Continuous Wound Infiltration After Hallux Valgus Surgery A Prospective, Randomized, Double-blind and Placebo-controlled Single-center Trial
Phase: PHASE4
Conditions: Hallux Valgus
Sponsor: Medical University Innsbruck

 
 
 
Continuous wound infiltration after hallux valgus surgery 
 
 
 
 
 
Study protocol, version 1.4, 28-02-2014 
Page 1 of 37 
STUDY PROTOCOL 
Version 1.4, 28-02-2014 
 
Confidential 
 
Title of the Study  
Continuous wound infiltration after hallux valgus surgery  
 
Abbreviated Designation 
CWI-HVS 
 
Study Design 
 
Prospective, randomized, double-blind and placebo-controlled  
 
Sponsor 
Medical University of Innsbruck 
as representative: Univ. Prof. Dr. Martin Krismer 
Innrain 52, Christoph-Probst-Platz 
6020 Innsbruck 
Austria 
 
 
Study protocol code 
of the sponsor 
CWI-HVS 
 
EudraCT Number 
2013-005106-64 

 
 
 
Continuous wound infiltration after hallux valgus surgery 
 
 
 
 
 
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SPONSOR OF THE STUDY 
 
  
 
 
 
 
Confidentiality 
The information provided in this protocol is strictly confidential and is made available to the principal investi-
gators, potential principal investigators, health authorities, and ethics committees for inspection and/or re-
view. It is prohibited to publish any information without prior written consent. Exempted herefrom shall be the 
act of obtaining a declaration of consent from a potential study participant. After execution, the regulations 
set out in this protocol shall be binding on all parties. 
Declaration of the sponsor 
The present study protocol has undergone critical review. The content is in accordance with the current 
risk/benefit assessment of the described methods as well as with the moral, ethical and scientific principles 
of Good Clinical Practice, the Declaration of Helsinki in its latest version and with local laws and ordinances. 
PD Dr. Rainer Biedermann 
Principal Investigator of the Study  
 Place, Date, Signature 
Univ. Prof. Dr. Krismer Martin 
Head of Organizational Unit 
Representative of the Medical University of Inns-
bruck 
Place, Date, Signature  
The signatories mentioned above confirm that they have read the present study protocol and confirm that the 
study protocol contains all information necessary for conducting the study. Moreover, they confirm to conduct 
the study according to the present study protocol. It is agreed that any information previously not published 
shall be subject to strict confidentiality. 

 
 
 
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SIGNATURES 
Trial Product: Ropinaest® (ropivacaine hydrochloride) 2mg/ml amp. 10ml/-20ml injection solution 
Study Title: Continuous wound infiltration after hallux valgus surgery 
Abbreviated Title: CWI-HVS 
EudraCT Number: 2013-005106-64 
 
Declaration of the biometrician, the study coordinator and the responsible monitor: 
I have read this study protocol and I agree with the content of this study protocol. I confirm that it contains all 
information necessary for conducting the study. I agree to conduct the study pursuant to the provisions set 
out in this protocol. In particular, I will comply with the moral, ethical and scientific principles of Good Clinical 
Practice (GCP), the Declaration of Helsinki in its latest version, the local laws and regulations as well as with 
the relevant regulatory requirements. 
I will immediately indicate any changes to the responsibility of each of the signatories. 
I confirm that I will treat with strictest confidentiality all information and documents which have not yet been 
published in advance. These documents include the study protocol, the Investigator’s Brochure, case report 
forms and other scientific data. 
Mag. Dennis Huber  
Biometrician 
 Place, Date, Signature 
PD Dr. Rainer Biedermann  
Study Coordinator 
Place, Date, Signature  
Dr. Braito Inge 
Responsible Monitor 
Place, Date, Signature  

 
 
 
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SIGNATURES 
Investigational Product: Ropinaest® (ropivacaine hydrochloride) 2mg/ml amp. 10ml/-20ml injection solution 
Study Title: Continuous wound infiltration after hallux valgus surgery 
Abbreviated Title: CWI-HVS 
EudraCT Number: 2013-005106-64 
Declaration of the center-specific principal investigator: 
I have read this study protocol and I confirm that it contains all information necessary for conducting the 
study. I agree to conduct the study pursuant to the provisions set out in this protocol. In particular, I will com-
ply with the moral, ethical and scientific principles of Good Clinical Practice (GCP), the Declaration of Helsin-
ki in its latest version, the local laws and regulations as well as with the relevant regulatory requirements. 
I confirm that I will treat with strictest confidentiality all information and documents which have not yet been 
published in advance. These documents include the study protocol, the Investigator’s Brochure, case report 
forms and other scientific data. 
 
 
 
Place, Date 
 
Name in capital letters 
 
 
 
 
 
Signature 
 

 
 
 
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Table of contents 
Page 
 
List of abbreviations 
........................................................................................................... 6 
Individuals/Institutions involved ...................................................................................................... 7 
Synopsis  ........................................................................................................................................... 8 
1 
Introduction ..................................................................................................... 13 
1.1 
Study background ....................................................................................................... 13 
1.2 
Need for the study to be conducted ............................................................................. 13 
1.3 
Risk/Benefit assessment ............................................................................................. 13 
2 
Study aims ...................................................................................................... 14 
2.1 
Primary study aim ....................................................................................................... 14 
2.2 
Secondary study aims ................................................................................................. 14 
3 
Description of the study ................................................................................. 14 
3.1 
Study design ............................................................................................................... 14 
3.2 
Primary endpoint of the study ...................................................................................... 14 
3.3 
Secondary endpoint of the study ................................................................................. 14 
3.4 
Number of patients ...................................................................................................... 15 
3.5 
Schedule ..................................................................................................................... 15 
4 
Patient population .......................................................................................... 15 
4.1 
Inclusion criteria .......................................................................................................... 15 
4.2 
Exclusion criteria ......................................................................................................... 15 
5 
Trial medication .............................................................................................. 15 
5.1 
Description of trial medication (cf. also specialist information) ..................................... 15 
5.2 
List of side effects and interactions .............................................................................. 16 
5.3 
Placebo, comparator product ...................................................................................... 18 
5.4 
Randomization ............................................................................................................ 18 
5.5 
Treatment scheme ...................................................................................................... 18 
5.5.1 
Administration instructions 
18 
5.5.2 
Emergency measures 19 
5.5.3 
Concomitant medication 
19 
5.6 
Storing, issuing and taking back as well as documenting the trial medication (drug 
accountability) ............................................................................................................. 19 
5.7 
Compliance ................................................................................................................. 19 
5.8 
Blinding and emergency envelopes ............................................................................. 19 
5.8.1 
Blinding 
19 

 
 
 
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5.8.2 
Emergency envelopes 19 
5.8.3 
Premature unblinding 20 
5.8.4 
Regular unblinding 
20 
6 
Course of study .............................................................................................. 20 
6.1 
Visit 1 (baseline, day 0) ............................................................................................... 20 
6.2 
Visit 2 (day 1 – 3) ........................................................................................................ 21 
6.3 
Visit 3 (day 7 ± 3) ........................................................................................................ 21 
6.4 
Visit 4 (day 14 ± 3) ...................................................................................................... 21 
6.5 
Visit 5 (final visit; day 42 ± 7) ....................................................................................... 21 
6.6 
Follow-up examinations ............................................................................................... 21 
6.6.1 
Assessment of effectiveness 
21 
6.6.2 
Safety assessment 
22 
6.6.3 
Radiographic examinations 
22 
6.7 
Further treatment of the patients after conclusion of the trial ....................................... 22 
6.8 
Drop-out of patients (drop-out) .................................................................................... 22 
6.9 
Premature termination of the clinical trial ..................................................................... 22 
7 
Adverse events, adverse reactions ............................................................... 23 
7.1 
Definitions ................................................................................................................... 23 
7.2 
Documentation of AEs ................................................................................................. 23 
7.3 
Documentation of SAEs .............................................................................................. 24 
7.4 
Reporting of Adverse Events and Adverse Reactions ................................................. 24 
7.4.1 
Definitions 24 
7.4.2 
Duty to report suspected unexpected serious adverse reactions (SUSARS) 
25 
8 
Documentation ................................................................................................ 25 
8.1 
Case report form (CRF) ............................................................................................... 26 
8.2 
Investigator site file ..................................................................................................... 26 
8.3 
Data storage ............................................................................................................... 26 
8.3.1 
Obligation of the sponsor to store data 
26 
8.3.2 
Obligation of the investigator to store data 
26 
9 
Monitoring and audit ...................................................................................... 27 
9.1 
Monitoring ................................................................................................................... 27 
9.2 
Audit ............................................................................................................................ 27 
10 
Data entry and data management ................................................................. 28 
11 
Statistics .......................................................................................................... 28 
11.1 
Sample size planning .................................................................................................. 28 
11.2 
Randomization ............................................................................................................ 29 

 
 
 
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11.3 
Statistical methods ...................................................................................................... 29 
11.3.1 
Dependent variables 
29 
11.3.2 
Definition of analysis sets 
30 
11.3.3 
Data analysis 
30 
12 
Reporting ......................................................................................................... 30 
12.1 
Trial report ................................................................................................................... 30 
12.2 
Publications ................................................................................................................. 30 
13 
Ethical, legal and administrative aspects ..................................................... 31 
13.1 
Responsibilities of sponsor and investigator ................................................................ 31 
13.2 
Decision of the ethics commission and notification to authorities ................................. 31 
13.3 
Patient information and declaration of consent ............................................................ 31 
13.4 
Patient insurance ........................................................................................................ 32 
13.5 
Data protection and obligation to secrecy .................................................................... 32 
14 
Changes to the study protocol (amendments) ............................................. 33 
15 
Annex ............................................................................................................... 34 
16 
Literature ......................................................................................................... 35 
 

 
 
 
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List of abbreviations 
AE 
Adverse Event  
AMG 
Medicinal Products Act (Arzneimittelgesetz) 
AR 
Adverse Reaction  
BASG 
Federal Office for Safety in Health Care (Bundesamt für Sicherheit im Gesundheitswesen) 
CRA 
Clinical Research Associate 
CRF 
Case Report Form  
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data Safety Monitoring Board  
eCRF 
Electronic Case Report Form  
FPFV 
First patient first visit 
GCP 
Good Clinical Practice 
GZGG 
Hallux Metatarsophalangeal Joint (Großzehengrundgelenk) 
i. v. 
intravenous 
ICH 
International Conference on Harmonization 
ISF 
Investigator Site File  
KKS 
Coordination Center for Clinical Studies (Koordinierungszentrum für Klinische Studien) 
LPLV 
Last patient last visit 
NA 
not applicable  
ND 
not done 
p. o. 
per os 
ROM 
Range of motion 
SAE 
Serious Adverse Event  
SAR 
Serious Adverse Reaction  
SAS 
Statistical Analysis System 
SDV 
Source Data Verification 
SOP 
Standard Operating Procedure 
SPSS 
Statistical Package for the Social Sciences 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
 
TMF 
Trial Master File 
UAR 
Unexpected Adverse Reaction  
VRS 
Verbal Rating Scale 
VPRS 
 
Verbal Pain Rating Scale

 
 
 
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Individuals/Institutions involved 
 
Sponsor: Medical University of Innsbruck, as representative: Univ. Prof. Dr. Martin Krismer, Innrain 
52, Christoph-Probst-Platz, A-6020 Innsbruck 
Study coordination: PD Dr. Rainer Biedermann; University Hospital for Orthopaedics of Innsbruck, 
Anichstraße 35, A-6020 Innsbruck; Phone: 0043/512/504-80315; Fax: 0043/512/504-22693; E-
Mail: rainer.biedermann@i-med.ac.at 
Data management: Dr. Matthias Braito; University Hospital for Orthopaedics of Innsbruck, An-
ichstraße 35, A-6020 Innsbruck; Phone: 0043/512/504-81214; Fax: 0043/512/504-22693; E-Mail: 
matthias.braito@tilak.at 
 
Monitoring: Dr. Braito Inge; Richardsweg 21, A-6020 Innsbruck 
 
Biometrics: Mag. Dennis Huber; Department for Experimental Orthopaedics, Innrain 36, A-6020 
Innsbruck; Phone: 0043/512/9003-71693; Fax: 0043/512/9003-73691; E-Mail: dennis.huber@i-
med.ac.at  
 

 
 
 
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Synopsis 
Sponsor 
Medical University of Innsbruck 
Title 
Continuous wound infiltration after hallux valgus surgery 
Abbreviated Des-
ignation 
CWI-HVS 
Target Population 
Patients who undergo hallux valgus surgery. 
Study Design 
Prospective, Randomized, Double-blind, Placebo-controlled Trial 
Study Aims 
Primary Study Aim : 
Proof that there is a significant difference in pain between continuous 
wound infiltration and placebo during the first 48 postoperative hours. 
Secondary Study Aim:  
Proof that there is a significant difference in patient satisfaction and in the 
amount of rescue medication needed between continuous wound infiltra-
tion and placebo during the first 48 postoperative hours. 
Study endpoints 
(dependent varia-
bles) 
Primary endpoint 
Average and maximum VPRS (verbal pain rating score) for pain during the 
first 48 postoperative hours. 
Secondary endpoints 
(1) Endpoints related to safety during treatment period: occurrence of AEs, 
ARs and UARs. 
(2) Endpoints related to effectiveness: patient satisfaction (VRS), clinical 
outcome (AOFAS forefoot score, ROM GZGG after 6 weeks), pain (VPRS) 
after 1, 2 and 6 weeks, need for rescue pain medication 
Number of Patients 50 
Schedule 
Study-related 
 
Recruitment time: 1 Year 
 
Planned Start (FPFV): 01-03-2014 
 
Planned Study Completion (LPLV): 06/2017 
Patient-related 
 
Duration of treatment: 6 weeks 
Inclusion Criteria 
 Male and female patients over the age of 18 years 
 Written consent of the patient after information 
 Patients undergoing a distal metatarsal osteotomy (only Chevron or 
Scarf) and lateral release of the adductor hallucis muscle with/without 
concomitant osteotomy of the proximal phalanx of the great toe (Akin) 
for idiopathic hallux valgus deformity. 

 
 
 
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Exclusion Criteria 
 
 
 
 
 A history of hypersensitivity / contraindication to one of the drugs ad-
ministered, their ingredients or to drugs with a similar chemical struc-
ture. 
 Other methods of hallux valgus surgery / additional surgeries than those 
mentioned.  
 Neurological disorder that affects the sensorimotor function.  
 Surgery with general anaesthesia. 
 Surgery on the same leg within the last month. 
 Existing pregnancy. 
Course of the 
Study 
 
 
 
See study protocol: 
Visit 1 (day 0): admission and consent to study 
Visit 2 (day 1-3): surgery (day 1) and stay in hospital 
Visit 3 (day 7 ± 3): 1st outpatient follow-up 
Visit 4 (day 14 ± 3): 2nd outpatient follow-up 
Visit 5 (final visit, day 42 ± 7): 3rd outpatient follow-up 
Study-related Pro-
cedures and La-
boratory Examina-
tions 
AOFAS forefoot score (1x presurgical and 1x postsurgical), 1x presurgical 
pregnancy test 
Trial Medication 
Agent: ropivacaine 0.2 % 
Trade name: Ropinaest®2 mg/ml 
Manufacturer: Gebro Pharma GmbH, Fieberbrunn, Austria 
Treatment Plan 
Treatment Group:  
 
Trial Medication: ropivacaine 0.2 % 
Dose: 2 mg/ml 
Route of Administration: continuous wound infiltration 
Frequency: 2 ml/h 
Duration of Therapy: 24 hours 
 
Control Group:  
 
Trial Medication: NaCl 0.9 % 
Dose: 9 mg/ml 
Route of Administration: continuous wound infiltration 
Frequency: 2 ml/h 
Duration of Therapy: 24 hours 

 
University Hospital for Orthopaedics 
 
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Visit Plan 
 
1 
Day 0 
(Baseline Visit) 
2 
Day 1 - 3 
3 
Day 7 ± 3 
4 
Day 14 ± 3 
XX 
Day 24 ± 7 
(Final Visit) 
Declaration of consent 
 
 
 
 
 
Inclusion / Exclusion criteria 
 
 
 
 
 
Demographic data 
 
 
 
 
 
AOFAS forefoot score 
 
 
 
 
 
ROM GZGG 
 
 
 
 
 
Randomization 
 
 
 
 
 
Laboratory examination of women of 
childbearing age (pregnancy test) 
 
 
 
 
 
Trial medication1 
 
 (24 hours) 
 
 
 
VRS pain  
 
 (every 4 hours) 
 
 
 
Need for rescue medication 
 
 
 
 
 
AEs, SAEs and SUSARs 
 
 
 
 
 
__________ 
1 Ropinaest® 2 mg/ml or or [sic] NaCl 0.9 % (physiological saline solution) to allow continuous wound infiltration at a rate of 2 ml/h for 24 hours 
 

 
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1 Introduction 
1.1 
Study background 
Hallux valgus surgeries are orthopaedic surgeries which are performed on a frequent basis and 
which lead to significant pain, in particular within the first 24 postoperative hours. Continuous 
wound infiltration by means of local anaesthetic in the framework of multi-modal pain therapy has 
already been tested in many other surgeries (abdominal surgery, shoulder surgeries, hip and knee 
joint endoprosthetics). 
1.2 
Need for the study to be conducted 
In particular within the first 24 postoperative hours, hallux valgus surgeries lead to significant pain 
even though NSAR and opiates are routinely administered. In order to further improve pain thera-
py, a multi-modal pain therapy is necessary. So far, the use of continuous wound infiltration follow-
ing hallux valgus surgery has not been investigated. In order to prove the effectiveness of continu-
ous wound infiltration by means of a local anaesthetic, the comparison with a placebo group is 
necessary. The routine use of continuous wound infiltration could further improve postsurgical pain 
therapy following hallux valgus, and could thus contribute to a higher patient satisfaction. 
 
1.3 
Risk/Benefit assessment 
So far, other studies have reported no increased rate in local or systemic complications by inser-
tion of a pain catheter and by usage of continuous wound infiltration, even when higher doses of 
the local anaesthetic were administered. The advantage of the method lies in particular in the local 
action mechanism with only small effects on the rest of the body. 
Ropivacaine is, due to its favourable side effect profile, the local anaesthetic used most frequently 
for this indication. Possible side effects of ropivacaine include decrease/increase in blood pressure 
as well as in the heart rate, vertigo, headaches, nausea including vomiting, tingling and fever. 
Sudden life-threatening allergic reactions are rare and concern 1 to 10 treated persons out of 
10000. Further serious side effects, which could be caused by an overdosage of Naropin, include 
problems when speaking, muscle twitching, trembling, convulsions and loss of consciousness. 
Applying the study therapy could result in a reduced need for systemically effective analgesics and 
in less postsurgical pain. The head of the study deems the risk/benefit ratio favourable.  
The study visits will be carried out in the course of the routine clinical follow-up examinations after 
1, 2 and 6 weeks. This does not result in any additional risk or any additional stress for the pa-
tients. 
 
 

 
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2 Study aims 
2.1 
Primary study aim 
The aim of this study is to document the effect of a postsurgical continuous wound infiltration in 
comparison with standard treatment. The average and maximum postsurgical pain during the first 
48 postoperative hours was chosen as primary endpoint, which shall be recorded by means of 
VRS (verbal rating scale) for pain: 
The null hypothesis is as follows: during the first 48 hours, there is no significant difference in 
postsurgical pain between continuous wound infiltration with Ropinaest® and placebo.  
The alternative hypothesis is as follows: during the first 48 hours, there is a significant difference in 
postsurgical pain between continuous wound infiltration with Ropinaest® and placebo. 
The significance level is chosen with p < 0.05. 
 
2.2 
Secondary study aims 
The need for rescue pain medication, the patients’ satisfaction with surgery and pain therapy (col-
lected by means of VRS) and the clinical outcome (collected by means of AOFAS forefoot score) 
were defined as parameters of secondary objective. Furthermore, the occurrence of UAEs and 
AEs is collected. These shall be collected in a purely descriptive manner. 
 
 
 
3 Description of the study 
3.1 
Study design 
This is a monocentric, randomized, double-blind, placebo-controlled study. 
 
3.2 
Primary endpoint of the study 
The average and maximum postsurgical pain during the first 48 postoperative hours was chosen 
as primary endpoint which shall be recorded by means of VPRS (verbal pain rating scale) for pain. 
 
3.3 
Secondary endpoint of the study 
The need for rescue pain medication, the patients’ satisfaction with surgery and pain therapy (col-
lected by means of VRS) and the clinical outcome (collected by means of AOFAS forefoot score) 
were defined as parameters of secondary objective. Furthermore, the occurrence of UAEs and 
AEs as well as the need for rescue pain medication is collected. 
 
 

 
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3.4 
Number of patients 
The study includes a total of 50 patients, 25 of which are in the verum group and 25 of which are in 
the placebo group. 
 
3.5 
Schedule 
The time needed for recruitment is estimated to be 1 year. Planned start (FPFV) is on 01-03-2014, 
planned study completion (LPLV) is on 31-06-2017. The duration of treatment including follow-up 
examination is 6 weeks. 
 
 
4 Patient population 
4.1 
Inclusion criteria 
 Male and female patients over the age of 18 years 
 Written consent of the patient after information 
 Patients undergoing a distal metatarsal osteotomy (only Chevron, Scarf) and lateral release of 
the adductor hallucis muscle with/without concomitant osteotomy of the proximal phalanx of the 
great toe (Akin) for idiopathic hallux valgus deformity. 
 
4.2 
Exclusion criteria 
 A history of hypersensitivity / contraindication to one of the drugs administered or to their ingre-
dients or to drugs with a similar chemical structure. 
 Other methods of hallux valgus surgery and additional surgeries of the little toes other than 
those mentioned. 
 Neurological disorder that affects the sensory-motor function.  
 Refusing to participate in the study or refusal of consent to study. 
 Existing pregnancy. 
 Surgery on the same leg within the last month. 
 Surgeries with general anaesthesia. 
 
 
 
5 Trial medication 
5.1 
Description of trial medication (cf. also specialist information) 
 
Agent: ropivacaine 0.2 % 
 
Trade name: Ropinaest® 2 mg/ml 

 
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 
Manufacturer: Gebro GmbH, 6391 Fieberbrunn, Austria 
 
Ingredients: The agent is: ropivacaine hydrochloride. Ropinaest® 2 mg/ml contains 2 mg of 
ropivacaine hydrochloride per ml solution (in the form of ropivacaine hydrochloride 1 H2O). 
Further components are: sodium chloride, hydrochloric acid and sodium hydroxide for pH 
regulation, water for the purpose of injection. 
 
Packaging: Naropin is a clear, colorless solution for injection. 10 ml and 20 ml ampoules of 
polypropylene in sterile blister packs with 5 pieces or 5x5 pieces (hospital pack). 
 
Storage: Keep the medicinal product out of the sight and reach of children. The medicinal 
product may not be used after the expiry date stated on the label and the carton. The expiry 
date refers to the last day of the indicated month. Do not store at temperatures above 25°C. 
Do not freeze. Normally, Ropinaest is stored at your doctor’s practice or at the hospital. 
They are also responsible for the quality of the product if it is opened but not immediately 
used. The medicinal product must be visually inspected before use. The solution shall only 
be used if it is clear and practically free of particles and if the container is not damaged. 
They are also responsible for the right disposal of any Ropinaest that has not been used. 
 
Shelf life: From a microbiological point of view, the product shall be applied immediately 
after opening. If it is not applied immediately, the user – before using the medicinal product 
– is responsible for the duration and conditions of storage after opening which, in general, 
should not exceed 24 hours at 2 – 8°C. 
 
Precautions, incompatibilities: ropivacaine infusion solution is chemically and physically 
compatible with: Fentanyl citrate, sufentanil citrate, morphine sulfate, clonidine hydrochlo-
ride. From a microbiological point of view, mixtures should be used immediately. If they are 
not used immediately, the user – before using the medicinal product – is responsible for the 
duration and conditions of storage after opening which, in general, should not exceed 24 
hours at 2 – 8°C. 
 
5.2 
List of side effects and interactions 
The side-effect profile of ropivacaine is similar to the side-effect profile of other long-acting local 
anaesthetics of the amide type. Side effects are to be distinguished from physiological effects 
caused by the block anaesthesia itself (e.g. decrease of blood pressure and bradycardia during 
spinal/epidural anaesthesia). 
Very frequently (> 1/10)  
 
Angiopathies: hypotension 
 
Disorders of the gastro-intestinal tract: nausea 
Frequently (> 1/100)  
 
Diseases of the nervous system: headache, paraesthesia, daze Cardiac diseases: brady-
cardia, tachycardia  
 
Angiopathies: hypertonia  
 
Diseases of the gastro-intestinal tract: vomitingb 

 
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 
Diseases of the kidney and urinary tract: urinary retention  
 
General disorders and administration site conditions: rise in temperature, rigor, back pain 
Occasionally (> 1/1000) 
 
Psychiatric disorders: fearfulness  
 
Diseases of the nervous system: symptoms of a CNS toxicity (convulsions, grand mal type 
convulsions, epileptic seizures, daze, perioral paraesthesia, numbness of the tongue, hy-
peracousis, tinnitus, visual impairment, dysarthria, muscle twitching, tremor)**, hypoesthe-
sia  
 
Angiopathies: syncope 
 
Diseases of the respiratory tract, chest and mediastinum: dyspnoea  
 
General disorders and administration site conditions: hypothermia 
Rare (< 1/1000) 
 
Cardiac diseases: cardiac arrest, cardiac dysrhythmias  
 
General disorders and administration site conditions: allergic reactions (anaphylactic reac-
tions, angioneurotic oedema and urticaria) 
Acute systemic toxicity 
Systemic toxic reactions mainly affect the central nervous system (CNS) and the cardiovascular 
system (CVS). Such reactions are caused by high blood concentrations of a local anaesthetic 
which may occur following (unintended) intravascular injection, overdosage or unusually quick ab-
sorption in highly vascularized areas. CNS reactions are similar in all amide-type local anaesthet-
ics, whereas cardial reactions rather depend on the agent as far as quantity as well as quality are 
concerned. 
CNS toxicity 
CNS toxicity reactions occur gradually with signs and symptoms of increasing severity. Early symp-
toms such as visual and hearing impairments, perioral numbness, vertigo, light dizziness, tingling 
and paraesthesias are observed. Dysarthria, muscle rigidity and muscle twitching are more severe 
and may indicate the onset of generalized convulsions. These signs may not be falsely interpreted 
as neurotic behaviour. Unconsciousness and grand mal may follow which may last from a few sec-
onds to several minutes. During the convulsions, hypoxia and hypercapnia, together with a breath-
ing disturbance, quickly occur due to the increased muscular activity. In severe cases even apnoea 
may occur. Respiratory and metabolic acidosis increases and prolongs the toxic effects of the local 
anaesthetics. Improvement occurs after redistribution of the local anaesthetic from the central 
nervous system and the ensuing metabolism and elimination. Improvement can occur quickly if no 
great dosages of the medicinal product were injected. 
Toxicity to the cardiovascular system 
Cardiovascular toxicity proves to be a more serious condition. Hypotension, bradycardia, arrhyth-
mia and even cardiac arrest may occur as a result of high systemic concentrations of the local an-
aesthetic. I. v. infusion of ropivacaine in subjects caused a reduction in impulse conduction and 

 
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contractility. In general, toxic effects to the cardiovascular system are first manifested with CNS 
toxicity symptoms, except for when the patient receives general anaesthesia or if he/she is pro-
foundly sedated with substances such as benzodiazepines or barbiturates. 
 
5.3 
Placebo, comparator product 
 
Agent: sodium chloride 0.9 % 
 
Trade name: physiological saline solution “Fresenius” 
 
Manufacturer: Fresenius Kabi Austria GmbH Hafnerstraße 36, 8055 Graz, Austria 
 
Ingredients: the agent is: sodium chloride. The other components are: hydrochloric acid, 
sodium hydroxide, water for injection purposes. 
 
Packaging: physiological saline solution “Fresenius” is a clear and colorless infusion solu-
tion, available in glass bottles, polyethylene bottles, polypropylene bottes, intravenous 
bags, vials, polyethylene ampoules and polypropylene ampoules. 
 
5.4 
Randomization 
Randomization takes place in 2 groups as balanced randomization by means of a computer-
generated random number sequence. This random number sequence is generated with the help of 
the website www.random.org (numbers, random sequence generator). The first 25 results are as-
signed to the verum group, the other 25 results are assigned to the placebo group. Upon admis-
sion to the study, the patients receive at random one of these numbers which are contained in 
sealed envelopes on which the numbers 1 to 50 are written. The randomization envelope is 
opened by an independent member of the nursing staff – who is not involved in the further treat-
ment of the patient – several minutes prior to the start of surgery. Such member will fill a 50 ml 
perfusor syringe with either ropivacaine 0.2 % or physiological saline solution. The patients, sur-
geons as well as the care-taking nursing staff are blinded as regards the content. The deciphering 
list will only be opened after conclusion of the last follow-up examination. 
 
 
5.5 
Treatment scheme 
5.5.1 Administration instructions 
At the end of every patient's surgery, a pain catheter (InfiltraLong Katheter 19G x 420mm, Pajunk 
Medizintechnologie GmbH) is placed in the surgical wound through which ropivacaine 0.2 % 
(verum) or NaCl 0.9 % (placebo) is continuously administered at a rate of 2 ml/h during the first 24 
postsurgical hours via a syringe pump. The catheter is removed on the following day in the course 
of the routine change of dressing. 
As for standard pain treatment (Non Investigational Medicinal Product, NIMP), the patients receive 
naproxen 500 mg (Naprobene®, ratiopharm Arzneimittel Vertriebs-GmbH, Wien, Austria) p.o. in 
the morning and in the evening from day 1 to 8 as well as hydromorphine 2.6 mg (Hydal®, Mundi-
pharma Ges.m.b.H., Austria) p.o. in case of VRS > 3 (every 4 hours at maximum) from day 1 to 3. 
 

 
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5.5.2 Emergency measures 
In the unlikely case that an allergic reaction or signs of a systemic toxicity occur(s), the supply of 
the trial substance is interrupted immediately and emergency treatment in accordance with the 
responsible doctor is provided. 
 
5.5.3 Concomitant medication 
As for standard pain treatment (NIMP), the patients receive naproxen 500 mg (Naprobene®, rati-
opharm Arzneimittel Vertriebs-GmbH, Wien, Austria) p.o. in the morning and in the evening as well 
as hydromorphine 2.6 mg (Hydal®, Mundipharma Ges.m.b.H., Austria) p.o. in case of VRS > 3 
(every 4 hours at maximum) in the course of their stay in hospital. After discharge on the 2nd day 
following surgery, the patient is prescribed naproxen 500 mg 2x each day for 5 days. 
 
 
5.6 
Storing, issuing and taking back as well as documenting the trial medication 
(drug accountability) 
The trial medication is provided by the nursing staff of the pain outpatient department of the Uni-
versity Hospital of Innsbruck. The investigator is responsible for issuing, taking back and docu-
menting the trial medication in the trial center. The trial medication (including the pain catheters 
used) may only be used in the framework of this study and may not be used after its expiry date. 
Issuing and taking back the trial medication is documented in the Drug Accountability Log in the 
investigator site file (identification of patient, date and amount of medication issued). Upon receipt 
of the trial medication, the patients are to be carefully informed on how to use the trial medication. 
5.7 
Compliance 
The continuous administration of the trial substance is ensured by the syringe pump catheter sys-
tem and observed by the nursing staff. 
5.8 
Blinding and emergency envelopes 
5.8.1 Blinding 
The patients are assigned to one of the 2 treatment groups by means of random, computer-
generated numbers which are contained in sealed envelopes on which the numbers 1-50 are writ-
ten. The envelopes are provided by the investigator. The randomization envelope is opened by an 
independent member of the nursing staff – who is not involved in the further treatment of the pa-
tient – several minutes prior to the start of surgery. Such nursing staff of the pain outpatient de-
partment of the University Hospital of Innsbruck prepares the trial substance in a perfusor syringe 
and hands it over to the surgical nursing staff. 
 
5.8.2 Emergency envelopes 
Emergency envelopes for the identification of the trial substance are deposited at the ward’s head 
of the respective care-taking station and are only opened in case of a probable vital threat caused 
by the trial substance.  
 
 

 
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5.8.3 Premature unblinding 
Unblinding only takes place in case of a vital threat caused by the trial substance.  
5.8.4 Regular unblinding 
Regular unblinding only takes place after conclusion of the last follow-up examination including 
documentation. 
 
 
6 Course of study 
See also visit plan. On the day of hospitalization (visit 1, baseline, day 0) for hallux valgus surgery, 
the measures mentioned under point 6.1 are carried out as part of informing the patient on the sur-
gery. On day 1, hallux valgus surgery is performed under local anaesthesia, at the end of the sur-
gery the pain catheter (InfiltraLong-Katheter 19G x 420mm, Pajunk Medizintechnologie GmbH) is 
inserted to allow for continuous wound infiltration with ropivacaine 0.2 % or with physiological sa-
line solution. After surgery, the care-taking nursing staff of the respective ward documents the pain 
level under continuous wound infiltration and standard pain treatment every 4 hours via VRS (visit 
2, see point 6.2). On day 2 (first postsurgical day), the pain catheter is removed in the course of the 
first routine change of dressing during morning visit (approx. 07.30 a.m.). Under standard pain 
treatment, the care-taking nursing staff continues to document the pain level every 4 hours via 
VPRS. On day 3 (second postsurgical day), the patient is discharged from hospital. He/she re-
ceives a prescription for the intended pain medication as well as further follow-up appointments in 
1 (visit 3), 2 (visit 4) and 6 weeks (visit 5). In the course of these outpatient postsurgical follow-ups, 
the examinations described under points 6.3 to 6.5 are carried out and AEs and SAEs are record-
ed. Visit 5 (outpatient 6 weeks follow-up) represents the end of the study’s follow-up period. After 
conclusion of the study, the examining doctor decides on further outpatient follow-ups. 
 
 
6.1 
Visit 1 (baseline, day 0) 
Prior to admission to the clinical trial, every patient must be informed in detail on the study. Infor-
mation takes place in person by the treating doctor and in writing by means of the patient infor-
mation. Only after all questions of the patient have been answered, he/she will be asked to sign 
two copies of the declaration of consent and to personally date it. Following this, the patient re-
ceives a copy of the patient information/declaration of consent; the second copy is kept in the in-
vestigator site file. 
Upon visit 1, demographic data (age, sex, weight, size, BMI, side) is recorded. Furthermore, physi-
cal examination is carried out, including examination of the range of motion (ROM) of the hallux 
metatarsophalangeal joint (GZGG) as well as assessment of AOFAS forefoot score by means of 
the “AOFAS Hallux Metatarsophalangeal-Interphalangeal Scale” questionnaire and the average 
and maximum VPRS. Women of childbearing age undergo laboratory testing to exclude pregnan-
cy. After final examination of the inclusion and exclusion criteria, the patient is admitted to the 
study, including his admission to one of the two treatment groups according to randomization as 
explained above. 
 

 
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6.2 
Visit 2 (day 1 – 3) 
On day 1, hallux valgus surgery is performed under local anaesthesia, at the end of the surgery the 
pain catheter (InfiltraLong-Katheter 19G x 420mm, Pajunk Medizintechnologie GmbH) is inserted 
to allow for continuous wound infiltration with ropivacaine 0.2 % or with physiological saline solu-
tion. After surgery, the care-taking nursing staff of the respective ward documents the pain level 
under continuous wound infiltration and standard pain treatment (see point 5.5) every 4 hours via 
VPRS. On day 2 (first postsurgical day), the pain catheter is removed in the course of the first rou-
tine change of dressing during morning visit (approx. 07.30 a.m.). Under standard pain treatment, 
the care-taking nursing staff continues to document the pain level every 4 hours via VPRS. On day 
3 (second postsurgical day), the patient is discharged from hospital. He/she receives a prescription 
for the intended pain medication as well as further follow-up appointments in 1 (visit 3), 2 (visit 4) 
and 6 weeks (visit 5). Occurring AEs or SAEs are recorded in the course of the entire hospital stay. 
 
6.3 
Visit 3 (day 7 ± 3) 
Routine outpatient wound check. Occurring AEs or SAEs, and the maximum and average pain 
level (VPRS) are documented. 
 
6.4 
Visit 4 (day 14 ± 3) 
Routine outpatient suture removal. Occurring AEs or SAEs, and the maximum and average pain 
level (VPRS) are documented. 
 
6.5 
Visit 5 (final visit; day 42 ± 7) 
Routine outpatient 6 weeks follow-up including x-ray foot in 2 planes. Occurring AEs or SAEs, and 
the maximum and average pain level (VPRS) are documented. Furthermore, physical examination 
is carried out, including examination of the range of motion (ROM) of the hallux metatarsophalan-
geal joint (GZGG) as well as assessment of AOFAS forefoot score by means of the “AOFAS Hallux 
Metatarsophalangeal-Interphalangeal Scale” questionnaire. Patient satisfaction is collected by 
means of VRS. 
 
6.6 
Follow-up examinations 
After conclusion of the study, the examining doctor decides on further outpatient follow-ups. 
 
6.6.1 Assessment of effectiveness 
Effectiveness is assessed by the care-taking nursing staff – which is blinded as regards the thera-
py group – collecting data concerning the VPRS for pain during the patient’s stay in hospital which 
is repeated every 4 hours. For this, the patient indicates the current pain level on a scale ranging 
from 0 - 10 (0 meaning no pain, 10 meaning the maximum pain imaginable). 
Before surgery and in the course of the postsurgical outpatient follow-ups, the respective care-
taking doctor assesses not only the pain level by means of VPRS for pain but also the ROM of the 
hallux metatarsophalangeal joint. Furthermore, upon visit 1 and 5, AOFAS forefoot score is as-
sessed by means of the „AOFAS Hallux Metatarsophalangeal-Interphalangeal Scale“ question-

 
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naire 
(see 
annex) 
and 
patient 
satisfaction 
is 
assessed 
by 
means 
of 
VRS. 
 
6.6.2 Safety assessment 
AEs, ARs, UARs and SAEs are recorded during the patient’s stay in hospital and during outpatient 
follow-up examinations. AEs to be expected include in particular wound healing disorders and 
wound infections. 
 
6.6.3 Radiographic examinations 
6 weeks after surgery there is a routine x-ray of the foot in 2 planes in the course of the final follow-
up. This is the standard treatment in our department and is thus no examination specific to the 
study. 
 
6.7 
Further treatment of the patients after conclusion of the trial 
After conclusion of the study, the examining doctor decides on further outpatient follow-ups. 
 
6.8 
Drop-out of patients (drop-out) 
Patients may – at any time at their own wish – withdraw from the clinical study prematurely and 
without giving reasons and without facing any consequences for their future treatment. Further-
more, the investigator may exclude patients from the study for reasons of health risks. 
The reason for the patient’s drop-out of the study is recorded in the CRF. All patients who drop out 
of the study have to undergo a final examination (corresponding to visit 5) after 6 weeks, the re-
sults 
of 
which 
are 
documented 
in 
the 
CRF. 
 
6.9 
Premature termination of the clinical trial 
The sponsor is entitled to prematurely terminate the study due to relevant medical/administrative 
causes. The reasons for discontinuing the study are documented in detail. Patients who are still 
under treatment when the trial is cancelled, have to undergo a final examination which is docu-
mented in the CRF. If the investigator has ethical concerns regarding the continuation of the study, 
this has to be reported to the sponsor immediately. 
The sponsor is entitled to terminate the clinical trial prematurely, if 
 
the patient recruitment rate is insufficient, 
 
serious problems with the quality of the collected data, which cannot be solved, occur, 
 
unforeseeable circumstances have occurred in the respective trial center which do not allow 
for the clinical study to be continued, 
 
early proof is provided that one treatment group is superior or, respectively, inferior to the oth-
er treatment group (determined by interim evaluation), 
 
unjustifiable risks and toxicities have occurred (decision following renewed risk/benefit as-
sessment), 
 
new scientific findings, which appear when the study is being carried out, do not allow for the 
study to be continued. 
 

 
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The head of the study may decide on cancelling the study with the sponsor or the protocol commit-
tee. 
 
 
7 Adverse events, adverse reactions 
7.1 
Definitions 
An Adverse Event (AE) is any noxious occurrence in a person concerned (study participant) who 
has been administered an investigational product, and which is not necessarily causally related to 
this treatment. This may be disorders, clinical signs or symptoms which occur or worsen after the 
patient has been included in the study. 
An Adverse Reaction (AR) is any adverse and noxious reaction to an investigational product, re-
gardless of its dose. 
An Unexpected Adverse Reaction (UAR) is an adverse reaction, the nature or severity of which 
is not consistent with the available information on the investigational product. 
A Serious Adverse Event (SAE) or, respectively, Serious Adverse Reaction (SAR) is any unto-
ward event or any adverse reaction which  
 
results in death or 
 
is life threatening or 
 
results in persistent or significant disability or incapacity or 
 
requires inpatient hospitalization or causes prolongation of existing hospitalization or 
 
results in congenital anomalies or birth defects. 
A suspected unexpected serious adverse reaction is called Suspected Unexpected Serious 
Adverse Reaction (SUSAR) according to the Clinical Trials Directive (Directive 2001/20/EC). 
 
7.2 
Documentation of AEs 
All Adverse Events, including intercurrent disorders, are to be documented in the patient’s file and 
subsequently in the CRF. 
In case an Adverse Event occurs, the patient is to be observed in any case until the symptoms 
have disappeared or until the pathological laboratory results have returned to their original values, 
regardless of the causal relationship between the event and the trial medication. Should a persis-
tent secondary disease result from the Adverse Event, this is to be appropriately documented upon 
conclusion of the study. All findings and results have to be documented on the respective page for 
Adverse Events in the patient’s file as well as in the CRF. The following information is necessary: 
 
nature of Adverse Event (sign, symptom or disease) 
 
differentiation (serious/not serious) 
 
beginning and end of occurrence 
 
intensity  
 
causality to investigational product 

 
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 
measures as regards the investigational product or actions to restore or ameliorate the pa-
tient's well-being. 
 
outcome of event. 
 
 
7.3 
Documentation of SAEs 
For documenting the SAEs, the following points are to be strictly complied with: 
 
The SAE has to be documented on the respective AE page in the CRF and on the SAE form. 
 
Every SAE has to be reported, in a way as complete as possible, by the investigator to the 
sponsor within 24 hours . 
 
The monitor has to check the investigator's data for completeness and has to ensure that the 
information included in the SAE report matches the information in the database and in addi-
tional data sources. 
 
7.4 
Reporting of Adverse Events and Adverse Reactions 
All adverse events which occur during the present study which are reported spontaneously or re-
ported after consultation with the doctor or which are observed by the same are to be documented 
and commented in the case report form. Unexpected adverse events are to be documented in rela-
tion to their effect on the risk/benefit situation of the subjects, and are to be reported to the spon-
sor, to the Clinical Trials Coordination Center (KKS) of the Medical University of Innsbruck as well 
as to the responsible ethics commission. 
 
Should, from the investigator’s point of view, the adverse event observed, regardless of whether it 
is serious or not, challenge the continuation of the study, the study is to be suspended immediate-
ly. Thereafter, the decisions of the responsible parties (Data Safety Monitoring Board, ethics com-
mission, investigator, sponsor) on how to proceed are to be awaited. If the investigator deems the 
adverse event not relevant in this regard, the other committees mentioned (ethics commission) are 
free to order the study to be stopped (subsequently decision on continuation or termination of the 
study). So, in principle, each of the parties mentioned (investigator, ethics commission, sponsor) 
may issue a study stop. Within a committee, the regulations on taking decisions internally agreed 
upon, shall apply. 
 
7.4.1 Definitions 
See point 7.1 
 
SUSAR criteria:  
 
The adverse reaction has to be serious.  
 
A causal relationship between investigational product and adverse reaction must be suspect-
ed.  
 
The adverse reaction has to be unexpected. The definition of unexpectedness of an event is 
oriented towards the reference safety information. 
 
 

 
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7.4.2 Duty to report suspected unexpected serious adverse reactions (SUSARS) 
The sponsor must notify the ethics commission as well as the Austrian Federal Office for Safety in 
Health Care (Bundesamt für Gesundheit und Sicherheit, BASG) on SUSARs (additionally noting 
them in the respective case report form) by means of the official form (including additional narrative 
brief description, if available anonymized enclosures such as copy of results of an autopsy, etc., 
and, in the case of an unexpected serious adverse event, comment on the new up-to-date 
risk/benefit situation for the subject). Adverse reactions which have occurred as part of the same 
clinical trial at home or abroad are subject to notification (sec. 41 e of the AMG). 
Deadlines for notification: 
 
In case of death or life-threatening reactions: within seven calendar days at the latest; infor-
mation on further measures is to be transmitted within an additional time limit of eight days. 
 
All other SUSARs: immediately after they become known, however, within 15 calendar days at 
the latest. 
 
The obligation to notify BASG of SUSARs begins once all requirements for conducting the study 
are met (favourable opinion given by the ethics commission and non-prohibition by BASG). The 
obligation to notify ends upon completion of the respective study in Austria, provided that the na-
tional end of study has been reported to the authority (in an informal letter). 
 
Once a year, the sponsor has to transmit an annual safety report (Development Safety Update 
Report, DSUR pursuant to ICHE2F) with all suspected serious adverse reactions (SSARs) to 
BASG and to the ethics commission.  
 
 
8 Documentation 
The investigator is responsible to ensure that the trial is conducted in accordance with the GCP 
guidelines, AMG as well as the study protocol, and that the data is correctly entered into the CRF. 
All data collected in this study has to be entered into the CRF by persons authorized to do so. This 
also applies to data belonging to patients who were excluded from trial. 
The investigator notes the participation on a special patient identification list. This list enables a 
later identification of the patients and contains the patient number, the patient’s full name, his/her 
date of birth, and the date of admission to the clinical trial. The patient identification list remains in 
the trial center after conclusion of the trial. In addition, the participation of the patient in this clinical 
trial has to be noted in the patient’s file (trial medication, patient number/randomization number, 
start and end of trial). 
Furthermore, it has to be ensured that the person who is responsible for documentation in the CRF 
can be identified. A list with signature and initials of the persons who may make entries in the CRF 
will be recorded in the investigator site file (ISF) and in the Trial Master File. 
 
 
 

 
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8.1 
Case report form (CRF) 
Any and all patient data and examination results shall be entered into the CRFs (Case Report 
Forms) specifically created for this study.  
The case report forms may only be completed with a black ballpoint pen. Corrections are to be 
made in such a way that old entries remain legible (it is not allowed to use correction products). 
Corrections are to be signed and dated by the authorized person who makes the corrections. Data 
which is not available or which has not been collected, has to be clearly marked as such (NA or 
ND). The reasons to do so should be documented, if necessary. 
The investigator ensures that any and all patients’ data is entered into the CRFs immediately, legi-
bly, completely, correctly and in accordance with the patients’ files. 
The monitor serves the completed original pages after they have been checked for plausibility and 
completeness on the sponsor; a copy remains with the investigator and is stored for 15 years. 
 
8.2 
Investigator site file 
An investigator site file is made available to the trial center. The investigator stores all those docu-
ments which are required for the clinical trial in this file. As part of the monitoring, the investigator 
site file is checked for up-to-datedness and completeness according to the regulations. After the 
study has been concluded or cancelled, the investigator site file is to be stored for 15 years. 
 
8.3 
Data storage 
8.3.1 Obligation of the sponsor to store data 
All essential data relating to the clinical trial has to be stored by the sponsor for a duration of 15 
years after completion or cancellation of the clinical trial. The sponsor shall archive the data and 
documents 
relevant 
to 
the 
trial 
pursuant 
to 
legal 
provisions. 
 
8.3.2 Obligation of the investigator to store data 
Records and documents relating to testing or issuing trial medication (e.g. case report forms, dec-
larations of consent, lists on the medication distribution and other relevant documents) are to be 
stored by the investigators for at least 15 years.  
The medical charts and other original data shall be stored for the longest possible period that the 
hospital, the institution or the private practice enables. 
 
 

 
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9 Monitoring and audit 
Monitoring and audits are carried out in the context of the clinical trial for the purpose of quality 
assurance. 
 
9.1 
Monitoring 
The investigator agrees that the monitor checks data in order to ensure satisfying data collection 
and compliance with the study protocol. 
Furthermore, the investigator agrees to collaborate with the monitor and provide him, whenever 
necessary, all necessary information. This includes access to all documents relating to the study, 
including the originals of the patients’ files relevant to the study. The task of the investigator covers 
ensuring that the patients’ files are as complete as possible, i.e. recording information on anamne-
sis, concomitant diseases, admission to the trial, visitor data, examination results, drug issuing as 
well as Adverse Events. It shall also be made possible for the monitor to check data as well as to 
compare it with the relevant patients’ files pursuant to the SOPs and the ICH GCP guidelines in the 
predetermined time intervals in order to ensure compliance with the study protocol and continuous 
recording of data. For that, all original medical findings which are necessary as a source for the 
data in the database are checked. By signing the declaration of consent, the patient has agreed to 
such checking. 
Further tasks of the monitor include: 
 
checking whether the trial center complies with the requirements of the clinical trial (patient 
population, equipment, storage of study materials, etc.) 
 
instructing the investigator and the study staff on the clinical trial 
 
checking the investigator site file for completeness and up-to-datedness 
 
documenting patient status 
 
source data verification 
 
checking the prescribed notification of SAEs 
 
checking proper and safe storage as well as storage life of the trial medication 
 
counting the trial medication returned (drug accountability), checking compliance. 
The monitor shall treat all information as confidential and shall maintain the patients’ fundamental 
right to integrity and protection of their privacy. 
 
9.2 
Audit 
In order to guarantee that the trial is conducted pursuant to GCP guidelines, internal (e.g. by the 
sponsor) and external (e.g. by the authorities) audits may be conducted. The auditor is independ-
ent vis-à-vis the employees who are involved in the trial.  
During the audit, the following points are checked, amongst others: 
 
conduction of the trial according to the study protocol 
 
validity of data 
 
quality of trial pursuant to GCP guidelines. 
 
 

 
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Following every external audit, the investigator receives an audit confirmation by the auditor. This 
confirmation must be kept in the investigator site file in order to have it at disposal in case of an 
inspection by the authorities. The audit report is transmitted to the study sponsor. At the end of the 
trial, an audit certificate is enclosed to the final report. In addition, authorities may conduct audits 
and inspections pursuant to the Austrian Medicinal Product Act. 
 
10 Data entry and data management 
Study with paper-based documentation 
Data is managed and processed by the data manager by means of the software SPSS Statistics 
(company IBM, Armonk, New York, USA) and Excel (company Microsoft, Redmond, WA, USA). 
Data is validated by the programmed range, validity and consistency checks. Additionally, there is 
a manual/visual check for medical plausibility pursuant to the requirements of GCP. If necessary, 
queries may occur which are to be transmitted to the respective trial center on special forms. On 
the basis of the forms, the investigator has to review and answer those discrepancies. These forms 
are then returned to data management where those discrepancies are corrected in the database 
accordingly. The forms are stored together with the case report form at the trial center and by data 
management. 
Upon study completion, the database is closed after all entries have been entered and all queries 
have been resolved. This process is documented. 
 
11 Statistics  
11.1 Sample size planning 
Statistical planning and analysis takes places under the direction of Mag. Dennis Huber of the Insti-
tute for experimental orthopaedics. 
By using the software G*Power (Franz Faul, University of Kiel, Germany), an a priori sample size 
analysis is carried out. The following parameters shall be assumed for the calculation of the opti-
mal sample size: 
 
Primary target variable: average VRS (verbal rating scale; 0-10) for pain 
 
Clinically-relevant difference: 1 
 
Number of groups: 2 (same group size) 
 
Statistical methods: 
o Test family: t-test 
o Statistical test: means; difference between two independent means (groups) 
o Type of power analysis: a priori 
 
Formulation of hypothesis: two pages 
 
Effect size: Cohen’s d = 1 (large effect size) 
o assumed mean difference: 1 
o assumed standard deviation: 1 
 
Type 1 error: 5 % 
 
Type 2 error: 20% 
 
Test power: 80% 

 
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 
Group size: N1=N2 
 
Drop-out rate: approx. 10 % 
 
An a priori sample size analysis using the parameters mentioned above, results in a targeted min-
imal power of 0.80 and with a Cohen’s d of 1 (reveals large effects) results in a number of 34 peo-
ple necessary (17 per group). Considering that the drop-out rate is expected to be at 10 %, the 
optimal sampling size is 40 feet (20 per group). By means of the sampling size used by us, it 
should be possible to reveal effects of large size with sufficient power. 
11.2 Randomization 
Randomization takes place in 2 groups as balanced randomization by means of a computer-
generated random number sequence. This random number sequence is generated with the help of 
the website www.random.org (numbers, random sequence generator). The first 20 results of this 
list are assigned to the verum group, the other 20 results are assigned to the placebo group. Upon 
admission to the study, the patients receive at random one of these numbers which are contained 
in sealed envelopes on which the numbers 1 to 40 [sic] are written. The randomization envelope is 
opened by an independent member of the nursing staff – who is not involved in the further treat-
ment of the patient – several minutes prior to the start of surgery. Such member will fill a 50 ml 
perfusor syringe with either ropivacaine 0.2 % or physiological saline solution. The patients, sur-
geons as well as the care-taking nursing staff are blinded as regards the content. The deciphering 
list will only be opened after conclusion of the last follow-up examination. 
 
11.3 Statistical methods 
11.3.1 Dependent variables 
Primary dependent variable (primary study endpoint) 
 
Average VPRS (verbal pain rating scale; 0-10) for pain during the first 48 postoperative 
hours. 
 
Maximum VPRS (verbal pain rating scale; 0-10) for pain during the first 48 postoperative 
hours. 
Secondary dependent variables (secondary study endpoints) 
 
Endpoints related to safety during the treatment period: Occurrence of AEs, ARs and 
UARs. 
 
Endpoints related to the effectiveness: Patient satisfaction (VRS), clinical outcome (AOFAS 
forefoot score, ROM GZGG after 6 weeks), maximum and average pain (VPRS) after 1, 2 
and 6 weeks, need for rescue pain medication 
 
 

 
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11.3.2 Definition of analysis sets 
The intent-to-treat population to be analysed includes all randomized patients to whom the trial 
medication has been given. The statistical analysis of this set decides on the statement statistically 
significant or not statistically significant. The per protocol population is also analysed, i.e. those 
patients for whom no major protocol deviations have occurred. 
 
11.3.3 Data analysis 
Confirmatory data analysis 
The primary dependent variables (average and maximum VRS for pain during the first 48 postop-
erative hours) shall be analysed in a confirmatory way for two independent samples using a t-test. 
This shall be done by means of the current version of the software SPSS Statistics (company IBM, 
Armonk, New York, USA). 
Exploratory data analysis 
All secondary dependent variables – patient satisfaction (VRS), clinical outcome (AOFAS forefoot 
score, ROM GZGG after 6 weeks), maximum and average pain (VPRS) after 1, 2 and 6 weeks – 
shall be analysed in a purely descriptive way by means of using the currrent version of the soft-
ware SPSS Statistics (company IBM, Armonk, New York, USA). 
 
 
12 Reporting 
Minutes of the meetings of the different committees are drawn up in order to document the process 
and development of the study. 
 
12.1 Trial report 
Any and all information concerning this clinical trial are to be treated as confidential. The investiga-
tor carries out the statistical analysis and draws up an integrated final report; these are then evalu-
ated and signed by the sponsor as well as by all other responsible persons. All information con-
tained 
in 
this 
report 
are 
strictly 
confidential.  
 
12.2 Publications 
The final results of this clinical trial shall be published in a renowned specialist journal. Dr. Braito 
Matthias will be lead author, PD Dr. Rainer Biedermann will be corresponding author. The publica-
tion or presentation of the results is to be commented and approved a priori by the investigator and 
the sponsor. Data protection concerning all patient data has to be safeguarded for all publications. 
It is not planned to publish interim or partial results. Prior to its start, the study is registered on 
www.clinicaltrials.gov. 
 

 
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13 Ethical, legal and administrative aspects 
13.1 Responsibilities of sponsor and investigator 
Pursuant to the AMG, the sponsor of the clinical trial assumes responsibility for launching, organis-
ing and financing the clinical trial to be conducted. In this context, sponsor and investigator ensure 
that the clinical trial is conducted in compliance with existing laws and regulations, pursuant to the 
ICH GCP guidelines (1996), the declaration of Helsinki (1996) as well as the dispositions set out in 
the AMG and GCP ordinance (2004). The investigator accepts the requirements of the under-
signed study protocol.  
Responsibilities of the investigator include amongst others: 
 
understanding of the properties of the trial medication described in the Investigator's Brochure 
or in the specialist information 
 
understanding and implementation of the treatment plan 
 
ensuring that enough time and capacities for conducting the trial are available 
 
correct collection and documentation of data, reporting 
 
supplying any and all data to the sponsor, monitor or to the respective authorities for audits 
and/or inspections 
 
ensuring that information on patients as well as all information obtained from the sponsor are 
treated as confidential by all persons involved in the trial. 
Pursuant to the AMG, each investigator assumes responsibility for conducting the clinical trial in 
the trial center. 
 
13.2 Decision of the ethics commission and notification to authorities 
PD Dr. Rainer Biedermann (representative of the sponsor) applies to the ethics commission of the 
Medical University of Innsbruck and to the Austrian Federal Office for Safety on behalf of the spon-
sor. 
 
13.3 Patient information and declaration of consent 
Prior to the start of the trial, each patient must declare his/her consent to the investigator in writing, 
after first having been informed – orally and in writing – on the nature, meaning and consequences 
of the clinical trial in a way that is complete and understandable for him. The content of this infor-
mation is documented on the declaration of consent. The patient is informed if significant new find-
ings on the trial medication emerge during the study. 
The patient’s declaration of consent for the participation in the clinical trial is dated and signed by 
the patient as well as by the doctor. The patient receives a copy of the signed patient infor-
mation/declaration of consent. The second copy is filed in the investigator site file by the doctor.  
It is expressly noted that no examinations related to the study may be performed until a legally val-
id declaration of consent of the patient is submitted. 
 
 

 
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13.4 Patient insurance 
On behalf of the sponsor, the patient insurance prescribed pursuant to the AMG has been taken 
out for all patients with the following insurance company: 
Company name: Zürich Versicherungs-Aktiengesellschaft, SBU-Firmenkunden 
Insurance number: 07208763-1 
Address: Schwarzenbergplatz 15; 1010 Vienna 
 
Phone: +43 (01) 501 25 1240 
 
 
Fax: +43 (01) 501 25 1507  
With this, damages to health are insured against with a maximum coverage sum of 370,000.00 
euros for each participant. This insurance covers all possible damages that the patient suffers di-
rectly or indirectly because of the trial medication or because of operations in connection with the 
clinical trial.  
In order not to lose their insurance coverage, the patients have to strictly follow the instructions 
given by the trial staff. Furthermore, the patients may not undergo any other medical treatment 
during the clinical trial without consent of the investigator (an exception to this are emergencies). 
Patients must inform the investigator immediately on any emergency treatment. The patients have 
to immediately report to the investigator and to the insurance company any damage to health 
which may have resulted from the clinical trial. Furthermore, the patients must take all appropriate 
measures which serve the purpose of elucidating the cause and extent of the damage that has 
occurred. 
The patient may inspect the insurance conditions at the investigator’s place and, if requested, 
he/she may obtain a copy.  
 
13.5 Data protection and obligation to secrecy 
Collection, transfer, storage and analysis of personal data within this clinical trial is made pursuant 
to legal dispositions (Federal Data Protection Act). The prerequisite for this is the voluntary consent 
of the patients within the framework of the declaration of consent prior to the participation in the 
clinical trial. During their information on this clinical trial, the patients are informed in this regard on 
the following: 
1. 
Data that is collected as part of this clinical trial is recorded on paper forms or electronic data 
carriers, is treated as confidential and may only be passed on, without the patients being men-
tioned by name (pseudonymized), to 
 
the commissioner of the study in order to conduct a scientific analysis and assessment of 
adverse events, 
 
the competent federal authority, the ethics commission of the Medical University of Inns-
bruck and the European Database in order to review the orderly conduction of the study 
as well as to evaluate study results and adverse events. 
2. 
Insofar as it is necessary for reviewing the clinical trial, representatives of the commissioner 
(monitors, auditors) and/or of the competent monitoring authority who are authorized and 
sworn to secrecy may inspect the personal data available at the investigator. For this measure, 
the investigator is released from his professional obligation to secrecy. 

 
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3. 
The consent to the collection and processing of personal data in the framework of this clinical 
trial is irrevocable. A patient will be instructed that he may end his/her participation in the clini-
cal trial at any time – without giving reasons and without facing any subsequent detriments. In 
case the declaration of consent is revoked, the data stored up to this point will still be used 
without the patient being mentioned by name, if necessary, in order to assess the effects of 
the medicinal product at trial and to ensure that interests of the person concerned which are 
worth protecting are not harmed. 
 
14 Changes to the study protocol (amendments) 
In order to ensure that broadly comparable results are obtained in all trial centers, as well as in the 
interest of proper data evaluation, a change to the trial conditions agreed upon and set out in this 
study protocol is not intended. 
However, in exceptional cases changes to the trial conditions are possible. These are only made 
after mutual agreement has been reached between the investigator and the sponsor. Any change 
to the study procedure as set out in the study protocol has to be made in writing, giving the respec-
tive reasons, and has to be signed by all persons responsible for the study. The changes shall then 
be deemed as part of the study protocol. If necessary (e.g. when changing the medication dose 
and/or in case of other significant changes which indicate a direct influence on the safety of the 
study participants), approval of the changes to the study protocol has to be obtained from the rele-
vant ethics commission and/or authorities as well as from the patients, and the amendment is to be 
submitted to the federal authority. 

 
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15 Annex 
 
 
 
VRS for Pain 
no pain  
 
□ 0 □ 1 □ 2 □ 3 □ 4 □ 5 □ 6 □ 7 □ 8 □ 9 □ 10 
worst possible pain 
VRS for overall satisfaction with operation / pain management 
not satisfied 
□ 0 □ 1 □ 2 □ 3 □ 4 □ 5 □ 6 □ 7 □ 8 □ 9 □ 10 
very satisfied 
 
 

 
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