharm Ther 1996;21:261-282.
R99-0976
Schachtel BP, Furey SA, Thoden WR. Nonprescription ibuprofen and 
acetaminophen in the treatment of tension-type headache. 24th Ann Mtg 
of the American College of Clinical Pharmacology, Rockville, 22 Sep 
1995 J Clin Pharmacol 1996;36:1120-1125.
R10-1410
Roland, M., Fairbank, J. The Roland–Morris Disability Questionnaire 
and the Oswestry Disability Questionnaire Spine 25(24): 3115-3124 
(2000)
R11-1488
Kenward, M. G. and Roger, J. H. Small Sample Inference for Fixed 
Effects from Restricted Maximum Likelihood. Biometrics, 53, 983 - 997 
(1997)


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R12-4427
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)
R12-4428
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)
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 multicentre 
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)
R16-0043
Fairbank, J. Why different versions of the Oswestry Disability Index? J. 
Neurosurg Spine 20: 83-86 (2014)
UNPUBLISHED REFERENCES
9.2
U13-3353-02
A single-centre, double-blind, randomised, two-stage, parallel-group
study to assess the efficacy and safety of the fixed dose combination 
of ibuprofen 400 mg and caffeine 100 mg versus ibuprofen 400 mg, 
caffeine 100 mg and placebo in patients with postoperative dental 
pain.
1335.1 Clinical Trial Report
c02098879-06
Ibuprofen and Caffeine Investigator Brochure, Version 2 (BI project 
number. PDN 1335.P1), 25 Sept. 2015
c02330821-01
 A single-centre, double-blind, 
randomised, two-stage, parallel-group study to assess the efficacy and 
safety of the fixed dose combination of ibuprofen 400 mg and caffeine 
100 mg versus ibuprofen 400 mg, caffeine 100 mg and placebo in 
patients with postoperative dental pain. 1335.1. III. 25-Sept-2014


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
05-AUGUST-2016
EudraCT number
2016-000902-12
BI Trial number
1335.5
BI Investigational Product(s)
Ibuprofen + Caffeine
Title of protocol
A randomized, placebo- and active-controlled 
multi-country, multi-centre parallel group study 
to evaluate the efficacy and safety of a fixed dose 
combination of 400 mg ibuprofen and 100 mg 
caffeine compared to ibuprofen 400 mg and 
placebo in patients with acute lower 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
X
Section to be changed
Title Page and Header 
Description of change
Version Number and Final Date. 
Rationale for change
The protocol was revised because approval 
workflow had been initiated instead of an e-
signature workflow. Content was not changed


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c08887804
2.0
clinical-trial-protocol
A randomized, placebo- and active-controlled multi-country, multi-centre parallel
group study to evaluate the efficacy and safety of a fixed dose combination of 400
mg ibuprofen and 100 mg caffeine compared to ibuprofen 400 mg and placebo in
patients with acute lower back or neck pain
Approval-Therapeutic Area 
05 Aug 2016 15:11 CEST
Author-Team Member Medicine
07 Aug 2016 17:39 CEST
Approval-Trial Clinical Monitor
07 Aug 2016 22:05 CEST
Author-Statistician
08 Aug 2016 10:55 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c08887804
2.0

SAP_000.pdf: 
 
Statistical Analysis Plan 
PROTOCOL 1335.5 
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Document: 
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Author: 
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Version Date: 
29AUG2017 
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Effective Date: 01Apr2016 
 
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Transnational Corp. All rights reserved. 
The contents of this document are confidential and proprietary to
Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
1335.5 
A RANDOMISED, PLACEBO- AND ACTIVE-CONTROLLED MULTI-
COUNTRY, MULTI-CENTRE PARALLEL GROUP STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF A FIXED DOSE COMBINATION OF 400 MG 
IBUPROFEN AND 100 MG CAFFEINE COMPARED TO IBUPROFEN 400 
MG AND PLACEBO IN PATIENTS WITH ACUTE LOWER BACK OR NECK 
PAIN 
 
 
AUTHOR:
VERSION NUMBER AND DATE: VERSION 1.0, 29AUG2017  
 
 


 
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Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
 


 
Statistical Analysis Plan 
PROTOCOL 1335.5 
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Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
Modification History 
 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorised Version 
1.0 
29AUG2017 
 
Not applicable – First version 
 
 
 


 
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Effective Date: 01Apr2016 
 
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The contents of this document are confidential and proprietary to
Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
TABLE OF CONTENTS 
1. INTRODUCTION ................................................................................................................................ 8 
2. STUDY OBJECTIVES ......................................................................................................................... 8 
2.1. 
Primary Objective ........................................................................................................................................8 
2.2. 
Secondary Objective ....................................................................................................................................8 
3. STUDY DESIGN .................................................................................................................................. 8 
3.1. 
General Description .....................................................................................................................................8 
3.2. 
Schedule of Event ........................................................................................................................................9 
3.3. 
Changes to Analysis from Protocol ..............................................................................................................9 
4. PLANNED ANALYSES ....................................................................................................................... 9 
4.1. 
Data Monitoring Committee (DMC) .............................................................................................................9 
4.2. 
Final Analysis ...............................................................................................................................................9 
5. ANALYSIS SETS AND IMPORTANT PROTOCOL VIOLATIONS (IPVS) ............................ 10 
5.1. 
Analysis sets .............................................................................................................................................. 10 
5.2. 
Important Protocol Violations (IPVs) ......................................................................................................... 11 
6. GENERAL CONSIDERATIONS ..................................................................................................... 16 
6.1. 
Reference Start Date and Relative Day ...................................................................................................... 16 
6.2. 
Baseline ..................................................................................................................................................... 17 
6.3. 
Retests, Unscheduled Visits ....................................................................................................................... 17 
6.4. 
Windowing Conventions and Study Periods .............................................................................................. 17 
6.5. 
General Statistical Tests and Calculations .................................................................................................. 18 


 
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Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
6.6. 
Software Version ....................................................................................................................................... 19 
7. STATISTICAL CONSIDERATIONS ............................................................................................. 20 
7.1. 
Adjustments for Covariates to be Included in Analyses ............................................................................. 20 
7.2. 
Multi-centre Studies .................................................................................................................................. 20 
7.3. 
Missing data .............................................................................................................................................. 20 
7.4. 
Multiple Comparisons/ Multiplicity ........................................................................................................... 20 
7.4.1. 
Primary Endpoint ......................................................................................................................................20 
7.4.2. 
Secondary Endpoints ................................................................................................................................21 
 
 
8. OUTPUT PRESENTATIONS ......................................................................................................... 22 
8.1. 
Dates & Times ........................................................................................................................................... 22 
8.2. 
Spelling ...................................................................................................................................................... 22 
8.3. 
Presentation of Treatment Groups and Visits ............................................................................................ 22 
9. DISPOSITION AND PREMATURE DISCONTINUATION ...................................................... 22 
9.1. 
Derivations ................................................................................................................................................ 23 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ...................................... 23 
10.1. 
Derivations ............................................................................................................................................ 23 
11. 
HISTORICAL, CONCOMITANT THERAPIES AND BASELINE CONDITIONS ............... 24 
11.1. 
Derivations ............................................................................................................................................ 24 
12. 
MEDICAL HISTORY ................................................................................................................... 25 
12.1. 
Derivations ............................................................................................................................................ 25 
13. 
TRIAL MEDICATION EXPOSURE AND COMPLIANCE ...................................................... 25 


 
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Transnational Corp. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
13.1. 
Derivations ............................................................................................................................................ 26 
14. 
EFFICACY ANALYSIS ................................................................................................................. 26 
14.1. 
Primary Efficacy Endpoint ...................................................................................................................... 26 
14.1.1. 
Primary Endpoint and Analysis of the Primary Efficacy Variable ..............................................................26 
14.1.2. 
Missing Data .............................................................................................................................................27 
14.1.3. 
Mixed model repeated measures (MMRM) .............................................................................................27 
 
 
14.2. 
Secondary Efficacy Endpoints ................................................................................................................ 29 
14.2.1. 
Analysis of Key Secondary Efficacy Variables ...........................................................................................29 
14.2.1.1. 
Area Under the Curve (AUC) for POMwp between Baseline and the morning of Day 4 
(POMwpAUC72h) and between Baseline and the moring of Day 6 (POMwpAUC120h) ......................................29 
14.2.2. 
Missing Data .............................................................................................................................................30 
14.2.3. 
Analysis of Other Secondary Efficacy Variables ........................................................................................31 
14.2.3.1. 
Change in Pressure Algometry (PA) between baseline and Day 2 morning, 2 hours after drug 
intake 
31 
14.2.3.2. 
Global assessment of efficacy by the patient at the end of treatment (Day 6 morning) .................31 
14.2.3.3. 
Missing Data .....................................................................................................................................32 
14.2.3.4. 
Number of patients with a decrease in POMwp of at least 30% between Baseline and Day 2 
morning, 2 hours after drug intake ......................................................................................................................32 
14.2.3.5. 
Number of patients with a decrease in POMwp of at least 50% between Baseline and Day 2 
morning, 2 hours after drug intake ......................................................................................................................33 
14.2.3.6. 
Time to first meaningful POMwp relief (≥2) within 2 hours after the first dose of trial medication33 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15. 
SAFETY OUTCOMES .................................................................................................................. 37 
15.1. 
Adverse Events and Serious Adverse Events .......................................................................................... 37 
15.1.1. 
All Adverse Events ....................................................................................................................................37 


 
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15.1.2. 
Other significant adverse events (according to ICH E3) ...........................................................................38 
15.2. 
Derivations ............................................................................................................................................ 38 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
17. 
REFERENCES ............................................................................................................................... 42 
APPENDIX 1. PARTIAL DATE CONVENTIONS .............................................................................. 43 
Algorithm for Treatment- Emergence of Adverse Events: ..................................................................................... 43 
Imputation algorithm for partial date for historical and concomitant therapies: .................................................. 43 
 
 


 
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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of efficacy and 
safety data for Protocol 1335.5. It describes the data to be summarised and analysed, including specifics of the 
statistical analyses to be performed.  
This statistical analysis plan (SAP) is based on protocol version 2.0, dated 05 August 2016. 
2. STUDY OBJECTIVES 
2.1. PRIMARY OBJECTIVE 
The primary objective of this study is to demonstrate superior efficacy of a 400 mg ibuprofen/100 mg caffeine 
tablet over a 400 mg ibuprofen tablet only and a placebo tablet only. 
2.2. SECONDARY OBJECTIVE 
The secondary objective is to access the safety and tolerability of a 400 mg ibuprofen/100 mg caffeine tablet in 
comparison to a 400 mg ibuprofen tablet only and a placebo tablet only. 
3. STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
This is a Phase III, multi-centre, double-blind, parallel-group study, with a total of 650 research patients (with the 
aim to have 600 evaluable patients) randomised in a 2:2:1 ratio to three treatment groups as described in Table 
1: Treatment Groups, below: 
Table 1: Treatment Groups 
Presentation 
Order 
Treatment Group 
Number of Patients 
Interventions 
1 
Placebo 
~130 
Placebo tablet 
2 
Ibuprofen 
~260 
400 mg ibuprofen tablet 
3 
Ibuprofen + caffeine 
~260 
400 mg ibuprofen and 100 mg caffeine tablet  


 
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3.2. SCHEDULE OF EVENT 
Schedule of events can be found in Section 6.2: Details of Trial Procedures at Selected Visits as well as in the flow 
chart of the protocol. 
3.3. CHANGES TO ANALYSIS FROM PROTOCOL 
No changes were made to the planned analysis. 
4. PLANNED ANALYSES 
4.1. DATA MONITORING COMMITTEE (DMC) 
There will be no DMC for this study. 
4.2. FINAL ANALYSIS 
The unblinded final, planned analysis identified in this SAP and supporting TLF shells will be performed by 
 Biostatistics. The final analysis is planned following: 
• 
Boehringer Ingelheim’s authorisation of: 
o 
Final version of the SAP. 
o 
Relevant set of TLF shells. 
o 
Final analysis sets and reason(s) for exclusion/important protocol violations. 
• 
Final database lock (DBL). 
• 
Routine study unblinding. 
• 
Identification of treatment deviations. 
The final analysis is planned when all patients have completed study participation. 
The final analysis will be performed on a clean database snapshot: 
• 
All outstanding data issues and queries resolved, as far as feasible and as indicated in the authorised data 
issues log. 
• 
All unresolved data issues documented in the authorised data handling report (DHR) from data 
management (DM). 
• 
All coding of medical history (MH), concomitant medication (CM) and adverse events (AEs) completed. 


 
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• 
Serious adverse event (SAE) and interactive web response system (IWRS) reconciliation completed by data 
management. 
5. ANALYSIS SETS AND IMPORTANT PROTOCOL VIOLATIONS (IPVS) 
Boehringer Ingelheim’s authorisation of the analysis set assignment, identification for reasons for exclusion from 
analysis sets in addition to important protocol violations identified during the clinical conduct of study is required 
prior to database lock and the routine unblinding of the study and final analysis.  
5.1. ANALYSIS SETS 
There are three analysis sets defined as follows for this study: 
• 
Treated set (TS): 
o 
All randomised patients; 
o 
Who took at least one dose of the trial medication. 
 
Patients having received the wrong treatment will be analysed within the planned 
(randomised) treatment group in the efficacy analysis and within the actual (as treated) 
treatment group in the safety analysis. 
 
Patients who are incorrectly randomised into the stratum not containing their POMWP will be 
included in TS as randomised, but will be allotted to the stratum with the POMWP. 
• 
Full analysis set (FAS): 
o 
All patients included in the TS; 
o 
Who provided a baseline value for  at Visit 1 (Day 1) before drug intake; 
o 
Provided at least one post-baseline  assessment at the following time points: 
 
Visit 1 (Day 1, 120 minutes after drug intake). 
 
Visit 2 (Day 2, 120 minutes after drug intake). 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Additionally a limited number of presentations will be based on the following two patient sets: 


 
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• 
Enrolled patients: 
o 
All patients who were screened in this study (provided informed consent). 
 
 
 
 
These patient/analysis sets will be utilised in the domain-specific analysis as detailed in Table 2: Analysis Set 
Relevant to Domain-specific Analysis, below: 
Table 2: Analysis Set Relevant to Domain-specific Analysis 
Domain 
Analysis Set 
Disposition 
Enrolled patients 
 
 
IPVs 
TS (as randomised) 
Demographics and other baseline characteristics 
Concomitant therapies 
Treatment compliance 
Efficacy analysis: primary endpoints 
FAS (primary) 
 
Efficacy analysis: secondary 
 endpoints 
TS (as randomised) 
Safety analysis 
TS (as treated) 
5.2. IMPORTANT PROTOCOL VIOLATIONS (IPVS) 
The IPVs defined for this study are provided in Table 3: Detailed List of IPVs, below. Based on the response to the 
programmatically identified in the last column of Table 3, the IPVs will be identified as follows: 
• 
Yes: 
o 
Programmed check by the biostatistics team to identify the patients with these IPVs. 
• 
No: 
o 
IPVs identified by the clinical team on an ongoing basis. 
o 
These manual IPVs will be documented in Clinical Trial Management System (CTMS) as a protocol violation. 
o 
These manual IPVs will be transferred to the biostatistics team for incorporation in the analysis. 
• 
Yes/No: 
o 
IPVs identified by the medical/clinical team on an ongoing basis. 


 
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o 
The biostatistics team can provide relevant outputs to assist in the identification of these IPVs, in which case 
the noted IPVs will be noted on the provided outputs to be considered during the analysis. 
Table 3: Detailed List of IPVs 
Category/ 
Code 
IPV Description 
Comment/Example 
Efficacy/ 
Safety 
(E/S) 
Programmatically 
Identified 
A 
Entrance criteria not met 
A.1 
Inclusion criteria not met 
A1.01 
Diagnosis of acute back pain or neck 
pain < 24 hours or ≥ 21 days 
IN2 
E 
Yes/No 
A1.02 
Any baseline POM procedure missing or 
not done 
IN3 
E 
Yes/No 
A1.03 
POM < 5 for all 5 baseline procedures 
IN3 
E 
Yes 
A1.04 
Sensitivity to algometric pressure on the 
painful trigger point > 25 N/cm² 
IN4 
E 
Yes 
A.2 
Exclusion criteria met 
A2.01 
History of 3 or more episodes of back or 
neck pain in the last 6 months excluding 
the current episode. 
EX1 
E 
Yes/No 
A2.02 
Pain at rest ≥ 9  
EX2/EX3 
E 
Yes 
A2.03 
Patient with chronic back or neck pain 
as defined as pain for 3 weeks or longer. 
EX4 
E 
Yes/No 
A2.04 
Back or neck pain that is attributable to 
any identifiable cause 
EX5 
E 
Yes/No 
A2.05 
Any strains of the back or neck muscles 
documented by clinical evaluation and 
anamnesis that occurred 21 days to 3 
months prior to the screening visit 
EX6 
E 
Yes/No 
A2.06 
Surgery due to back or neck pain or 
rehabilitation due to back or neck pain 
in the last 12 months 
EX7 
E 
No 
A2.07 
Prior use within the last 3 days before 
Visit 1 or concomitant use of any anti-
inflammatory drugs, heparinoids, 
muscle relaxants or analgesics (see CTP 
for exceptions) 
EX8 
E, S 
Yes/No 


 
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Category/ 
Code 
IPV Description 
Comment/Example 
Efficacy/ 
Safety 
(E/S) 
Programmatically 
Identified 
A2.08 
Spinal injections or  long-acting 
glucocorticoids not discontinued in due 
time  
EX9 
E 
No 
A2.09 
Known severe hepatocellular 
insufficiency, severe renal insufficiency 
or Gilbert’s syndrome 
EX10 
S 
No 
A2.10 
Use of CNS or other psychotropic drugs, 
or any nutritional supplement known to 
have psychotropic effects 
EX11 
S 
No 
A2.11 
Any other medical condition that would 
interfere with efficacy and safety 
assessments 
EX12 
E, S 
No 
A2.12 
Known intolerance or hypersensitivity 
to the active ingredients or any 
excipient(s) 
EX13 
S 
No 
A2.13 
Patient not able to understand and 
comply with trial requirements based 
on investigators judgment 
EX14 
E, S 
Yes 
A2.14 
Major surgery performed within 12 
weeks prior to randomization or 
planned within timeframe of this study 
EX15 
E, S 
No 
A2.15 
Patient must or wishes to continue the 
intake of restricted medications or any 
drug considered likely to interfere with 
the safe conduct of the trial 
EX16 
E, S 
Yes 
A2.16 
Previous enrolment in this trial 
EX17 
E, S 
No 
A2.17 
Currently enrolled in another 
investigational device or drug study, or 
less than 30 days since ending another 
investigational device or drug study(s), 
or receiving other investigational 
treatment(s) 
EX18 
E, S 
No 
A2.18 
Habituation to analgesic drugs or 
caffeine (see CTP for further 
specification) 
EX19 
E, S 
No 


 
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Category/ 
Code 
IPV Description 
Comment/Example 
Efficacy/ 
Safety 
(E/S) 
Programmatically 
Identified 
A2.19 
History of allergic reaction (see CTP for 
further specification) 
EX20 
S 
No 
A2.20 
Chronic alcohol or drug abuse or any 
condition that, in the investigator’s 
opinion, makes the patient an 
unreliable study subject or unlikely to 
complete the trial 
EX21 
E, S 
No 
A2.21 
Women who are pregnant, nursing, or 
who plan to become pregnant while in 
the trial 
EX22 
S 
Yes 
A2.22 
Prior use of any type of analgesic or 
NSAID within 5 half-lives of that drug 
before initial dosing in the trial 
EX23 
E, S 
No 
A2.23 
Presence or history (within 2 years of 
enrolment) of bleeding disorder or 
peptic ulcer disease 
EX24 
S 
No 
A2.24 
Has a clinically significant abnormal 
electrocardiogram (ECG) at screening as 
determined by the investigator 
EX25 
S 
Yes 
A2.25 
Has known impaired liver function (see 
CTP for further specification) 
EX26 
S 
No 
A2.26 
The patient is a member of the study 
site staff either directly involved with 
the study, an employee of the Sponsor, 
or a relative of study site personnel 
directly involved with the study or 
Sponsor 
EX27 
No 
B 
Informed consent 
B1 
Informed consent not given 
Date of informed 
consent missing 
E, S 
Yes 
B2 
Informed consent given too late 
Date of informed 
consent not obtained 
prior to any study 
related procedure 
S 
Yes 
C 
Trial medication and randomisation 


 
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Category/ 
Code 
IPV Description 
Comment/Example 
Efficacy/ 
Safety 
(E/S) 
Programmatically 
Identified 
C1 
Incorrect trial medication taken 
Less or more than 4 
tablets taken until Visit 2 
E 
Yes/No 
C2 
Randomisation order not followed 
Patient received trial 
medication from 
medication kit not 
assigned to them. If 
patients actually receive 
the correct medication, 
despite receiving the 
wrong kit, they will not 
be excluded from the 
PPS. 
E, S 
Yes/No 
C3 
Medication code broken 
Medication code broken 
inappropriately 
E 
No 
C4 
Incorrect stratum (back/neck) selected 
based on POMWP. 
If a patient is not 
randomised into the 
stratum containing the 
POMWP. 
E 
Yes 
D 
Concomitant medication 
D1 
Medications not stable at least 2 weeks 
before randomisation 
visit 
Antidepressants or 
antipsychotics not stable 
from at least 2 weeks 
before randomisation 
E 
Yes 
D2 
Prohibited medication use during the 
treatment period 
Prohibited use of 
concomitant treatments 
as described in CTP 
section 4.2.2.1 
E 
Yes/No 
D3 
Improper use of rescue medication 
More than 4 
paracetamol tablets (of 
500mg) taken on 
treatment day 1 
E, S 
Yes/No 
F 
Incorrect timing 
F1 
Incorrect timing of visits 


 
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Category/ 
Code 
IPV Description 
Comment/Example 
Efficacy/ 
Safety 
(E/S) 
Programmatically 
Identified 
F1.1 
V2 completed outside of time window 
Visit 2 not performed on 
day 2 between 7 and 12 
am 
E 
Yes 
F1.2 
Follow-up period too short 
Follow-up visit 
completed < 24 hours 
after the day of the last 
dose of trial medication 
S 
Yes 
F2 
Incorrect timing of measurements 
F2.1 
POM assessment not between 115 
minutes and 125 minutes after 
application of trial medication  
IPV only on day of 
primary endpoint 
E 
Yes 
G 
Other 
G1 
Other PV affecting efficacy and possibly safety 
G1.1 
Assessment of POM by untrained staff 
E, S 
No 
G1.2 
Assessment of POM on screening, 
randomisation and day 2 not done by 
the same person (within a patient) 
E 
Yes 
G2 
Other PV affecting safety only 
G2.1 
Pregnancy test not performed 
Missing pregnancy test 
result for any women of 
childbearing potential 
S 
Yes 
G3 
Significant GCP non-compliance 
It should be described 
carefully in the DBL 
meeting minutes, which 
analyses are affected 
S 
No 
6. GENERAL CONSIDERATIONS 
6.1. REFERENCE START DATE AND RELATIVE DAY 
Relative day is calculated from the reference start date, and will be used to show start/stop day of assessments 
and events.  


 
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Reference start date is defined as date/time of first administration of trial medication. The first occurrence of 
either Ibuprofen + caffeine or Ibuprofen or placebo tablet will be considered for all patients.  
• 
If the date/time of the assessment/event is on or after the reference start date then:  
o 
Relative Day = (Date/time of assessment/event – Reference start date/time) + 1. 
• 
If the date/time of the assessment/event is prior to the reference start date then:  
o 
Relative Day = (Date/time of assessment/event – Reference start date/time). 
Unless otherwise specified, if the assessment/event date is partial or missing, relative day, and any 
corresponding durations will not be calculated and will be presented as missing in the listings. For further details 
regarding the partial date conventions, refer to APPENDIX 1: Partial Date Conventions. 
6.2. BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing assessment prior to the first 
administration of trial medication (reference start date/time). In the case where the last non-missing assessment 
and the reference start date/time coincide, that assessment will be considered as occurring prior to the start of 
administration of the trial medication and will be used as the baseline assessment.  
However, AEs and medications commencing on the reference start date will be considered post-baseline if there 
is only a date available, e.g. as treatment-emergent AEs or concomitant medications. If a date/time is available 
for AEs and CMs then the events/medication will be assigned accordingly.  
For assessments with time available, baseline is calculated as the last non-missing assessment prior to the first 
start date and time of trial medication. Time of assessment relative to time of first administration of the trial 
medication will be used to differentiate between pre- and post-administration assessments. 
6.3. RETESTS, UNSCHEDULED VISITS 
In general, for by-visit summaries, data recorded at the scheduled visits will be presented. There are no 
unscheduled visits available on the eCRF (e.g. between scheduled visits) for this study and subsequently 
unscheduled data is not collected. 
 
 
 
6.4. WINDOWING CONVENTIONS AND STUDY PERIODS 
Time windows for visits are shown in the flow chart in the clinical trial protocol. Visits 1 and 2 must be carried out 
on the specified days, for visit 3 and 4 there is a time window of ± 1 days. 
Endpoint variables captured outside the defined visit window will be flagged in the IPVs. 


 
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If a single scheduled visit is completed outside of the visit window, as defined in the protocol, that visit will be 
assigned to the scheduled visit. For example, if a patient completes a visit in the afternoon of day 2, the visit 
would be assigned to visit number 2. 
If more than one consecutive scheduled visits are missed, and a single visit completed to compensate for the 
missed visits, the completed visit will be assigned to the closest scheduled visit among those missed visits. 
The study periods are defined in Table 4: Study Periods, below. 
Table 4: Study Periods 
Study Period 
Start of Period 
End of Period 
Screening (S) 
Informed consent obtained 
First intake of trial medication 
On-treatment (OT) 
First intake of trial medication 
Day and time of last administration of 
trial medication + 24 hours 
Post-treatment (PST) 
Day and time last administration of trial 
medication + 24 hours 
Trial termination date 
Post-study (PS) 
Trial termination date 
Post-trial termination date 
6.5. GENERAL STATISTICAL TESTS AND CALCULATIONS 
This section provides general details on the descriptive statistical analysis. The details regarding statistical testing 
is described in the domain-specific analysis sections.  
The default significant level will be (5%); confidence intervals will be 95% and all tests will be two-sided, unless 
otherwise specified in the description of the analyses. 
Unless otherwise specified, the default summary statistics are: 
• 
Quantitative variables: 
o 
Number of patients with non-missing values in each category. 
o 
Mean. 
o 
Standard violation (SD). 
o 
Minimum. 
o 
Q1 (lower quartile). 
o 
Median. 
o 
Q3 (upper quartile). 
o 
Maximum. 
• 
Qualitative variables: 
o 
Number of patients with non-missing values in each category. 
o 
The percentage of patients (rounded to one decimal place) in each category (%) presented relative the total 
number of patients in the respective treatment group. 
o 
For categorical and ordinal data, all possible categories will be displayed. 


 
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The category missing will be displayed only if there are actually missing values. 
All values will be rounded using the SAS® function ROUND as the last step prior to presentation. 
If the original data has N decimal places (as derived from the raw data), then the summary statistics for the 
quantitative data will contain the following number of decimal places (with a maximum of 4 decimal places): 
• 
Minimum and maximum: N. 
• 
Mean and median: (N+1). 
• 
Standard deviation: (N + 2). 
All p-values will be presented with 4 decimal places, if less than 0.0001 (after rounding to 4 decimal places) the p-
value will be displayed as < 0.0001. Odds ratios and CIs will be presented to 3 decimal places. 
Patient data listings will be based on the randomised set. 
For all efficacy analysis pertinent to the WP-site and applicable only the FAS, any patient who is incorrectly 
randomised into the stratum (back/neck) not containing the POMWP will be included in the stratum with the 
POMWP. 
Common Calculations: 
• 
Change in  between  and  will be calculated as follows: 
o 
Change in  =  at  -  at  
o 
The same calculation will be applied for change in pressure algometry (PA). 
 
 
 
 
• 
For quantitative measurements, % change from baseline will be calculated as: 
o 
% Change from baseline at Visit X = (Change from baseline at visit X/baseline) X 100. 
For descriptive analysis, if a result is missing, change from baseline will be presented as missing in the listing; 
hence no imputation for a missing change from baseline will be performed. 
Date/time of first and last trial medication administration: 
• 
First: Chronologically sorting date/time of the trial medication administrations within a patient and 
selecting the earliest date/time available. 
• 
Last: Chronologically sorting date/time of the trial medication administrations within a patient and 
selecting the latest date/time available. 
6.6. SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.4.  


 
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7. STATISTICAL CONSIDERATIONS 
7.1. ADJUSTMENTS FOR COVARIATES TO BE INCLUDED IN ANALYSES 
Due to the stratification of randomisation, country and worst procedure site (wp-site) (back/neck) will be 
analysed as covariates. Additional covariates are detailed in the relevant domain-specific analysis sections. 
7.2. MULTI-CENTRE STUDIES 
This study will be conducted by multiple investigators at multiple sites in Germany and Russia.  Randomisation to 
treatment groups is stratified by country.   
The following research centres are included in this study: 
• 
Germany: All centres starting with
 
• 
Russia: All centres starting with 
. 
7.3. MISSING DATA 
For missing baseline data, no imputation will be implemented. 
Missing safety data will not be imputed, 
 
  
Missing efficacy data will be handled as described in Section 14: Efficacy Analysis, of this analysis plan. 
For the handling of missing or partial dates, refer to APPENDIX 1: Partial Date Conventions. 
7.4. MULTIPLE COMPARISONS/ MULTIPLICITY 
7.4.1. 
PRIMARY ENDPOINT 
In order to demonstrate efficacy, two-sided tests and a 0.05 level of significance will be used. To this purpose the 
following is hypothesized: 
Null hypotheses: 
There is no difference in change in POMwp between baseline and Day 2 morning, 2 hours after drug intake 
between patients treated with the combination ibuprofen + caffeine and the patients treated with ibuprofen or 
placebo. 
Alternative hypotheses: 


 
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There is a difference in Change in POMwp between baseline and Day 2 morning, 2 hours after drug intake 
between patients treated with the combination ibuprofen + caffeine and the patients treated with ibuprofen and 
patients treated with placebo only. 
The hypotheses can be written as: 
	: 	,:   =   	,:   =  
versus 
	: 	,:   ≠    	,:   ≠  
where ,  and  is the adjusted (for country and wp-site effect, and baseline POMwp) mean 
change in POMwp between baseline and the morning of Day 2, 2 hours after trial medication intake, for patients 
treated with the combination ibuprofen + caffeine, ibuprofen and placebo only, respectively. 
Since both partial hypotheses 	,, and 	, must be rejected in order to reject the null hypothesis 	, no 
adjustment for multiplicity issues will be made and thus statistical testing of 	 will be performed using a two-
sided, alpha = 0.05 level of significance. 
In case 	 can be rejected, the same hypothesis will be tested with respect to the strata back and neck pain using 
the Hochberg procedure. 
Step 1: 
In case all p-values (obtained without multiplicity adjustments) for the four treatment comparisons (back: 
ibuprofen + caffeine vs. ibuprofen and placebo respectively; neck:  ibuprofen + caffeine vs. ibuprofen and 
placebo respectively) are below 0.05, superiority of the combination ibuprofen + caffeine versus ibuprofen and 
placebo only can be concluded for both strata, otherwise the following procedure will be performed: 
Step 2: 
In case there is a stratum with both p-values for the 2 comparisons below alpha/2 = 0.025, superiority of the 
combination ibuprofen + caffeine versus ibuprofen and placebo can be concluded for the respective stratum, 
otherwise superiority cannot be concluded for any stratum. 
7.4.2. 
SECONDARY ENDPOINTS 
The key secondary endpoints will be analysed for the total population hierarchically (POMWPAUC72h first) in a 
confirmatory way only, when statistical significance with the total population was achieved for the primary 
endpoint. Analysis of the key-secondary endpoints for the strata back and neck pain will be descriptive in nature. 
All other secondary endpoints will be considered as supportive only. 
 
 
 
 
 
 
 
 


 
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8. OUTPUT PRESENTATIONS 
8.1. DATES & TIMES 
Depending on data available, dates and times are to take the form yyyy-mm-ddThh:mm. Partial dates will not be 
imputed and hence displayed as partial in the planned listings. For further details regarding the handling of 
partial dates and assigning therapies to study periods, refer to APPENDIX 1: Partial Date Conventions. 
8.2. SPELLING 
English UK spelling will be applied.  
Note that verbatim terms, specifications (e.g. the reason a specific assessment was not done) in the TLF shells 
that contain the suffix (eCRF), contain free text fields which may include spelling mistakes. Verbatim text will be 
presented in the listings as is and no manual hard-coding corrections of such data will be made. 
8.3. PRESENTATION OF TREATMENT GROUPS AND VISITS 
Refer to Table 1: Treatment Groups for the details regarding the treatment groups and order of presentation. 
Refer to Error! Reference source not found. for the details regarding the planned visits and labelling. 
9. DISPOSITION AND PREMATURE DISCONTINUATION 
All patients who provide informed consent will be accounted for in this study.  


 
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Patient disposition and primary reason for premature trial discontinuation, analysis sets (as defined in section 
5.1: Analysis sets) and IPVs (as defined in section 5.2: Important Protocol Violations (IPVs)) will be summarised. 
The reasons for exclusion from analysis set (IPVs) will be reviewed and authorised by Boehringer Ingelheim at the 
final BDR meeting. 
Patient disposition, reasons for non-inclusion and discontinuation, analysis sets and reasons for exclusion as well 
as IPVs will be listed. 
Treatment violations will be identified by using the report provided by Almac and the CTMS report: 
9.1. DERIVATIONS 
Study completion: 
• 
Completed study Yes: If the patient did not prematurely stop the trial medication is selected on the 
Termination of Trial Medication eCRF. 
• 
Completed study No: If one of the following is selected: 
o 
Adverse event: 
 
Unexpected worsening of disease under study. 
 
Unexpected worsening of other pre-existing disease. 
 
Other adverse event. 
o 
Lack of efficacy. 
o 
Non-compliant with protocol. 
o 
Lost to follow-up. 
o 
Patient refusal to continue taking trial medication. 
o 
Other. 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
No statistical testing will be carried out for demographic or other baseline characteristics. 
Demographics and baseline clinical signs of disease will be listed and summarised descriptively by treatment 
group and total based on the Treated set. 
10.1. DERIVATIONS 
• 
Age will be summarised as collected on the eCRF and not rederived. 
• 
Age class (years): Refer to section 7.5: Examination of Subgroups for the relevant age class defined for 
analysis. 
• 
 
 
 


 
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11. HISTORICAL, CONCOMITANT THERAPIES AND BASELINE CONDITIONS 
Historical medication as well as medication taken at baseline or during the treatment period will be summarised 
by World Health Organization-Drug Dictionary (WHO-DD) preferred term (PT), and presented by treatment group 
and all patients combined.  
Patients with more than one finding will be counted only once per preferred term. The table will be presented by 
preferred term by total descending frequency. Where different preferred terms have the same total frequency, 
the preferred terms will be sorted alphabetically. 
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. 
Historical and concomitant therapies will be coded using the most recent WHO-DD version. Uncoded terms will 
be displayed last within the category Uncoded and utilising the verbatim term entered on eCRF as WHO-DD drug 
name (e.g. Uncoded/Ointment). 
Analgesic therapies will be identified through a medical review of all therapies recorded in the database by 
Boehringer Ingelheim. 
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 
11.1. DERIVATIONS 
All therapies will be classified as detailed in Table 5: Therapy Classification, below: 
Table 5: Therapy Classification 
Historical 
Concomitant 
Post-treatment 
Ending at first intake of 
trial medication 
Between first trial medication 
and Day 2 morning 2 hours  
Starting later than Day 2 
morning 2 hours 
Starting after last intake of 
trial medication 
Therapies ending before the first administration is classified as historical therapies. Therapies can be both 
concomitant and post-treatment if taken within both periods as define in Table 5: Therapy Classification, above. 
In the therapy listings, analgesic therapies will be indicated by a *. 
Partial therapy dates will be imputed as detailed in APPENDIX 1: Partial Date Conventions. 
Indication/Specification (eCRF): 
• 
Medical History will be concatenated with the actual medical history verbatim term by merging the 
medical history number on the Prior and Concomitant Medication eCRF with the medical history number 
on the Medical History eCRF: 
o 
Medical history/Medical history verbatim term. 


 
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• 
Adverse event will be concatenated with the actual AE verbatim term by merging the AE number on the 
Adverse Events/Serious Adverse Event eCRF with the AE number on the Prior and Concomitant Medication 
eCRF. 
o 
Adverse event/Adverse event verbatim term. 
12. MEDICAL HISTORY 
Medical history findings will be summarised by treatment group and total based on the Treated set. 
Patients with multiple medical history findings will be counted only once per primary System Organ Class (SOC) 
and Preferred Term (PT). 
The table will be presented by primary SOC by total descending frequency and by PT by total descending 
frequency within SOC. Where different SOCs or PTs have the same total frequency, the SOCs or PTs will be sorted 
alphabetically. 
Medical history findings will be coded using the most recent MedDRA version. Uncoded terms will be displayed 
last within the category Uncoded and utilising the verbatim term entered on the Medical History eCRF as PT (for 
example Uncoded/Soft tummy). 
12.1. DERIVATIONS 
No imputation of partial or missing dates will be performed and partial dates will be presented as collected on 
the Medical History eCRF. 
Treatment/Specification (eCRF): 
• 
Treatment specification (verbatim term) will be mapped from the Prior and Concomitant Medication eCRF 
by merging the medical history sequence number on the Medical History eCRF  with the medical history 
sequence number from the Prior and Concomitant Medication eCRF (for example Augmentin). 
13. TRIAL MEDICATION EXPOSURE AND COMPLIANCE 
Trial medication exposure and trial medication compliance will be summarised overall and per study day by 
treatment group and total based on the Treated set. 
Exposure will be summarised descriptively in terms of the number of tables taken. Furthermore, duration of 
treatment exposure will be determined for each patient during the randomised treatment period. 
Compliance data will be summarised as % compliance both overall as well as at Day 2 morning. Additionally the 
frequency distribution of number of tables administered overall and per study day will be presented. 
Per protocol administration should be one tablet three times daily with intervals of 6 to 8 hours over 5 days (up 
to Day 6 morning). 


 
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The trial medication administration variables, as presented in the planned TLF shells, will be collected on the 
Patient Diary and Patient Diary-Last Day eCRFs. 
13.1. DERIVATIONS 
• 
Duration of treatment exposure (days): 
o 
Number of days on treatment = Treatment discontinuation date – treatment date +1. 
• 
Hours since previous tablet = (Current administration date/time - previous administration date/time). 
• 
Hours since first medication intake and Day 2 morning = (Day 2 morning first intake (date/time) – First 
medication intake (date/time)). 
• 
Day 2, morning compliance to trial medication (%) = 
(#$%&'( )* +,&-'+. ,/+$,--0 +,1'2)
(#$%&'( )* +,&-'+. 456/5 .5)$-7 5,8' &''2 +,1'2,9,0 ,%)(262:)     
x 100 
o 
Expected number of tablets to be taken by Day 2, morning: 
 
If first intake on Day 1 was on or before 12:00, then expected # = 4. 
 
If first intake on Day 1 was later than 12:00, then expected # = 3. 
• 
Overall compliance to trial medication (%) = 
(#$%&'( )* +,&-'+. ,/+$,--0 +,1'2)
(#$%&'( )* +,&-'+. 456/5 .5)$-7 5,8' &''2 +,1'2 )    x 100 
o 
Expected number of tablets = (Number of days on treatment x 3) - 2 
• 
Compliance (%) classified as: 
o 
< 80. 
o 
≥ 80 to ≤ 120. 
o 
> 120. 
14. EFFICACY ANALYSIS  
Efficacy analysis will be presented for patients in the full analysis set and repeated for the per protocol set for the 
primary efficacy endpoint and for the Treated set for the secondary endpoints. 
14.1. PRIMARY EFFICACY ENDPOINT 
14.1.1. 
PRIMARY ENDPOINT AND ANALYSIS OF THE PRIMARY EFFICACY VARIABLE 
The primary efficacy variable is change in pain on movement worst procedure (POMwp), between baseline (Day 
1 [pre-dose]) and Day 2 morning, 2 hours after trial medication intake (Day 2 [120 min]). The POMwp is assessed 
on a 0 to 10 numerical rating scale (NRS). 
The POMwp is defined as the pain on movement procedure with the highest pain score at baseline. 


 
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Descriptive statistics overall as well as by relevant subgroups (refer to section 7.5: Examination of Subgroups) 
and treatment group for the POMwp result as well as the change in POMwp (refer to section 0: Common 
Calculations for the relevant calculation of change). 
Relevant time points for the analysis of the primary endpoint include the following: 
• 
 =  ;< 1 (>? −ABC?) (included as a covariate in the statistical model) 
• 
  =  ;< 1 (120 FGH) 
• 
 =  ;< 2 (120 FGH)  
14.1.2. 
MISSING DATA 
Missing data points will not be imputed. The mixed model repeated measures (MMRM) is the primary analysis 
method compensating for missing data. 
14.1.3. 
MIXED MODEL REPEATED MEASURES (MMRM) 
The primary endpoint will be analysed utilising a restricted maximum likelihood (REML) based repeated 
measures approach, using the time points as noted in section14.1.1: Primary Endpoint and Analysis of the 
Primary Efficacy Variable. 
Differences between the treatment group effects (ibuprofen + caffeine vs. ibuprofen and ibuprofen + caffeine vs. 
placebo) with regard to the change in POMwp between Day 1 (pre-dose) and Day 2 (120 min) will be estimated 
by reference to the adjusted least square means (IJ −IJ, IJ −IJ) and the 
corresponding 95% confidence intervals (CI). All statistical testing will be performed using a two-sided, alpha = 
0.05 level of significance. 
The statistical model will include the fixed, categorical effects of treatment, country, wp-site (back/neck), time 
and treatment-by-time interaction, as well as the continuous, fixed covariates of baseline POMwp and baseline-
by-time interaction.  
An unstructured covariance structure will be used to model the within-patient errors. In case this analysis fails to 
converge, in a first step the ‘singular’ option in the model statement of PROC MIXED may be adjusted to singular 
=1E-10 (or 1E-9) instead of the default of approximately 1E-12. In case convergence still fails, other covariance 
structures will be employed following the order ANTE(1), ARH(1) and AR(1). 
The Kenward-Roger approximation will be used to estimate the denominator degrees of freedom. 
The following model will be fitted: 
proc mixed data=<data> method=reml cl covtest; 
class treatment country wp_site time patient; 
model cfb =  
treatment baselinePOMwp country wp_site time treatment*time baselinePOMwp*time / 
ddfm=KenwardRoger s; 
repeated time / type=UN subject=patient; 


 
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lsmeans treatment*time / diff cl; 
run; 
where 
cfb 
 
= Change in POMwp from baseline 
Treatment 
= Treatment group (Ibuprofen + caffeine/ibuprofen/placebo). 
Country  
= Germany/Russia. 
Wp_site  
= Worst procedure site (back/neck). 
Time 
 
= Time point (Day 1 (120min), Day 2 (120min)). 
 


 
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14.2. SECONDARY EFFICACY ENDPOINTS 
The secondary efficacy analyses will be performed for the Treated set. 
 
 
 
 
14.2.1. 
ANALYSIS OF KEY SECONDARY EFFICACY VARIABLES 
Descriptive statistics overall as well as by relevant subgroups (refer to section 7.5: Examination of Subgroups) 
and treatment group will be presented for the relevant key secondary efficacy endpoint. In addition, the key 
secondary endpoints will be analysed using an analysis of covariance (ANCOVA). 
14.2.1.1. 
Area Under the Curve (AUC) for POMwp between Baseline and the morning of Day 4 
(POMwpAUC72h) and between Baseline and the morning of Day 6 (POMwpAUC120h) 
Area under the curve (AUC) will be calculated as the area under the curve from zero to 72 and 120 hours, using 
the trapezoidal rule divided by the observation time. 
KLM = 1
NO
P 1
2 ((NQ) + (N)) × (N −NQ)
O
T
 


 
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KL = 1
NU
P 1
2 ((NQ) + (N)) ∗(N −NQ)
U
T
 
The dates and time of trial medication intake related to the POMwp assessments will be the basis for the 
calculation of respective time intervals: 
N = 0 is related to POM assessment 1 (Day 1 pre-dose), 
N = WX;YNZ;[ A;N?\]^ _]` ] ab ccccd\]  − ;YNZ;[ A;N?_c] \]^ (ec] )f × 24h
+ W;YNZ;[ NGF?\]^ _]` ] ab ccccd\]  − ;YNZ;[ NGF?_c] \]^ (ec] )h 
 N, N, NO, NU are related to POM assessments 2 (Day 1,120 min), 3 (Day 2, 120 min), 4 (Day4, 120min) and 5 (Day 
6, 120min), respectively. 
The ANCOVA model will include treatment, country, and wp-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 following SAS code will be used to fit the ANCOVA model: 
proc mixed data=<data> method=reml; 
class treatment country wp_site; 
model AUC = treatment country wp_site baselinePOMwp / solution; 
lsmeans treatment / pdiff cl; 
run; 
where 
AUC 
 
= POMwpAUC72h 
Treatment 
= Treatment group (Ibuprofen + caffeine/ibuprofen/placebo). 
Country  
= Germany/Russia. 
Wp_site  
= Worst procedure site (back/neck). 
BasePOMwp 
= Baseline POMwp. 
14.2.2. 
MISSING DATA 
For the calculation of POMwpAUC72h and POMwpAUC120h, the following imputation rules for missing POMwp 
assessments will be applied: 
• 
One or more missing assessments in between assessments will be imputed using the planned assessment 
time(s) 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(s) and LOCF will be used to impute the POMwp value. 


 
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Linear interpolation formula: 
< −< = < −<
i −i
(i −i1) 
Where the two known points are given by the coordinates (x1,y1) and (x2,y2), the linear interpolant is the 
straight line between these points. The planned assessment time are presented in in Table 6: Planned 
Assessment Times below. 
Table 6: Planned Assessment Times 
Assessment 
ti
1 (Baseline) 
t0 = 0
2 (Day 1, 120min) 
t1 = 2h
3 (Day 2, 120min) 
t2 = 26h 
4 (Day 4, 120min) 
t3 = 74h 
5 (Day 6, 120min) 
t4 = 122h 
14.2.3. 
ANALYSIS OF OTHER SECONDARY EFFICACY VARIABLES 
14.2.3.1. 
Change in Pressure Algometry (PA) between baseline and Day 2 morning, 2 hours after 
drug intake 
Analysis will be analogously to the primary endpoint using all available longitudinal PA observations. All available 
time points, baseline, Day 1 (120 min), Day 2 (120 min) will be used. 
The model will be applied to the analysis of change from baseline (Day 1 [pre-dose]) in PA at Day 1 (120 min) and 
Day 2 (120 min). 
The same PROC MIXED model will be applied as detailed for the primary analysis (refer to section 14.1.3: Mixed 
model repeated measures (MMRM)), POMwp will be replaced by PA. 
14.2.3.2. 
Global assessment of efficacy by the patient at the end of treatment (Day 6 morning) 
The number and percentage of patients within each category will be presented by treatment group. 
For the multinomial endpoint global assessment of efficacy by the patient at the end of treatment (Day 6 
morning) an ordinal logistic regression model adjusting for the categorical variables country and wp-site will be 
used. The likelihood-ratio test will be used to test for treatment differences. Adjusted odds ratios together with 
95% profile likelihood based confidence intervals and the associated p-values will be used to quantify the 
treatment effect, comparing ibuprofen + caffeine to ibuprofen and to placebo only. 
An ordinal logistic regression model will be fitted. The covariates of interest in terms of efficacy are treatment, 
country and wp-site (back/neck) and will be included in the model as such: 
proc genmod data=<data> order=descending; 
class treatment country wp_site; 


 
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model effic = treatment country wp_site /  
dist=multinomial aggregate=treatment link=cumlogit; 
lsmeans treatment / diff cl; 
run; 
where: 
Effic 
 
= Efficacy rating reported by the patient at the end of treatment (Day 6 morning) 
 (coded as 0 = poor, 1 = fair, 2 = good, 3 = very good). 
Treatment 
= Treatment group (Ibuprofen + caffeine/ibuprofen/placebo). 
Country  
= Germany/Russia. 
Wp_site  
= Worst procedure site (back/neck). 
14.2.3.3. 
Missing Data 
For the calculations of global assessment of efficacy by the patient at the end of treatment, the following 
imputation rules for missing efficacy assessments will be applied:  
• 
Missing entries for the assessment of efficacy will be assigned the least favourable category (0 = poor), if a 
patients has discontinued the study due to lack of efficacy as recorded on the Termination of Trial 
Medication eCRF. 
• 
Missing assessment resulting from early discontinuation that is clearly not related to treatment of the 
patient will not be imputed. 
14.2.3.4. 
Number of patients with a decrease in POMwp of at least 30% between Baseline and 
Day 2 morning, 2 hours after drug intake 
This endpoint will be analysed using a logistic regression model, adjusting for the categorical covariates country 
and wp-site (back/neck). The likelihood-ratio test will be used to test for differences between treatments. 
Adjusted odds ratios together with 95% Wald confidence intervals will be used to quantify the effect of 
treatment, comparing all treatments to the treatment of ibuprofen + caffeine as the reference treatment. In 
addition, residual plots and goodness of fit measures will be evaluated, but not displayed in output. 
A logistic regression model for the binary, dependent variable will be fitted. The covariates of interest are 
treatment (Ibuprofen + caffeine/ibuprofen/ placebo) and country (Germany/Russia) and wp-site (back/neck) and 
will be included in the model as such: 
proc genmod data=<data> order=descending; 
class treatment country wp_site; 
model POMwp_30 = treatment country wp_site / dist=bin; 
run; 
where: 


 
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POMwp_30 
= Yes (=1), if % reduction in POMwp from baseline ≥30%, no (=0) otherwise. 
Treatment 
= Treatment groups (Ibuprofen + caffeine/ibuprofen/placebo). 
Country  
= Germany/Russia. 
Wp_site  
= Worst procedure site (back/neck). 
14.2.3.5. 
Number of patients with a decrease in POMwp of at least 50% between Baseline and 
Day 2 morning, 2 hours after drug intake 
This endpoint will be analysed analogously to 14.2.3.4: Number of patients with a decrease in POMwp of at least 
30% between Baseline and Day 2 morning, 2 hours after drug intake. 
The POMwp_30 will be replaced by POMwp_50 = yes (=1), if % reduction in POMwp from baseline ≥50%, no (=0) 
otherwise. 
14.2.3.6. 
Time to first meaningful POMwp relief (≥2) within 2 hours after the first dose of trial 
medication 
For this endpoint a Kaplan-Meier analysis will be performed and stratified log-rank test adjusting for the 
categorical variables country and wp-site will be used to test the difference between treatment groups.  
Kaplan-Meier estimates for median time to first meaningful POMwp relief score of ≥2 with 95% CI for the 
median, 25th and 75th percentiles, adjusted for country and wp-site as covariates in the model will be displayed. 
Kaplan-Meier estimates for time to first meaningful POMwp relief score of ≥2 will be displayed graphically by 
treatment group using Kaplan-Meier (KM) curves.  
Patients who experienced a meaningful POMwp relief score of ≥2 will be counted as patients with events, while 
patients with no event will be censored at 2 hours after first use of trial medication. The survival distribution of 
time to first meaningful POMwp relief score of ≥2 will be compared between treatment groups by means of the 
log-rank test. The SAS® procedure PROC LIFETEST including covariates, country and wp-site, will be used as 
follows:  
proc lifetest data=<data> outsurv=grapdata plots=(s) gout=graphname; 
time time*censor(1); 
strata wp_site country / group=treatment; 
run; 
 
where 
Time 
 
= Time (hours) to first POMwp relief score of ≥2. 
Censor(1) 
= Indicates patients with no event of meaningful POMwp relief score of ≥2 (1=censored). 
Wp_site  
= Worst procedure site (back/neck). 
Country  
= Germany/Russia. 
Treatment 
= Treatment groups (Ibuprofen + caffeine/ibuprofen/placebo). 
 


 
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Time point of first meaningful POMwp relief score: 
• 
Chronologically sorting all dates and times of the POMwp relief score within a patient and selecting the 
earliest date/time of the POMwp relief score ≥2 available. 
Patients with an event: 
• 
The time point at which the first meaningful POMwp review is observed is used to identify the time 
interval in which the relief was noted. 
Patients with no event (censored): 
• 
The time point at which the first meaningful POMwp review is observed > 120 min. 
The following time intervals will be displayed: 
• 
0 - ≤10 min, 
• 
>10 - ≤20 min, 
• 
>20 - ≤30 min, 
• 
>30 - ≤60 min, 
• 
>60 - ≤120 min  
• 
> 120 min 


 
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15. SAFETY OUTCOMES 
The Treated set will be used all safety analyses. There will be no statistical comparisons between the treatment 
groups for safety data, unless otherwise specified within the relevant section. 
15.1. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
15.1.1. 
ALL ADVERSE EVENTS  
The number of patients with at least one AE in each category (patients with multiple AEs in each category will be 
counted only once in each category) will be presented. 
The percentage (%) of patients with at least one AE in each category will be calculated relative to the total 
number of patients in the Treated set by treatment group.  
The incidence tables will be presented by primary SOC by total descending frequency and by PT by total 
descending frequency within SOC. Where different SOCs or PTs have the same total frequency, the SOCs or PTs 
will be sorted alphabetically. 
All AEs and SAEs will be coded using the most recent MedDRA version. Uncoded terms will be displayed last 
within the category Uncoded and utilising the verbatim term entered on the eCRF as PT (for example 
Uncoded/Soft tummy). 
Intensity: 
• 
If a patient reports an AE more than once within that SOC/ PT, the AE with the worst case intensity will be 
used in the corresponding by worst intensity summaries. 
• 
Patients with multiple events in each category are counted only once in each category at worst intensity 
(increasing intensity: mild, moderate and severe). 


 
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Relationship to trial medication: 
• 
Causal relationship between the event and the trial medication: 
o 
Yes: Related. 
o 
No: Not related. 
Serious adverse events (Including Death): 
• 
Serious AEs are those events where was event serious is indicated as yes. The AEs leading to death are 
those events where outcome of event is recorded as fatal and/or criteria for SAE is recorded as results in 
death. 
Adverse events leading to discontinuation of trial medication: 
• 
Adverse events leading to discontinuation of the trial medication are those events where action taken is 
indicated as drug permanently discontinued. 
Adverse events of special interest: 
• 
Adverse events of special interest are those events where adverse event of special interest is indicated as 
yes on the eCRF. 
o 
Refer to the section 5.3.7.1 of the clinical trial protocol for the definition of AESIs (hepatic injury). 
15.1.2. 
OTHER SIGNIFICANT ADVERSE EVENTS (ACCORDING TO ICH E3) 
Other significant adverse events (according to ICH E3) include the following events: 
• 
Marked laboratory abnormalities (other than those meeting the definition of serious). 
o 
These will be identified through a medical review of all the reported adverse events. 
• 
Any event that led to an intervention, including withdrawal of trial medication, dose reduction, or 
significant additional concomitant therapy (other than those reported as serious adverse events). 
o 
The events leading to trial medication withdrawal or dose reduction will be identified as any event where 
the action taken is indicated as: 
 
Dose permanently reduced. 
 
Drug permanently discontinued. 
o 
The events leading to significant additional therapy will be identified through a medical review of all the 
reported adverse events. 
15.2. DERIVATIONS 
Adverse events are classified according to the event start date as note in Table 4: Study Periods. 
Refer APPENDIX 1: Partial Date Conventions for handling of partial dates for AEs. 
In the listing, adverse events of special interest will be indicated by means of *, other significant adverse events 
(according to ICH E3) will be indicated by means of a #. 


 
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17. REFERENCES 
BI1335.5 Clinical Trial Protocol, Version 2.0 Final, dated 05AUG2016. 
BI1335.5 Annotated Study Book, Version 3.0, 16DEC2016. 
 
 


 
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APPENDIX 1. PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings, these dates will only be used for the assignment of records 
to the relevant study periods. 
ALGORITHM FOR TREATMENT- EMERGENCE OF ADVERSE EVENTS: 
Adverse event dates (start and end) are required items in the eCRF, therefore cannot be missing or partial. 
If adverse event time is missing, then first dose date (without the time) will be used to classify the adverse event 
as treatment-emergent or not. 
IMPUTATION ALGORITHM FOR PARTIAL DATE FOR HISTORICAL AND CONCOMITANT THERAPIES: 
• 
Start date: 
o 
If the day of the start date is missing, then start date is set to first day of the month. 
o 
If the day and month of the start date are missing, then the start date is set to 1st January of the year. 
• 
End date: 
o 
If the day of the end date is missing, then the end date is set to last day of the month. 
o 
If the day and month of the end date are missing, then the end date is set to 31st December of the year. 
 


 
  
 
D o c u m e nt A p pr o v al Si g n at ur e( s)  
T hi s d o c u m e nt h a s b e e n si g n e d el e ctr o ni c all y i n c o m pli a n c e wit h  
 el e ctr o ni c  
s i g n at ur e p oli ci e s a n d pr o c e d ur e s. T hi s p a g e i s a m a nif e st ati o n of t h e el e ctr o ni c si g n at ur e s, 
w hi c h m a y b e c o nfir m e d wit hi n t h e  
 s o ur c e s y st e m i n a c c or d a n c e wit h  
 
r e c or d s r et e nti o n p oli ci e s. 
N ot e:  t h e Titl e fi el d i n t h e si g n at ur e bl o c k h a s  b e e n i nt e nti o n all y l eft bl a n k.  
 
 
 
U s er N a m e:
Titl e:  
D at e: W e d n e s d a y, 0 6 S e pt e m b er 2 0 1 7, 0 8: 1 2 A M   E a st er n Ti m e
M e a ni n g: I A p pr o v e t h e D o c u m e nt
 = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = =