Clinical trial NCT04908748
Conditions: Soft Tissue Injuries Contusions Strains Sprains Bruises
Keywords: Blunt Trauma
Sponsor: Teikoku Seiyaku Co., Ltd.
Start date: 2021-05-20; Completion date: 2021-12-15
Enrollment: 200 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Objective of this study is:

to determine efficacy and safety of a Esflurbiprofen Hydrogel Patch compared to placebo in patients with acute strains, sprains or bruises of the extremities following blunt trauma, e.g. sports injuries.

to demonstrate that the Esflurbiprofen Hydrogel Patch is superior to placebo, and that the patch has acceptable local tolerability.

Detailed description:
Study Design Randomized (1:1) (stratified by center and 2 subgroups), controlled, double-blind, multi-centric study in parallel groups. Patient Population/Sample size/Study Sites

The clinical trial population will consist of male or female patients, 18 - 60 years suffering from acute; strains, sprains or bruises of the extremities following blunt trauma, and meeting all clinical trial entry criteria.

200 patients will be enrolled (assumes a drop-out-rate of ≤10%).

The study will be performed in Germany in 3 sites

Arms: arm 1: Esflurbiprofen Hydrogel Patch containing 165 mg Esflurbiprofen arm 2: Placebo patch that does not contain the active ingredient but is otherwise indistinguishable from the investigational drug Esflurbiprofen Hydrogel Patch
Interventions: intervention 1: Esflurbiprofen Hydrogel Patch
Intervention descriptions: intervention 1: Esflurbiprofen is a cyclooxygenase (COX) inhibitor

Protocol documents:
Prot_000.pdf: 




 
 
Teikoku Seiyaku Co Ltd.                          Confidential 
Clinical Trial Protocol: TK-254R-0201  Final Version 3.0                                                                        Page 3 
 
Table of contents 
Table of contents .................................................................................................................3 
List of tables and figures .....................................................................................................5 
List of abbreviations ............................................................................................................6 
Glossary of terms.................................................................................................................8 
Protocol Synopsis ................................................................................................................9 
1     Background.................................................................................................................16 
2     Purpose and rationale .................................................................................................17 
3     Objectives ...................................................................................................................17 
3.1                Primary objective .........................................................................................17 
3.2                Secondary objective .....................................................................................18 
4     Study design ...............................................................................................................18 
5     Population...................................................................................................................19 
5.1                Inclusion criteria...........................................................................................19 
5.2                Exclusion criteria..........................................................................................19 
6     Treatment....................................................................................................................21 
6.1                Investigational drug and reference drugs .....................................................21 
6.2                Treatment arms.............................................................................................21 
6.3                Treatment assignment ..................................................................................22 
6.4                Treatment blinding .......................................................................................22 
6.5                Treating the patient.......................................................................................22 
6.5.1        Patient numbering ..........................................................................22 
6.5.2        Dispensing the study drug..............................................................23 
6.5.3        Study drug supply, storage and tracking ........................................23 
6.5.4        Instructions for prescribing and taking the study drug...................23 
6.5.5        Rescue medication .........................................................................24 
6.5.6        Other concomitant treatment..........................................................24 
6.5.7        Patient card.....................................................................................25 
6.5.8        Diary...............................................................................................25 
6.5.9        Study drug discontinuation and premature patient withdrawal......25 
6.5.10      Emergency unblinding of treatment assignment............................26 
6.5.11      Study completion and post-study treatment...................................26 
6.5.12      Early study termination ..................................................................27 
7     Visit schedule and assessments ..................................................................................27 
7.1                Information to be collected on screening failures ........................................30 
7.2                Patient demographics/other baseline characteristics/medical history ..........30 
7.3                Assessment of injury ....................................................................................31


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7.4                Treatment exposure and compliance ............................................................31 
7.5                Efficacy ........................................................................................................31 
7.5.1        Clinic visit efficacy assessments ....................................................31 
7.5.2        Appropriateness of efficacy measurements ...................................35 
7.6                Safety............................................................................................................35 
7.6.1        Physical examination .....................................................................35 
7.6.2        Vital signs.......................................................................................35 
7.6.3        Height and Weight .........................................................................35 
7.6.4        Pregnancy and assessments of fertility ..........................................35 
7.6.5        Appropriateness of safety measurements.......................................35 
8     Safety monitoring .......................................................................................................35 
8.1                Adverse events .............................................................................................35 
8.2                Serious adverse event reporting ...................................................................37 
8.3                Pregnancies...................................................................................................38 
9     Data review and database management......................................................................38 
9.1                Site monitoring.............................................................................................38 
9.2                Data collection..............................................................................................39 
9.3                Database management and quality control...................................................39 
9.4                Populations for analysis ...............................................................................40 
9.5                Demography/other baseline characteristics..................................................40 
9.6                Treatments (study drug, rescue medication, other concomitant therapies, 
compliance) ..................................................................................................41 
9.7                Efficacy ........................................................................................................41 
9.7.1        Outcomes........................................................................................41 
9.7.2        Statistical hypothesis, model, and method of analysis ...................42 
9.7.3        Handling of missing values/censoring/discontinuations................43 
9.8                Safety............................................................................................................45 
9.9                Sample size caulation ...................................................................................45 
9.10              Interim analysis ............................................................................................45 
10   Ethical considerations.................................................................................................46 
10.1              Regulatory and ethical compliance ..............................................................46 
10.2              Informed consent procedures .......................................................................46 
10.3              Insurance ......................................................................................................46 
10.4              Responsibilities of the Investigator and IRB/IEC/REB ...............................46 
10.5              Quality Assurance Audits and Health Authority Inspections ......................47 
10.6              Publication of study protocol and results .....................................................47


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11   Protocol adherence .....................................................................................................48 
11.1              Protocol Amendments ..................................................................................48 
12   End of Trial………………………………………………………………………….48 
13   References ..................................................................................................................49 
 
 
 
List of tables and figures 
Table 4–1: Study site visits........................................................................................................... 
Table 7–1: Assessment schedule .................................................................................................. 
Figure 7.5.1: Exercise to assess pain-on-movement of the upper limbs ......................................


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List of abbreviations AE                   
Adverse event ANCOVA       
Analysis-of-covariance AUC                
Area under the curve 
BOCF             Baseline-observation-carried-forward 
cGCP              Current Good Clinical Practice 
CMH               Cochran-Mantel-Haenszel 
 
CRF                Case Report/Record Form 
 
CRO                Contract Research Organization 
 
CSR                Clinical Study Report 
 
DSP                Drug Safety and Pharmacovigilance 
 
EU                  European Union 
 
FAS                 Full Analysis Set 
 
FDA                Food and Drug Administration 
 
GCP                Good Clinical Practice 
 
GEA                Global Efficacy Assessment 
 
GP                   General practitioner 
 
IB                    Investigator’s Brochure 
 
ICH                 International  Conference  on  Harmonization  of  Technical  Requirements  for 
Registration of Pharmaceuticals for Human Use 
 
ICF                  Informed consent form 
i.e.                   Id est, that is 
IEC                 Independent Ethics Committee 
 
IRB                 Institutional Review Board 
 
 
 
MedDRA        Medical Dictionary for Regulatory Activities 
 
NSAID            Non-steroidal anti-inflammatory drug 
 
 
 
PAR                Pain at Rest 
 
POM               Pain-on-movement 
 
QA                  Quality assurance 
 
REB                Research Ethics Board


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RICE               Rest - ice - compression - elevation 
 
SAE                Serious adverse event 
 
SAF                Safety set 
 
SAP                Statistical Analysis Plan 
 
SD                   Standard deviation 
 
S.E.                 Standard error 
 
SOP                Standard Operating Procedure 
 
VAS                Visual Analogue Scale WHO               
World Health Organization WOCBP          
Women of child-bearing potential


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Glossary of terms 
 
 
Assessment 
A measurement 
Control (or reference) drug 
A study drug used as a comparator to reduce assessment 
bias, preserve blinding of investigational drug,  assess 
internal study validity, and/or evaluate comparative effects 
of the investigational drug 
Early termination 
Termination prior to the planned completion of all study 
drug administration and assessments 
Enrollment 
Point/time of patient entry into the study; the point at which 
informed consent must be obtained (i.e. prior to starting 
any of the procedures described in the protocol) 
Investigational Medicinal 
Product (IMP) 
A pharmaceutical form of an active ingredient or placebo 
being tested or used as a reference 
Investigational drug 
The study drug whose properties are being tested in the 
study; this definition is consistent with US CFR 21 Section 
312.3  and is synonymous with “investigational new drug.” 
Medication number 
A unique identifier on the label of each medication package 
in studies that dispense medication using an IVR system 
Patient number 
A number assigned to each patient who is randomized into 
the study (or who is officially entered in some other fashion 
if there is no randomization). When combined with the 
center number, a unique identifier is created for each 
patient in the study. 
Stage 
A major subdivision of the study timeline; begins and ends 
with major study milestones such as enrollment, 
randomization, completion of treatment, etc. 
Period 
A minor subdivision of the study timeline; divides stages 
into smaller functional segments such as screening, 
baseline, titration, washout, etc. 
Termination 
Point/time at which the patient came in for a final evaluation 
visit or when study drug was discontinued whichever is 
later 
Study  drug discontinuation 
Point/time when patient permanently stops taking study 
drug for any reason; may or may not also be the point/time 
of early termination 
Outcome 
Information used in the data analysis 


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Protocol Synopsis 
 
Protocol Number        TK-254R-0201 
Date of Final 
Protocol                      08 March 2021 
 
Sponsor                       Teikoku Seiyaku Co Ltd., 567 Sanbonmatsu, Higashikagawa, Kagawa 
769-2695, Japan 
 
Study Title                  Randomized, controlled, double-blind, multi-center trial to evaluate the 
efficacy and safety of an Esflurbiprofen Hydrogel Patch vs. placebo in 
the local symptomatic and short-term treatment of pain in acute strains, 
sprains or bruises of the extremities following blunt trauma, e.g. sports 
injuries. 
 
Study Phase                II (proof-of-concept) 
 
 
Indication                    Local symptomatic and short-term treatment of pain in acute strains, 
sprains or bruises of the extremities following blunt trauma. 
Key Dates                   Estimated start (first patient in): 
Estimated end (last patient out): 
Principal & 
Coordinating 
Investigator 
 
 
 
 
Study Sites                 
 
 
 
 
 
 
Ethics Committee       Physician’s Chamber of North Rhine Westphalia 
Regulatory 
Oversight 
Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM).
Study Objectives        To determine efficacy and safety of a Esflurbiprofen  Hydrogel Patch 
compared to placebo in patients with acute strains, sprains or bruises of 
the extremities following blunt trauma, e.g. sports injuries.


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To demonstrate that the Esflurbiprofen Hydrogel Patch is superior to 
placebo, and that the patch has acceptable local tolerability. 
 
 
Study Design              Randomized (1:1) (stratified by center and 2 subgroups), controlled, 
double-blind, multi-centric study in parallel groups. 
Patient 
Population/Sample 
size/Study Sites 
The clinical trial population will consist of male or female patients, 18 – 
60 years suffering from acute; strains, sprains or bruises of the 
extremities following blunt trauma, and meeting all clinical trial entry 
criteria. 
 
In order to ensure at least 90 evaluable patients per group, up to 200 
patients will be enrolled (assumes a drop-out-rate of ≤10%). 
 
The study will be performed in Germany in 3 sites. Each site should 
enroll a minimum of 30 and a maximum of 90 patients.
Statistical 
Considerations 
Sample size 
 
The calculation of 90 per treatment group is based on the following 
assumptions and considerations: 
    Primary efficacy outcome is the change from baseline for POM at 
72 hours after initiating treatment. 
    Two-sided t-test situation with α = 5%. 
    Assuming SD = 20 mm, the sample size provides approximately 
80% power to detect a difference of 10 mm between two treatment 
groups if 64 patients per group are analysed. 
 
 However, the sample size will be stipulated to n=90 per group in 
order to power also the two subgroup comparisons. 
 
 Moreover, the sample size will be a total of 200 patients because 
a dropout-rate of approximately 10 % is taken into account 
 
Analysis 
Analysis-of-covariance for primary variable with baseline as covariate 
and treatment, center and subgroup as factors. An a priori ordered testing 
procedure controlling the multiple α-level of 5 % will be carried out: 
 
1)  Ho: µE=µP vs. H1: µE≠µP. 
 
In  case  of  a  significant  result  for  this  first  hypothesis  two  further 
hypotheses regarding the subgroups “sprains” and “contusions” will be


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then be also tested by means of the same baseline adjusted ANCOVA 
model to the 5 % level. 
 
2a) Ho: µE(str)=µP(str)  vs. H1: µE(spr/str)≠µP(spr/str) in the 
subgroup 
“sprains/strains”, 
2b) Ho: µE(con)=µP(con)  vs. H1: µE(con)≠µP(con) in the 
subgroup 
“contusions”. 
 
The primary analysis population is the Full Analysis Set (FAS). 
 
Other important secondary efficacy outcomes are pain-on-movement on 
VAS at 12, 24, 48, 96 and 168 hours after initiating treatment in the FAS 
population. These will be analyzed with an analysis-of-covariance 
(ANCOVA) model and center and subgroup as main effects which will 
be more detailed described in the Statistical Analysis Plan (SAP). All other 
continuous efficacy outcomes will be analyzed based on the same model 
(excluding the baseline covariate when there is no appropriate baseline). 
 
Differences between treatments on categorical outcomes will be tested with  
Cochran-Mantel-Haenszel  tests  of  treatment  mean  ridits  or  of general 
association, stratified by center. 
 
Inclusion Criteria       The following must apply: 
 acute sports-related soft-tissue injury/contusion (strains, sprains, 
bruises) of the upper or lower limb 
 location of injury such that pain-on-movement (POM) is elicited 
on passive manipulation of nearest joint by investigator 
    enrollment within 6 hours of the injury 
    baseline VAS score for POM of injured extremity > 50 mm on a 
100 mm VAS 
    size of injury, as assessed by investigator, ≥ 25 cm2 and ≤ 120 cm2 
    adult male or female patients 
    age 18 to 60 years 
    having given written informed consent 
 satisfactory health as determined  by the Investigator based on 
medical history and physical examination 
 
Exclusion Criteria      The following must  not apply: 
 significant concomitant injury in association with the index acute 
sports-related soft-tissue injury/contusion; e.g. fracture, nerve 
injury, ligament disruption, tear of muscle or cartilage, or open 
wound 
 excessively hairy skin at application site, cutting the hair in the 
injured site prior to patch application will qualify for inclusion


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    current skin disorder or shaving hair at application site 
 history    of    excessive    sweating/hyperhidrosis    inclusive    of 
application site 
 intake of NSAIDs or analgesics within 36 hours, opioids within 7 
days, or corticosteroids within 60 days of inclusion in the study 
 intake of long-acting NSAIDs or application of topical medication 
since the injury (RICE allowed) 
 participation in a clinical study within 30 days before inclusion in 
the study or concomitantly 
    drug or alcohol abuse in the opinion of the investigator 
    pregnant and lactating women 
 women  of  child-bearing  potential  without  medically  accepted 
contraception 
 known hypersensitivity to Esflurbiprofen or one of the excipients 
of the patch 
 patients with any ongoing condition that may interfere with the 
absorption,  distribution,  metabolism,  or  excretion  of 
Esflurbiprofen 
    history of previous significant injury to the same extremity within 
6 months 
 patients with a disease affecting the same limb, such as synovitis, 
rheumatoid arthritis, arthrosis, etc. 
 patients  having  an  ongoing  painful  condition  associated  with 
sports-related injury/contusion 
 patients  suffering  from  symptoms  of  an  infectious  disease 
including swelling of any joint of the affected upper or lower 
limbs 
 patients who had surgery of the affected upper or lower limb 
within one year of study entry 
 patients with significant diseases (defined as a disease which, in 
the opinion of the investigator, may either put the patient at risk 
because  of participation  in the study or a disease which may 
influence the results of the study or the patient’s ability to 
participate in the study; includes patients with a history of 
gastrointestinal bleeding, significant cardiovascular, liver or renal 
disease). 
    patients with a blood coagulation disorder 
    patients who use any impermissible medication (see below) 
 
 
Concomitant 
Treatment 
1.   Rescue medication 
In  case  of  unbearable   pain,  patients   are  allowed  to  take 
paracetamol tablets (2 x 500 mg). Patients needing more than 6


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tablets (3 g) per day or another drug from the list of impermissible 
medication will be withdrawn from the study as non-responders. 
Application of standard care by rest, ice, compression (non-
occlusive bandage), or elevation (RICE) can be considered at the 
discretion of the Investigator. 
Also allowed are: 
the use of crutches, 
elastic, temporary bandages, that could be easily removed to assess 
the primary variable. 
Physiotherapeutic measures (i.e. isomeric exercises to train the 
muscles) if they don’t interact with the injured area 
 
2.   Impermissible medication 
Use of systemic or topical NSAIDs, analgesics (other than 
paracetamol), opioids, corticosteroids  (except for topical 
treatment of bronchial asthma), heparin, or psychotropic agents, 
as well as the use of adhesive and fixing tapes and casts that would 
jeopardize the assessment of the primary variable (pain on 
movement). 
 
3.   Other treatments 
.  Ultrasound,  physical therapy and acupuncture will not be 
allowed 
 
Dosage                       Patients will be randomly assigned to one of the following treatment arms 
in a ratio of 1:1. 
 
A: Esflurbiprofen Hydrogel Patch applied once per day to the affected 
injury site 
 
B: Placebo patch applied once per day to the affected injury site 
 
The dose regimen is a single hydrogel patch (investigational drug) applied 
topically to the injured site once a day for 7 days. The hydrogel patch 
should be positioned directly over the injury site and marked with a water- 
resistant pen to ensure the patch is applied at the same site throughout the 
study. The placebo patch (placebo) is identical in composition to the 
Esflurbiprofen 165 mg Hydrogel Patch, without the active ingredient. 
Placebo is applied as described for the investigational drug. Both patients 
and investigators will be blinded to study treatment. If the hydrogel patch 
begins to peel-off (>10% of the total surface), the edges of the topical 
system may be pressed down. If problems with adhesion persist, patients 
may overlay the topical system with a mesh netting sleeve, where 
appropriate (e.g., to secure topical systems applied to ankles, knees, or 
elbows). The mesh netting sleeve must allow air to pass through and not 
be occlusive (non-breathable) 
 
 
 
 
 
 
 


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No. of Visits              A total of 7 visits 
 
Visit Schedule                      Visit 1 on Day 1 (enrollment) 
    Visit 2 on Day 1/2, depending on am/pm enrollment (12 hours) 
    Visit 3 on Day 2 (24 hours) 
    Visit 4 on Day 3 (48 hours) 
    Visit 5 on Day 4 (72 hours) 
    Visit 6 on Day 5 (96 hours) 
    Visit 7 on Day 8 (168 hours). 
Assessments               Efficacy will be assessed based on the following: 
Primary assessment: 
 Pain-on-movement (POM) measured by 100 mm VAS [performing 
standardized movements as described in Section 7.5.1] at baseline, 
12, 24, 48, 72, 96 and 168 hours 
 
Secondary assessments: 
    AUC over time between baseline and the first 12, 24, 48, 72, 96 and 
168 hours for POM measured by VAS 
 Pain at rest measured by VAS (at baseline, 12, 24, 48, 72, 96 and 168 
hours) 
 Time to meaningful/optimal reduction of pain defined as 30% 
(meaningful) and 50% (optimal) reduction of baseline VAS for 
POM. Both time points will be calculated 
    Responder rate 1 (defined as the number of patients achieving 50% 
reduction from baseline in the VAS score for POM at 72 hours) 
 Global efficacy assessments by physician (GEA, 5 point scale: 0=no 
response; 1=poor response; 2=fair response; 3=good response; 
4=excellent response) at 48, 72 and 168 hours 
 Global efficacy assessments by patient (GEA, 5 point scale: 0=no 
response; 1=poor response; 2=fair response; 3=good response; 
4=excellent response) at 48, 72 and 168 hours 
    Use of rescue medication at every visit except Visit 1 
 Responder rate 2 (defined as the number of patients able to resume 
training / normal physical activity by 168 hours) 
 
Other assessments include patch adhesion and patch safety as follows: 
 
Patch adhesion: 
 Adhesive power of the patch measured by a 5 point numerical scale 
(0=≥ 90% adhered / 1= ≥75% to <90% adhered / 2=≥50% to <75% 
adhered / 3=>0% to <50% adhered / 4=completely detached) at 
every visit except V1 
 
Safety assessments: 
    Physical examination at V1 and V7 
    Pregnancy test (female patients only) at V1 and V7 
 Local tolerability (skin damage/reaction seen at patch removal 
according to an 8-point scale) at every visit except V1 and V2


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    Vital signs (including blood pressure and pulse rate) at V1 and V7 
    Adverse events (AEs) at every visit 
 
 
Efficacy 
Variables 
Primary efficacy outcome: 
 
 Change from baseline in pain-on-movement (POM) at injured 
site in mm measured using a 100 mm Visual Analogue Scale 
(VAS) to Visit 5 (72 hours after commencement of study 
treatment) 
 
The analysis of the primary endpoint will be adjusted for baseline 
values. The baseline adjusted difference between active treatment and 
placebo at 72 hours should be > 10 mm. Magnitude of reduction in pain 
will be used to determine ‘responder rate’. 
 
Secondary efficacy variables: 
 
    POM at injured site in mm measured using a 100 mm VAS at 12, 
24, 48, 72, 96 and 168 hours after commencement of study 
treatment 
 AUC over time during first 24, 48, 72 and 96 hours for POM 
measured using a VAS; ordinate = POM score in mm, abscissa = 
time after treatment 
    Pain-at-rest (PAR) at injured site in mm measured using a 
100 mm VAS at 12, 24, 48, 72, 96 and 168 hours 
 Reduction in VAS for POM from baseline: o 
 
Time to meaningful reduction (30%) 
o Time to optimal reduction (50%) 
o    Time to complete resolution of pain 
    Responder rate 1 (defined as the proportion of patients achieving 
≥50% reduction from baseline in the VAS score for POM at 72 
hours) 
 Responder rate 2 (defined as the proportion of patients able to 
resume training / normal physical activity by 168 hours) 
 Clinical global assessment of efficacy as judged by investigator 
and patient at 48, 72 and 168 hours 
    Overall dose of rescue medication needed (paracetamol) 
 
Other: 
    Adhesive power of patch (5-point scale) 
 If there is significant use of rescue medication, a sensitivity 
analysis may be performed to assess impact on primary endpoint 
and responder rate.


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Variables of 
Tolerability and 
Safety 
Adverse events, vital signs, physical examinations including local 
examination for assessment of tolerability, sensitization & damage to 
skin associated with patch removal (8-point scale).
 
 
1            Background 
 
Blunt injuries consists of contusions, strains, sprains and combinations of thereof. Contusions 
are among the most common sports-related injuries [Best 1997, Nozaki 2008], second only to 
strains. Documented muscle contusions account for one third of all sports injuries.  Most blunt 
injuries are unreported and untreated.   They are caused by blunt trauma to skin, muscles, tendons 
and connective tissue structures resulting in tissue and cellular damage  [Best 1997]. 
 
A blunt injury is aggravated by blood that has escaped from damaged capillaries into the 
interstitial tissues. Within a few hours after the injury, the presence of necrotic tissue and 
hematoma initiates an inflammatory reaction [Farges 2002]. Because inflammation initiates 
macrophage action with subsequent phagocytosis of necrotic debris and stimulation of capillary 
production, it is vital to the process of tissue regeneration. However, inflammation invariably 
causes edema that leads to anoxia and further cell death. 
 
Fresh impact injuries usually resolve spontaneously, but may nevertheless cause considerable 
discomfort, marked functional limitation, absence from work and withdrawal from activities 
[Inklaar 1994]. The goal of therapy is to minimize hemorrhage and inflammation and control 
pain. NSAIDs are commonly used to reduce pain and inflammation  in order to facilitate 
rehabilitation and achieve earlier recovery [Dreiser 1993, Ekman 2002]. 
 
The efficacy and safety of topical NSAIDs in the treatment of acute, painful musculoskeletal 
conditions is widely recognized [Mason 2004, Rainsford 2008, Zacher 2008]. Over the past 20 
years, an increasing number of topical NSAID formulations (diclofenac, ibuprofen, 
indomethacin, ketoprofen, and naproxen) have been approved.  Topical NSAIDs, regardless of 
the status of the clinical condition (acute or chronic), must be applied at regular intervals in 
order to obtain maximum therapeutic benefit.  A topical NSAID formulation is therefore not 
intended to be applied as needed and so is distinct in its mode of use when compared to that of 
oral NSAIDs. 
 
Bioavailability studies suggest systemic absorption from topically applied NSAIDs is only 3- 
5% of the total systemic  absorption achieved  with oral administration  [Heyneman  2000]. 
Pharmacokinetic data have shown that diclofenac, when applied topically, penetrates the skin 
barrier to reach joints, muscles and synovial fluid, in sufficiently high concentration to exert local 
therapeutic activity [Zacher 2008]. Further advantages of topical delivery include circumventing 
the gastrointestinal tract and avoiding first-pass metabolism in the liver. 
 
Esflurbiprofen was approved by Pharmaceuticals and Medical Devices Agency of Japan 
(PMDA) on Sep 28, 2015. Esflurbiprofen is a cyclooxygenase (COX) inhibitor indicated for 
the treatment of osteoarthritis pain and inflammation.


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Esflurbiprofen is available on the Japanese market as a patch formulation, containing 40 mg of 
the active principle. 
 
 
2            Purpose and rationale 
 
Oral non-steroidal  anti-inflammatory  drugs (NSAIDs) are well known to reduce pain and 
inflammation  and improve physical function [Ogilvie-Harris  1995]. However, due to their 
systemic availability they can cause intolerable and potentially life-threatening side effects, 
such  as  gastrointestinal  symptoms  (upset  stomach,  ulceration,  hemorrhagic  ulceration), 
alteration of platelet function, impairment of renal function, and interaction with other agents. 
 
With an increasing number of people undertaking sports activities and with a parallel increase 
in the number of acute contusions, there is a need for an effective alternative treatment available 
with better tolerability. Topically applied Esflurbiprofen has been shown to have low systemic 
bioavailability. Based on those existing data the novel Esflurbiprofen 165 mg Hydrogel Patch 
which is the target treatment of this study is not expected to significantly exceed 10% of the 
systemic exposure  achieved following standard oral dosing with Flurbiprofen 100 mg tablets 
(3 times a day). Accordingly, it is appropriate to test the efficacy and safety of the Esflurbiprofen 
Hydrogel Patch in the treatment of blunt injuries. 
 
A parallel-group design is utilized as a within patient comparison based on repeated or 
simultaneous  contusions is clearly inappropriate.  Measurement  of pain and disability over 
approx. 72 hours should be sufficient to prove efficacy based on previous experience [Predel 
2004, Bonnekoh 1992, Hess 1996, Pabst 2001].  Dosing continues through resolution of the 
injury in order to adequately assess safety over the entire dosing interval. 
 
POM measured by VAS at 12, 24, 48 and 72 hours after initiating treatment (clinic visit) are 
important secondary endpoints to demonstrate an early and continued of treatment effect. 
 
The overall reduction of pain on movement after 72 hours is considered a good indicator to 
assess the postulated efficacy in the frame of this proof-of-concept study. 
 
Patients should be treated as soon as possible after the injury because early treatment may 
reduce  swelling,  thereby  increasing  the  likelihood  of  treatment  success.  Treatment  will 
therefore be initiated no more than 6 hours after the blunt injuries event. 
 
To minimize unnecessary risk to patients during study participation they will be screened at 
baseline to ensure absence of the various clinical disorders described in the exclusion criteria. 
This comprehensive process will include a baseline physical examination, vital signs, medical 
and drug history. 
 
To avoid bias, double blinding and randomization are important features of this study. 
 
 
3            Objectives 
 
3.1          Primary objective 
 
To evaluate the efficacy of a Esflurbiprofen  165 mg Hydrogel Patch  applied once a day 
compared with placebo in patients with acute blunt, soft tissue injuries of the limbs.


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 The primary efficacy outcome is pain-on-movement (POM) change from baseline 
assessed by Visual Analogue Scale (VAS) to Visit 5 (72 hours after initiating treatment). 
    Important secondary efficacy outcomes are POM on VAS at Visit 2, 3, 4, 6 and 7 (12, 24, 
48, 96 and 168 hours after initiating treatment). 
 
 
 
3.2          Secondary objective 
 
To assess the safety of Esflurbiprofen Hydrogel Patch compared with placebo applied once a 
day for up to seven days. 
 
 
4            Study design 
 
This is a Phase II randomized, double-blind, 2-arm (1:1) (stratified by center and subgroup), 
multi-center, placebo-controlled, parallel group study of the efficacy and safety of Esflurbiprofen 
Hydrogel Patch applied once a day for up to 8 days (maximum of 7 patches) to treat acute blunt, 
soft tissue injuries of the limbs. 
 
To qualify, patients must experience acute blunt, soft tissue injuries of the limbs. Patients should 
be randomized as soon as possible after the injury.  Anticipated time from injury until initial 
treatment should not exceed 6 hours. 
In order to ensure at least 90 evaluable patients per group, up to 200 patients (100 in each group) 
Approximately 200 patients suffering from acute blunt, soft tissue injuries of the limbs are to 
be randomized to be treated with Esflurbiprofen Hydrogel Patch or placebo (assumes a drop- 
out-rate of ≤10%). 
 
The study will be performed in Germany in 3 sites. Each site should enroll a minimum of 30 
and a maximum of 90 patients. 
 
The first five doses of study drug will be applied at the study site. The patients will be instructed 
on how to apply the patch once daily at home for the last two treatment days. 
 
After the randomization visit (V1), patients will return to the study center for post-baseline 
visits V2-V7 to complete efficacy and safety assessments.  In addition, patients will assess pain 
on movement and spontaneous pain intensity at rest at visits 2, 3, 4, 5, 6 and 7. 
 
The schedule of visits is described below. 
 
Table 4–1:  Study site visits 
 
 
Time after initiating 
treatment
Visit Day 
Randomization/Baseline visit V1
0 h 
Day 1 
1st interim visit V2 
12 h ( 1 h) after V1 
Day 1 
2nd interim visit V3 
24 h ( 2 h) after V1 
Day 2 
3rd interim visit V4 
48 h ( 4 h) after V1 
Day 3 


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4th interim visit V5 
72h ( 4 h) after V1 
Day 4 
5th interim visit V6 
96 h ( 4 h) after V1 
Day 5 
Final visit V7 
168 h ( 24 h) after V1 
Day 8  2day 
 
Rescue medication (paracetamol, 500 mg tablets, up to 3000 mg daily) is allowed during the 
study, except for the 6 hours prior to V5 (72h). 
 
 
5            Population 
 
The study population will consist of male or female patients aged 18-60 years with blunt, soft 
tissue injuries of the limbs. 
 
5.1          Inclusion criteria 
 
Patients eligible for inclusion in this study must fulfill all of the following criteria: 
The following must apply: 
1.   acute sports-related soft-tissue injury/contusion (strains, sprains, bruises) of the upper 
or lower limb 
2.   location of injury such that pain-on-movement (POM) is elicited on by the exercises 
described in Section 7.5 
3.   enrollment within 6 hours of the injury 
4.   baseline VAS score for POM of injured extremity > 50 mm on a 100 mm VAS 
5.   size of injury, as assessed by investigator, ≥ 25 cm2 and ≤ 120 cm2 
6.   adult male or female patients 
7.   age 18 to 60 years 
8.   having given written informed consent 
9.   satisfactory health as determined by the Investigator based on medical history and 
physical examination. 
 
5.2          Exclusion criteria 
 
Patients eligible for inclusion in this study must not fulfill any of the following criteria: 
 
1.   significant concomitant injury in association with the index acute sports-related soft- 
tissue injury/contusion; e.g. fracture, nerve injury, ligament disruption, tear of muscle 
or cartilage, or open wound 
 
2.   excessively hairy skin at application site, cutting the hair in the injured site prior to patch 
application will qualify for inclusion 
 
3.   current skin disorder or shaving hair at application site 
 
4.   history of excessive sweating/hyperhidrosis inclusive of application site 
 
5.   intake  of  NSAIDs  or  analgesics  within  36  hours,  opioids  within  7  days,  or 
corticosteroids within 60 days of inclusion in the study 
 
6.   intake of long-acting NSAIDs or application of topical medication since the injury 
(RICE allowed)


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7. participation in a clinical study within 30 days before inclusion in the study or 
concomitantly 
 
8.   drug or alcohol abuse in the opinion of the investigator 
 
9.   Pregnant and lactating women 
 
10. Women of child-bearing potential (defined as all women physiologically capable of 
becoming pregnant) who are not using an acceptable method of contraception defined 
as: 
    Surgical sterilization 
    Hormonal contraception 
    IUD 
    Double barrier method 
    Total abstinence throughout the study at the discretion of the Investigator. 
Periodic abstinence is NOT an acceptable method of contraception.  An acceptable method 
of contraception must be maintained throughout the study. 
A woman who is post-menopausal must have a negative urine pregnancy test at screening 
but will not need to comply with an acceptable method of contraception.  Women are 
considered post-menopausal and not of child bearing potential if they had 12 months of 
natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, 
history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH 
levels > 40 mIU/mL or have had surgical bilateral oophorectomy (with or without 
hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level assessment. 
 
11. known hypersensitivity to Esflurbiprofen or one of the excipients of the patch 
 
12. patients with any ongoing condition that may interfere with the absorption, distribution, 
metabolism, or excretion of Esflurbiprofen 
 
13. history of previous significant injury to the same extremity within 6 months 
 
14. patients with a disease affecting the same limb, such as synovitis, rheumatoid arthritis, 
arthrosis, etc. 
 
15. patients   having   an   ongoing   painful   condition   associated   with   sports-related 
injury/contusion 
 
16. patients suffering from symptoms of an infectious disease including swelling of any 
joint of the affected upper or lower limbs 
 
17. patients who had surgery of the affected upper or lower limb within one year of study 
entry 
 
18. patients with significant diseases (defined as a disease which, in the opinion of the 
investigator, may either put the patient at risk because of participation in the study or a 
disease which may influence the results of the study or the patient’s ability to participate


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in the study; includes patients with a history of gastrointestinal bleeding, significant 
cardiovascular, liver or renal disease). 
 
19. patients with a blood coagulation disorder 
 
20. patients who use any impermissible medication (section 6.5.6) 
 
 
 
 
6            Treatment 
 
6.1           Investigational drug and reference drugs 
 
CLINSEARCH will supply the study drugs and rescue medication (section 6.5.5). 
 
Study drugs will be packed and labelled by CSM, Clinical Supplies Management  Europe 
GmbH. 
 
Esflurbiprofen Hydrogel Patch and the placebo patches are packaged in 
 
. One sachet contains 1 plaster. 
 
The number of IMP units to be packaged will be specified prior to the start of the packaging 
operations, including units necessary for carrying out quality control and any retention samples 
to be kept. 
 
The clinical trial supplies  will be packed into  secondary  containers  (boxes). Supplies for 
replacements will be packed separately into further secondary containers. 
 
The IMPs will be labelled in accordance with the GMP Annex 13 and with the GCP regulation 
(“GCP-Verordnung”) § 5. 
 
Investigational drug: 
 
    Active ingredient: Esflurbiprofen Hydrogel Patch containing 165 mg Esflurbiprofen 
 
 Excipients:  
 
 
 
 
 
One unit dose of the drug is one patch applied to the painful area. 
 
Control drug: 
 
Placebo patch that does not contain the active ingredient but is otherwise indistinguishable from 
the investigational drug Esflurbiprofen Hydrogel Patch. 
 
Rescue medication: 
 
Paracetamol (500 mg tablets, up to 3000 mg daily) is allowed during the study, except for the 
6 hours prior to Visit 5 (72h). 
 
6.2           Treatment arms. 
 
Eligible patients will be randomized to one of two treatment arms in a ratio of 1:1


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    Esflurbiprofen Hydrogel Patch once a day 
 
    Placebo patch once a day 
 
6.3           Treatment assignment 
 
At Visit 1, all patients who fulfill all the inclusion/exclusion criteria will be given the lowest 
available number on the randomization list. This number assigns them to one of the treatment 
arms.  The Investigator or designee will enter the randomization number on the CRF. 
 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A 
randomization list – stratified by center and subgroup - will be produced by the independent 
statistician 
and a copy provided to CSM in order to package the 
clinical supplies accordingly.  Balanced stratification by indication subgroups (sprains/strains 
and contusions) will be achieved by assigning full randomization blocks to a respective group 
only. The packaging company (CSM) will verify the code assignments and block size against 
the randomization request and will distribute to investigator, as warranted. 
 
Randomization  data are kept strictly confidential by CRMB and the packaging  company, 
accessible only to authorized persons, until the time of unblinding. At the conclusion of the study, 
the occurrence of any emergency code breaks will be determined after return of all code break 
reports and unused drug supplies to the packaging company. Only when the study has been 
completed, the database locked, and the Statistical Analysis Plan finalized will the drug codes be 
broken and made available for data analysis. 
 
6.4           Treatment blinding 
 
The study will be double-blind. Patients, investigator staff, persons performing the assessments, 
monitors and data analysts will remain blinded to the identity of the treatment from the time of 
randomization until database lock, using the following methods: (1) Randomization data are 
kept strictly confidential, accessible only to authorized persons, until the time of unblinding. (2) 
the identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance and odor. 
 
Unblinding will only occur in the case of patient emergencies (see section 6.5.10) and at the 
conclusion of the study. 
 
6.5           Treating the patient 
 
6.5.1        Patient numbering 
 
Each patient is uniquely identified in the study by a randomization number, i.e. a combination 
of the center number and patient number. A center number is assigned by the packaging company 
to each investigative site. At Visit 1, each patient who qualifies for randomization will be given 
the lowest patient number available at the center. The Investigator or designee will enter the 
randomization  number on the CRF. Once assigned to a patient, a randomization number will 
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6.5.2        Dispensing the study drug 
 
Each of the investigator sites (study centers) will be supplied by the packaging company with 
study drug in packaging of identical appearance. 
 
The study medication packaging has a 2-part label. A unique randomization number is printed 
on each part of this label which corresponds to a treatment arm (active or placebo patch), 
according to the confidential randomization list. Immediately before dispensing study drug to the 
patient, investigator staff will detach the outer part of the label from the packaging, and affix it to 
the patient’s CRF. 
 
6.5.3        Study drug supply, storage and tracking 
 
Study drug must be received by a designated person at each study center, handled and stored 
safely and properly, and kept in a secured location to which only the Investigator and designated 
assistants have access. All study drugs should be stored according to the instructions specified 
on the drug label. The patches must be stored at room temperature (15-30C). Clinical supplies 
are to be dispensed only in accordance with the protocol. 
 
Medication labels will be in the local language (German) and comply with the legal requirements  
of the Germany.  They will  include  storage  conditions  for  the drug,  but no information 
about the patient except for the randomization number. 
 
The Investigator or designee must maintain an accurate record of the shipment and dispensing 
of study drug in a drug accountability ledger. Drug accountability will be monitored by the 
study monitor during monitoring visits and at the completion of the study. Patients will be asked 
to return all used and unused study drug and packaging at the end of the study or at the time of 
discontinuation. 
 
At the conclusion of the study, and as appropriate during the course of the study, the Investigator 
will return all used and unused study drug, packaging, drug labels, and a copy of the completed 
drug accountability ledger to the Clinsearch monitor or to the Clinsearch address provided in 
the investigator folder at each site. 
 
6.5.4        Instructions for prescribing and taking the study drug 
 
All patients will be treated with 1 patch of study drug at every visit during the first 6 visits (except 
for visit 2). The first five patches will be applied at the study center. The site of the first application 
will be marked with a water-resistant pen to ensure the same application site at every treatment. 
Additional 3 patches will be dispensed at Visit 6. The patients will be instructed to apply one 
patch every day at approx. the same time. Dosing times should be distributed as evenly as 
possible, preferably once every 24 hours after the last application. 
 
Patients can take a shower or bathe prior to the application. 
 
The Investigator or study staff will instruct the patients to apply the study drug exactly as 
prescribed and state that compliance is necessary for the patients’ safety and the validity of the 
study. The patients will be told to contact the Investigator or study staff if they are unable for 
any reason to apply the patch as prescribed. All dosages prescribed and dispensed to the patient


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and all dose changes during the study must be recorded on the Dosage Administration Record 
CRF page. 
 
If the hydrogel patch begins to peel-off (>10% of the total surface), the edges of the topical 
system may be pressed down. If problems with adhesion persist, patients may overlay the 
topical system with a mesh netting sleeve, where appropriate (e.g., to secure topical systems 
applied to ankles, knees, or elbows). The mesh netting sleeve must allow air to pass through 
and not be occlusive (non-breathable) 
 
6.5.5        Rescue medication 
 
The Investigator will provide rescue medication (paracetamol, 20 x 500 mg tablets) to the patients 
at the baseline visit (visit 1). 
 
Patients will be instructed to only take the rescue medication provided for pain in the injured 
area or  any  other  pain  (e.g.,  headache)  or  fever  (e.g.,  due to  common  cold)  they  might 
experience during the study. One or two tablets may be taken, repeated after at least 4 hours, if 
needed, up to a maximum of 3000 mg per day. No rescue medication is allowed within 6 hours 
immediately preceding Visit 5 (72h). 
 
The patient will receive a diary at Visit 1 to record the time and date that each dose of rescue 
medication is taken, the number of tablets taken and the reasons for the intake (for contusion- 
related pain or another reason). The patient will also assess spontaneous pain intensity 
immediately prior to each dose of rescue medication. At each visit, the Investigator or designee 
will review the diary. Empty packages and rescue medication not used will be shown to the 
Investigator or designee. The Investigator or designee will then compare the packages vs. the 
patient’s record of rescue medication use and any discrepancies will be noted in the CRF. Further 
instruction, how to use the diary are highlighted in Chapter 6.5.8 
 
The Investigator will further investigate any instances in which rescue medication was taken 
for reasons other than contusion and complete the Adverse Event Form, if appropriate. 
 
6.5.6        Other concomitant treatment 
 
Concomitant therapies prohibited during the study: 
 
The following treatments may NOT be used after the start of study drug: 
 
Use   of   systemic   or   topical   NSAIDs,   analgesics   (other   than   paracetamol),   opioids, 
corticosteroids (except for topical treatment of bronchial asthma), heparin, or psychotropic 
agents.  
 
Concomitant therapies allowed during the study: 
 
    Rescue medication (section 6.5.5) except for the 6 hours prior to visit 5 (72h). 
    Application of standard care by rest, ice, compression (non-occlusive bandage),    
       or elevation (RICE) can be considered at the discretion of the Investigator. 
 
The Investigator will instruct the patient to notify the study center about any new medications 
and significant non-drug therapies (i.e. RICE) he/she takes after the start of the study drug. All 
medications and significant non-drug therapies taken during the 30 days prior to Visit 1 (0h,


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Day 1) (including physical therapy and blood transfusions) or administered after the patient starts 
treatment with study drug must be listed on the Concomitant medications/Significant non- drug 
therapies CRF page. An AE CRF page should also be completed, if appropriate. 
 
6.5.7        Patient card 
 
To avoid the intake of non-permitted concomitant medication, it is important to inform other 
physicians who might treat the patient while participating in the study. Therefore, a card will 
be given to the patient at Visit 1 containing relevant information about his/her study participation,  
i.e., study  medication,  name and  address of the Investigator  with telephone numbers. 
 
6.5.8        Diary 
 
A diary will be handed out to the patient at Visit 1. 
 
The patient has to fill in the diary in handwriting and provide the following information: 
    Every time patch is applied the patient has to document the time and date of application. 
 Every time rescue medication is taken (not allowed within 6 hours before Visit 5 (72h)), 
the patient has to document: 
 
     The time and date of rescue. 
 
     The number of tablets taken. 
 
     The reason for rescue (blunt trauma pain/other). 
 
 If the pain is related to the blunt trauma, the spontaneous pain intensity prior to the intake 
on a VAS scale 
 
The Investigator or designee will ensure that all diary entries completed by the patient are legible. 
 
The Investigator or designee will review the diary at every visit and collect it at Visit 7 (Day 
8±2). 
 
6.5.9        Study drug discontinuation and premature patient withdrawal 
 
The study drug must be discontinued and the patient withdrawn from the study if the Investigator 
determines that continuing it would result in a significant safety risk for that patient. The following 
circumstances require study drug discontinuation: 
    Withdrawal of informed consent 
    Pregnancy 
    Emergence of any clinically relevant serious adverse events 
    Any other protocol deviation that results in a significant risk to the patient’s safety 
 
In addition to these requirements for study drug discontinuation, the Investigator should 
discontinue study drug for a given patient if, on balance, he/she thinks that continuation would 
be detrimental to the patient’s well-being.


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Patients may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, or fail to return for visits, or 
become lost to follow up for any other reason.  If premature withdrawal occurs for any reason, 
the Investigator must determine the primary reason for a patient’s premature withdrawal from 
the study and this information must be recorded on the Study Completion CRF. 
 
Patients who are prematurely withdrawn from the study will not be replaced. 
 
If a patient is discontinued or decides to withdraw from the study, all evaluations scheduled for 
the final visit will be performed within one week of study drug discontinuation. Every effort must 
be made to collect all the required data at the time of patient discontinuation.  The 
Investigator or designee must complete the Study Drug Discontinuation, giving the date and 
primary reason for stopping the study drug. 
 
For patients who are lost to follow-up (i.e. those patients whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the Investigator or 
designee should show "due diligence" by documenting in the source documents the steps taken 
to contact the patient, e.g. dates of telephone calls, registered letters, etc., in order to establish 
the reason for discontinuation and to check presence of any AEs. 
 
6.5.10      Emergency unblinding of treatment assignment 
 
An  individual  decoding  unit  containing  emergency  identification  of  the  package  will  be 
provided with each treatment unit.  These decoding units are not to be opened unless an actual 
medical emergency occurs. If the Investigator feels breaking the code is required, a Clinsearch 
representative should be consulted first, unless the delay would endanger the patient’s health. 
The date, time the code was broken and reason for breaking the blind must be recorded. In the 
event that a decoding unit is opened, the Project Manager at Clinsearch and the monitor must 
be informed within 24 hours. The unblinded treatment code should not be recorded on the CRF. 
 
It is the Investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the code break cards in case of emergency. The Investigator or designee will inform the patient 
who to contact in case of emergency when the investigator is unavailable. The protocol number, 
study drug name if available, patient number, and instructions for contacting the local Clinsearch 
affiliate (or any entity to which it has delegated responsibility for emergency code breaks) will 
be provided to the patient in case emergency unblinding is required at a time when the 
Investigator and backup are unavailable. 
 
Study drug must be discontinued after emergency unblinding. Study drug also must be 
discontinued for any patient whose treatment code has been broken inadvertently or for any 
non-emergency reason. 
 
6.5.11      Study completion and post-study treatment 
 
No continuation supplies will be made available for the patients as no further treatment is 
expected to be necessary at the end of the study. However, if necessary, the Investigator will 
continue to treat the patient until the injury is resolved. Alternatively, the Investigator will inform 
the patient’s general practitioner (GP) at the end of the study period and the patient will then be 
advised to visit his GP directly.


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6.5.12      Early study termination 
 
The study can be terminated at any time for any reason by the Sponsor, an IRB or a Health 
Authority. Such reasons may include, but are not limited to:  
 
- 
change in the risk/benefit assessment due to unexpected findings related to the potential risk 
of the treatment, 
- 
Detection of SUSARs that differ in severity, duration or frequency from the known safety 
profile 
-     Becoming aware of new evidence through publications or other clinical trials that would    
      negatively impact the risk/benefit assessment 
 
Should this be necessary, all patients should be seen as soon as possible and treated as described 
in section 7 for a prematurely withdrawn patient. The Investigator may be informed of additional 
procedures to be followed in order to assure that adequate consideration is given to the protection 
of the patient’s best interest. 
 
The Investigator will be responsible for informing the IRB/REB/IEC of the early termination 
of the study. In the EU CRMB (EU legal representative) and Clinsearch will be responsible for 
notifying IECs, local authorities and the German Competent Authority, of the early termination 
of the study. 
 
 
7            Visit schedule and assessments 
 
Visit 1 (0 hour, Day 1) - Randomization visit 
 
    Written informed consent (section 10.2). 
 
    Check inclusion/exclusion criteria (section 5.1). 
 
    Demographic data (section 7.2). 
 
    Brief, general physical examination is performed including vital signs, weight and height. 
Urine dipstick pregnancy test (WOCBP and postmenopausal women who are not surgically 
sterile only) (section 7.6). 
 
    Medical history (previous and concomitant diseases) (section 7.2). 
 
    Concomitant medication (section 6.5.6). 
 
    Assessment of injury (size of traumatization and localization). 
 
    Spontaneous pain intensity, pain at rest (PAR) (section 7.5.1) 
 
    Injury site pain-on-movement (POM) (section 7.5.1). 
 
    Eligible patients receive a randomization number (section 6.5.1). 
 
 The Investigator or a study nurse/doctor’s assistant applies the first dose of study drug at 
the study center. Record information on AEs that occur after treatment (section 8.1). 
 
    Dispense rescue medication and instruct the patient about appropriate use (section 6.5.5). 
 
Visits 2 (12h  ± 1h),  3 (24h  ± 2h),  4 (48h  ± 4h) 
 
These visits will entail the following procedures, except as noted: 
 
    Apply next dose of study medication. 
 
    Count used/unused patches & collect used patches 


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    Documentation of use of rescue medication, if needed (diary check). 
 
    Record changes in the use of concomitant medication (section 6.5.6). 
 
    Record information on AEs (section 8.1). 
 
    Spontaneous pain intensity, pain at rest (PAR) (section 7.5.1) 
 
    Injury site pain-on-movement (POM) (section 7.5.1). 
 
    Visit 4: Global efficacy assessments (GEA) by patient and investigator (section 7.5.1). 
 
    Adhesive power of patch (section 7.5.1). 
 
    Local tolerability assessment (except V2). 
 
Visit 5 (72h±  4 h) 
 
    Apply next dose of study medication. 
 
    Count used/unused patches & collect used patches. 
 
    Check for last intake of rescue medication no later than 6 hours prior to Visit. 
 
    Documentation of use of rescue medication 
 
    Record changes in the use of concomitant medication (section 6.5.6). 
 
    Record information on AEs (section 8.1). 
 
    Spontaneous pain intensity, pain at rest (PAR) (section 7.5.1) 
 
    Injury site pain-on-movement (POM) (section 7.5.1). 
 
    Global efficacy assessments (GEA) by patient and investigator (section 7.5.1). 
 
    Responder rate 1 (number of patients achieving 50% reduction from baseline in the VAS 
 
score for POM) 
 
    Adhesive power of patch (section 7.5.1). 
 
    Local tolerability assessment. 
 
 
Visit 6 (96h+4h) 
 
    Apply next dose of study medication. 
 
    Count used/unused patches and collect used patches. 
 
    Use of rescue medication. 
 
    Record changes in the use of concomitant medication (section 6.5.6). 
 
    Record information on AEs (section 8.1). 
 
    Spontaneous pain intensity, pain at rest (PAR) (section 7.5.1). 
 
    Injury site pain-on-movement (POM) (section 7.5.1).


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    Adhesive power of patch (section 7.5.1). 
 
    Local tolerability assessment. 
 
 Dispense patient card (section 6.5.7) and diary (section 6.5.8) and instruct patient about 
appropriate use. 
 
    Dispense three patches to the patient. 
 
    The patient is instructed on the method and time of application of study drug (section 
6.5.4). 
 
Visit 7 (Day 8 ± 2 days) - Final visit 
 
Procedures for this visit are also to be completed if the patient terminates the study prematurely. 
 
    Count used/unused patches and collect used patches. 
 
    Record changes in the use of concomitant medication (section 6.5.6). 
 
    Record information on AEs (section 8.1). 
 
    Spontaneous pain intensity, pain at rest (PAR) (section 7.5.1) 
 
    Injury site pain-on-movement (POM) (section 7.5.1). 
 
    Global efficacy assessments (GEA) by patient and investigator (section 7.5.1). 
 
    Responder rate 2 (number of patients able to resume training/ normal physical activity) 
 
    Adhesive power of patch (section 7.5.1) 
 
    Local tolerability assessment. 
 
    Collect remaining unused study drug and rescue medication. 
 
    Collect diary. 
 
    Review diary 
o    Review the time and date of each patch application. 
o Review rescue medication use.  Count and document remaining rescue 
medication; (section 6.5.5). 
 
    Perform a brief, general physical examination including vital signs and weight (section 
7.6.1, 7.6.2). Urine dipstick pregnancy test (WOCBP and postmenopausal women who 
are not surgically sterile only) (section 7.6.4). 
 
    Record changes in the use of concomitant medication (section 6.5.6). 
 
    Record information on AEs (section 8.1). 
 
 Investigator  evaluates  whether the soft tissue injury/contusion  has resolved and, if 
resolved, records the day and time it resolved.




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    History of allergy. 
 
7.3         Assessment of injury 
 
The size of injury is measured by the Investigator. The size must be at least 25 cm2 and at most 
120 cm2  on the basis of the largest perpendicular diameters. The localization should also be 
documented in detail in the patient CRF. 
 
7.4         Treatment exposure and compliance 
 
The patient will record in the diary the date and time of every application of study drug. 
 
The patient will return the study drug (used or unused) at the last visit. The number of patches 
used and unused will be recorded in the accountability form in the CRF. 
 
The Investigator or designee will store the study drugs until the monitor arranges for their return. 
The Investigator must not destroy any drug.  The monitor will check the number of patches at 
every monitoring visit to verify the drug accountability details entered in the CRF. 
 
7.5         Efficacy 
 
7.5.1        Clinic visit efficacy assessments 
 
The following chronological sequence will be observed for the efficacy assessments below: 
1.   Pain at rest/spontaneous pain (PAR) 
2.   Pain-on-movement (POM) 
 
 
The global assessments may be completed at any time during the assessment process. 
 
Pain-at-rest (PAR) 
 
PAR will be measured at injured site in mm using a 100 mm VAS at Visits 1-7 
 
The patient will then answer the question: 
 
“How would you describe the pain in the injured area at rest?” 
 
The patient will draw a perpendicular line on a 100 mm Visual Analogue Scale (VAS) with a pen 
between 0 = “no pain” and 100 = “Extreme pain” to reflect the pain intensity at rest. 
 
 
|----------------------------------------------------------------------| 
 
No pain                                                                                             Extreme Pain 
 
 
Pain-on-movement (POM) 
 
POM will be assessed at the study center at Visits 1–7 using a 100 mm VAS. The result will be 
written in the CRF.


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To standardize the procedure for the assessment of pain-on-movement a special movement 
should be performed by the patient, either for the upper limb or the lower limb depending on 
which limb is injured. 
 
 To assess pain-on-movement of the upper limb, the patient will be instructed to grab 
a 3 kg bar with the hand of the injured arm, slowly lift the bar by bowing the elbow 
from the 0 position to a 160 degree position and then slowly move the arm back to 
the starting position. 
 
 
 
Figure 7.5.1: Exercise to assess pain-on-movement of the upper limbs 
 
The patient will then answer the question: 
 
“How would you describe the pain in the injured area while you were moving your arm?” 
 
 To assess the pain-on-movement of the lower limb, the patient will be instructed to 
slowly walk 5 steps on an even surface. The patient must initiate the walk with the 
injured limb (i.e. take 3 of the 5 steps with the injured limb). 
 
The patient will then answer the question: 
 
“How would you describe the pain in the injured area while you were walking?”


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The patient will draw a perpendicular line on a 100 mm Visual Analogue Scale (VAS) with a 
pen between 0 = “no pain” and 100 = “Extreme pain” to reflect the pain intensity during 
movement. 
 
 
 
 
 
 
|----------------------------------------------------------------------| 
 
No pain                                                                                    Extreme Pain 
 
 
 
 
Global efficacy assessments 
 
The global efficacy assessments are evaluated by the patient at Visits 4, 5 and 7 as the response 
to following questions: 
 
 “Considering all the ways this treatment has affected you since you started in the study, how 
well are you doing?” It is assessed on the following 5-point Likert scale: 
 
0 = very good 
 
1 = good 
 
2 = fair 
 
3 = poor 
 
4 = very poor. 
 
 “How do you rate this medication as a treatment for your soft tissue injury/contusion?”  It 
is assessed on the following 5-point Likert scale: 
 
0=excellent 
 
1=very good 
 
2=good 
 
3=fair 
 
4=poor 
 
The global efficacy assessments are evaluated by the Investigator at Visits 4, 5 and 7 as the 
response to following questions: 
 
•          “Considering all the ways this treatment has affected the patient since he/she started in 
the study, how well is he/she doing?” It is assessed on the following 5-point Likert scale: 
 
0 = very good 
 
1 = good 
 
2 = fair


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3 = poor 
 
4 = very poor. 
 
 
 
 
 
 
Adhesive power of the patch 
 
The adhesive power of the patch will be measured by a 5 point numerical scale (0=≥ 90% adhered / 1= 
≥75% to <90% adhered / 2=≥50% to <75% adhered / 3=>0% to <50% adhered / 4=completely detached) 
at every visit except V1. 
 
 
Assessment of local tolerability of the patch 
 
Local tolerability will be assessed by the Investigator according to the following numerical scale: 
 
 
Score 
Definition 
0 
No evidence of irritation 
1 
Minimal erythema, barely perceptible 
2 
Definite   erythema,   readily   visible,   minimal 
edema or minimal papular response 
3 
Erythema and papules 
4 
Definite edema 
5 
Erythema, edema and papules 
6 
Vesicular eruption 
7 
Strong reaction spreading beyond test site 
 
 
Use of rescue medication 
 
Each use of rescue medication will be recorded in the CRF or in the diary. The Investigator/ the 
patient will record the date and time, the number of tablets taken and the reason for rescue (blunt 
trauma pain or other). 
 
 
 
Resolution of soft tissue injury/contusion 
 
Resolution of soft tissue injury/contusion is assessed by the Investigator at the final study visit. 
Time to resolution is the time of last application of study medication because the soft tissue 
injury/contusion has resolved. This is based on the record of applications of study medication 
and the assessments of efficacy.


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7.5.2           Appropriateness of efficacy measurements 
 
The efficacy outcomes selected are standard for this indication. 
 
7.6         Safety 
 
7.6.1        Physical examination 
 
A brief, general physical examination will be performed at Visit 1 (randomization visit) and at 
Visit 7 (study termination - final visit), as well as when judged necessary by the Investigator. 
Examination will include: general condition, dermatologic, eyes, ears, nose, throat, neck, thyroid, 
heart, respiratory system, abdomen, kidneys, skeletal system, extremities, lymphatic system, 
CNS, neurological conditions according to the state of the art. 
 
7.6.2        Vital signs 
 
Vital signs (including systolic blood pressure, diastolic blood pressure and pulse rate) will be 
measured at Visit 1 and at final visit: 
-       Blood pressure: Measurement after at least 5 minutes at rest in sitting position. 
-       Pulse rate: Measured after at least 5 minutes at rest in sitting position. 
 
7.6.3        Height and Weight 
 
Height in centimeters (cm) and body weight (kg, in indoor clothing, but without shoes) will be 
measured at Visit 1. Body weight only will be measured at Visit 7. 
 
7.6.4        Pregnancy and assessments of fertility 
 
All women of child-bearing potential (WOCBP) and postmenopausal  women who are not 
surgically sterile will have a urine pregnancy test with a dipstick at Visit 1 (randomization visit). 
Patients with a positive urine pregnancy test result must not be randomized. A urine dipstick 
pregnancy test will also be performed at Visit 7 (final visit). 
 
7.6.5        Appropriateness of safety measurements 
 
The safety assessments selected are standard for this indication/patient population. 
 
 
8            Safety monitoring 
 
8.1         Adverse events 
 
An adverse event (AE) is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after starting the study drug even if the event is not considered to 
be related to study drug. Study drug includes the investigational drug under evaluation and the 
comparator drug or placebo that is given during any phase of the study. Medical 
conditions/diseases present before starting study drug are only considered adverse events if they 
worsen after starting study drug 
 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered


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by the patient during or between visits or through physical examination, , or other assessments. 
All  adverse  events  must  be  recorded  on  the  Adverse  Events  CRF  with  the  following 
information: 
 
1.   the severity grade (mild, moderate, severe) 
 
2.   its relationship to the study drug(s) (suspected/not suspected) 
 
3.   its duration (start and end dates or if continuing at final exam) 
 
4.   whether it constitutes a serious adverse event (SAE) 
An SAE is defined as an event which: 
    is fatal or life-threatening 
 
    results in persistent or significant disability/incapacity 
 
    constitutes a congenital anomaly/birth defect 
 
 requires  inpatient  hospitalization  or  prolongation  of  existing  hospitalization,  unless 
hospitalization is for: 
 
o elective or pre-planned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since the start of study drug 
o treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
o social reasons or respite care in the absence of any deterioration in the patient’s 
general condition 
 is medically significant, i.e., defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
 
Unlike routine safety assessments,  SAEs are monitored continuously and have special 
reporting requirements. 
All AEs and SAEs will be recorded, including their severity, their duration and relationship to 
study drug. 
 
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: 
 
    no action taken (i.e., further observation only); 
 
    study drug dosage temporarily interrupted; 
 
    study drug permanently discontinued due to this adverse event; 
 
    concomitant medication given; 
 
    non-drug therapy given; 
 
    patient hospitalized/patient’s hospitalization prolonged.


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The action taken to treat the adverse event should be recorded on the Adverse Event CRF page. 
 
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study drug, the interventions required 
to treat it, and the outcome. 
 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed. 
 
8.2         Serious adverse event reporting 
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until 30 days after the patient has stopped study 
participation (defined as time of last dose of study drug taken or last visit whichever is later) must 
be reported to CRMB (EU Legal Representative) and Clinsearch immediately without undue 
delay, but latest within 24 hours of learning of its occurrence. 
 
The CRMB (EU Legal Representative) Drug Safety & Pharmacovigilance fax number is: 
 
 
 
The CRMB (EU Legal Representative) Drug Safety & Pharmacovigilance email is: 
 
 
 
Any SAE experienced after this 30 day period should only be reported to CRMB and Clinsearch 
if the Investigator suspects a causal relationship to the study drug. 
 
Recurrent episodes, complications, or progression of the initial SAE must be reported as follow- 
up to the original episode, regardless of when the event occurs. This report must be submitted 
within  24 hours  of the Investigator  receiving  the follow-up  information.  An SAE that is 
considered completely unrelated to a previously reported one should be reported separately as 
a new event. 
 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report Form. 
The Investigator must assess the relationship to study drug, complete the SAE Report Form in 
English, and send the completed, signed form by fax within 24 hours to CRMB and Clinsearch 
DSP. The original copy of the SAE Report Form and the fax confirmation sheet must be kept 
with the case report form documentation at the study center. 
 
Follow-up information will be sent to the same person to whom the original SAE Report Form 
will be sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. The follow-up information should 
describe whether the event has resolved or continues, if and how it was treated, whether the blind  
was  broken  or  not,  and  whether  the  patient  continued  or  withdrew  from  study participation. 
 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study drug, a DSP associate may urgently require


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further information from the Investigator for Health Authority reporting. Clinsearch may need 
to issue an Investigator Notification (IN) to inform all investigators involved in any study with 
the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be reported to the competent authorities and relevant ethics committees in 
accordance with the applicable regulatory requirements. 
 
8.3         Pregnancies 
 
To ensure patient safety, each pregnancy in a patient on study drug must be reported to CRMB 
and Clinsearch within 24 hours of learning of its occurrence. The pregnancy should be followed 
up to determine outcome, including spontaneous or voluntary termination, details of the birth, 
and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. 
 
Pregnancy  should  be recorded  on a Clinical  Study  Pregnancy  Form  and  reported  by the 
Investigator to the Clinsearch Safety department (as above in section 8.2) Pregnancy follow-up 
should  be recorded  on  the same  form  and  should  include  an assessment  of the possible 
relationship  to  the  study  drug  of any  pregnancy  outcome.  Any  SAE  experienced  during 
pregnancy must be reported on the SAE Report Form. 
 
 
9            Data review and database management 
 
9.1         Site monitoring 
 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Clinsearch 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, the study monitors will visit the site regularly to check the completeness of patient 
records, the accuracy of entries on the CRFs, the adherence to the protocol and to Good Clinical 
Practice, the progress of enrollment, and to ensure that study drug is being stored, dispensed, and 
accounted for according to specifications, according to the ICH-GCP-Guidelines and the related 
SOPs. Site personnel must be available to assist the study monitors during these visits. Source 
data verification is done by direct inspection of the patient’s original files by authorized persons. 
 
The Investigator must maintain source documents for each patient in the study, consisting of case 
and visit notes (hospital or clinic medical records) containing demographic and medical 
information, and the results of any other tests or assessments. All information on CRFs must be 
traceable to these source documents in the patient's file. Data not requiring a separate written 
record will be defined before study start (i.e. efficacy assessments described in section 7.5.1) 
and will be recorded directly on the CRFs. The Investigator must also keep the original informed 
consent form signed by the patient (a signed copy is given to the patient). 
 
Study documents, including the Essential Documents collected in the Investigator File, must be 
kept at the site until at least two (2) years after the last approval of a marketing application in 
an ICH region or after the formal discontinuation of the clinical development of the 
investigational product or for at least 15 years after the study end, whichever is the longest.  It 
is the responsibility of Clinsearch to inform the Investigator as to when these documents no 
longer need to be retained.


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The Investigator must give the study monitors access to all relevant source documents to confirm 
their consistency with the CRF entries. Clinsearch monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and the recording of data that will be used for all primary and safety 
outcomes. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. No information in source documents about the 
identity of the patients will be disclosed in the monitoring reports. 
 
9.2         Data collection 
 
Designated investigator staff must enter the information required by the protocol onto the CRFs 
that are printed on 3-part, non-carbon-required paper. Study monitors will review the CRFs for 
completeness and accuracy and instruct site personnel to make any required corrections or 
additions. The CRFs are then forwarded to the Data Management CRO (CRMB) working on 
behalf of Clinsearch by study monitors or by the investigational site, with one readable copy 
being retained at the investigational site. Once the CRFs are received at Data Management, their 
receipt is recorded, the original copy is placed in Central Files, and the non-carbon-required copy 
is forwarded to the responsible Data Management staff for processing. 
 
9.3         Database management and quality control 
 
The  study  database  is  constructed,  validated  and  maintained  by  the  designated  Data 
Management CRO. Data items from the CRFs are entered, using double entry, into the study 
database by the CRO Data Management staff following their own internal standard operating 
procedures that have been reviewed and approved by Clinsearch. 
 
Subsequently, the entered data are systematically checked by Data Management staff, using error 
messages printed from validation programs and database listings. Obvious errors are corrected 
by authorized Data Management personnel. Other errors or omissions are entered on Data Query 
Forms, which are returned to the investigational site for resolution. The signed original and 
resolved Data Query Forms are kept with the CRFs at the investigator site, and a copy is sent to 
the Data Management CRO so the resolutions can be entered into the database. Quality control 
audits on all key safety and efficacy data in the database are to be performed by the Data 
Management CRO prior to locking the database. 
 
Concomitant medications entered into the database will be coded using the WHO Drug Reference 
List (current version), which employs the Anatomical Therapeutic Chemical (ATC) classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA, current version) terminology. 
 
At the conclusion of the study, the occurrence of any emergency code breaks will be determined 
after  return  of all code  break  reports  The occurrence  of  any  protocol  deviations  will  be 
determined. After these actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis. Any changes to the database after that time can only be made by 
joint written agreement between the Clinical Project Leader, the Project Statistician and the


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Project Data Manager with authorization from Teikoku Seiyaku Co Ltd. Director & Executive 
Officer, Clinical Development & Regulatory Strategy center . 
Data Analysis 
A review of the database will be conducted shortly before the study is unblinded in the Blind 
Data Review  Meeting,  and any decisions  made  at that meeting concerning  the statistical 
analysis, e.g., additional outcomes and populations, pooling of centers for efficacy analysis, 
will be documented in the Statistical Analysis Plan. Any changes that must be made after the 
study is unblinded will be documented separately, as well as any changes that must be made to 
the study database after the study is unblinded. 
 
9.4          Populations for analysis 
 
Full Analysis Set    The Full Analysis Set will be all randomized patients who received at least 
one dose of study drug.  The FAS population will be primary population 
for the analysis of efficacy. Any exclusions from the FAS population will 
be made and documented before unblinding (e.g. never used study 
medication, randomized twice). Additional secondary populations may be 
defined before unblinding and will be described in detail in the SAP. 
 
Safety Set               The safety set (SAF)  will include all randomized patients who received 
at least one dose of the study drug.  Safety will be analyzed in this 
population. 
 
Before the study is unblinded, each actual post-baseline visit will be mapped to the target visit 
time to which it is chronologically closest. This corresponds to the following visit windows: Visit 
2 (Hours 12), Visit 3 (Hours 22-24), Visit 4 (Hours 44-52), Visit 5 (Hours 68-76), Visit 6 (Hours 
92-100), Visit 7 (Hours 168+). The numbering of the actual visits (from Visit 1 to Visit 7) 
will then be changed as needed to improve the correspondence of the actual visit times to the 
protocol-specified schedule. Final determinations will also be made and documented before the 
study is unblinded to address visits that are equidistant to two nominal visit times (Hours 12, 
24, 48, 72, 96, 168) or any other irregularities. 
 
Before the study is unblinded, the timing of the diary assessments will be reviewed, and 
assessments will be reclassified into time slots as appropriate to ensure that all assessments in 
a given comparison were made a comparable amount of time after start of treatment. 
 
9.5           Demography/other baseline characteristics 
 
Demography and other baseline characteristics will be summarized descriptively overall and by 
treatment group as well as by subgroup (sprains/strains, contusions). For quantitative data, 
means, medians, standard deviations and extremes will be determined. For qualitative data, 
absolute and relative frequencies will be calculated. Important baseline characteristics will be 
further summarized by sex, race and age.


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9.6          Treatments (study drug, rescue medication, other concomitant 
therapies, compliance) 
 
Compliance is defined in terms of the total number of study medication patches used and total 
number of applications made through Visit 7 as follows: 
 
    Good:  80% of the patch has been applied and > 80% of scheduled applications made, 
 
    Moderate: not Good and not Poor 
    Poor: < 50% of the patch has been applied or < 50% of scheduled applications made. 
Compliance in patients with missing data on patch counts will be documented in the SAP before 
unblinding. 
 
The % of patch used through Visit 7 will be computed relative to the actual number of 
applications made from randomization through Visit 7. Scheduled applications will include all 
scheduled applications through Visit 7. 
 
Compliance will be summarized descriptively as (1) % of scheduled applications made, (2) % 
of patches used relative to number of actual applications and (3) compliance category 
(Good/Moderate/Poor). 
 
Use of concomitant therapies will be listed. Use of rescue medication is an efficacy outcome 
and is discussed further below. Exposure to study drug will be summarized descriptively as (1) 
number of applications made and (2) total amount of patch used. 
 
9.7         Efficacy 
 
9.7.1        Outcomes 
 
Primary Outcome 
 
Change from baseline in pain-on-movement (POM) at injured site in mm measured using a 100 
mm Visual Analogue Scale (VAS) to Visit 5 (72 hours after commencement of study treatment) 
 
The analysis of the primary endpoint will be adjusted for baseline values. The baseline adjusted 
difference between active treatment and placebo at 72 hours should be > 10 mm. Magnitude of 
reduction in pain will be used to determine ‘responder rate’. 
 
 
 
Secondary Outcomes 
 
Secondary efficacy variables: 
 
 POM at injured site in mm measured using a 100 mm VAS at 12, 24, 48,72, 96 and 168 
hours after commencement of study treatment 
 
    AUC over time during first 12, 24, 48, 72, 96 and 168 hours for POM measured using a 
VAS; ordinate = POM score in mm, abscissa = time after treatment 
 
    Pain-at-rest (PAR) at injured site in mm measured using a 100 mm VAS at 12, 24, 48 
72, 96 and 168 hours


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    Reduction in VAS for POM from baseline: 
 
    Time to meaningful reduction (30%) 
 
    Time to optimal reduction (50%) 
 
    Time to complete resolution of pain 
 
 Responder rate 1 (defined as the proportion of patients achieving ≥50% reduction from 
baseline in the VAS score for POM at 72 hours) 
 
 Responder rate 2 (defined as the proportion of patients able to resume training / normal 
physical activity by 168 hours) 
 
 Clinical global assessment of efficacy as judged by investigator and patient at 48, 72 
and 168 hours 
 
    Overall dose of rescue medication needed (paracetamol) 
 
 
 
Other: 
 
Adhesive power of patch (5-point scale) 
 
If there is significant use of rescue medication, a sensitivity analysis may be performed to assess 
impact on primary endpoint and responder rate. 
 
 
 
Outcomes will be compared for all use of rescue medication and separately for use to treat blunt 
trauma.  Day 1 and the day of the final visit will count as full days for this purpose. Use of rescue 
medication on days after study medication has been discontinued will not be counted. 
 
9.7.2        Statistical hypothesis, model, and method of analysis 
For the primary variable an analysis-of-covariance (ANCOVA) with baseline as covariate and 
treatment, center and subgroup as factors will be carried out. An a priori ordered testing 
procedure controlling the multiple α-level of 5 % will be used in the analysis: 
 
1)  Ho: µE=µP vs. H1: µE≠µP. 
 
In case of a significant result for this first hypothesis two further hypotheses regarding the 
subgroups “sprains/strains” and “contusions” will be then be also tested by means of the same 
baseline adjusted ANCOVA model to the 5 % level. 
 
2a) Ho: µE(spr/str)=µP(spr/str) vs. H1: µE(spr/str)≠µP(spr/str) in the subgroup “Sprains/strains”, 
2b) Ho: µE(con)=µP(con)  vs. H1: µE(con)≠µP(con) in the subgroup 
“contusions”. The primary analysis population is the Full Analysis Set (FAS). 
Other important secondary efficacy outcomes are pain-on-movement on VAS at 12, 24, 48, 72, 
96 and 168 hours after initiating treatment in the FAS population. These will be analyzed with


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an analysis-of-covariance (ANCOVA) model and center and subgroup as main effects which will 
be more detailed described in the Statistical Analysis Plan (SAP). All other continuous efficacy 
outcomes will be analyzed based on the same model (excluding the baseline covariate when there 
is no appropriate baseline). 
 
 
Differences between treatments on categorical outcomes will be tested with Cochran-Mantel- 
Haenszel tests of treatment mean ridits or of general association, stratified by center. 
 
Figures will show the time course of outcomes by treatment group for key quantitative outcomes.  
The primary outcome will also be summarized by center (if there is evidence of a treatment-by-
center interaction), sex, age and race but without formal statistical comparisons of treatments. 
 
For quantitative outcomes assessed (POM, pain at rest) each null hypothesis will be tested with 
an analysis-on-covariance (ANCOVA) model including treatment group and center as main 
effects, and the baseline value as covariate (those outcomes for which there is a baseline). The 
model will be fit both with and without the treatment-by-center interaction.  The primary model 
will be the model without the interaction.   If the treatment/center interaction is statistically 
significant (p<0.05), additional ANCOVAs will be run to identify the center(s) driving the 
interaction  and to lay out the evidence  for efficacy  among  the centers  whose  results  are 
concordant and centers driving the interaction.   ANCOVA outputs will be presented in the 
Statistical Appendix for the primary and various secondary outcomes to allow an outside reviewer 
to assess the acceptability of the primary statistical model. 
 
The treatment effects will be estimated as mean differences between the active and placebo 
groups with 95% confidence intervals. 
 
The response outcome (POM reduced by 50% at Visit 5, Yes/No) will be analyzed by the CMH 
test of general association, stratified by center and also by subgroup. 
 
For ordered categorical outcomes, (the global assessments), differences between treatments will 
be tested with the CMH test of treatment mean ridits, stratified by center. 
 
Differences between treatments on each quantitative rescue medication outcome will be tested 
with the CMH test of treatment means, stratified by center. 
 
Differences between treatments in time-to-event outcomes will be tested with the log-rank test 
stratified by center. 
 
9.7.3        Handling of missing values/censoring/discontinuations 
Assessments at the site 
 
 If assessments at any visit for Visits 2 (12h) through Visit 7 (168h) are missing, they will 
be imputed as the average of the preceding and the following assessments. Fractional 
values will be rounded down (including ordered categorical assessments). 
    If a patient terminates prematurely, 
 all subsequent visits will be imputed by carrying the last non-missing observation 
forward.


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 for an adverse event suspected to be study-drug-related, then all subsequent visits will 
be imputed by carrying the baseline observation forward. 
 for lack of efficacy, all subsequent assessments will be imputed as the worst of the 
final assessment and the baseline assessment. 
 for lack of efficacy or for an adverse event suspected to be study-drug-related and 
does not complete the global assessment of treatment satisfaction, it will be assigned 
the worst possible score. 
 If a patient discontinues for any other reason, missing global assessments at Visit 7 
will be imputed by LOCF from Visit 5 and missing assessments at Visit 5 will not be 
imputed. 
 If a patient assesses efficacy at the site <6 hours after using rescue medication, imputation 
will be considered in the Statistical Analysis Plan, with consideration given to the 
frequency of this issue in the database and the elapsed time between rescue and 
assessment of efficacy. 
 If a patient assesses spontaneous pain intensity and spontaneous pain relief at the time of 
rescue taken because of blunt trauma pain, any assessment conducted in the following 6h 
will be replaced by the corresponding assessment done at the time of rescue. 
 If a patient assesses spontaneous pain intensity and spontaneous pain relief at the time of 
rescue taken for reason other than blunt trauma pain, any assessment conducted in the 
following 6h will be imputed as if the assessment were missed. 
    If there are no assessments in the 12-24h window, or the 24-48h window, 
 
 if the patient has not prematurely terminated, a value from the last preceding 
assessment or assessment window will be carried forward. 
 if the patient has prematurely terminated, imputation will proceed as described for 
assessments at the site. 
    If the patient provides no post-baseline efficacy data, imputation will be considered in the 
Statistical Analysis Plan. 
Censoring 
 Time to meaningful relief will be censored (if appropriate) at the time of the final 
assessment of meaningful relief.  If the patient discontinues for lack of efficacy before 
achieving meaningful relief, it will be censored at 24h. 
 Time to perceptible relief will be censored (if appropriate) at 24h or the time of final 
assessment of spontaneous pain relief (if earlier).  If the patient discontinues for lack of 
efficacy before achieving perceptible relief it will be censored at 24h. 
 Time to resolution of blunt trauma will be censored (if appropriate) at the day of the final 
visit.  If the patient discontinues for lack of efficacy, it will be censored at 7 days. 
 Time to first use of rescue medication will be censored (if appropriate) at the last day for 
which diary records are available. 
 
If  a  patient  takes  a  disallowed  analgesic  medication  and  subsequently  provides  efficacy 
assessments, rules will be established on a case-by-case basis, taking into consideration whether


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the disallowed analgesic medication was taken to treat pain in the injured area and the likely 
duration  of effect  of the medication.    The  rules  will  be documented  before  the study  is 
unblinded. 
Additional data handling rules will be specified in the Statistical Analysis Plan to cover issues 
not anticipated in the above stipulations. 
 
9.8          Safety 
 
The  assessment  of  safety  will  be  based  mainly  on  the  frequency  of  AEs  that  are treatment-
emergent.   Formal tests will not be conducted for differences in safety parameters between 
treatment groups. 
 
The incidence of all treatment-emergent  AEs will be after grouping by body system  and 
preferred term. For each preferred term and summarized over each body system overall, the table 
will present the number of patients in each treatment group in whom the event occurred and the 
rate (%) of occurrence.  The incidence  of all suspected-drug-related  AEs  will be tabulated 
similarly. The incidence of all treatment-emergent  AEs will also be tabulated by severity 
categories.  The summary of all AEs by treatment groups will also be presented within subgroups 
by sex, age and race. 
 
Safety will also be summarized with respect to vital signs and laboratory safety parameters as 
mean levels by visit and change from baseline.  Laboratory values will be further summarized 
with shift tables.  Abnormal observations on physical exams will be listed. 
 
9.9          Sample size calculation 
The calculation of 90 per treatment group is based on the following assumptions and 
considerations: 
 Primary efficacy outcome is the change from baseline for POM at 72 hours after 
initiating treatment. 
    Two-sided t-test situation with α = 5%. 
 Assuming SD = 20 mm, the sample size provides approximately 80% power to detect a 
difference of 10 mm between two treatment groups if 64 patients per group are analysed. 
 
 However, the sample size will be stipulated to n=90 per group in order to power also 
the two subgroup comparisons. 
 
 Moreover, the sample size will be a total of 200 patients because a dropout-rate of 
approximately 10 % is taken into account 
 
 
9.10        Interim analysis 
 
No interim analysis will be conducted.


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10          Ethical considerations 
 
10.1        Regulatory and ethical compliance 
 
This clinical study is designed and shall be implemented and reported in accordance with the 
ICH  Harmonized  Tripartite  Guidelines  for  Good  Clinical  Practice  [European  Medicines 
Agency 2006], with applicable local regulations (including European Directive 2001/20/EC, 
US Code of Federal Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare), 
and with the ethical principles laid down in the Declaration of Helsinki. 
 
10.2        Informed consent procedures 
 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent, The patient  must 
indicate assent by personally signing and dating the written informed consent document or a 
separate assent form. Informed consent must be obtained before conducting any study-specific 
procedures (i.e., all of the procedures described in the protocol). The process of obtaining 
informed consent should be documented in the patient source documents. 
 
Clinsearch will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH-GCP guideline and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
Investigator must be agreed to by Clinsearch/Teikoku before submission to the IRB/IEC/REB, 
and a copy of the approved version must be provided to the monitor after IRB/IEC/REB approval. 
 
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy occurs during the study and agree that in order 
to participate in the study they must adhere to the contraception requirement for the duration of 
the study. If there is any question that the patient will not reliably comply, they should not be 
entered in the study. 
 
10.3        Insurance 
 
CRMB will procure insurance for every patient enrolled in the clinical study in line with 
applicable  regulatory  requirements.  Every  patient  will  receive  an  information  sheet  on 
insurance coverage together with the patient information. 
 
10.4        Responsibilities of the Investigator and IRB/IEC/REB 
 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly  constituted  Institutional  Review  Board/Independent  Ethics  Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. A signed and dated statement that the protocol 
and informed consent have been approved by the IRB/IEC/REB must be given to Clinsearch 
before study initiation. Prior to study start, the Investigator is required to sign a protocol


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signature page confirming his/her agreement to conduct the study in accordance with these 
documents and all of the instructions and procedures found in this protocol and to give access 
to all relevant data and records to Clinsearch monitors, auditors, Quality Assurance 
representatives, designated agents of Clinsearch, IRBs/IECs/REBs, and regulatory authorities, 
as required..   Patient privacy and data confidentiality will be observed according to the applicable 
regulatory requirements and/or local laws. 
 
If an inspection of the clinical site is requested by a regulatory authority, the Investigator must 
inform Clinsearch immediately that this request has been made. SAEs will be reported by the 
Investigator to the IRB/IEC/REB, as required. 
 
10.5        Quality Assurance Audits and Health Authority Inspections 
 
The clinical investigator study site may be patient to quality assurance audits performed by 
Clinsearch or its agents on behalf of Clinsearch, and/or regulatory inspections by the appropriate 
health authorities. The Investigator and the institution will allow Clinsearch, its agents, and/or 
appropriate regulatory authorities direct access to study records including source records, CRFs 
and other study relevant documentation for review. Patient privacy and data confidentiality will 
be observed accordingly to the applicable regulatory requirements and/or local laws. 
 
The  Investigator  must  immediately  notify  Clinsearch  if  they  have  been  contacted  by  a 
regulatory agency concerning an upcoming inspection. It is important that investigators and 
their relevant personnel are available during audits and/or inspections and that sufficient time 
is devoted to the process. 
 
10.6         Publication of study protocol and results 
 
Clinsearch confirms that a synopsis of the study results will be submitted to the authorities and 
the Ethics Committees in ICH E3 format within one year after the end of the clinical trial. 
Furthermore, protocol information and clinical results will also be submitted in EudraCT within 
one year after the end of the clinical trial.  . In addition, upon study completion and finalization 
of the study report the results of this study will be either submitted for publication and/or posted 
in other publicly accessible database of clinical study results.


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11          Protocol adherence 
 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the Investigator contact Clinsearch or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the Investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Clinsearch 
and  approved  by  the  IRB/IEC/REB  it  cannot  be  implemented.  All  significant  protocol 
deviations will be recorded and reported in the CSR, as defined in the note for Guidance ICH 
E3. 
 
11.1        Protocol Amendments 
 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Clinsearch, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB   
approval.   Notwithstanding   the   need   for   approval   of   formal   protocol amendments, the 
Investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such cases, 
Clinsearch should be notified of this action and the IRB/IEC/REB at the study site should be 
informed within 10 working days. 
 
12.1        End of Trial 
 
The End of this clinical trial is defined as “the last visit of the last patient” included in the trial. 
 


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12          References 
 
[Best TM (1997) Soft-tissue injuries and muscle tears. Clin Sports Med; 16(3): 419-434.] 
 
[Bonnekoh A, Rost R, Völker K, Giannetti BM, Bulitta M, Ley F (1992) [Double-blind 
controlled clinical trial comparing the efficacy and safety of an Escin plus Diethylamine 
salicylate combination patch in patients with reinjection induced haematoma] [German] 
Dtsch Z Sportmed; 43; 3-7.] 
 
[Dreiser RL, Riebenfeld D (1993) A double-blind study of the efficacy of nimesulide in 
the treatment of acute ankle sprain in comparison with placebo. Drugs; 46(Suppl 1): 183- 
186.] 
 
[Ekman EF, Fiechtner JJ, Levy S, Fort JG (2002) Efficacy of celecoxib versus ibuprofen 
in the treatment of acute pain: a multicenter, double-blind, randomized controlled trial in 
acute ankle sprain. Am J Orthop; 31: 445-451.] 
 
[Farges MC, Balcerzak D, Fisher BD et al. (2002) Increased muscle proteolysis after local 
trauma mainly reflects macrophage-associated lysosomal proteolysis. Am J Physiol 
Endocrinol Metabol; 282(2): E326-335.] 
 
[Hess H, Groher W, Lenhart P, Thiel A, Bulitta M, Ley F (1996) [Efficacy and safety of 
an Escin plus Diethylamine salicylate combination patch in patients with sports impact 
injuries]. [German] Dtsch Z Sportmed; 47: 423-430.] 
 
[Heyneman C, Lawless-Liday C, and Wall GC (2000) Oral versus topical NSAIDs in 
rheumatic diseases. A comparison. Drugs; 60: 555-574.] 
[Inklaar H (1994) Soccer injuries. I: Incidence and severity. Sports Med; 18: 55-73.] Mason  
L, Moore  RA,  Edwards  JE,  et al.  (2004)  Topical  NSAIDs  for  acute pain:  a 
metaanalysis. BMC Fam Pract; 5: 10. 
 
[Nozaki M, Li Y, Zhu J et al. (2008) Improved muscle healing after contusion injury by 
the inhibitory effect of suramin on myostatin, a negative regulator of muscle growth. Am J 
Sports Med; 36(12): 2354-2362.] 
 
[Ogilvie-Harris DJ, Gilbart M (1995) Treatment modalities for soft tissue injuries of the 
ankle: A critical review. Clin J Sport Med; 5: 175-186.] 
 
[Pabst H, Segesser B, Bulitta M, Wetzel D, Bertram S (2001) Efficacy and tolerability of 
escin/diethylamine salicylate combination patches in patients with blunt injuries of the 
extremities. Int J Sports Medicine; 22: 430-436.] 
 
[Predel HG, Koll R, Pabst H, Dieter R, Gallacchi G, Giannetti B, Bulitta M, Heidecker JL, 
Mueller EA. Diclofenac patch for topical treatment of acute impact injuries: a randomised, 
double-blind, placebo-controlled, multicentre study. Br J Sports Med 2004;38:318-23.]


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[Rainsford KD, Kean WF, Ehrlich GE (2008) Review of the pharmaceutical properties and 
clinical effects of the topical NSAID formulation, diclofenac epolamine. Curr Med Res 
Opin; 24: 2967-2992.] 

SAP_001.pdf: 
 
Trial Substance: 
Esflurbiprofen Hydrogel Patch 
Study No.:              TK-254R-0201 
EudraCT No.:         2020-005165-14 
Short Title: 
Local symptomatic and short-term treatment of 
pain in acute strains, sprains or bruises of the 
extremities following blunt trauma 
Sponsor:   TEIKOKU SEIYAKU CO LTD.   
 
Statistical Analysis Plan – Final Version,09 December 2021– Page 1 of 22 
 
Statistical Analysis Plan 
 
 
 
Randomized, controlled, double-blind, multi-center trial to evaluate 
the efficacy and safety of an Esflurbiprofen Hydrogel Patch vs. 
placebo in the local symptomatic and short-term treatment of pain 
in acute strains, sprains or bruises of the extremities following blunt 
trauma, e.g. sports injuries. 
 
 
 (Study No.: TK-254R-0201, EudraCT-No.: 2020-005165-14) 
 
Protocol: 
 
Version 
Date 
Description 
3.0 
08 March 2021 
Final version 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAP: 
 
Version 
Date 
Author 
Description 
Draft 1.0 
20 August 2021 
 
 
Initial Version 
Draft 2.0 
16 November 2021 
 
 
Revised Version 
Final 
09 December 2021 
 
 
Finalized Version 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This document may not be published, reproduced or passed on without the written permission of 
the responsible authorities of Teikoku Seiyaku Co Ltd.  




 
Trial Substance: 
Esflurbiprofen Hydrogel Patch 
Study No.:              TK-254R-0201 
EudraCT No.:         2020-005165-14 
Short Title: 
Local symptomatic and short-term treatment of 
pain in acute strains, sprains or bruises of the 
extremities following blunt trauma 
Sponsor:   TEIKOKU SEIYAKU CO LTD.   
 
Statistical Analysis Plan – Final Version,09 December 2021– Page 3 of 22 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ......................................................................................... 1 
1 
INTRODUCTION ........................................................................................................... 7 
2 
DESIGN OF THE CLINICAL TRIAL ......................................................................... 7 
3 
TIME SCHEDULE ......................................................................................................... 7 
4 
TRIAL OBJECTIVES .................................................................................................... 7 
4.1.1 
Primary objective ................................................................................................ 7 
4.1.2 
Secondary objectives ........................................................................................... 7 
5 
SUBJECTS ASSESSMENTS ......................................................................................... 8 
5.1 
Efficacy variables .............................................................................................................. 8 
5.1.1 
Primary efficacy variable .................................................................................... 8 
5.1.2 
Secondary efficacy variables ............................................................................... 8 
5.2 
Safety variables ................................................................................................................. 9 
5.3 
Other variables ................................................................................................................. 10 
5.4 
Derived variables ............................................................................................................. 10 
5.5 
Withdrawal/discontinuation ............................................................................................ 10 
5.5.1 
Schedule of assessments .................................................................................... 10 
6 
SAMPLE SIZE .............................................................................................................. 12 
7 
DATA ENTRY AND VALIDATION .......................................................................... 12 
8 
COMPUTER SYSTEMS, SOFTWARE, AND VALIDATION OF PROGRAMS . 12 
8.1 
Hardware ......................................................................................................................... 12 
8.2 
Software ........................................................................................................................... 12 
8.3 
Validation of programs .................................................................................................... 13 
8.4 
Restitution of programs ................................................................................................... 13 
9 
CODING ......................................................................................................................... 13 
10 
DATA CHECKS ............................................................................................................ 13 
11 
QUERIES ....................................................................................................................... 13 
12 
BLIND REVIEW ........................................................................................................... 14 
13 
DATABASE CLOSURE ............................................................................................... 14 
14 
STATISTICAL EVALUATION .................................................................................. 14 
14.1 General ............................................................................................................................ 14 
14.2 Analysis populations ....................................................................................................... 14 
14.3 Patient Disposition and Characteristics ........................................................................... 15 
14.4 Efficacy ............................................................................................................................ 15 
14.4.1 
Primary efficacy variable .................................................................................. 15 
14.4.2 
Secondary efficacy variables ............................................................................. 16 
14.4.3 
Additional exploratory efficacy variables ......................................................... 17 
14.5 Safety ............................................................................................................................... 17 
14.5.1 
Adverse events .................................................................................................. 18 
14.5.2 
Other Variables Related to Safety ..................................................................... 18 
14.6 Multi-site study ................................................................................................................ 18 
14.7 Multiplicity ...................................................................................................................... 18 


 
Trial Substance: 
Esflurbiprofen Hydrogel Patch 
Study No.:              TK-254R-0201 
EudraCT No.:         2020-005165-14 
Short Title: 
Local symptomatic and short-term treatment of 
pain in acute strains, sprains or bruises of the 
extremities following blunt trauma 
Sponsor:   TEIKOKU SEIYAKU CO LTD.   
 
Statistical Analysis Plan – Final Version,09 December 2021– Page 4 of 22 
14.8 Missing data ..................................................................................................................... 18 
14.9 Censoring ......................................................................................................................... 19 
14.10 Interim Analysis .............................................................................................................. 20 
14.11 Subject disposition ........................................................................................................... 20 
14.12 Extent of exposure ........................................................................................................... 20 
14.13 Treatment compliance, rescue medication, other concomitant therapies ........................ 20 
14.14 Medical history ................................................................................................................ 21 
14.15 Previous and concomitant medications ........................................................................... 21 
15 
VISIT WINDOWS ......................................................................................................... 21 
16 
LANGUAGE AND HEADINGS .................................................................................. 22 
17 
ARCHIVING ................................................................................................................. 22 
18 
LIST OF STAFF ............................................................................................................ 22 
19 
REFERENCES .............................................................................................................. 22 
 


 
Trial Substance: 
Esflurbiprofen Hydrogel Patch 
Study No.:              TK-254R-0201 
EudraCT No.:         2020-005165-14 
Short Title: 
Local symptomatic and short-term treatment of 
pain in acute strains, sprains or bruises of the 
extremities following blunt trauma 
Sponsor:   TEIKOKU SEIYAKU CO LTD.   
 
Statistical Analysis Plan – Final Version,09 December 2021– Page 5 of 22 
Abbreviations 
Abbreviation 
Abbreviation in Full 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical, therapeutical, chemical 
AUC 
Area under the curve 
b. i. d. 
bis in die, two times daily 
BL 
Baseline 
BPd 
Blood Pressure diastolic 
bpm 
Beats per minute 
BPs 
Blood Pressure systolic 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case Report/Record Form 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
DD 
Drug Dictionary 
DMP 
Data Management Plan 
DBRM 
Data Blind Review Meeting 
FAS 
Full Analysis Set 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
LOCF 
Last-observation-carried-forward 
LS 
Least squares 
MedDRA 
Medical dictionary for regulatory activities 
PID 
Pain Intensity Difference 
POM 
Pain-on-movement 
PP 
Per Protocol 
o. d. 
once daily 
QC 
Quality control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SPID 
Sum of Pain Intensity Difference 


 
Trial Substance: 
Esflurbiprofen Hydrogel Patch 
Study No.:              TK-254R-0201 
EudraCT No.:         2020-005165-14 
Short Title: 
Local symptomatic and short-term treatment of 
pain in acute strains, sprains or bruises of the 
extremities following blunt trauma 
Sponsor:   TEIKOKU SEIYAKU CO LTD.   
 
Statistical Analysis Plan – Final Version,09 December 2021– Page 6 of 22 
TFL 
Table/Figure/Listing 
Vi 
Visit i, i=1, 2, …, 7 
VAS 
Visual Analogue Scale 
vs. 
versus 
WHO 
World Health Organization 
WOCBP 
Women of child-bearing potential 


 
Trial Substance: 
Esflurbiprofen Hydrogel Patch 
Study No.:              TK-254R-0201 
EudraCT No.:         2020-005165-14 
Short Title: 
Local symptomatic and short-term treatment of 
pain in acute strains, sprains or bruises of the 
extremities following blunt trauma 
Sponsor:   TEIKOKU SEIYAKU CO LTD.   
 
Statistical Analysis Plan – Final Version,09 December 2021– Page 7 of 22 
 
1 
INTRODUCTION 
General information on methods and procedures for the statistical evaluation are described in the 
Clinical Study Protocol (CSP), Final Version 3.0 dated 08 March 2021. The Statistical Analysis 
Plan (SAP) presented here outlines the evaluations to be performed in the final statistical 
analysis, including details with respect to endpoint derivation, applied statistical methods, and 
presentation of the results. 
 
This SAP refers to the latest version of the Study Protocol. There were no amendments to the 
CSP in this clinical trial. The SAP will be finalized after the Data Blind Review Meeting 
(DBRM) and contains a comprehensive and detailed elaboration of the statistical methodology 
section of the protocol. 
 
2 
DESIGN OF THE CLINICAL TRIAL 
The study is a Phase II (proof-of-concept), randomized, double-blind, multi-center, placebo-
controlled, parallel group clinical trial of the efficacy and safety of Esflurbiprofen Hydrogel 
Patch applied once a day versus placebo patch applied once a day in the local symptomatic and 
short-term treatment of pain in acute strains, sprains or bruises of the extremities following blunt 
trauma, conducted in Germany.  
 
It is planned to include a total of 200 patients (100 patients per active group and 100 per placebo 
group) in 3 sites.  
 
The duration of each patient’s participation in the study will be 7 (+1) consecutive days (from 
randomization (V1) to Final Visit (V7)). 
 
3 
TIME SCHEDULE 
The study consists of 7 visits: randomization visit (Visit 1, 0 h, Day 1), and post-baseline visits 
Visit 2 (12 h (±1 h) after first treatment, Day 1 or 2), Visit 3 (24 h (±2 h) after first treatment, 
Day 2), Visit 4 (48 h (±4 h) after first treatment, Day 3), Visit 5 (72 h (±4 h) after first treatment, 
Day 4), Visit 6 (96 h (±4 h) after first treatment, Day 5) and Visit 7 (168 h (±24 h) after first 
treatment, Day 8 (± 2 days)). A detailed schedule of Assessments is presented in the CSP, Final 
Version 3.0 dated 08 March 2021, Table 7-1, p. 30. 
 
4 
TRIAL OBJECTIVES 
4.1.1 Primary objective 
To evaluate the efficacy of a Esflurbiprofen 165 mg Hydrogel Patch applied once a day 
compared with placebo in patients with acute blunt, soft tissue injuries of the limbs. 
 
4.1.2 Secondary objectives 
The secondary objectives are: 
 
• To assess the efficacy of Esflurbiprofen Hydrogel Patch compared with placebo by 
means of secondary efficacy variables. 


 
Trial Substance: 
Esflurbiprofen Hydrogel Patch 
Study No.:              TK-254R-0201 
EudraCT No.:         2020-005165-14 
Short Title: 
Local symptomatic and short-term treatment of 
pain in acute strains, sprains or bruises of the 
extremities following blunt trauma 
Sponsor:   TEIKOKU SEIYAKU CO LTD.   
 
Statistical Analysis Plan – Final Version,09 December 2021– Page 8 of 22 
• To assess the safety of Esflurbiprofen Hydrogel Patch compared with placebo applied 
once a day for up to seven days. 
 
5 
SUBJECTS ASSESSMENTS 
5.1 
Efficacy variables 
5.1.1 Primary efficacy variable 
The primary efficacy outcome is pain-on-movement (POM) change from baseline assessed by 
Visual Analogue Scale (VAS) to Visit 5 (72 hours after initiating treatment).  
 
5.1.2 Secondary efficacy variables 
• POM at injured site in mm measured using a 100 mm VAS at 12, 24, 48, 72, 96 and 168 
hours after commencement of study treatment and will additionally presented by 
subgroups (table and Figure). 
• AUC over time during first 12, 24, 48, 72, 96 and 168 hours for POM measured using a 
VAS; ordinate = POM score in mm, abscissa = time after treatment  
• Pain-at-rest (PAR) at injured site in mm measured using a 100 mm VAS at 12, 24, 48 72, 
96 and 168 hours. 
• Reduction in VAS for POM from baseline:  
o Time to meaningful reduction (30%)  
o Time to optimal reduction (50%)  
o Time to complete resolution of pain 
• Responder rate 1 (defined as the proportion of patients achieving ≥50% reduction from 
baseline in the VAS score for POM at 72 hours)  
• Responder rate 2 (defined as the proportion of patients able to resume training / normal 
physical activity by 168 hours)  
• Clinical global assessment of efficacy as judged by investigator and patient at 48, 72 and 
168 hours  
• Overall dose of rescue medication needed (paracetamol). 
• POM on VAS by indication at Visit 5. 
 
 
Additional outcomes 
• Adhesive power of patch (5-point scale)  
• Mean adhesion by application site and/or net use. 
• If there is significant use of rescue medication, a sensitivity analysis may be performed to 
assess impact on primary endpoint and responder rate.  
• Outcomes will be compared for all use of rescue medication and separately for use to 
treat blunt trauma. Day 1 and the day of the final visit will count as full days for this 
purpose. Use of rescue medication on days after study medication has been discontinued 
will not be counted. 
• POM on VAS difference at V4, V5, V6 compared to V1 (BL) (PID V4, PID V5, PID V6) 
PID V4, PID V5 and PID V6 will be compared between treatment groups using 
ANCOVA with terms in the model for treatment group, site [as fixed effects], and 
baseline POM assessment [as a covariate]. Least square mean for each treatment and the 


 
Trial Substance: 
Esflurbiprofen Hydrogel Patch 
Study No.:              TK-254R-0201 
EudraCT No.:         2020-005165-14 
Short Title: 
Local symptomatic and short-term treatment of 
pain in acute strains, sprains or bruises of the 
extremities following blunt trauma 
Sponsor:   TEIKOKU SEIYAKU CO LTD.   
 
Statistical Analysis Plan – Final Version,09 December 2021– Page 9 of 22 
corresponding difference between least square means with the p-value and 95 % 
confidence interval will be presented from the specified ANCOVA model. 
• Sum of Pain Intensity differences (SPID) over 0-24, 0-48, 0-72 and 0-96 hours.  
SPID over 0-24, 0-48, 0-72 and 0-96 hours will be compared between treatment groups 
using ANCOVA with terms in the model for treatment group, site [as fixed effects], and 
baseline POM assessment [as a covariate]. Least square mean for each treatment and the 
corresponding difference between least square means (Active - placebo) with the p-value 
and 95 % confidence interval will be presented from the specified ANCOVA model. 
 
5.2 
Safety variables 
The following parameters are recorded to assess the safety of the study drug: 
 
• Adverse events (AEs). 
AEs will be documented at Visit 2 to Visit 7. 
 
• Vital signs. 
Pulse rate (bpm) and blood pressure (BPs, BPd (mmHg) will be documented at the 
Baseline Visit (Visit 1) and Final Visit (Visit 7)). 
 
• General physical examination. 
Physical examination will be performed at Visit 1 (randomization visit) and at Visit 7 
(final visit), as well as when judged necessary by the Investigator. Examination will 
include: general condition, dermatologic, eyes, ears, nose, throat, neck, thyroid, heart, 
respiratory system, abdomen, kidneys, skeletal system, extremities, lymphatic system, 
CNS, neurological conditions and other (to be specified). 
 
• Height and weight. 
Height in centimeters (cm, without shoes) and body weight (kg, in indoor clothing, but 
without shoes) will be measured at Visit 1. Body weight only will also be measured at 
Visit 7. 
 
• Pregnancy and assessments of fertility. 
All women of child-bearing potential (WOCBP) and postmenopausal women who are not 
surgically sterile will have a urine pregnancy test with a dipstick at Visit 1 
(Randomization Visit) at Visit 7 (Final Visit).  
 
• Local tolerability 
Local tolerability will be assessed by the Investigator according to the following numerical 
scale at Visits 3 to 7: 
0: 
No evidence of irritation 
1: 
Minimal erythema, barely perceptible 
2: 
Definite erythema, readily visible; minimal edema or papular response 
3: 
Erythema and papules 
4: 
Definite edema 
5: 
Erythema, edema, and papules 
6: 
Vesicular eruption 
7: 
Strong reaction spreading beyond test site 
 


 
Trial Substance: 
Esflurbiprofen Hydrogel Patch 
Study No.:              TK-254R-0201 
EudraCT No.:         2020-005165-14 
Short Title: 
Local symptomatic and short-term treatment of 
pain in acute strains, sprains or bruises of the 
extremities following blunt trauma 
Sponsor:   TEIKOKU SEIYAKU CO LTD.   
 
Statistical Analysis Plan – Final Version,09 December 2021– Page 10 of 22 
5.3 
Other variables 
The following other variables are documented in this clinical trial: 
 
• Demographics and other baseline characteristics (documented at Visit 1; age, sex, height, 
weight, race, ethnicity, localization of injury). 
• Check of contraception (at Visit 1). 
• Medical history (at Visit 1). 
• Concomitant medication (every visit).  
5.4 
Derived variables 
Area under the curves, calculated using the trapezoidal rule [1], will be determined for POM 
VAS pain scores. For quantitative variables the absolute changes from baseline (Visit 1) will also 
be determined. 
 
5.5 
Withdrawal/discontinuation 
The study can be terminated at any time for any reason by the Sponsor, an IRB or a Health 
Authority. Such reasons may include, but are not limited to:  
 
- 
change in the risk/benefit assessment due to unexpected findings related to the potential 
risk of the treatment, 
- 
Detection of SUSARs that differ in severity, duration or frequency from the known safety 
profile  
- 
Becoming aware of new evidence through publications or other clinical trials that would 
negatively impact the risk/benefit assessment  
 
Should this be necessary, all patients should be seen as soon as possible and treated as described 
in Section 7 of CSP for a prematurely withdrawn patient. The Investigator may be informed of 
additional procedures to be followed in order to assure that adequate consideration is given to the 
protection of the patient’s best interest.  
 
The Investigator will be responsible for informing the IRB/REB/IEC of the early termination of 
the study. In the EU CRMB (EU legal representative) and Clinsearch will be responsible for 
notifying IECs, local authorities and the German Competent Authority, of the early termination 
5.5.1 Schedule of assessments 
The following table shows the Assessment Schedule of the clinical trial.




 
Trial Substance: 
Esflurbiprofen Hydrogel Patch 
Study No.:              TK-254R-0201 
EudraCT No.:         2020-005165-14 
Short Title: 
Local symptomatic and short-term treatment of 
pain in acute strains, sprains or bruises of the 
extremities following blunt trauma 
Sponsor:   TEIKOKU SEIYAKU CO LTD.   
 
Statistical Analysis Plan – Final Version,09 December 2021– Page 12 of 22 
6 
SAMPLE SIZE 
The calculation of 90 per treatment group is based on the following assumptions and 
considerations: 
 
• Primary efficacy outcome is the change from baseline for POM at 72 hours after 
initiating treatment.  
• Two-sided t-test situation with α = 5%. 
• Assuming SD = 20 mm, the sample size provides approximately 80% power to detect a 
difference of 10 mm between two treatment groups if 64 patients per group are analysed. 
• However, the sample size will be stipulated to n=90 per group in order to power also the 
two subgroup comparisons. 
• Moreover, the sample size will be a total of 200 patients because a dropout-rate of 
approximately 10 % is taken into account. 
 
 
7 
DATA ENTRY AND VALIDATION 
The data entry of all records documented in the CRFs is carried out by two independent data 
entry persons and result in two different data sets, which will be compared. Trial Master File will 
be corrected until conformity is proved. Furthermore, the data will be analyzed for completeness 
and several plausibility checks will be carried out (see Chapter 10). 
 
8 
COMPUTER SYSTEMS, SOFTWARE, AND VALIDATION OF PROGRAMS 
8.1 
Hardware 
Used Hardware at CRMB is: 
• Network servers: 
• TERRA SERVER 6530 G3, 946 GB SSD, 16 GB Ram. 
• Desktops (workstations): 
6 Desktops based on AMD and Intel 
• Scanners: 
F-Secure Antivirus 7.0 for Windows Server 
ESET NOD 32 Antivirus Version 9 is used on the desktops 
• Backup method: 
Continous backup using VEEM. 
On every Friday a full backup with Acronis True Image echo for Windows server is 
performed (system and data). For the rest of the week a differential backup is created. 
The backups are stored on internal (RAID 5) and external hard discs. 
 
8.2 
Software 
Used Software at CRMB is: 
• DMSys from Sigmasoft, Version 5.1, 
• SAS Version 9.4, 
• Windows Server 2019 Network servers, 
• Windows 10 on Workstations, 
• Microsoft Office 2019 and Adobe Professional for reports, tracking of CRFs. 


 
Trial Substance: 
Esflurbiprofen Hydrogel Patch 
Study No.:              TK-254R-0201 
EudraCT No.:         2020-005165-14 
Short Title: 
Local symptomatic and short-term treatment of 
pain in acute strains, sprains or bruises of the 
extremities following blunt trauma 
Sponsor:   TEIKOKU SEIYAKU CO LTD.   
 
Statistical Analysis Plan – Final Version,09 December 2021– Page 13 of 22 
 
The data management is performed using the validated Data Management System DMSys, 
Version 5.1, and the statistical analysis is performed using the validated statistical analysis 
program SAS, Version 9.4 under Windows 10.  
 
8.3 
Validation of programs 
All SAS programs start with a header in which the following information is contained: 
 
• Name of the program,  
• author,  
• date of creation, 
• used analysis DATA sets. 
 
All tables, graphics and listings contain in footer the name of the program with which they were 
created, and the date of creation. 
 
All formats will be filed in a permanent format catalogue. 
 
All SAS programs will be checked by a second SAS programmer responsible for the quality 
control (QC). He/she will also check all LOG files for ERROR messages and WARNINGS. 
ERRORs must not occur. WARNINGs must be checked as to whether they lead to wrong results. 
Furthermore, the SAS programmer responsible for the QC will check the tables, figures, and 
listing for completeness and consistency. The review will be documented on the Program 
Validation Form. 
 
The biometrician responsible for evaluation will make sure that the specifications of planned 
analysis have been correctly converted in SAS programs. 
 
8.4 
Restitution of programs 
All SAS programs used in the analysis as well as the OUTPUT (listings, tables) will be stored, 
and archived together with the source code of the programs at CRM Biometrics GmbH. 
 
9 
CODING 
Concomitant medications will be coded by means of the Drug Dictionary (WHO-DD, June 
2021). Adverse events and diseases will be coded using MedDRA (Version 24.0), respectively. 
 
10 DATA CHECKS 
Before starting the statistical analysis, plausibility checks will be performed. A detailed list of 
edit checks can be found in the Data Management Plan (DMP, Appendix 5). 
 
11 QUERIES 
After performing the plausibility checks and the comparisons of the two data entry databases, the 
errors of the data entry will be corrected. Queries/Data Clarification Forms will be generated in 
the case of inconsistencies or missing data in the CRF. According to the resolved queries, 
changes of the data will be performed in the Master file, if necessary. In the case of remaining 


 
Trial Substance: 
Esflurbiprofen Hydrogel Patch 
Study No.:              TK-254R-0201 
EudraCT No.:         2020-005165-14 
Short Title: 
Local symptomatic and short-term treatment of 
pain in acute strains, sprains or bruises of the 
extremities following blunt trauma 
Sponsor:   TEIKOKU SEIYAKU CO LTD.   
 
Statistical Analysis Plan – Final Version,09 December 2021– Page 14 of 22 
unsolved queries, the Principal Investigator, the responsible statistician, the medical advisor and 
the project manager will decide how to handle these data and all decisions taken will be 
documented in detail. 
 
12 BLIND REVIEW 
A blind review meeting will take place before unblinding the randomization code. Any potential 
factors that could lead to unblinding of the study will be considered before this review. A listing 
of all protocol deviations with the proposed classification into minor and major protocol 
deviations and a list of all data irregularities or unresolved queries and a proposal for how the 
data are to be handled in the analysis, if necessary, will be provided in the Blind Review Meeting. 
At least the responsible biometrician and the Clinical Project Manager will sign the Blind 
Review protocol. 
 
13 DATABASE CLOSURE 
After all queries have been replied, the master file will be corrected, if necessary, and the 
decisions regarding the handling of the unresolved queries will be made, and the database will be 
closed. 
 
14 STATISTICAL EVALUATION 
14.1 General 
All statistical analyses will be performed in accordance with the ICH E9 guideline. 
 
14.2 Analysis populations 
The following analysis populations will be used for analysis of study data: 
 
Safety population: The safety population will include all randomized patients who received at 
least one dose of the IMP. Safety (e.g., AEs) will be analyzed in this population. 
 
Full Analysis Set (FAS): The Full Analysis Set (FAS) will be all randomized patients who 
received at least one dose of IMP. The FAS population will be primary for the analysis of 
efficacy. Any exclusions from the FAS population will be made and documented before 
unblinding (e.g. never used IMP, ankle is not sprained, randomized twice). The Intention to treat 
(ITT) population is identical to the Full Analysis Set (FAS). 
 
Per protocol (PP) population: The Per protocol (PP) population will include all patients who 
are randomized to the clinical trial, satisfy all of the inclusion/exclusion criteria, receive the 
correct IMP (as randomized), have efficacy data at the 72 hours assessment, with an adhesion 
score of 0, 1, 2, have taken no pain medication and have no other major protocol violations as 
defined during a blinded review meeting.  
 
Moreover, the PP population for the adhesion analysis (PP-PA) will include all TDS except those 
that were intentionally removed early in the study (e.g. because of unacceptable irritation) or 
those that were on patients who discontinued use of the TDS before the end of the labeled 
duration of wear for reasons unrelated to adhesion (e.g. because of a protocol violation). The 
exclusions from the PP-PA population will be described in detail in the CSR. All exclusions will 
be discussed in the Blind Review Meeting before DBL. 


 
Trial Substance: 
Esflurbiprofen Hydrogel Patch 
Study No.:              TK-254R-0201 
EudraCT No.:         2020-005165-14 
Short Title: 
Local symptomatic and short-term treatment of 
pain in acute strains, sprains or bruises of the 
extremities following blunt trauma 
Sponsor:   TEIKOKU SEIYAKU CO LTD.   
 
Statistical Analysis Plan – Final Version,09 December 2021– Page 15 of 22 
 
Only the outcomes regarding primary and secondary efficacy variables will be analyzed using 
this clinical trial population. 
 
Before the study is unblinded, each actual post-baseline visit will be mapped to the target visit 
time to which it is chronologically closest. This corresponds to the following visit windows: 
Visit 2 (Hours 12), Visit 3 (Hours 22-24), Visit 4 (Hours 44-52), Visit 5 (Hours 68-76), Visit 6 
(Hours 92-100), Visit 7 (Hours 168+). The numbering of the actual visits (from Visit 1 to 
Visit 7) will then be changed as needed to improve the correspondence of the actual visit times to 
the protocol-specified schedule. Final determinations will also be made and documented before 
the study is unblinded to address visits that are equidistant to two nominal visit times (Hours 12, 
24, 48, 72, 96, 168) or any other irregularities. 
Before the study is unblinded, the timing of the diary assessments will be reviewed, and 
assessments will be reclassified into time slots as appropriate to ensure that all assessments in a 
given comparison were made a comparable amount of time after start of treatment. 
 
14.3 Patient Disposition and Characteristics 
Demography and other baseline characteristics will be summarized descriptively for both the 
FAS and Safety population (if different), overall and by treatment group. Demography and other 
baseline characteristics will be summarized descriptively overall and by treatment group as well 
as by subgroup (sprains/strains, contusions). For quantitative data, means, medians, standard 
deviations and extremes will be determined. For qualitative data, absolute and relative 
frequencies will be calculated. Important baseline characteristics will be further summarized by 
sex, race and age. 
 
14.4 Efficacy 
14.4.1 Primary efficacy variable 
Change from baseline in pain-on-movement (POM) at injured site in mm measured using a 100 
mm Visual Analogue Scale (VAS) to Visit 5 (72 hours after commencement of study treatment) 
The analysis of the primary endpoint will be adjusted for baseline values. The baseline adjusted 
difference between active treatment and placebo at 72 hours should be > 10 mm. Magnitude of 
reduction in pain will be used to determine ‘responder rate’. 
 
For the primary variable an analysis-of-covariance (ANCOVA) with baseline as covariate and 
treatment, center and subgroup as factors will be carried out. A closed testing procedure 
controlling the multiple α-level of 5 % will be used in the analysis:  
 
1) H0: µE=µP vs. H1: µE≠µP. In case of a significant result for this first hypothesis two 
further hypotheses regarding the subgroups “sprains/strains” and “contusions” will be 
then be also tested by means of the same baseline adjusted ANCOVA model to the 5 % 
level. In case of significance, the following subhypotheses are simultaneously tested at 
the 5 % level of significance. 
2a) H0: µE(spr/str)=µP(spr/str) vs. H1: µE(spr/str)≠µP(spr/str) in the subgroup “Sprains/strains”,  
2b) H0: µE(con)=µP(con) vs. H1: µE(con)≠µP(con) in the subgroup “contusions”.  
 


 
Trial Substance: 
Esflurbiprofen Hydrogel Patch 
Study No.:              TK-254R-0201 
EudraCT No.:         2020-005165-14 
Short Title: 
Local symptomatic and short-term treatment of 
pain in acute strains, sprains or bruises of the 
extremities following blunt trauma 
Sponsor:   TEIKOKU SEIYAKU CO LTD.   
 
Statistical Analysis Plan – Final Version,09 December 2021– Page 16 of 22 
The primary analysis population is the Full Analysis Set (FAS). 
14.4.2 Secondary efficacy variables 
• POM at injured site in mm measured using a 100 mm VAS at 12, 24, 48, 72, 96 and 168 
hours after commencement of study treatment and will additionally presented by 
subgroup (table and Figure). 
• AUC over time during first 12, 24, 48, 72, 96 and 168 hours for POM measured using a 
VAS; ordinate = POM score in mm, abscissa = time after treatment  
• Pain-at-rest (PAR) at injured site in mm measured using a 100 mm VAS at 12, 24, 48 72, 
96 and 168 hours. 
• Reduction in VAS for POM from baseline:  
• Time to meaningful reduction (30%)  
• Time to optimal reduction (50%)  
• Time to complete resolution of pain 
• Responder rate 1 (defined as the proportion of patients achieving ≥50% reduction from 
baseline in the VAS score for POM at 72 hours)  
• Responder rate 2 (defined as the proportion of patients able to resume training / normal 
physical activity by 168 hours)  
• Clinical global assessment of efficacy as judged by investigator and patient at 48, 72 and 
168 hours  
• Overall dose of rescue medication needed (paracetamol). 
 
Statistical test results for secondary variables will only be interpreted exploratorily. 
 
Other important secondary efficacy outcomes are pain-on-movement on VAS at 12, 24, 48, 72, 
96 and 168 hours after initiating treatment in the FAS population. These will be analyzed with an 
analysis-of-covariance (ANCOVA) model and center and subgroup as main effects. All other 
continuous efficacy outcomes will be analyzed based on the same model (excluding the baseline 
covariate when there is no appropriate baseline).  
 
Differences between treatments on ordinal outcomes will be tested with Wilcoxon, stratified by 
center and subgroup.  
 
Figures will show the time course of outcomes by treatment group for key quantitative outcomes. 
The primary outcome will also be summarized by center (if there is evidence of a treatment-by-
center interaction), sex, age and race but without formal statistical comparisons of treatments.  
 
For quantitative outcomes assessed (POM, pain-at-rest) each null hypothesis will be tested with 
an analysis-on-covariance (ANCOVA) model including treatment group and center as main 
effects, and the baseline value as covariate (those outcomes for which there is a baseline). The 
model will be fit both with and without the treatment-by-center interaction. The primary model 
will be the model without the interaction. If the treatment/center interaction is statistically 
significant (p<0.05), additional ANCOVAs will be run to identify the center(s) driving the 
interaction and to lay out the evidence for efficacy among the centers whose results are 
concordant and centers driving the interaction. ANCOVA outputs will be presented in the 
Statistical Appendix for the primary and various secondary outcomes to allow an outside 
reviewer to assess the acceptability of the primary statistical model.  
 


 
Trial Substance: 
Esflurbiprofen Hydrogel Patch 
Study No.:              TK-254R-0201 
EudraCT No.:         2020-005165-14 
Short Title: 
Local symptomatic and short-term treatment of 
pain in acute strains, sprains or bruises of the 
extremities following blunt trauma 
Sponsor:   TEIKOKU SEIYAKU CO LTD.   
 
Statistical Analysis Plan – Final Version,09 December 2021– Page 17 of 22 
The treatment effects will be estimated as mean differences between the active and placebo 
groups with 95% confidence intervals.  
 
The response outcome (POM reduced by 50% at Visit 5, Yes/No) will be analyzed by the CMH 
test of general association, stratified by center and also by subgroup.  
 
Differences between treatments in time-to-event outcomes will be tested with the log-rank test 
stratified by center. 
 
14.4.3 Additional exploratory efficacy variables 
•  
• Mean adhesion by application site and/or net use. 
• If there is significant use of rescue medication, a sensitivity analysis may be performed to 
assess impact on primary endpoint and responder rate.  
• Outcomes will be compared for all use of rescue medication and separately for use to 
treat blunt trauma. Day 1 and the day of the final visit will count as full days for this 
purpose. Use of rescue medication on days after study medication has been discontinued 
will not be counted. 
• POM on VAS difference at V4, V5, V6 compared to V1 (BL) (PID V4, PID V5, PID V6) 
PID V4, PID V5 and PID V6 will be compared between treatment groups using 
ANCOVA with terms in the model for treatment group, site [as fixed effects], and 
baseline POM assessment [as a covariate]. Least square mean for each treatment and the 
corresponding difference between least square means with the p-value and 95 % 
confidence interval will be presented from the specified ANCOVA model. 
• Sum of Pain Intensity differences (SPID) over 0-24, 0-48, 0-72 and 0-96 hours.  
SPID over 0-24, 0-48, 0-72 and 0-96 hours will be compared between treatment groups 
using ANCOVA with terms in the model for treatment group, site [as fixed effects], and 
baseline POM assessment [as a covariate]. Least square mean for each treatment and the 
corresponding difference between least square means (Active - placebo) with the p-value 
and 95 % confidence interval will be presented from the specified ANCOVA model. 
14.5 Safety 
The assessment of safety will be based mainly on the frequency of AEs that are treatment-
emergent. Formal statistical tests will not be conducted for differences in safety parameters 
between treatment groups.  
 
The incidence of all treatment-emergent AEs will be after grouping by body system and 
preferred term. For each preferred term and summarized over each body system overall, the table 
will present the number of patients in each treatment group in whom the event occurred and the 
rate (%) of occurrence. The incidence of all suspected-drug-related AEs will be tabulated 
similarly. The incidence of all treatment-emergent AEs will also be tabulated by severity 
categories. The summary of all AEs by treatment groups will also be presented within subgroups 
by sex, age and race.  
 
Safety will also be summarized with respect to vital signs and laboratory safety parameters as 
mean levels by visit and change from baseline. Laboratory values will be further summarized 
with shift tables. Abnormal observations on physical exams will be listed 


 
Trial Substance: 
Esflurbiprofen Hydrogel Patch 
Study No.:              TK-254R-0201 
EudraCT No.:         2020-005165-14 
Short Title: 
Local symptomatic and short-term treatment of 
pain in acute strains, sprains or bruises of the 
extremities following blunt trauma 
Sponsor:   TEIKOKU SEIYAKU CO LTD.   
 
Statistical Analysis Plan – Final Version,09 December 2021– Page 18 of 22 
14.5.1 Adverse events 
Adverse events will be coded according to MedDRA, Version 24.0.  
 
The incidence of all treatment-emergent AEs will be tabulated after grouping by body system 
and preferred term. For each preferred term and summarized over each body system overall, the 
table will present the number of patients in each treatment group in whom the event occurred and 
the rate (%) of occurrence. The incidence of all suspected-drug-related AEs will be tabulated 
similarly. The incidence of all treatment-emergent AEs will also be tabulated by severity 
categories. 
 
14.5.2 Other Variables Related to Safety 
Summary statistics for the absolute vital sign value and the changes from baseline will be 
presented using n, mean, standard deviation, median, minimum, and maximum. 
 
Abnormal observations on physical examinations will be listed. 
 
Furthermore, weight, pregnancy and assessments of fertility data will only be listed. 
 
Local tolerability assessment will be summarized descriptively by visit. 
 
14.6 Multi-site study 
Individual site results will be presented by means of descriptive statistical methods for the 
demographical and primary efficacy data. Moreover, the treatment-by-site interaction will be 
assessed by means of an ANCOVA model for the primary variable and other selected secondary 
variables. 
 
14.7 Multiplicity 
A closed test procedure will be carried out for the primary variable. Therefore, no α-adjustments 
are necessary. The multiple level of α= 5 % is controlled by this procedure. 
 
14.8 Missing data 
• If assessments at any visit for Visits 2 (12 h) through Visit 6 (96 h) are missing, they will 
be imputed as the average of the preceding and the following assessments. Fractional 
values will be rounded down (including ordered categorical assessments).  If assessment 
at Visit 7 is missing, the last observation will be carried forward. 
• If a patient terminates prematurely,   
o all subsequent visits will be imputed by carrying the last non-missing observation 
forward. 
o for an adverse event suspected to be study-drug-related, then all subsequent visits 
will be imputed by carrying the baseline observation forward.  
o for lack of efficacy, all subsequent assessments will be imputed as the worst of all 
documented assessments. 
o for lack of efficacy or for an adverse event suspected to be study-drug-related and 
does not complete the global assessment of treatment satisfaction, it will be 
assigned the worst possible score.  


 
Trial Substance: 
Esflurbiprofen Hydrogel Patch 
Study No.:              TK-254R-0201 
EudraCT No.:         2020-005165-14 
Short Title: 
Local symptomatic and short-term treatment of 
pain in acute strains, sprains or bruises of the 
extremities following blunt trauma 
Sponsor:   TEIKOKU SEIYAKU CO LTD.   
 
Statistical Analysis Plan – Final Version,09 December 2021– Page 19 of 22 
o If a patient discontinues for any other reason, missing global assessments at Visit 
7 will be imputed by LOCF from Visit 5 and missing assessments at Visit 5 will 
not be imputed. 
• If a patient assesses efficacy at the site < 6 hours after using rescue medication, 
imputation will be discussed in the Blind Review Meeting, with consideration given to 
the frequency of this issue in the database and the elapsed time between rescue and 
assessment of efficacy. 
• If a patient assesses spontaneous pain intensity and spontaneous pain relief at the time of 
rescue taken because of blunt trauma pain, any assessment conducted in the following 6 h 
will be replaced by the corresponding assessment done at the time of rescue. 
• If a patient assesses spontaneous pain intensity and spontaneous pain relief at the time of 
rescue taken for reason other than blunt trauma pain, any assessment conducted in the 
following 6 h will be imputed as if the assessment were missed.  
• If there are no assessments in the 12-24 h window, or the 24-48 h window,  
o if the patient has not prematurely terminated, a value from the last preceding 
assessment or assessment window will be carried forward.  
o if the patient has prematurely terminated, imputation will proceed as described for 
assessments at the site.  
• If the patient provides no post-baseline efficacy data, imputation will be considered in the 
Blind Review Meeting. 
 
A Blind Review Meeting will take place before unblinding the randomization code. Handling of 
missing values/censoring/discontinuation, if necessary, will be provided and discussed in the 
Blind Review Meeting. Additional data handling rules will be specified in the BRM minutes to 
cover issues not anticipated in the above stipulations. 
 
14.9 Censoring 
• Time to meaningful relief will be censored (if appropriate) at the time of the final 
assessment of meaningful relief. If the patient discontinues for lack of efficacy before 
achieving meaningful relief, it will be censored at 24 h.  
• Time to perceptible relief will be censored (if appropriate) at 24h or the time of final 
assessment of spontaneous pain relief (if earlier). If the patient discontinues for lack of 
efficacy before achieving perceptible relief it will be censored at 24 h.  
• Time to resolution of blunt trauma will be censored (if appropriate) at the day of the final 
visit. If the patient discontinues for lack of efficacy, it will be censored at 7 days.  
• Time to first use of rescue medication will be censored (if appropriate) at the last day for 
which diary records are available.  
 
If a patient takes a disallowed analgesic medication and subsequently provides efficacy 
assessments, rules will be established on a case-by-case basis, taking into consideration 
whether the disallowed analgesic medication was taken to treat pain in the injured area and 
the likely duration of effect of the medication. The rules will be documented before the study 
is unblinded.  
 
Additional data handling rules will be specified in the minutes of the BRM, if any,  to cover 
issues not anticipated in the above stipulations. 


 
Trial Substance: 
Esflurbiprofen Hydrogel Patch 
Study No.:              TK-254R-0201 
EudraCT No.:         2020-005165-14 
Short Title: 
Local symptomatic and short-term treatment of 
pain in acute strains, sprains or bruises of the 
extremities following blunt trauma 
Sponsor:   TEIKOKU SEIYAKU CO LTD.   
 
Statistical Analysis Plan – Final Version,09 December 2021– Page 20 of 22 
14.10 Interim Analysis 
Not applicable. 
 
14.11 Subject disposition 
Subject disposition data (number of subjects screened, assigned to treatment, completing each 
assessment and the primary reason for withdrawal, number of each analysis population, subjects 
excluded from each analysis population) will be summarized overall for all subjects. 
 
A by-subject listing will be provided showing all screened subjects who were not eligible to be 
assigned to treatment together with the reason for non-eligibility.  
 
Number and percentage of subjects assigned to treatment who discontinued the study 
prematurely will be summarized for the overall population and stratified by reason for study 
discontinuation. Multiple reasons are possible. 
 
A by-subject listing will be provided showing for all subjects assigned to treatment whether they 
completed study (yes/no), the reason(s) for study discontinuation (where applicable), and the 
dates of: 
 
• the informed consent, 
• the first application of study medication, 
• the last application of study medication, 
• discontinuation / withdrawal, where applicable. 
 
14.12 Extent of exposure 
For each subject, the individual study duration will be calculated in days as “dlastVisit – dVisit 1 +1”, 
where dlastVisit is the date of last visit documented and dVisit 1 is the date of Visit 1, respectively. 
 
Exposure to IMP will be summarized descriptively as (1) number of applications made and (2) 
Study duration (in days). 
 
Summary statistics will be tabulated for the safety population. 
 
14.13 Treatment compliance, rescue medication, other concomitant therapies 
Compliance is defined in terms of the total number of study medication patches used and total 
number of applications made through Visit 7 as follows:   
• Good: > 80% of the patch has been applied and > 80% of scheduled applications made,   
• Moderate: not Good and not Poor  
• Poor: < 50% of the patch has been applied or < 50% of scheduled applications made.  
 
Compliance in patients with missing data on patch counts will be documented in the Blind 
review meeting before unblinding.  
 
The % of patch used through Visit 7 will be computed relative to the actual number of 
applications made from randomization through Visit 7. Scheduled applications will include all 
scheduled applications through Visit 7.  


 
Trial Substance: 
Esflurbiprofen Hydrogel Patch 
Study No.:              TK-254R-0201 
EudraCT No.:         2020-005165-14 
Short Title: 
Local symptomatic and short-term treatment of 
pain in acute strains, sprains or bruises of the 
extremities following blunt trauma 
Sponsor:   TEIKOKU SEIYAKU CO LTD.   
 
Statistical Analysis Plan – Final Version,09 December 2021– Page 21 of 22 
 
Compliance will be summarized descriptively as (1) % of scheduled applications made, (2) % of 
patches used relative to number of actual applications and (3) compliance category 
(Good/Moderate/Poor).  
 
Use of concomitant therapies will be listed. Use of rescue medication is an efficacy outcome and 
is discussed further below. Exposure to study drug will be summarized descriptively as (1) 
number of applications made and (2) total amount of patch used. 
 
14.14 Medical history 
Diseases will be coded according to MedDRA Version 24.0.  
 
Details of the Medical History will be listed. 
 
14.15 Previous and concomitant medications 
Medications will be coded by means of DRL (WHO-DD).  
 
A previous medication is a medication used only before the date of first dose of study medication 
(medication end date < date of first dose of study medication). All other medications are 
concomitant.  
 
If medication start and/or stop dates are missing or partial, the dates will be compared as far as 
possible with the date of first dose of study medication. Medications will be assumed to be 
concomitant, unless there is clear evidence (through comparison of partial dates) to suggest that 
the medication started and stopped prior to the first dose of study medication. If there is clear 
evidence to suggest that the medication stopped prior to the first dose of study medication, the 
medication will be assumed to be previous. 
 
Medications starting after the completion/withdrawal date will be listed but will not be classified 
or summarized.  
 
Information on previous and/or concomitant medication will be listed with flags to differentiate 
previous and/or concomitant medications. 
 
15 VISIT WINDOWS 
All data will be organized and analyzed according to the scheduled visits outlined in the protocol. 
 
Visit 
1 
2 
3 
4 
5 
6 
7 
Day 
1 
1 or 2 
2 
3 
4 
5 
7, 8 or 9 
Time after 1st treatment 
0 h 
12 h 
(±1 h) 
24 h  
(±2 h) 
48 h  
(±4 h) 
72 h 
(±4 h) 
96 h  
(±4 h) 
7 d 
(±1 d) 
 


 
Trial Substance: 
Esflurbiprofen Hydrogel Patch 
Study No.:              TK-254R-0201 
EudraCT No.:         2020-005165-14 
Short Title: 
Local symptomatic and short-term treatment of 
pain in acute strains, sprains or bruises of the 
extremities following blunt trauma 
Sponsor:   TEIKOKU SEIYAKU CO LTD.   
 
Statistical Analysis Plan – Final Version,09 December 2021– Page 22 of 22 
16 LANGUAGE AND HEADINGS 
All tables, figures and listings as well as the Integrated Clinical Trial Report (ICTR) will be 
produced in English language. 
 
17 ARCHIVING 
After the finalization of the analysis and the reporting, the following documents will be provided 
to the sponsor for archiving purposes: 
 
• the CRFs, 
• the resolved queries, 
• the Statistical Analysis Plan (pdf format), 
• the Blind Review protocol (pdf format), 
• database on CD (SAS files), 
• the Clinical Study Report (CSR) (WORD 2010 format and pdf format). 
 
18 LIST OF STAFF 
A list of key study personnel can be found in the Data Management Plan (DMP, Appendix 1). 
 
19 REFERENCES 
[1] 
Gibaldi M, Perrier D. Estimation of Areas. Pharmakokinetics. Marcel Dekker Inc, 
New York, 1982, 445-449.