A Randomized Controlled Trial to Evaluate the Effectiveness of Cryocompression After Total Knee Arthroplasty (TKA)
Phase: NA
Conditions: Cryotherapy Effect
Sponsor: University of Applied Sciences and Arts of Southern Switzerland

 
  
 Clinical Investigation Plan (CIP)  
  
A randomized, controlled trial to investigate the effectiveness of cryotherapy with intermittent dynamic 
compression after total knee arthroplasty  
  
Intermittent compression and cryotherapy after total knee arthroplasty  
  
Type of investigation:  
Clinical investigation concerning medical devices (MD).  
Categorisation:  
Category according to Art 6 ClinO-MD (A1).  
Registration:  
SNCTP (follows)  
Clinicaltrials.gov NCT05395273  
Identifier:  
2022-D0056  
Principal Investigator and 
Sponsor, or 
SponsorInvestigator:  
University of Applied Sciences and Arts Southern Switzerland  
Department of Business Economics, Health and Social Care  
Physiotherapy Graubünden  
Weststrasse 8  
7302 Landquart  
+41 81 300 01 70  
  
Contact / Director of Studies  
Clijsen Ron, PhD  
University of Applied Sciences and Arts Southern Switzerland  
Physiotherapy Graubünden  
Weststrasse 8  
7302 Landquart +41 
81 300 01 75 
ron.clijsen@supsi.ch  
Sponsor representative (if the  
Sponsor is not located in  
Switzerland)  
Thim van der Laan AG Thim 
van der Laan jr.   
Weststrasse 8 / CH- 7302 Landquart  
Medical Device:  
The Game Ready GR PRO 2.1 is a certified medical device that 
complies with European regulations, directives and standards 
(93/42/EEC, EN60601-1, EC 60601-1-2, CE 0086).  
Originally in German, translated into English 

 
CIP Version and Date:  
Version 2 (21.06.2022)  
  
CONFIDENTIAL  
"The information contained in this document is confidential and the property of the University of Applied 
Sciences and Arts Southern Switzerland (SUPSI), Department of Business Economics, Health and 
Social Care, Physiotherapie Graubünden (or "Sponsor"). The information may not - in full or in part - be 
transmitted, reproduced, published, or disclosed to others than the applicable Competent Ethics 
Committee(s) and Regulatory Authority(ies) without prior written authorisation from the Sponsor except 
to the extent necessary to obtain informed consent from those who will participate in the investigation.  
  
  

 
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Table of Contents  
  
SYNOPSIS ............................................................................................................................................. 9 
ABBREVIATIONS ................................................................................................................................ 14 
SUMMARY OF THE REVISION HISTORY IN CASE OF AMENDMENTS .......................................... 15 
INVESTIGATION SCHEDULE ............................................................................................................. 15 
1. INVESTIGATION ADMINISTRATIVE STRUCTURE ....................................................................... 17 
1.1 Sponsor, Sponsor-Investigator ....................................................................................................... 17 
1.2 Principal Investigator(s) .................................................................................................................. 17 
1.3 Statistician ("Biostatistician") .......................................................................................................... 17 
1.4 Research laboratory ....................................................................................................................... 17 
1.5 Monitoring institution ...................................................................................................................... 18 
1.6 Data Safety Monitoring Committee ................................................................................................ 18 
1.7 Any other relevant Committee, Person, Organization, Institution ................................................... 18 
2. ETHICAL AND REGULATORY ASPECTS ...................................................................................... 19 
2.1 Registration of the investigation ..................................................................................................... 19 
2.2 Categorisation of the investigation ................................................................................................. 19 
2.3 Competent Ethics Committee (CEC) .............................................................................................. 19 
2.3.1  
Reporting duties to the Competent Ethics Committee .................................................... 20 
2.4 Ethical Conduct of the Investigation ............................................................................................... 20 
2.5 Declaration of interests ................................................................................................................... 20 
2.6 Patient Information and Informed Consent ..................................................................................... 20 
2.7 Subject privacy and confidentiality ................................................................................................. 20 
2.8 Early termination of the investigation ............................................................................................. 21 
2.9 Clinical investigation plan amendments ......................................................................................... 21 
2.10 Deviation from the Clinical Investigation Plan .............................................................................. 21 
3. BACKGROUND AND RATIONALE ................................................................................................. 22 
3.1 Background and Rationale for the clinical investigation ................................................................. 22 
3.2 Identification and description of the Investigational Medical Device .............................................. 22 
3.3 Preclinical Evidence ....................................................................................................................... 24 
3.4 Clinical Evidence to Date ............................................................................................................... 24 
3.5 Justification for the design of the clinical investigation ................................................................... 25 
3.6 Explanation for choice of comparator ............................................................................................. 25 
3.7 Risk evaluation (Risk-to-Benefits rationale) ................................................................................... 26 
3.8 Justification of the choice of the investigation population ............................................................... 26 
4. CLINICAL INVESTIGATION OBJECTIVES .................................................................................... 27 
4.1 Overall Objective ............................................................................................................................ 27 
4.2 Primary Objective ........................................................................................................................... 27 
4.3 Secondary Objectives .................................................................................................................... 27 
4.4 Safety Objectives ........................................................................................................................... 27 
5. CLINICAL INVESTIGATION OUTCOMES ...................................................................................... 27 
5.1 Primary Outcome ........................................................................................................................... 27 

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5.2 Secondary outcomes ...................................................................................................................... 28 
5.3 Other Outcomes of Interest ............................................................................................................ 28 
5.4 Safety Outcomes ............................................................................................................................ 29 
6. CLINICAL INVESTIGATION DESIGN ............................................................................................. 29 
6.1 General clinical investigation design and justification of design ..................................................... 29 
6.2 Methods for minimising bias ........................................................................................................... 29 
6.2.1  
Randomization ................................................................................................................ 29 
6.2.2  
Blinding procedures ........................................................................................................ 29 
6.2.3  
Other methods for minimising bias .................................................................................. 29 
6.3 Unblinding Procedures (Code break) ............................................................................................. 29 
7. CLINICAL INVESTIGATION POPULATION .................................................................................... 29 
7.1 Eligibility criteria .............................................................................................................................. 29 
7.2 Recruitment and screening ............................................................................................................ 30 
7.3 Assignment to investigation groups ................................................................................................ 30 
7.4 Criteria for withdrawal / discontinuation of subjects ....................................................................... 30 
8. CLINICAL INVESTIGATION INTERVENTION ................................................................................ 32 
8.1 Identity of the medical device under investigation .......................................................................... 32 
8.1.1  
Experimental Intervention (medical device) .................................................................... 32 
8.1.2  
Control Intervention (standard/routine/comparator) ........................................................ 33 
8.1.3  
Labelling and Supply (re-supply) ..................................................................................... 33 
8.1.4  
Storage Conditions .......................................................................................................... 33 
8.2 Discontinuation or modifications of the intervention ....................................................................... 33 
8.3 Compliance with clinical investigation intervention ......................................................................... 33 
8.4 Data Collection and Follow-up for withdrawn subjects ................................................................... 33 
8.5 Clinical investigation specific preventive measures ....................................................................... 33 
8.6 Concomitant Interventions (treatments) ......................................................................................... 33 
8.7 Medical Device Accountability ........................................................................................................ 33 
8.8 Return, Analysis or Destruction of the Medical Device ................................................................... 34 
9. CLINICAL INVESTIGATION ASSESSMENTS ................................................................................ 35 
9.1 Clinical investigation flow chart(s) / table of clinical investigation procedures and assessments ... 36 
9.2 Assessments of outcomes .............................................................................................................. 38 
9.2.1  
Assessment of primary outcome ..................................................................................... 38 
9.2.2  
Assessment of secondary outcomes .............................................................................. 39 
9.2.3  
Assessment of other outcomes of interest ...................................................................... 39 
9.2.4  
Assessment of safety outcomes ..................................................................................... 39 
9.2.5  
Assessments in subjects who prematurely stop the clinical investigation ....................... 39 
9.2.6  
Follow-up of the subjects after the regular termination of the clinical investigation ........ 40 
9.3 Procedures at each visit ................................................................................................................. 40 
9.3.1  
Single measurement ....................................................................................................... 40 
9.3.2  
Multiple visits ................................................................................................................... 40 
10. SAFETY ......................................................................................................................................... 40 
10.1 Definition and Assessment of (Serious) Adverse Events and other safety related events ........... 40 
10.2 Adverse events categorization ..................................................................................................... 42 
10.3 Documentation and reporting in Medical Device Category A clinical investigations ..................... 42 

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10.3.1 Foreseeable adverse events and anticipated adverse device effects ................................ 42 
10.3.2 Reporting of Safety related events ..................................................................................... 43 
11. STATISTICAL METHODS .............................................................................................................. 43 
11.1 Hypothesis .................................................................................................................................... 43 
11.2 Determination of Sample Size ...................................................................................................... 44 
11.3 Statistical criteria of termination of the investigation ..................................................................... 45 
11.4 Planned Analyses ......................................................................................................................... 45 
11.4.1 Datasets to be analysed, analysis populations ................................................................... 45 
11.4.2 Primary Analysis ................................................................................................................. 45 
11.4.3 Secondary Analyses ........................................................................................................... 45 
11.4.4 Interim analyses .................................................................................................................. 46 
11.4.5 Deviation(s) from the original statistical plan ...................................................................... 46 
11.5 Handling of missing data and drop-outs ....................................................................................... 46 
12. QUALITY ASSURANCE AND CONTROL ..................................................................................... 46 
12.1 Data handling and record keeping / archiving .............................................................................. 46 
12.1.1 Case Report Forms ............................................................................................................ 46 
12.1.2 Specification of source data and source documents .......................................................... 46 
12.1.3 Archiving of essential clinical investigation documents ...................................................... 46 
12.2 Data management ........................................................................................................................ 46 
12.2.1 Data Management System ................................................................................................. 46 
12.2.2 Data security, access and back-up ..................................................................................... 47 
12.2.3 Analysis and archiving ........................................................................................................ 47 
12.2.4 Electronic and central data validation ................................................................................. 47 
12.3 Monitoring ..................................................................................................................................... 47 
12.4 Audits and Inspections ................................................................................................................. 47 
12.5 Confidentiality, Data Protection .................................................................................................... 47 
13. PUBLICATION AND DISSEMINATION POLICY ........................................................................... 47 
14. FUNDING AND SUPPORT ............................................................................................................ 48 
14.1 Funding ........................................................................................................................................ 48 
14.2 Other Support ............................................................................................................................... 48 
15. INSURANCE .................................................................................................................................. 48 
16. REFERENCES ............................................................................................................................... 49 
17. APPENDICES ................................................................................................................................ 50 
 
  
  
  

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SYNOPSIS  
Sponsor / 
SponsorInvestigator  
Sponsor:  
Thim van der Laan AG Thim 
van der Laan jr.   
Weststrasse 8 / CH- 7302 Landquart  
  
Investigator:  
University of Applied Sciences and Arts Southern Switzerland (SUPSI)   
Department of Business Economics, Health and Social 
Care Physiotherapy Graubünden Attn: Ron Clijsen, PhD 
Weststrasse 8   
CH-7302 Landquart  
Title:  
A randomized, controlled trial to investigate the effectiveness of  
Cryotherapy with intermittent dynamic compression after kneeTotal 
arthroplasty  
Short title /  
Investigation ID:  
Intermittent compression and cryotherapy after total knee arthroplasty  
Clinical Investigation 
Plan, version and 
date:  
Version 02 – 21.06.2022  
Registration:  
SNCTP (follows)  
Clinicaltrials.gov NCT05395273  
Category and its 
rationale:  
Category according to Art 6 ClinO-MD (A1).  
Name of the MD,  
Unique Device  
Identification (UDI), 
name of the 
manufacturer  
The Game Ready GR PRO 2.1 is a certified medical device that complies with 
European regulations, directives and standards (93/42/EEC, EN60601-1, EC 
60601-1-2, CE 0086). The system can administer ice-free cold treatment (5-
13°C), with or without intermittent pneumatic compression treatment (5-75 
mmHg). It is a closed system (device and pressure cuff) and is therefore 
hygienic and safe to use in the clinic. The device is already being used in 
several Swiss clinics and institutions.  
Stage of 
development:  
Step 5: Product launch and postlaunch assessment  
 

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Background and 
rationale:  
The rehabilitation process after surgery is characterized by pain, swelling and 
inflammation in the perioperative tissues. This also applies after total knee 
endoprosthesis (TKA), as pain, swelling and inflammation are promoted due to 
the high concentration of nerve endings, the amount of bone resection, and 
bleeding in a closed space (joint capsule). These factors can complicate the 
prescribed postoperative physical therapy program for mobilization. 
Consequently, the patient's functional abilities are compromised with 
postoperative pain, swelling, and inflammation and can affect the final 
outcome.  
Compression and cryotherapy are traditionally used in postoperative recovery 
from TKA to mitigate these factors. Compression is believed to reduce edema 
by increasing hydrostatic pressure, thereby promoting the outflow of fluid into 
the interstitial space. Cold therapy can reduce the migration of leukocytes and 
slow down the transmission of nerve signals, resulting in a reduction in 
inflammation and having a short-term analgesic effect (Su et al. 2012).  
One study speaks of similar effects of cold compression bandages in simple 
arthroscopy, anterior cruciate ligament reconstruction and total arthroplasty 
(Thienpont 2014). Increased clearance is thought to lower inflammatory 
mediators, which often lead to edema and pain.  
In addition, physical pressure on hypertonic surrounding soft tissues and 
mechanical stretching of the contractile component of the muscles can improve 
tissue tension, which can potentially lead to a further reduction in edema and 
pain (Ebert et al. 2013).  
Game Ready is a medical product that, according to the manufacturer, 
provides faster, deeper penetrating and longer-lasting cooling with a dual 
function (pneumatic compression and continuous cold delivery). The cooling 
and intermittent compression is not permanent, but controlled (by a controller) 
in sessions of 30 minutes. After 30 minutes, the system switches to standby 
mode for 30 or 60 minutes. Thus, the processes important for healing are not 
suppressed and the tissue is not damaged by too intensive cooling. The 
healing processes are controlled (unnecessary swelling and pain reduced) and 
optimally supported thanks to intermittent compression (the tissue is supplied 
with fresh blood, oxygen and nutrients and inflammation-based waste products 
are removed via the lymphatic system.  
At the moment, there are still few studies in the literature that have investigated 
the effect of cryotherapy with intermittent dynamic compression with Game 
Ready after total knee arthroplasty (Su et al. 2012; Leegwater et al. 2012; 
Waterman et al. 2012; Murgier and Cassard 2014; Klaber, Greeff, and 
O'Donnell 2019; Nabiyev et al. 2018; Bellon et al. 2019). Further randomized, 
controlled trials are needed to investigate the effect of cryotherapy with 
intermittent dynamic compression.  

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Objective(s):  
In this study, the effect of repeated cold application with dynamic compression 
with the Game Ready and a control group will be investigated. The influence 
of these interventions and their effects will be investigated after a total knee 
endoprosthesis operation has been performed during the hospital stay. The 
change in the following parameters is examined: questionnaire on everyday 
activity and patient satisfaction, joint circumference in mm, skin temperature in 
C°, range of motion in degrees, morphine consumption in number per day,  
Pain sensation with the VAS, the length of the days of stay, the 10-meter walking 
test and the timed up-and-go in seconds.  
The aim is to determine the effects of cold application with dynamic 
compression in order to be able to make recommendations. The current 
scientific knowledge requires further studies to substantiate or refute effects 
that have already been established.  
Outcome(s):  
Primary outcomes  
-Questionnaire Everyday Activity [Score]  
-Patient satisfaction [cm]  
-Joint circumference [mm]  
-Range of motion [degrees]  
-Skin temperature [°C]  
-Morphine consumption [number]  
- Visual analog pain scale [cm]  
-Duration of stay [days]  
-10-meter walk test[s]  
-Timed-Up-and-Go [s]  
Design:  
Randomized, controlled trial  
 

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Inclusion / exclusion 
criteria:  
Inclusion Criteria:  
• 
Signed Informed Consent by the participant  
• 
Diagnosed gonarthrosis  
• 
Planned implantation of a primary total knee endoprosthesis by the 
Regional Hospital Surselva AG Exclusion criteria:  
• 
Decompensated hypertension in the affected area  
• 
Acute inflammatory phlebitis in the affected area  
• 
Patients with acute paroxysmal cold hemoglobinuria, or 
cryoglobulinemia  
• 
significant vascular disorder in the affected area (e.g., due to previous 
frostbite, significant atherosclerosis, diabetes, or ischemic vascular 
disease)  
• 
History of pulmonary embolism or risk factors for deep vein 
thrombosis or pulmonary embolism in the affected area  
• 
No increased venous or lymph reflux in the affected leg is desirable 
due to e.g. by carcinoma  
• 
Raynaud's disease  
• 
Hypersensitivity to cold  
• 
Fear of cold/compression  
Measurements and 
procedures:  
Recruitment:  
The subject information and declaration of consent are sent to the  
Subjects during the preoperative consultation with Dr. med. Martin Wonerow, 
Regionalspital Surselva AG, Spitalstrasse 6, CH7130 Ilanz. Questions may be 
asked. If the test subjects agree with the information, they are called up for the 
first screening. This includes the explanations, the signature of the declaration 
of consent, and the completion of the health questionnaire. If all the criteria of 
the inclusion and exclusion criteria are met, the subject will be included in the 
study.  
 

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Intervention:   
The Game Ready GR PRO 2.1 is a certified product that complies with 
European regulations, directives and standards.  
The system can administer ice-free cold treatment and intermittent pneumatic 
compression treatment, providing healthcare professionals with options for 
different patients, procedures, injuries and rehabilitation stages.  
The following intervention is performed according to the manufacturer's protocol 
for patients with primary total knee arthroplasty: 48 hours after the  
The operation starts the Game Ready Intervention, if tolerable, with little 
compression (level 1 = 5-15 mmHg) and cooling at the coldest level tolerable 
by the participant (corresponds to program 2). The cooling should be perceived 
as "pleasant" by the participant. The intervention lasts one hour, of which 30 
minutes are on and 30 minutes off cycles. The on cycle includes the duration 
of the intervention (cooling and compression), while the off cycles include the 
rest period. After 60 minutes, the device is removed. If compression is not 
tolerated, it can also be omitted (corresponds to program 1). The intervention 
is performed twice a day for the first four days after surgery. The coldest 
tolerable temperature level is determined anew with each treatment. The 
compression level can be increased depending on the participant. Medium 
compression may only be applied from the second day onwards (corresponds 
to programme 3).  
Control intervention 
(if applicable):  
In order to obtain high-quality study results, the test subjects are exposed to 
only one experimental condition at a time. There are two groups. In order to 
maintain the quality of the study, a randomized controlled trial design will be 
chosen. The division into the groups is randomized. The data collected in this 
way is pooled by outcome or group.  
The control group will receive ordinary physiotherapy treatment, without Game 
Ready application.  
Number of subjects 
with rationale:  
n=28 (14 per group)  
G-Power analysis: effect size at 0.8  
Duration of the 
investigation:  
May 2022 – December 2024  
Investigation 
schedule:  
May 2022- subject –In (planned)  
June 2023- subject –Out (planned)  

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Investigator(s):  
Examiner:  
Ron Clijsen, PhD 1,2,3  
Hohenauer Erich, PhD 1,2,3   
Friday Livia 2   
Herten Miriam 2  
Bianchi Giannina 2  
Elke Pollock 2  
1 
University College Physiotherapy Thim van der Laan, Weststrasse 8, 
7302 Landquart  
2 
University of Applied Sciences and Arts Southern Switzerland, 
Rehabilitation and Exercise Science Laboratory (RESlab), Department of 
Business Economics, Health and Social Care, Physiotherapy Graubünden, 
Weststrasse 8, 7302 Landquart   
3 
Vrije Universiteit Brussels, Faculty of Physical Education and Physical 
Therapy, Pleinlann 2, 1050 Brussels  
  
Contact / Principal Investigator:  
Clijsen Ron, PhD  
University of Applied Sciences and Arts Southern Switzerland  
Physiotherapy Graubünden  
Weststrasse 8  
7302 Landquart +41 
81 300 01 75 
ron.clijsen@supsi.ch  
Investigational 
Site(s):  
Single-centric investigation:  
Regionalspital Surselva AG  
Spitalstrasse 6  
CH-7130 Ilanz  
Statistical 
considerations:  
Repeated measure ANOVA  
Two-way  
Bonferroni correction  
Factors:  
-Task  
-Time  
The significance level is set at p<0.05, and the statistical data analysis is carried 
out with SPSS.  
Compliance 
statement:  
This investigation will be conducted in compliance with the CIP, the current 
version of the Declaration of Helsinki, ISO14155, ICH-GCP (as far as 
applicable) as well as all national legal and regulatory requirements.   
  
  
  
ABBREVIATIONS  
  
AE  
Adverse Event   
GOODBYE  
Adverse Device Effect  
ASADE  
Anticipated Serious Adverse Device Effect  
ASR  
Annual Safety Report  

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CA  
Competent Authority (e.g. Swissmedic)  
CEC  
Competent Ethics Committee  
CIP  
Clinical investigation plan  
ClinO  
Ordinance on Clinical Trials in Human Research (in German KlinV, in French Oclin, 
in Italian OSRUm)  
ClinO-MD  
Ordinance on Clinical Trials with Medical Devices (in German: KlinV-Mep, in French: 
Oclin-Dim, in Italian: OSRUm-Dmed)  
CRF  
Case Report Form (pCRF paper CRF; eCRF electronic CRF)  
DD  
Device Deficiency  
DMC / DSMC  
Data Monitoring Committee, Data Safety Monitoring Committee  
Ho  
Zero hypothesis  
H1  
Alternative hypothesis  
HRA  
Federal Act on Research involving Human Beings (in German: HFG, in French: LRH, 
in Italian: LRUm)  
IB  
Investigator's Brochure  
ICF  
Informed Consent Form  
ICH-GCP  
International Council for Harmonisation – guidelines of Good Clinical Practice  
IFU  
Instruction For Use  
ISF  
Investigator Site File  
ISO  
International Organisation for Standardisation  
ITT  
Intention to treat  
MedDO  
Medical Devices Ordinance (in German: MepV, in French: Odim, in Italian: Odmed)  
MD  
Medical Device   
MDR  
Medical Device Regulation (EU) 2017/745 of 5 April 2017  
PI  
Principal Investigator  
SADE  
Serious Adverse Device Effect  
SAE  
Serious Adverse Event  
SDV  
Source Data Verification   
SNCTP  
Swiss National Clinical Trials Portal  
SOP  
Standard Operating Procedure  
USADE  
Unanticipated Serious Adverse Device Effect  
  
  
SUMMARY OF THE REVISION HISTORY IN CASE OF AMENDMENTS  
Version Nr, 
Version Date  
Chapter  
Description of change  
Reason for the change  
01  
-  
-  
-  
  
  
INVESTIGATION SCHEDULE  
  
Jan  
Feb  
Mar  
Apr  
May  
Jun  
Jul  
Aug  
Sep  
Oct  
Nov  
Head  

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2022  
  
  
  
  
Planning, 
Organization  
 
Screening, data collection  
 
  
 
 
 
 
 
2023   
Screening, data collection  
 
Statistics  
 
  
 
 
 
 
 
2024   
Writing the article  
 
Publication  
 
  
  
  
 

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1. INVESTIGATION ADMINISTRATIVE STRUCTURE   
1.1 Sponsor, Sponsor-Investigator   
Thim van der Laan AG  
Weststrasse 8  
7302 Landquart  
  
Thim van der Laan jr.  
+41 81 300 01 70  
t.vanderlaan@physioschule.ch  
1.2 Principal Investigator(s)   
University of Applied Sciences and Arts Southern Switzerland  
Department of Business Economics, Health and Social Care  
Physiotherapy Graubünden   
  
Ron Clijsen, PhD  
Weststrasse 8  
7302 Landquart +41 
81 300 01 75 
ron.clijsen@supsi.ch  
1.3 Statistician ("Biostatistician")   
University of Applied Sciences and Arts Southern Switzerland  
Department of Business Economics, Health and Social Care  
Physiotherapy Graubünden  
  
Erich Hohenauer, PhD  
Weststrasse 8  
7302 Landquart +41 81 
300 01 75 
erich.hohenauer@supsi.ch  
1.4 Research laboratory  
Ron Clijsen, PhD ron.clijsen@supsi.ch  
  
Hohenauer Erich, PhD erich.hohenauer@supsi.ch  
  
Friday Livia livia.freitag@supsi.ch  
  
Herten Miriam 
miriam.herten@supsi.ch 
Giannina Bianchi 
giannina.bianchi@supsi.ch  
  

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Elke Pollock  
polloelk@students.zhaw.ch  
  
Weststrasse 8  
7302 Landquart  
+41 81 300 01 75  
1.5 Monitoring institution  
Vrije Universiteit Brussels   
Faculty of Physical Therapy  
Prof. Peter Clarys, PhD  
  
Pleinlaan 2 1050 
Brussels 
peter.clarys@vub.ac.be  
  
1.6 Data Safety Monitoring Committee  
All data obtained from the study participants will be encoded and not passed on to other people. Personal 
data and personal details are stored in paper form in a locked filing cabinet. Only the study supervisor, 
the head of the research laboratory and the study director at the same time have access here, with the 
management of the documents being the responsibility of the head of the research laboratory.  
All digital data is encoded. No conclusions can be drawn about individuals. The digital data is stored and 
archived on internal computers and is not released to outsiders.   
Employees involved in data processing have no insight into the personal data and the coding of it.  
1.7 Any other relevant Committee, Person, Organization, Institution   
Regionalspital Surselva AG  
Dr. med. Martin Wonerow  
Spitalstrasse 6  
CH-7130 Ilanz  
m.wonerow@spitalilanz.ch  
  
Regionalspital Surselva AG  
Dr. med. Sebastian Ulsamer  
Spitalstrasse 6  
CH-7130 Ilanz  
s.ulsamer@spitalilanz.ch  
  
The study is being led and coordinated by the University of Applied Sciences and Arts Southern 
Switzerland, Physiotherapy Graubünden, Weststrasse 8, CH7302 Landquart, in the research laboratory 
of the research group, which is officially called the Rehabilitation and Exercise Science Laboratory 
(RESlab).  
The study is being carried out at the Regional Hospital Surselva AG, Spitalstrasse 6, CH-7130 Ilanz. The 
test product and all measuring equipment are stored in the orthopaedics department. The measurements 
are taken in a room prepared for this purpose. The applications with the test product are carried out in 
the hospital room of the test subjects.  

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The mentioned sponsor, Thim van der Laan AG, is responsible for the management according to KlinV 
§2c.  
As far as is known, no further studies with this order are taking place in the institutions mentioned 
(University of Applied Sciences and Arts of Southern Switzerland and Regional Hospital Surselva AG, 
Spitalstrasse 6, CH-7130 Ilanz).  
  
  
Table 1 - Summary of responsibilities and tasks  
Range  
 
Sponsor  
Inspector  
Responsibilities  
 
Management  
Financing  
Responsibility of the study  
Management, 
coordination, 
practical implementation in the  
Sponsor's mission  
Compensation for 
Inspectors  
the  -  
No further compensation 
planned  
Privacy  
 
Responsible  
for  
the  
Compliance with data protection  
Adopts the Sponsor's order 
regarding the  
Privacy  
Data ownership  
 
Responsible and disposes of the 
data  
-  
Publication  
 
-  
Takes over the work steps of the 
publication on behalf of the 
sponsor  
  
  
  
2. ETHICAL AND REGULATORY ASPECTS   
The final positive decision of the CEC on the conduct of the investigation will be made and given in 
writing to the Sponsor before the investigation can start. Additional requirements set by the authorities 
must be implemented.  
2.1 Registration of the investigation  
The study is registered under the following two registries:  
- SNCTP (follows, date xx.xx.xxxx)  
-Clinicaltrials.gov (NCT05395273, Date 18.05.2022)  
2.2 Categorisation of the investigation  
The study falls under the following category:  
Category A clinical trial, subcategory A1.  
Reason: no other invasive or otherwise stressful procedures are examined in the study or are the content 
of the study. The medical device under investigation is CE marked, is used in accordance with the 
instructions for use and is not prohibited in Switzerland (Art. 6 para. 1 KlinVMep).  
2.3 Competent Ethics Committee (CEC)  
The Sponsor-Investigator will submit the investigation to the CEC and obtain ethical committee approval 
before the start of the investigation. The PI ensures that approval from the CEC is obtained and filed in 
the Investigator site file before the investigation starts.   

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2.3.1  
Reporting duties to the Competent Ethics Committee  
Amendments are reported according to Art. 15 ClinO-MD (see also 2.10).  
The regular or premature end of the investigation as well as the interruption of the investigation is 
reported to the CEC within 15 days (within 24 hours if it is due to security reasons) (Art. 36 ClinO-MD). 
The reasons for a premature end or an interruption have to be explained.  
A final report shall be submitted within one year after the regular end of the investigation and within 3 
months after a premature end of the investigation (Art. 37 ClinO-MD).  
2.4 Ethical Conduct of the Investigation   
The investigation will be carried out according to the CIP and with principles enunciated in the current 
version of the Declaration of Helsinki, the European Regulation on medical devices 2017/745 (MDR), 
the Norms ISO14155 and ISO14971, the ICH-guidelines of Good Clinical Practice (GCP) as applicable, 
the Swiss Human Research Act (HRA) and its Ordinances and Swiss regulatory authority's 
requirements. The CEC will receive the Annual Safety Report (ASR) and interim reports and be notified 
about investigation stop/end in agreement with local requirements.  
2.5 Declaration of interests   
There is no financial conflict of interest on the part of the sponsor/investigator, nor is there a 
corresponding relationship of dependency.  
2.6 Patient Information and Informed Consent  
The PI explains to each subject the nature of the investigation, its purpose, the procedures involved, the 
expected duration, the potential risks and benefits and any discomfort it may entail. Each subject is 
informed that the participation in the investigation is voluntary and that he/she may withdraw from the 
investigation at any time and that withdrawal of consent will not affect his/her subsequent medical 
assistance and treatment. The subjects are informed that he/she can ask any question, and consult with 
family members, friends, their treating physicians or other experts before deciding about their 
participation in the investigation. Enough time is given to the subjects.  
The subjects are informed that authorised individuals other than their treating physician may examine 
his/her medical records.  
All subjects a given a subject information sheet and a consent form describing the investigation and 
providing sufficient information for the subjects to make an informed decision about their participation in 
the investigation.  
The formal consent of a subject, using the approved consent form, is obtained before the subject is 
submitted to any investigation procedure.  
The subject should read, understand, and voluntarily agree before signing and dating the informed 
consent form, and is given a copy of the signed document. The consent form is signed and dated by the 
subject and the PI (or her/his designee). The signed consent form it is retained as part of the investigation 
records.  
2.7 Subject privacy and confidentiality   
The Sponsor and the PI affirm and uphold the principle of the subjects' right to privacy and that they 
shall comply with applicable privacy laws. Especially, anonymity of the subjects shall be guaranteed 
when presenting the data at scientific meetings or publishing them in scientific journals.   
Individual subject medical information obtained as a result of this investigation is considered confidential 
and disclosure to third parties is prohibited.  
For data verification purposes, authorised representatives of the Sponsor, the CEC may require direct 
access to parts of the medical records relevant to the investigation, including subjects' medical history.  
All data obtained from the study participants will be encoded and not passed on to other people. Personal 
data and personal details are stored in paper form in a locked filing cabinet. Only the study supervisor, 
the head of the research laboratory and the study director at the same time have access here, with the 
management of the documents being the responsibility of the head of the research laboratory.  
All digital data is encoded. No conclusions can be drawn about individuals. The digital data is stored and 
archived on internal computers and is not released to outsiders.   

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Employees involved in data processing have no insight into the personal data and the coding of it.  
2.8 Early termination of the investigation  
The Sponsor may terminate the investigation prematurely according to certain circumstances, for 
example:  
• 
ethical concerns,  
• 
insufficient subject recruitment,  
• 
when the safety of the subjects is doubtful or at risk, respectively,  
• 
alterations in accepted clinical practice that make the continuation of the investigation unwise,   
• 
early evidence of benefit or harm of the experimental intervention.  
2.9 Clinical investigation plan amendments  
Substantial amendments are only implemented after approval by the CEC (Art. 15 ClinO-MD). The use 
of waivers from the CIP is prohibited (Annex XV, Chapter 2, Art. 3.10 MDR).  
Under emergency circumstances, deviations from the CIP to protect the rights, safety and well-being of 
the subjects may proceed without prior approval by the Sponsor and the CEC. Such deviations shall be 
documented and reported to the Sponsor and the CEC within 2 days (Art. 34 ClinO-MD).  
All non-substantial amendments are communicated to the CEC together with the Annual Safety Report 
(ASR) (Art. 15 ClinO-MD). The ASR shall include any deviations from the CIP that may have affected 
the rights, safety or well-being of the subject or the scientific integrity of the investigation (ISO14155).  
2.10 Deviation from the Clinical Investigation Plan  
The use of waivers from the CIP is prohibited (Annex XV, Chapter 2, Art. 3.10 MDR).  
Adjustments and changes to the current study are only permissible after review by the CEC.  
Short-term (non-substantial) changes to the protocol prior to an audit by the CEC may be made to ensure 
the rights and safety of participants. However, such adjustments must be documented and reported to 
the CEC with the annual safety report (Art. 15 para. 5 ClinO-MD).  
Significant changes are only permissible after a review of the CEC. Any other changes must be notified 
to the CEC as soon as possible and listed in the annual report.  
  
  
 

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3. BACKGROUND AND RATIONALE   
3.1 Background and Rationale for the clinical investigation  
Recovery after surgery is characterized by pain, swelling, and inflammation in the perioperative tissues. 
This also applies after total knee endoprosthesis (TKA). Due to the high concentration of nerve endings, 
the amount of bone resection and bleeding in a closed space (joint capsule), pain, swelling and 
inflammation are promoted. These factors can complicate the prescribed postoperative physical therapy 
program for mobilization. Consequently, the patient's functional abilities are compromised with 
postoperative pain, swelling, and inflammation and can affect the final outcome. Compression and 
cryotherapy have traditionally been used in the postoperative treatment of TKA to mitigate these factors. 
Compression is believed to reduce edema by increasing hydrostatic pressure, thereby promoting the 
outflow of fluid into the interstitial space. Cold therapy can reduce leukocyte migration and slow down 
the transmission of nerve signals, resulting in a reduction in inflammation and having a short-term 
analgesic effect (Su et al. 2012).  
One study showed similar effects of cold compression bandages in simple arthroscopy, anterior cruciate 
ligament reconstruction and total arthroplasty (Thienpont 2014). The authors also mentioned other 
applications of cryotherapy, including first-generation cryotherapy with crushed ice in a plastic bag, cold 
or gel packs; Second-generation cryotherapy with circulating ice water with or without compression such 
as Cryo/Cuff (Aircast, Vista, CA, USA) or Game Ready (CoolSystems Inc, Concord, CA, USA); and 
advanced third-generation computerized devices with continuous controlled cryotherapy (cTreatment, 
Waegener, Beerse, Belgium; and CTM 5000, Ener-C AG, Baar, Switzerland).  
Game Ready GR PRO 2.1 is a medical product that provides faster, deeper penetrating and longer-
lasting cooling with dual function (pneumatic compression and continuous cold delivery) and the cuff 
construction with maximum body contact. The cooling and intermittent compression in Game Ready is 
not permanent, but optimized (by a control) in sessions of 30 minutes. After 30 minutes, the system 
switches to standby mode for 30 or 60 minutes. Thus, the processes important for healing are not 
suppressed and the tissue is not damaged by too intensive cooling. The healing processes are optimized 
(swelling and pain are reduced) and supported thanks to intermittent compression. The tissue is supplied 
with blood, oxygen and nutrients and inflammation-based waste products are transported away via the 
lymphatic system (MTR 2021). The additional compression in the form of pressure on hypertonic 
surrounding soft tissues and the mechanical stretching of the contractile component of the muscles 
improve tissue tension, which can potentially lead to further improvement of edema and pain (Ebert et 
al. 2013).  
At the moment, there are only a few studies in the literature that have investigated the effect of 
cryotherapy with intermittent dynamic compression with Game Ready after total knee arthroplasty.  
Aim of the study  
In this project, the effect of repeated cold application with dynamic compression with the Game Ready 
and a control group will be investigated. The influence of these interventions and their effects will be 
investigated after a primary total knee endoprosthesis operation during the hospital stay. The change in 
the following parameters is examined: questionnaire on everyday functions and patient satisfaction, joint 
circumference in mm, range of motion in degrees, skin temperature in C°, morphine consumption per 
day, pain perception with the VAS, the 10-meter walk test, timed-up-and-go and the length of the days 
of stay.  
The aim is to determine the effects of cold application with dynamic compression in order to be able to 
make recommendations. The current scientific knowledge requires further studies to substantiate or 
refute effects that have already been established.  
3.2 Identification and description of the Investigational Medical Device  
The Game Ready GR PRO 2.1 builds on the groundbreaking Game Ready technology and is a 
multimodality recovery device for professional users. The system can deliver ice-free cold treatment and 
intermittent pneumatic compression treatment, providing healthcare professionals with flexible options 
for different patients, procedures, injuries and rehabilitation stages.  
Established principles such as PECH (pause, ice, compression, elevation) can be taken to a new level 
with the state-of-the-art Game Ready GR PRO 2.1. Cumbersome procedures for contrast treatment will 
be simplified with the compact, practical device. In addition, these can be monitored and controlled more 
consistently than conventional methods.  

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The unit consists of the following parts: the GRPro 2.1 control unit, connecting hose, the wrap (sleeve 
and heat exchanger), power supply and cable (see Figure 1). Only the cuff comes into contact with the 
patient's skin (see also Figure 2, right). The device is controlled via a touchscreen computer interface 
on the control unit. The user can choose between different treatment modalities and easily change and 
monitor the settings for treatment duration, temperature and compression. The double-acting 
(cryotherapy and compression) and anatomically designed Game Ready cuffs can be used specifically 
for specific parts of the body.  
  
Figure 1 - Game Ready GR PRO 2.1 (https://gameready.com/gr-pro-cold-therapy-unit/)  
  
This device is used for the treatment of post-traumatic, post-operative (medical and/or surgical) and 
acute injuries, as well as for the reduction of edema, swelling and pain when cold and compression are 
indicated.  
According to the manufacturer, the following foreseeable serious adverse events and product defects 
may occur:  
-tissue damage due to improper or too long use than described by the manufacturer,  
-burning, itching, increasing swelling, pain, blisters, increasing redness, discoloration and other visible 
changes during treatment,  
-Change in wound conditions (if the wrap is not applied over the bandage or clothing),  
-Risk of electric shock (if other power supplies are used, housing parts are removed, or damaged cables 
and connecting hoses are used) and  
-Device damage (if there is no or too hot water in the ice box, the device is lifted up by the lid, or wraps 
from other manufacturers have been used).  
Despite the points listed above, the risk is classified as minimal, as no serious events can occur if used 
correctly and observed during application.  
The following contraindications must be observed:  
-patients with acute inflammatory phlebitis in the affected area,  
-Patients with a history of or risk factors for deep vein thrombosis or pulmonary embolism in the affected 
area to be treated (including long periods of bedriddenness), -Patients with significant atherosclerosis 
or other ischemic vascular disease in the affected area,  
-Patients with a condition in which increased venous or lymphatic reflux in the affected arm or leg is not 
desired (e.g. carcinoma),  
-Patients with significant circulatory disorders in the affected area (e.g. due to previous frostbite, 
diabetes, arteriosclerosis or ischemia),  
-Patients with acute paroxysmal cold hemoglobinuria or cryoglobulinemia.  
 

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Figure 2 - Game Ready GR PRO 2.1 (https://gameready.com/gr-pro-cold-therapy-unit/)  
The manufacturer of the device is the company CoolSystems®, Inc. (Concord, California 94520, USA). 
The GR PRO 2.1 device is provided for the study by MTR Health & Spa AG.  
3.3 Preclinical Evidence  
A limited number of studies have already shown that cooling in combination with compression has been 
able to achieve a positive influence compared to non-cooling measures. These positive effects could be 
presented on both a subjective and an objective level (Su et al. 2012; Leegwater et al. 2012; Waterman 
et al. 2012; Murgier and Cassard 2014; Klaber, Greeff, and O'Donnell 2019; Nabiyev et al. 2018; Bellon 
et al. 2019).  
3.4 Clinical Evidence to Date  
Current research results regarding the cooling and compression effects, on which this study is based, 
have been presented in chap. 3.3.  
Ache  
Waterman and colleagues found a significant difference in pain perception after 6 weeks in favor of 
cryotherapy in combination with compression, in patients with anterior cruciate ligament reconstruction 
(Waterman et al. 2012). Other studies also found less subjective pain postoperatively when cryotherapy 
with dynamic intermittent compression is used than static pain (Murgier and Cassard 2014; Klaber, 
Greeff, and O'Donnell 2019).  
Questionnaires  
With regard to different questionnaires (Lysholm; assesses different functions of the knee, SF-36; 
assesses daily activity or SANE; assesses the disease state), no significant differences could be found 
at any time (Waterman et al. 2012).  
Range of motion  
When the average knee flexion movement is measured, strongly significant results could be found in 
favor of cryopneumatic intervention (Murgier and Cassard 2014).  
Medication  
In a study with patients who received cryopneumatic intervention after a total knee prosthesis, it was 
shown that significantly fewer narcotic drugs were consumed 2 weeks postoperatively compared to the 
control group who received ice with static compression (Su et al. 2012). This is also confirmed by a study 
by Murgier and Cassard, which found statistically significant results in the average morphine application. 
Although there were no statistical differences in tramadol use, there was a clear trend in favor of 
dynamically intermittent cryocompression (Murgier and Cassard 2014). These results confirm another 
study that used pneumatic compression and cryotherapy after elective hip arthroplasty (Leegwater et al. 
2012).  
Functional outcomes  
 

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Functional outcomes such as the 6-minute walk test or the timed-up-and-go test were not significantly 
different in a study after 2 and 6 weeks, but showed a trend in the intervention group (Su et al. 2012).  
Contentment  
In the study by Su and her colleagues, subjective satisfaction was also assessed and showed significant 
results in contrast to the control intervention (Su et al. 2012).  
Duration of stay  
Two studies found that a combination with pneumatic compression and cryotherapy can lead to a shorter 
hospital stay compared to a normal compression bandage or standardized cryotherapy (Leegwater et al. 
2012; Klaber, Greeff, and O'Donnell 2019).  
These still discursive study results suggest that further research is needed to provide clear evidence-
based recommendations regarding pneumatic compression in combination with cryotherapy. Currently, 
no research with the product GR PRO 2.1 or any other device from Game Ready (Concord, California, 
USA) is taking place in the research laboratory of the University of Applied Sciences and Arts Southern 
Switzerland, Physiotherapy Graubünden and the Regional Hospital Surselva AG, Spitalstrasse 6, CH-
7130 Ilanz.  
3.5 Justification for the design of the clinical investigation   
In this study, the product Game Ready GR PRO 2.1 is used. This thermotherapy device is used as part 
of the intended application. The examiners apply cold including compression. The applied temperatures 
do not pose a danger to the test subjects at any time. The Game Ready GR PRO 2.1 generates 
temperatures from +5°C to +13°C.  We will follow the following treatment program in this study: 48 hours 
after surgery, the intervention will start, if tolerable, with little compression (level 1 = 5-15 mmHg) and 
cooling at the coldest level tolerable by the participant (equivalent to program 2). The cooling should be 
perceived as "pleasant" by the participant. The intervention lasts one hour, of which 30 minutes are on 
and 30 minutes off cycles. The on cycle includes the duration of the intervention (cooling and 
compression), while the off cycles include the rest period. After 60 minutes, the device is removed. If 
compression is not tolerated, it can also be omitted (corresponds to program 1). The intervention is 
performed twice a day for the first four days after surgery. The coldest tolerable temperature level is 
determined anew with each treatment. The compression level can be increased depending on the 
participant. Medium compression may only be applied from the second day onwards (corresponds to 
programme 3). Doctors and physiotherapists can opt for cold treatments in their treatment. The question 
of whether the rehabilitation phase can be shortened or whether reintegration into everyday life can be 
increased by means of cooling applications including compression therapy is a legitimate question. 
These two parameters include not only objective values, but also subjective data.  
3.6 Explanation for choice of comparator  
Cooling/compression vs. control  
Two groups are compared to each other in order to compare the effects of cooling including compression 
compared to the control group. For example, the efficiency of cooling including compression is to be 
examined for rehabilitation capability. The following treatment program is adhered to: 48 hours after the 
operation, the intervention starts, if tolerable, with little compression (level 1 = 5-15 mmHg) and cooling 
at the coldest level tolerable by the participant (corresponds to program 2). The cooling should be 
perceived as "pleasant" by the participant. The intervention lasts one hour, of which 30 minutes are on 
and 30 minutes off cycles. The on cycle includes the duration of the intervention (cooling and 
compression), while the off cycles include the rest period. After 60 minutes, the device is removed. If 
compression is not tolerated, it can also be omitted (corresponds to program 1). The intervention is 
performed twice a day for the first four days after surgery. The coldest tolerable temperature level is 
determined anew with each treatment. The compression level can be increased depending on the 
participant. Medium compression may only be applied from the second day onwards (corresponds to 
programme 3). The control group does not receive any cooling in addition to standard therapy.  
Randomization  
In order to produce a high-quality study, the subjects are each assigned to a group, which are later 
compared with each other.  
The assignment is carried out randomly. Randomization is guaranteed by drawing a lot.  

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3.7 Risk evaluation (Risk-to-Benefits rationale)   
There is minimal risk for the test subjects during cooling. The test subjects are expressly informed that 
they can stop the maximum tolerable cooling at any time. This also applies to integrated compression 
therapy. Furthermore, at least one examiner will be next to the subject during the cooling application in 
order to stop the intervention in the event of circulatory or other complaints. A fully equipped emergency 
kit is in the examination room at all times during the examinations. Since the intervention and 
measurements will take place on the premises of the Regionalspital Surselva AG, Spitalstrasse 6, CH-
7130 Ilanz, first aid can be ordered directly in the event of circulatory and other problems. This 
information is communicated to the test persons (subject information). The device is used as 
recommended by the manufacturer.  
3.8 Justification of the choice of the investigation population   
Furthermore, any injuries and illnesses were defined as an exclusion criterion in order not to take the 
risk of intervention. The listed criteria are also recommended by the manufacturer.  
More information on securing the test subjects can be found in chap. 8.1.1.   
 

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4. CLINICAL INVESTIGATION OBJECTIVES  
4.1 Overall Objective  
In this study, the effect of a maximum of 2x60 minutes of body section cooling including compression 
per day on the subjective assessment of everyday functions [score] as well as patient satisfaction [cm] 
and physiological inflammation parameters such as swelling [mm],  
The pain scale [cm], skin temperature [°C], range of motion [degrees], morphine consumption [number] 
and length of stay [days] were examined. In addition, two assessments are used to assess everyday 
function: the 10-metre walk test [sec] and the timed-up-and-go [sec]. The effects of thermal application 
are compared to a control group and compared preoperatively, postoperatively (4th postoperative day) 
and after 6 weeks after surgery. The aim is to substantiate the state of scientific knowledge and to provide 
therapists and physicians with further insights. This study can benefit all those who work with patients 
after primary total knee arthroplasty.  
4.2 Primary Objective  
In this project, the effect of postoperative cooling on physiological parameters is measured and 
compared with the control group.  
-Physical Function [Score]  
-Patient satisfaction [cm]  
-Joint circumference [mm]  
-Range of motion [degrees]  
-Skin temperature [°C]  
-Morphine consumption [number]  
-Visual analog scale [cm]  
-Length of stay [days]  
-10-meter walk test [sec]  
-Timed-Up-and-Go [sec]  
4.3 Secondary Objectives  
-  
4.4 Safety Objectives  
No short-term risks are to be expected from this study other than those discussed so far.  
  
  
5. CLINICAL INVESTIGATION OUTCOMES   
5.1 Primary Outcome  
This study aims to investigate the effects of cryotherapy with intermittent dynamic compression with 
Game Ready during a hospital stay. The preoperative measurement is the baseline, the 4th 
postoperative day is the primary endpoint and the measurement 6 weeks postoperative is declared as 
follow-up. The following parameters are examined for this purpose:  
Questionnaire Physical Function [Score]  
To determine the subjective assessment of physical function, the KOOS questionnaire is handed out, 
evaluated and documented. The KOOS questionnaire is highly valid for knee complaints and refers to 
the subjective impression of the patients (Roos and ToksvigLarsen 2003). The measurement moments 
take place preoperatively, on the 4th postoperative day and 6 weeks postoperatively.  
Patient satisfaction [cm]  
In order to evaluate the patient satisfaction of the intervention group (Game Ready), the test subjects 
are asked the question "How satisfied are you with the cooling intervention?" immediately after the 
intervention. With the help of the Visual Analog Scale, the test subjects rate their satisfaction with a 
number between 0 (not at all satisfied) and 10 (maximally satisfied). The measurement moments take 
place twice a day (each time after the cooling intervention) during the  

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hospital stay.  
Joint circumference [mm]  
The joint circumference measurement is carried out by hand with a tape measure. This measurement 
method showed a high level of reliability. 5cm, 10cm, 15cm above the knee joint space, at the level of 
the knee joint space, 15cm below the knee joint space, above the lateral malleolus and above the 
scaphoid bone (Oesch 2007). Both sides are measured. The measurement moments take place 
preoperatively, on the 4th postoperative day and 6 weeks postoperatively.  
Range of motion [degrees]  
To estimate the range of motion of knee flexion, the "RoMot" app from OT Bioelettronica (Turin, Italy) is 
used. The patient is in the supine position. The two sensors are applied to the lower and thigh legs. In 
response to the start command, the test subject tries to bend his knee as much as possible. The heel 
remains in bed and the longitudinal axis of the leg is also taken into account. Then the other side is 
measured. The number of degrees indicated by the software on the corresponding tablet is documented. 
Wireless Bluetooth sensors, for determining the amount of motion, show a high correlation compared to 
the goniometer measurements, which are currently the most commonly used in practice (Kumar et al. 
2015). The measurement moments take place preoperatively, on the 4th postoperative day and 6 weeks 
postoperatively.  
Skin temperature [°C]  
Skin temperature is also recorded with the help of an infrared thermometer (Voltcraft IR800-20D, Conrad 
Electronic, Hirschau, Germany). Handheld infrared thermal devices have high measurement accuracy 
(due to contact-free measurement) and practical handling (Stoop et al. 2020). Skin temperature is 
measured at four locations of the knee: superolateral, superomedia, inferiorlateral, and inferiordial 
margin of the patella (Zeng et al. 2016). The subject is in a supine position during the measurements. 
Both sides are measured. The measurement moments take place preoperatively, on the 4th 
postoperative day and 6 weeks postoperatively.  
Morphine consumption [number]  
The number of morphine preparations taken per day is counted and documented.  
Visual Analog Pain Scale [cm]  
The Visual Analog Pain Scale is documented at rest (supine position). The scale is scaled from 0 (no 
pain) to 10 (greatest pain imaginable) in cm increments. The test subjects are asked the following 
question: "How severe is your knee pain?" The measurement moments take place preoperatively, on 
the 4th postoperative day and 6 weeks postoperatively.  
10-meter walk test [sec]  
The 10-meter walking test is used because it is considered a valid and reliable measuring instrument for 
evaluating walking speed (Peters, Fritz, and Krotish 2013). In this assessment, the subject is asked to 
walk a distance of 10 meters as quickly and safely as possible. The examiner documents the time in 
seconds. The measurement moments take place preoperatively, on 4.  
postoperative day and 6 weeks postoperatively.  
Timed-Up-and-Go [sec]  
The time-up-and-go is used because it is considered a valid and reliable measuring instrument for the 
evaluation of physical activity after hip and knee prostheses (Dobson et al. 2012). The subject is asked 
to rise from a chair while sitting and walk three meters, turn around and sit down again. The time spent 
on this task is measured in seconds. The measurement moments take place preoperatively, on the 4th 
postoperative day and 6 weeks postoperatively.  
Length of stay [days]  
The number of hospitalisation days (from admission to and with discharge) is counted and documented.  
5.2 Secondary outcomes  
None available.  
5.3 Other Outcomes of Interest  
None available.  

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5.4 Safety Outcomes  
No further outcomes are included that serve safety. Discontinuation of the experiment is the 
responsibility of the examiners with regard to the subject's resilience. If this is estimated to be too low, 
the examiner can stop the experiment. If the subject does not feel well according to his or her own 
subjective assessment, he or she can discontinue the experiment and withdraw participation in the study. 
If the cold application is not justifiable for the test subject, he or she can discontinue the application. 
There are no disadvantages for him/her as a result. The current regulations of the Canton of Graubünden 
and those of the FOPH for protection against the coronavirus will be taken into account and implemented 
when conducting the study.  
  
  
6. CLINICAL INVESTIGATION DESIGN   
6.1 General clinical investigation design and justification of design   
Randomized, controlled trial  
It is a clinical investigation concerning medical devices (MD), Category according to Art 6 ClinO-MD 
(A1), whereby a CE-certified medical device is tested in the intervention group.  
The group size of the participants is n=28 people (per group n=14 people). The group assignment is 
randomized.  
6.2 Methods for minimising bias   
All measurements are carried out and logged by the same inspector in a standardized manner. The 
laboratory and hospital conditions are always the same.  
6.2.1  
Randomization   
The allocation to the two different groups (Game Ready or Control group) takes place randomly when a 
ticket is drawn.   
6.2.2  
Blinding procedures   
Blinding the participants is not possible in this study. The examiners are blinded by the addition of another 
examiner who operates the apparatus. The responsible statistician is blinded and has no access to the 
personal data of the test persons and is not present when the data is collected.  
6.2.3  
Other methods for minimising bias   
The content of the conversation between the test persons and the examiner is kept to a minimum.  
6.3 Unblinding Procedures (Code break)  
There is no provision for the removal of the blinding of the statistician and the examiners.  
The blinding of the examiners and the statistician is only permissible if an unforeseen incident would 
occur.  
In the event of incidents (AEs) that occur during or shortly after study participation and may be attributable 
to the intervention, the principal investigator may, at his or her discretion, immediately waive the blinding 
of the study participant and the investigators present to ensure adequate treatment of the study 
participant.  
In the case of incidents (AE) that occur longer than 24 hours, clarification by a doctor is mandatory and 
a doctor's certificate is required for the lifting of blindness. Data may then also be passed on to the 
attending physician with the consent of the study participant concerned. This approach is justified 
because no life-threatening incidents are to be expected due to the interventions used here.  
  
  
7. CLINICAL INVESTIGATION POPULATION   
7.1 Eligibility criteria   
Subjects fulfilling all of the following inclusion criteria are eligible for the investigation:  
• 
Signed Informed Consent by the participant  

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• 
Diagnosed gonarthrosis  
• 
Planned implantation of a primary total knee endoprosthesis by the Regional Hospital Surselva 
AG  
  
The presence of any one of the following exclusion criteria will lead to the exclusion of the subject:  
• 
Decompensated hypertension in the affected area  
• 
Acute inflammatory phlebitis in the affected area  
• 
Patients with acute paroxysmal cold hemoglobinuria, or cryoglobulinemia  
• 
significant vascular disorder in the affected area (e.g., due to previous frostbite, significant 
atherosclerosis, diabetes, or ischemic vascular disease)  
• 
History of pulmonary embolism or risk factors for deep vein thrombosis or pulmonary embolism 
in the affected area  
• 
Diseases such as active carcinomas or inflammation in the affected area, in which increased 
venous or lymphatic reflux is not desirable (as tumor cells and inflammatory parameters can be 
distributed throughout the body due to reflux)  
• 
Severe or decompensated heart failure  
• 
Raynaud's disease  
• 
Hypersensitivity to cold  
• 
Fear of cold/compression  
The test subjects will be comprehensively informed about the process and possible risks before they are 
accepted to participate in the study. You will also receive the information in written form and have the 
opportunity to ask questions. The declaration of consent explains to them what their rights and 
obligations are when participating. In addition, they are informed that they may withdraw from 
participation at any time without giving reasons, without incurring any disadvantages as a result.   
7.2 Recruitment and screening   
Recruitment  
It is advertised in the consultation hours of the orthopaedists of the Regionalspital Surselva AG, 
Spitalstrasse 6, CH7130 Ilanz with the help of the created advertisement (see attachment). The exact 
texts have been prepared according to the checklist of the Cantonal Ethics Commission Zurich.  
Screening  
At the first contact, the potential participants are informed about the course and risks of the study, as well 
as its conditions and the amount of compensation.  
Advertisement  
The advertisement for the first contact can be found in the attachment.  
7.3 Assignment to investigation groups   
The group assignment is hidden with the help of a ticket in a sealed envelope, which is drawn under the 
supervision of the study director. This lot shows whether the subject is going through the Game Ready 
or Control intervention.  
7.4 Criteria for withdrawal / discontinuation of subjects   
If a participant withdraws from the study, the allocation lot is returned to the pot in a new envelope and 
a new participant is sought.  
The already completed consent form is kept in the locked filing cabinet. In the event of a revocation of 
consent, the data and samples already collected must be included in the evaluation for scientific and 
security reasons. Only after the analysis are they anonymised (Art. 9 ClinO).  
The conditions for the termination of the experiment were described in chap. 5.4.  

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There is no disadvantage for the participants in the event of a termination of the  
Study participation.  
  
 

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8. CLINICAL INVESTIGATION INTERVENTION   
8.1 Identity of the medical device under investigation   
8.1.1  
Experimental Intervention (medical device)  
The Game Ready GR PRO 2.1 builds on the groundbreaking Game Ready technology and is a 
multimodality recovery device for professional users. The system can deliver ice-free cold treatment and 
intermittent pneumatic compression treatment, providing healthcare professionals with flexible options 
for different patients, procedures, injuries and rehabilitation stages.  
Proven principles such as PITCH (pause, ice, compression, elevation) can be taken to a new level with 
the state-of-the-art Game Ready GR PRO 2.1. Cumbersome procedures for cold treatment will be 
simplified with the compact, practical device. In addition, these can be monitored and controlled more 
consistently than conventional methods. The device is controlled via a touchscreen computer interface. 
The user can choose between different treatment modalities and easily change and monitor the settings 
for treatment duration, temperature and compression. The double-acting (cryotherapy and compression) 
and anatomically designed Game Ready cuffs can be used specifically for specific parts of the body.  
This device is used for the treatment of post-traumatic, post-operative (medical and/or surgical) and 
acute injuries, as well as for the reduction of edema, swelling and pain when cold and compression are 
indicated. It works in a closed circle with the help of the cuff described above and is therefore hygienic 
and safe to use in the clinic. The device is already being used in several Swiss clinics and institutions.  
  
  
Figure 3 - Game Ready GR PRO 2.1 (https://gameready.com/gr-pro-cold-therapy-unit/)  
In addition to standard physiotherapy (see Chapter 8.1.2 for more information), the subjects in the 
intervention group will receive the following intervention (according to the manufacturer's protocol for 
patients with total knee endoprosthesis): 48 hours after the operation, the intervention starts, if tolerable, 
with little compression (level 1 = 5-15 mmHg) and cooling at the coldest level tolerable by the participant 
(corresponds to program 2). The cooling should be perceived as "pleasant" by the participant. The 
intervention lasts one hour, of which 30 minutes are on and 30 minutes off cycles. The on cycle includes 
the duration of the intervention (cooling and compression), while the off cycles include the rest period. 
After 60 minutes, the device is removed. If compression is not tolerated, it can also be omitted on the 
first postoperative day (corresponds to program 1). The intervention is performed twice a day for the first 
four days after surgery. The coldest tolerable temperature level is to be determined anew for each 
treatment. The compression level may be increased, although medium compression may only be applied 
from the second day onwards (corresponds to program 3).  
Securing study participants  
The Game Ready applications represent a commonly used cooling and compression intervention in the 
literature. Nevertheless, the test subjects can discontinue the treatment at any time if they feel unwell. 
During the cooling applications and measurements, at least one or two examiners will always be next to 
the test subject in order to discontinue the treatment in case of discomfort. Further precautions are 
described in chap. 3.7. Risk/Benefits Described.  

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8.1.2  
Control Intervention (standard/routine/comparator)   
The test subjects receive standard physiotherapy, without Game Ready application. Standard 
physiotherapy after a total knee prosthesis includes the following interventions: The first 
physiotherapeutic treatment begins on the first postoperative day and consists of immediate loading of 
the operated leg (full weight bearing permitted according to the symptoms). Knee mobilisation with a 
passive movement machine and active knee mobilisation, instructed by the physiotherapist, are carried 
out. The treatment is carried out and documented by qualified and training physiotherapists at the 
Regional Hospital Surselva AG, Spitalstrasse 6, CH-7130 Ilanz. The cooling applications with Game 
Ready do not conflict with standard therapy.  
8.1.3  
Labelling and Supply (re-supply)   
The Game Ready GR PRO 2.1 is a certified medical device that complies with European regulations, 
directives and standards (93/42/EEC, EN60601-1, EC 60601-1-2, CE 0086).  
8.1.4  
Storage Conditions   
The Game Ready must be stored inside a room. The appliance is therefore located all year round in a 
closed room at room temperature and low humidity.  
8.2 Discontinuation or modifications of the intervention  
No further side effects are expected from participation in the study, as it is not an invasive method or 
drug intervention. As in chap. 8.5, the predefined inclusion and exclusion criteria as well as the health 
questionnaire are used to ensure safe participation. However, if reasons arise, the study participant 
reserves the right to withdraw from the study early. The test person reserves the right to exclude a 
participant from the study for the following reasons: safety aspects (feeling unwell, dissatisfaction of the 
participant), occurrence of one of the predefined exclusion criteria, at the request of the participant, 
revocation of consent (also possible without justification). Further information in this case can be found 
under chap. 9.2.5 and 7.4.  
8.3 Compliance with clinical investigation intervention   
Due to the fact that at least one research employee will be present during the Game Ready applications 
and the measurements, the compliance of the study participants can be classified as high. No additional 
measures are taken to improve compliance.  
8.4 Data Collection and Follow-up for withdrawn subjects   
The medical follow-up of subjects who drop out of the examination prematurely is described in chapters 
9.2.5 and 9.2.6. There is no disadvantage for the participants if they discontinue their participation in the 
study and no further interventions are necessary for follow-up treatment.  
8.5 Clinical investigation specific preventive measures  
Furthermore, any injuries and illnesses were defined as an exclusion criterion in order not to take the 
risk of intervention. The questionnaire also asks about any diseases and influences that preclude 
participation in the study. If there are doubts that are not medically proven, the study leader reserves the 
right to have them checked and thus exclude a test subject from participation.  
8.6 Concomitant Interventions (treatments)  
No interventions will be carried out in the study other than those described in Chapter 8.1. Therefore, no 
further side effects are expected from participation in the study.  
8.7 Medical Device Accountability  
The trials are taking place exclusively at the Regional Hospital Surselva AG, Spitalstrasse 6, CH-7130 
Ilanz. This means that there is no transport of the products and measuring instruments used. There is 
therefore no liability for the transport of the product.  

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8.8 Return, Analysis or Destruction of the Medical Device  
The Game Ready GR PRO 2.1 will be returned to MTR at the end of the measurement period. In the 
event of product defects, including malfunctions, usability issues, or insufficient information from the 
manufacturer, including labeling, the products will be returned to the sponsor for analysis.  

 
  
9. CLINICAL INVESTIGATION ASSESSMENTS  
Procedure Game Ready - Study 
 
  
  
  
Preopera've  
Mee'ng 
Opera'on 
Weeks  
6 
postop 
Interven'on ( usual care + Game  Ready ) 
- KOOS 
- KOOS 
- Circumfer
- ROME 
- Tskin 
- VAS Scale 
- sa9sfac9on 
- MGT 
10 
/TUG 
- KOOS 
- Circumfer
- ROME 
- Tskin 
- VAS Scale 
- 10 MGT /TUG 
Control ( usual care + no cooling) 
- VAS Scale 
- Tskin 
- Circumfer
- ROME 
- KOOS 
- VAS Scale 
- Tskin 
- Circumfer
- ROME 
- Morphine 
- Dura9on of stay 
- 10 MGT /TUG 
- MGT 
10 
/TUG 
4 .  Postop 
Day 

 
  
9.1 Clinical investigation flow chart(s) / table of clinical investigation 
procedures and assessments  
The test subject information is sent to the test subjects' homes in advance or given in person during the 
orthopaedic consultation. All rounds take place on the premises of the Regional Hospital Surselva AG.  
1. 
Subject Information & Informed Consent Meeting  
30 min (questions and ambiguities will be discussed individually here)  
2. 
Running the Test Log  
Test log  
Cooling group  
Control group  
Visit 1: Screening and baseline preoperatively:  
information, written consent, examination of 
/Exclusion criteria, health questionnaire  
Physical Function [Score]  
Joint circumference [mm]  
Range of motion [degrees]  
Skin temperature [°C]  
Visual Analog Pain Scale [cm]  
10-meter walk test [sec]  
Timed-up-and-Go [sec]  
Visit 1: Preoperative screening and baseline  
information, written consent, examination of 
/Exclusion criteria, health questionnaire  
Physical Function [Score]  
Joint circumference [mm]  
Range of motion [degrees]  
Skin temperature [°C]  
Visual Analog Pain Scale [cm]  
10-meter walk test [sec]  
Timed-up-and-Go [sec]  
Daily cooling intervention  
In addition to the usual physiotherapeutic 
treatment:  
Daily  Cooling  
and 
compression.  One  
detailed treatment 
description can be found in chap. 8.1.1.  
Daily Control Intervention  
In addition to the usual physiotherapeutic  
Treatment: No refrigeration (see chapter 8)  
Visit 4: Follow up 4th postoperative day  
Physical Function [Score]  
Joint circumference [mm]  
Range of motion [degrees]  
Skin temperature [°C]  
Visual Analog Pain Scale [cm]  
Patient satisfaction [cm]  
10-meter walk test [sec]  
Timed-up-and-Go [sec]  
Visit 4: Follow up 4th postoperative day  
Physical Function [Score]  
Joint circumference [mm]  
Range of motion [degrees]  
Skin temperature [°C]  
Visual Analog Pain Scale [cm]  
10-meter walk test [sec]  
Timed-up-and-Go [sec]  

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Visit 5: Follow up 6 weeks postoperatively  
Physical function [Score] Joint circumference 
[mm]  
Range of motion [degrees]  
Skin temperature [°C]  
Visual Analog Pain Scale [cm]  
Visit 5: Follow up 6 weeks postoperatively  
Physical function [Score] Joint circumference 
[mm]  
Range of motion [degrees]  
Skin temperature [°C]  
Visual Analog Pain Scale [cm]  
10-meter walk test [sec]  
Timed-up-and-Go [sec]  
Length of stay [days]  
Morphine consumption [number]  
10-meter walk test [sec]  
Timed-up-and-Go [sec]  
Length of stay [days]  
Morphine consumption [number]  
  
Test log  
 
Rounds  
Time exposure  
Visit 1: Screening and baseline preoperatively:  
information, written consent, examination of 
/Exclusion criteria, health questionnaire  
Physical Function [Score]  
Joint circumference [mm]  
Range of motion [degrees]  
Skin temperature [°C]  
Visual Analog Pain Scale [cm]  
10-meter walk test [sec]  
Timed-up-and-Go [sec]  
60 min  
Daily cooling intervention  
In addition to the usual physiotherapeutic 
treatment:  
Daily  Cooling  
and 
compression.  One  
detailed treatment 
description can be found in chap. 8.1.1.  
2x daily one treatment of 60 min = 120 min per 
day  
4x 120 min per day = 480 min per stay  
Visit 2: Follow up 4th postoperative day  
Physical Function [Score]  
Joint circumference [mm]  
Range of motion [degrees]  
Skin temperature [°C]  
Visual Analog Pain Scale [cm]  
Patient satisfaction [cm]  
10-meter walk test [sec]  
Timed-up-and-Go [sec]  
30 min  

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Visit 3: Follow up 6 weeks postoperatively  
Physical Function [Score]  
Joint circumference [mm]  
Range of motion [degrees]  
Skin temperature [°C]  
Visual Analog Pain Scale [cm]  
10-meter walk test [sec]  
Timed-up-and-Go [sec]  
Length of stay [days]  
Morphine consumption [number]  
40 min  
Total time commitment:  
610 min  
Any adverse events must be recorded during each visit. These possible time expenditures are not 
included in the test protocol.  
9.2 Assessments of outcomes   
The following data are collected during all tests described in the sub-protocols in chap. 9.1.  
9.2.1  
Assessment of primary outcome  
Questionnaire Physical Function [Score]  
To determine the subjective assessment of physical function, the KOOS questionnaire is handed out, 
evaluated and documented. The KOOS questionnaire is highly valid for knee complaints and refers to 
the subjective impression of the patients (Roos and ToksvigLarsen 2003). The measurement moments 
take place preoperatively, on the 4th postoperative day and 6 weeks postoperatively.  
Patient satisfaction [cm]  
In order to evaluate the patient satisfaction of the intervention group (Game Ready), the test subjects 
are asked the question "How satisfied are you with the cooling intervention?" immediately after the 
intervention. With the help of the Visual Analog Scale, the test subjects rate their satisfaction with a 
number between 0 (not at all satisfied) and 10 (maximally satisfied). The measurement moments take 
place twice a day (each time after the cooling intervention) during the  
hospital stay.  
Joint circumference [mm]  
The joint circumference measurement is carried out by hand with a tape measure. This measurement 
method showed a high level of reliability. 5cm, 10cm, 15cm above the knee joint space, at the level of 
the knee joint space, 15cm below the knee joint space, above the lateral malleolus and above the 
scaphoid bone (Oesch 2007). Both sides are measured. The measurement moments take place 
preoperatively, on the 4th postoperative day and 6 weeks postoperatively.  
Range of motion [degrees]  
To estimate the range of motion of knee flexion, the "RoMot" app from OT Bioelettronica (Turin, Italy) is 
used. The patient is in the supine position. The two sensors are applied to the lower and thigh legs. In 
response to the start command, the test subject tries to bend his knee as much as possible. The heel 
remains in bed and the longitudinal axis of the leg is also taken into account. Then the other side is 
measured. The number of degrees indicated by the software on the corresponding tablet is documented. 
Wireless Bluetooth sensors, for determining the amount of motion, show a high correlation compared to 
the goniometer measurements, which are currently the most commonly used in practice (Kumar et al. 
2015). The measurement moments take place preoperatively, on the 4th postoperative day and 6 weeks 
postoperatively.  
Skin temperature [°C]  
Skin temperature is also recorded with the help of an infrared thermometer (Voltcraft IR800-20D, Conrad 
Electronic, Hirschau, Germany). Handheld infrared thermal devices have high measurement accuracy 
(due to contact-free measurement) and practical handling (Stoop et al. 2020). Skin temperature is 
measured at four locations of the knee: superolateral, superomedia, inferiorlateral, and inferiordial 

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margin of the patella (Zeng et al. 2016). The subject is in a supine position during the measurements. 
Both sides are measured. The measurement moments take place preoperatively, on the 4th 
postoperative day and 6 weeks postoperatively.  
Morphine consumption [number]  
The number of morphine preparations taken per day is counted and documented.  
Visual Analog Pain Scale [cm]  
The Visual Analog Pain Scale is documented at rest. The scale is scaled from 0 (no pain) to 10 (greatest 
pain imaginable) in cm increments. The test subjects are asked the following question: "How severe is 
your knee pain?" The measurement moments take place preoperatively, on the 4th postoperative day 
and 6 weeks postoperatively.  
10-meter walk test [sec]  
The 10-meter walking test is used because it is considered a valid and reliable measuring instrument for 
evaluating walking speed (Peters, Fritz, and Krotish 2013). In this assessment, the subject is asked to 
walk a distance of 10 meters as quickly and safely as possible. The examiner documents the time in 
seconds. The measurement moments take place preoperatively, on the 4th postoperative day and 6 
weeks postoperatively.  
Timed-Up-and-Go [sec]  
The time-up-and-go is used because it is considered a valid and reliable measuring instrument for the 
evaluation of physical activity after hip and knee prostheses (Dobson et al. 2012). The subject is asked 
to rise from a chair while sitting and walk three meters, turn around and sit down again. The time spent 
on this task is measured in seconds. The measurement moments take place preoperatively, on the 4th 
postoperative day and 6 weeks postoperatively.  
Length of stay [days]  
The number of hospitalisation days (from admission to and with discharge) is counted and documented.  
9.2.2  
Assessment of secondary outcomes  
None available.  
9.2.3  
Assessment of other outcomes of interest  
None available.  
9.2.4  
Assessment of safety outcomes  
No corresponding parameters are collected.  
9.2.4.1  Adverse events   
-  
9.2.4.2  Laboratory parameters  
-  
9.2.4.3  Vital signs  
-  
9.2.5  
Assessments in subjects who prematurely stop the clinical investigation  
For the participants, there is no disadvantage in the event of an (arbitrary) discontinuation of study 
participation and no further interventions are necessary for follow-up treatment.  
However, if study participation was discontinued due to an injury sustained during study participation, 
this will be recorded and reported to the sponsor, the head of the research laboratory, the study leader 
and the supervisor of the study. The report is then sent to the business liability insurance of Thim van 
der Laan AG in order to ensure the appropriate follow-up treatment.  
The following are recorded:  
- 
Date and time of the incident  
- 
Course of the incident  

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- 
Persons involved & witnesses  
- 
Study ID (issued by the CEC)  
- 
Personal details of the person concerned (if not previously recorded)  
9.2.6  
Follow-up of the subjects after the regular termination of the clinical investigation  
Since the Game Ready GR PRO 2.1 thermotherapy device used is only used in the context of the 
intended use, no additional care of the subject is required after the end of his or her participation in the 
clinical trial, nor are arrangements made for subsequent care.  
9.3 Procedures at each visit  
All rounds take place on the premises of the Regional Hospital Surselva AG.  
9.3.1 Single measurement  
The project consists of multiple visits with a total duration of 850 minutes, which takes place as follows:  
9.3.2  
Multiple visits  
Responsibility for conducting the study and protecting participants Responsibility: Dr. 
Ron Clijsen  
  
1. Subject Information & Informed Consent  
The "Visit 1: Screening" includes the following steps: The test subjects are subjected to a screening 
before being accepted  
participation in the study is comprehensively informed about the process and possible risks. You will also 
receive the information in written form and have the opportunity to ask questions. The declaration of 
consent explains to you what your rights and obligations are when participating and that you may 
withdraw from participation at any time without giving reasons, without any disadvantage to you. More 
detailed information can be found in chap. 2.7. Responsibility: Dr. med. Martin Wonerow, Dr. med. 
Sebastian Ulsamer  
  
2. Running the Test Log  
Visit 1: Screening describes the collection of baseline values (preoperatively) as well as any further 
information, written consent, examination of all inclusion/exclusion criteria, and the health questionnaire.  
Start of the cooling intervention: In addition to the usual physiotherapeutic treatment: Daily  
Cooling and compression. A detailed description of the intervention can be found in chap. 8.1.1.  
Visit 2 and 3: The measurements are carried out in the same way as the test protocol and the data is 
collected.  
Responsibility: Research staff of the University of Applied Sciences and Arts Southern Switzerland  
  
3. Indemnification and Conclusion  
After completion of the measurements (6 weeks postoperatively), the subject will receive the 
compensation due according to the information in the advertisement: a flat rate of CHF 50 after 
completion of the measurements.  
Responsibility: Research staff of the University of Applied Sciences and Arts Southern Switzerland  
  
  
10. SAFETY   
10.1 Definition and Assessment of (Serious) Adverse Events and other safety 
related events  
Adverse Event (AE) (Art. 2 para. 57 MDR)  
Any untoward medical occurrence, unintended disease or injury or any untoward clinical signs (including 
an abnormal laboratory finding) in subjects, users or other persons whether or not related to the MD.  

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Serious Adverse Event (SAE) (Art. 2 para. 58 MDR) Any 
adverse event that led to any of the following:  
(a) Death  
(b) serious deterioration in the health of the subject that resulted in any of the following:  
(i) 
life-threatening illness or injury,  
(ii) permanent impairment of a body structure or a body function,  
(iii) hospitalisation or prolongation of patient hospitalisation,  
(iv) medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function,  
(v) chronic disease,  
(c) foetal distress, foetal death or a congenital physical or mental impairment or birth defect.  
Note: planned hospitalization for pre-existing condition, or a procedure required by the CIP, without a 
serious deterioration of the health status of the subject, is not considered an SAE  
  
Device deficiency (Art. 2 para. 59 MDR)  
Inadequacy of a medical device related to its identity, quality, durability, reliability, safety or performance, 
of an investigational device, including malfunction, user errors and inadequate information supplied by 
the manufacturer.  
  
Malfunction (ISO14155)  
Failure of an investigational device to perform in accordance with its intended purpose when used in 
accordance with the instructions for use or the CIP.  
  
Device deficiency with Serious Adverse Device Effect (SADE) potential (Art. 80 para. 1 letter c 
MDR; ISO14155)  
Any device deficiency that might have led to a serious adverse event if appropriate action had not been 
taken, intervention had not occurred, or circumstances had been less fortunate.  
  
Adverse Device Effect (ADE) (ISO14155)  
Adverse event possibly, probably or causally related to the use of an investigational device or 
procedures.   
  
Serious Adverse Device Effect (SADE) (ISO14155)  
Adverse device effect (ADE) that has resulted in any of the consequences characteristic of a serious 
adverse event.  
  
Unanticipated Serious Adverse Device Effect (USADE) (ISO14155)  
Serious adverse device effect (SADE) which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report.  
  
Causal Relationship of SAE (MDCG 2020-10/1)  
A causal relationship towards the medical device or the procedure of the investigation should be rated 
by the PI and the Sponsor as follows:  
• 
Not related: The relationship to the device or procedures can be excluded.  
• 
Possible: The relationship with the use of the investigational device is weak but cannot be ruled 
out completely. Alternative causes are also possible.  
• 
Probable: The relationship with the use of the investigational device seems relevant and/or the 
event cannot reasonably be explained by another cause.  

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• 
Causal relationship: The serious event is associated with the investigational device or with 
procedures beyond reasonable doubt.  
  
10.2 Adverse events categorization  
The adverse events are categorized by the PI and the Sponsor using the following algorithm: Does 
the AE meet the seriousness criteria?  
o 
No, it is not serious  
• 
Is the relationship to the device or the procedure possible, probable or causal?  
• 
No: non-related AE  
• 
Yes: ADE  
o 
Yes, it is serious: SAE  
• 
Is the relationship to the device or the procedure possible, probable or causal?  
• 
No: non-related SAE  
• 
Yes: SADE  
o 
Is it anticipated (within expected type, severity and frequency of the complications)?  
• 
No: unanticipated SADE (USADE)  
• 
Yes: anticipated SADE (ASADE)  
  
10.3 Documentation and reporting in Medical Device Category A clinical 
investigations  
Device deficiencies (DD) and all adverse events (AE) including all serious adverse events (SAE) are 
collected, fully investigated and documented in the source document and appropriate case report form 
(CRF) during the entire investigation period, i.e. from patient's informed consent until the last CIPspecific 
procedure, including a safety follow-up period.  
• Documentation of AEs (including SAEs) by the PI includes diagnosis or symptoms, start and stop 
dates of event, event treatment, event resolution, assessment of seriousness and causal 
relationship to MD and/or investigation procedure (Art. 32 ClinO-MD, ISO14155).  
• Documentation of DDs by the PI includes description of event, start date, investigational device 
information, action taken with regard to the investigational device, and whether the DD led to an 
AE. The Sponsor shall review all DDs and determine and document in writing whether they could 
have led to a SAE (DD with SADE potential) (Art 32. ClinO-MD, ISO14155).  
The project works with a CE-certified product. It is a study with 30 or fewer subjects. The study focuses 
on basic findings. The study aims to gain fundamental knowledge in the field of cryotherapy in 
combination with compression. The monitoring for quality assurance is carried out by Prof. Peter Clarys, 
PhD.  
  
10.3.1 Foreseeable adverse events and anticipated adverse device effects  
The following foreseeable serious adverse events and product defects may occur:  
-tissue damage due to improper or too long use than described by the manufacturer,  
-burning, itching, increasing swelling, pain, blisters, increasing redness, discoloration and other visible 
changes during treatment,  
-Change in wound conditions (if the wrap is not applied over the bandage or clothing),  
-Risk of electric shock (if other power supplies are used, housing parts are removed, or damaged cables 
and connecting hoses are used) and  
-Device damage (if there is no or too hot water in the ice box, the device is lifted up by the lid, or wraps 
from other manufacturers have been used).  
  
Participants who complain of ongoing adverse events after graduation/discontinuation of their studies 
will be contacted by telephone two weeks after graduation and asked about their state of health. If the 

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undesirable events still exist, the participants will be called up for an additional visit to the Surselva 
Regional Hospital AG. During this visit, the ongoing events are assessed and documented.  
  
10.3.2 Reporting of Safety related events  
Reporting to the Sponsor:  
All SAEs, device deficiencies and health hazards that require measures are reported to the Sponsor by 
the PI (or authorized designee) within 24 hours after becoming aware of the event. Device deficiencies 
are assessed regarding their potential to lead to an SAE. DD are assessed regarding their potential to 
lead to an SAE.  
Reporting to the Competent Ethics Committee:  
The Sponsor reports to the CEC promptly any serious adverse event which has a causal relation with 
the MD, comparator or procedure/test method or where a causal relation appears to be possible (Art. 
33 ClinO-MD).  
In order to ensure prompt notification, the Sponsor may initially submit an incomplete notification.   
If safety and health hazards that require measures must be taken immediately during the conduct of the 
investigation, the Sponsor notifies the CEC within 2 days of these measures and the circumstances 
which made them necessary (Art. 34 ClinO-MD).  
  
Periodic safety reporting (Art. 35 ClinO-MD):  
An Annual Safety Report (ASR) is submitted by the Sponsor to the CEC, yearly. The ASR contains a list 
of all SADEs and DDs and a report on their degree of seriousness, causal relationship with the MD and 
procedure and on subjects' safety.  
  
Other reporting is done according to provisions of MD vigilance as per Art. 87-90 MDR (Art. 33 para. 4.b 
ClinO-MD) and Art. 67 MedDO.   
  
  
11. STATISTICAL METHODS   
11.1 Hypothesis  
Physical Function [AU]  
H0: The use of cryotherapy with intermittent dynamic compression has no positive effect on the 
physical functions of patients after a total knee arthroplasty.  
H1: The use of cryotherapy with intermittent dynamic compression has a positive effect on the 
physical functions of patients after a total knee arthroplasty.  
  
Patient satisfaction [cm]  
H0: The use of cryotherapy with intermittent dynamic compression has no positive effect on 
patient satisfaction of patients after a total knee arthroplasty.  
H1: The use of cryotherapy with intermittent dynamic compression has a positive effect on 
patient satisfaction of patients after a total knee arthroplasty.  
  
Joint circumference [mm]  
H0: The joint circumference is not reduced by cryotherapy with intermittent dynamic 
compression compared to the control group during a hospital stay.  
H1: The joint circumference is reduced by cryotherapy with intermittent dynamic compression 
compared to the control group during a hospital stay.  
  
Skin temperature [C°]  

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H0: The skin temperature is not reduced by cryotherapy with intermittent dynamic compression 
compared to the control group during a hospital stay.  
H1: The skin temperature is reduced by cryotherapy with intermittent dynamic compression 
compared to the control group during a hospital stay.  
  
Morphine consumption [number]  
H0: The intake of morphine is not reduced by cryotherapy with intermittent dynamic compression 
compared to control groups during hospitalization.  
H1: The intake of morphine is reduced by cryotherapy with intermittent dynamic compression 
compared to the control group during a hospital stay.  
  
Visual analog scale [cm]  
H0: The sensation of pain with the Visual Analog scale is not reduced by cryotherapy with 
intermittent dynamic compression compared to the control group during a hospital stay.  
H1: The sensation of pain with the Visual analog scale is reduced by cryotherapy with 
intermittent dynamic compression compared to the control group during a hospital stay.  
  
10-meter walk test [sec]  
H0: The 10-metre gait test is not reduced by cryotherapy with intermittent dynamic compression 
compared to control groups during a hospital stay.  
H1: The 10-metre gait test is reduced by cryotherapy with intermittent dynamic compression 
compared to the control group during a hospital stay.  
  
Timed-Up-and-Go [sec]  
H0: The timed up-and-go is not reduced by cryotherapy with intermittent dynamic compression 
compared to control groups during a hospital stay.  
H1: The timed-up-and-go is reduced by cryotherapy with intermittent dynamic compression 
compared to control groups during a hospital stay.  
  
Length of stay [days]  
H0: The length of stay in hospital is not shortened by cryotherapy with intermittent dynamic 
compression compared to control groups during a hospital stay. H1: The length of stay in 
hospital is shortened by cryotherapy with intermittent dynamic compression compared to 
control groups during a hospital stay.  
11.2 Determination of Sample Size   
A power analysis was performed using the G*Power App (Düsseldorf, North Rhine-Westphalia, DEU), 
where a minimum number of 28 subjects was deemed necessary to ensure the statistical power (0.95) 
to detect a parameter difference at the 5% significance level. The figure below shows the G-Power 
calculation that was used to determine the sample size.  
Figure 4: Sample Size Calculation  

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11.3 Statistical criteria of termination of the investigation   
Only data from subjects who have completed the entire protocol will be included in the study. This 
ensures that all data has been collected under the same conditions and thus remains homogeneous 
and comparable.  
11.4 Planned Analyses   
11.4.1 Datasets to be analysed, analysis populations  
Only complete data sets will be included in the study. Data that contains only part of the protocol is not 
included in the analysis. No new subjects are being sought to replace the missing data.  
11.4.2 Primary Analysis  
The statistical data analysis will be carried out by Dr. Erich Hohenauer after completion of the data 
collection of the entire project.  
Repeated measures analysis of variance (MANOVA) 2 
factors:  
Factor 1: Intervention (Game Ready vs. Control Intervention)  
Factor 2: Time (baseline, 4th postoperative day and 6 weeks)  
The significance level is set to p<0.05. Statistical data analysis is carried out with SPSS.  
11.4.3 Secondary Analyses  
Repeated measures analysis of variance (MANOVA) 2 
factors:  
Factor 1: Intervention (intervention side vs. control side)  

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Factor 2: Time (baseline, 4th postoperative day and 6 weeks)  
The significance level is set to p<0.05. Statistical data analysis is carried out with SPSS.  
11.4.4 Interim analyses  
The data is processed after the end of the respective subprotocol. Thus, the data analysis for the entire 
study takes place in stages. No additional interim analyses are planned.  
11.4.5 Deviation(s) from the original statistical plan   
Deviations from the planned statistical analysis are recorded and justified and reported to the CEC in 
the annual report.  
11.5 Handling of missing data and drop-outs   
If a test subject does not complete the experiment, any data that has already been collected is retained, 
but is not further incorporated into the final data analysis.  
  
  
12. QUALITY ASSURANCE AND CONTROL   
12.1 Data handling and record keeping / archiving   
12.1.1 Case Report Forms   
Data protection and confidentiality are guaranteed and no personal data is presented or published. The 
signed declaration of consent, as well as the completed questionnaire with the other personal data and 
demographic and medical personal data are stored in the original as a study document in a locked filing 
cabinet. The identity of the test persons is encoded in accordance with the encryption (coding) of a 
person when participating in a research project, as accepted by swissethics. Only a person's year of 
birth (YYYY) is documented along with a coding number in the CRF. The project manager is responsible 
for the secure storage of the key for the data encrypted as part of the clinical trial or research project. 
Direct access to the personal data will continue to be allowed only to authorized persons of the CEC.  
12.1.2 Specification of source data and source documents   
The data collected in writing are recorded on paper in the enclosures and are marked as study data. In 
a double-blind process, the data is transferred from the CRF to an Excel database for the analyses. 
They are therefore subject to data protection and are regulated in accordance with the provisions set 
out in chap. 12.1.1.  
12.1.3 Archiving of essential clinical investigation documents  
All the documents of the investigation must be archived for a minimum of 10 years after regular or 
premature termination of the investigation. Data protection will continue to be guaranteed.  
12.2 Data management   
12.2.1 Data Management System   
The questionnaire for recording physical function is obtained by hand. All other outcomes (joint 
circumference, range of motion, morphine consumption, VAS scale, length of stay, 10-metre walk test, 
timed-up-and-go) are noted on the data collection form. Excel is used for further data analysis. Windows 
Excel will also be used for data pooling and for the graphical representation of® the end data. All data 
is processed on the central research computer. This research computer is located at all times in 
Landquart (research laboratory). Only the study director and the examiners know the password to unlock 
this computer. All digital documents are read-only by a password. Only the study director and the 
examiners know the passwords of the digital documents. The digital documents will be given version 
numbers. Changes made to the digital documents are saved as a new version number. In addition, all 
versions will be printed out and signed by the Director of Studies. The printed documents are stored in 
a separate, lockable filing cabinet. This filing cabinet also contains the password combinations to decrypt 
the computer and edit the documents. Only the director of studies has the key to this filing cabinet.  

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12.2.2 Data security, access and back-up   
The data is encrypted and treated confidentially, access to the personal data is not allowed to third 
parties. The digital data collected is stored solely on the institute's own computers and is not passed on 
to any external persons or to other parties.  
Transfer computer. Access to the computers of the research laboratory at the "University of Applied 
Sciences and Arts Southern Switzerland" is only granted to the head of studies and the examiners as 
well as persons authorised by the CEC.  
12.2.3 Analysis and archiving  
After collection, the data is encrypted and stored on another external hard drive for further backup. This 
is stored in a locked filing cabinet to ensure data protection.  
12.2.4 Electronic and central data validation   
Immediately after data collection, the quality of the data is checked and verified with the help of the visual 
representation.  
12.3 Monitoring   
The collected data can be viewed by authorized persons at any time. Remote monitoring of the study is 
planned by the following person:  
Prof. Peter Clarys, PhD  
Vrije Universiteit Brussels  
Faculty of Physical Therapy Pleinlaan 
2, 1050 Brussels 
peter.clarys@vub.ac.be  
Monitoring is regulated in a separate agreement. The monitoring of the study will be carried out externally 
and virtually (without physical presence). The documents to be checked are made available to the 
monitor for inspection on a protected page of the Microsoft Teams platform.  
12.4 Audits and Inspections   
A report on the current status of the study is sent monthly to the study supervisor (Prof. Dr.  
Peter Clarys). This also includes demonstrating and presenting results and statistical analyses. An 
annual report on the course of the study will be submitted to the CEC. Authorized persons of the CEC 
can view the data forms as well as the digital data on the institute's own computers at any time. Data 
protection is guaranteed at all times.  
12.5 Confidentiality, Data Protection   
The examiners ensure that the privacy of the participants is maintained. In particular, data protection 
and confidentiality are guaranteed and no personal data is presented or published. The signed 
declaration of consent, as well as the completed questionnaire with the other personal details, are kept 
in the original as a study document in a locked filing cabinet. The data is encrypted and treated 
confidentially, access to the personal data is not allowed to third parties. The digital data collected is 
stored solely on the institute's own computers and is not passed on to any external persons or 
transferred to other computers. Direct access to the personal data is only allowed to authorized persons 
of the CEC.  
  
  
13. PUBLICATION AND DISSEMINATION POLICY   
The examiners ensure that the privacy of the participants is maintained. In particular, the data protection 
and confidentiality of the data are guaranteed and no personal data is presented or published nor passed 
on to outsiders and unauthorized persons.  
  
  
 

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14. FUNDING AND SUPPORT   
14.1 Funding   
The study is funded by the University of Applied Sciences and Arts Southern Switzerland, Physiotherapy 
Graubünden. The auditors are employed by this institute and are remunerated for their work on this 
study in accordance with their employment contracts. No further financial support is needed.  
14.2 Other Support   
The Game Ready GRPro 2.1 thermotherapy device is kindly provided by the Swiss distributor MTR 
Health & Spa AG for the entire duration of the study. There is no written agreement. However, no 
obligations have been entered into towards the company and the independence of data analysis and 
discussion is thus guaranteed. MTR Health & Spa AG  
Fällmisstrasse 64  
CH-8832 Wilen b. Wollerau  
Phone: +41 (0)44 787 70 80  
Fax: +41 (0)44 787 70 81  
15. INSURANCE   
There is a business liability insurance with Baloise Insurance for Thim van der Laan AG in Landquart. 
Any damage in connection with the research activities at the Regionalspital Surselva AG is covered by 
the public liability insurance of the Regionalspital Surselva AG. A confirmation is attached to this 
application.  
  
  
 

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16. REFERENCES   
1. Declaration of Helsinki, Version October 2013  
(http://www.wma.net/en/30publications/10policies/b3/index.html )   
2. Human Research Act, HFG Federal Act on Human Research (Federal Act on Human Research, 
HFA) of 30 September 2011/ Loi fédérale relative à la recherche sur l'être humain (loi relative à 
la recherche sur l'être humain,  
LRH) du 30 septembre 2011 / Legge federale concernente la ricerca sull'essere umano  
(Legge sulla ricerca umana, LRUm) del 30 settembre 2011  
3. Ordinance on Clinical Trials on Medical Devices (ClinV-Mep) of 1 July 2020 / Ordonnance sur 
les essais cliniques de dispositifs médicaux (OClin-Dim) du 1er juillet 2020 /. Ordinanza sulle 
sperimentazioni cliniche con dispositivi medici (OSRUm-Dmed) del 1 luglio 2020  
4. Ordinance on Clinical Trials in Human Research (Ordinance on Clinical Trials, KlinV) of 20 
September 2013 / Ordonnance sur les essais cliniques dans le cadre de la recherche sur l'être 
humain (Ordonnance sur les essais cliniques, OClin) du 20 septembre 2013.  
(Ordinanza sulle sperimentazioni cliniche, OSRUm) del 20 settembre 2013  
5. Medical Devices Regulation (MedDO) of 17 October 2001 / Ordonnance sur les dispositifs 
médicaux (ODim) du 17 octobre 2001 / Ordinanza relativa ai dispositivi medici (ODmed) del 17 
ottobre 2001  
6. Medical Device Regulation (EU) 2017/745 of 5 April 2017 (MDR) (https://eurlex.europa.eu/legal-
content/EN/TXT/?uri=CELEX%3A32017R0745)  
7. MDCG 2020-10/1 Safety reporting in clinical investigations of medical devices under the  
Regulation (EU) 2017/745  
(https://ec.europa.eu/health/sites/health/files/md_sector/docs/md_mdcg_2020-
101_guidance_safety_reporting_en.pdf)  
8. EN ISO 14155: Clinical investigation of medical devices for human subjects - Good clinical 
practice (www.iso.org)  
9. EN ISO 10993: Biological evaluation of medical devices (www.iso.org)  
10. EN ISO 14971: Application of risk management to medical devices (www.iso.org)  
11. WHO, International Clinical Trials Registry Platform (ICTRP) (http://www.who.int/ictrp/en/)   
12. Radiation Protection Ordinance (StSV) of 26 April 2017 / Ordonnance sur la radioprotection 
(ORaP) du 26 avril 2017 / Ordinanza sulla radioprotezione (ORaP) del 26 aprile 2017.  
13. International Conference on Harmonization (ICH) Guideline for Good Clinical Practice E6(R2). 
(http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__ 
Step_4.pdf)  
Bellon, M., D. Michelet, N. Carrara, T. Vacher, B. Gafsou, B. Ilhareborde, K. Mazda, E. Ferrero, A. L. Simon, F. 
Julien-Marsollier, and S. Dahmani. 2019. "Efficacy of the Game Ready((R)) cooling device on 
postoperative analgesia after scoliosis surgery in children." Eur Spine J 28 (6): 1257-1264.  
https://doi.org/10.1007/s00586-019-05886-6. https://www.ncbi.nlm.nih.gov/pubmed/30847706.  
Dobson, F., R. S. Hinman, M. Hall, C. B. Terwee, E. M. Roos, and K. L. Bennell. 2012. "Measurement properties 
of performance-based measures to assess physical function in hip and knee osteoarthritis: a systematic 
review." Osteoarthritis Cartilage 20 (12): 1548-62. https://doi.org/10.1016/j.joca.2012.08.015.  
Ebert, Jay R., Brendan Joss, Berit Jardine, and David J. Wood. 2013. "Randomized Trial Investigating the Efficacy 
of Manual Lymphatic Drainage to Improve Early Outcome After Total Knee Arthroplasty." Archives of 
Physical Medicine and Rehabilitation 94 (11): 2103-2111. https://doi.org/10.1016/j.apmr.2013.06.009. 
https://doi.org/10.1016/j.apmr.2013.06.009.  
Klaber, Ianiv, Eugene Greeff, and John O'Donnell. 2019. "Compressive cryotherapy is superior to cryotherapy 
alone in reducing pain after hip arthroscopy." Journal of Hip Preservation Surgery. 
https://doi.org/10.1093/jhps/hnz048.  
Kumar, Yogaprakash, Shih-Cheng Yen, Arthur Tay, Wang Wei Lee, Fan Gao, Ziyi Zhao, Jingze Li, Benjamin Hon, 
Tim Tian-Ma, Angela Cheong, Karen Koh, Yee-Sien Ng, Effie Chew, Gerald Koh, and Tianma Xu. 2015. 
"Wireless wearable range-of-motion sensor system for upper and lower extremity joints: A validation 
study." Healthcare Technology Letters 2: 12-17. https://doi.org/10.1049/htl.2014.0100.  
Leegwater, N. C., J. H. Willems, R. Brohet, and P. A. Nolte. 2012. "Cryocompression therapy after elective 
arthroplasty of the hip." Hip Int 22 (5): 527-33. https://doi.org/10.5301/HIP.2012.9761. 
https://www.ncbi.nlm.nih.gov/pubmed/23112075.  
MTR. 2021. "Game Ready Med4Elite." https://www.mtr-ag.ch/game-ready-de/game-ready-med4elite-tm.html.  

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Murgier, J., and X. Cassard. 2014. "Cryotherapy with dynamic intermittent compression for analgesia after anterior 
cruciate ligament reconstruction. Preliminary study." Orthop Traumatol Surg Res 100 (3): 30912. 
https://doi.org/10.1016/j.otsr.2013.12.019. https://www.ncbi.nlm.nih.gov/pubmed/24679367.  
Nabiyev, V. N., S. Ayhan, P. Adhikari, E. Cetin, S. Palaoglu, and R. E. Acaroglu. 2018. "Cryo-Compression 
Therapy After Elective Spinal Surgery for Pain Management: A Cross-Sectional Study with Historical 
Control." Neurospine 15 (4): 348-352. https://doi.org/10.14245/ns.1836070.035. 
https://www.ncbi.nlm.nih.gov/pubmed/30531660.  
Oesch, Peter. 2007. "Skilful use of the tape measure." Physiopraxis 1.  
Peters, D. M., S. L. Fritz, and D. E. Krotish. 2013. "Assessing the reliability and validity of a shorter walk test 
compared with the 10-Meter Walk Test for measurements of gait speed in healthy, older adults." J Geriatr 
Phys Ther 36 (1): 24-30. https://doi.org/10.1519/JPT.0b013e318248e20d.  
Roos, E. M., and S. Toksvig-Larsen. 2003. "Knee injury and Osteoarthritis Outcome Score (KOOS) - validation 
and comparison to the WOMAC in total knee replacement." Health Qual Life Outcomes 1: 17. 
https://doi.org/10.1186/1477-7525-1-17.  
Stoop, Rahel, Erich Hohenauer, Dirk Aerenhouts, André Barel, Tom Deliens, Ron Clijsen, and Peter Clarys. 2020. 
"Comparison of two skin temperature assessment methods after the application of topical revulsive 
products: Conductive iButton data logger system vs contact-free infrared thermometry." Skin Research 
and Technology 00: 1-6. https://doi.org/10.1111/srt.12847.  
Su, E. P., M. Perna, F. Boettner, D. J. Mayman, T. Gerlinger, W. Barsoum, J. Randolph, and G. Lee. 2012. "A 
prospective, multi-center, randomised trial to evaluate the efficacy of a cryopneumatic device on total 
knee arthroplasty recovery." The Journal of Bone and Joint Surgery. British volume 94-B (11_Supple_A): 
153-156. https://doi.org/10.1302/0301-620X.94B11.30832. 
https://doi.org/10.1302/0301620X.94B11.30832.  
Thienpont, Emmanuel. 2014. "Does Advanced Cryotherapy Reduce Pain and Narcotic Consumption After Knee 
Arthroplasty?" Clinical Orthopaedics and Related Research® 472 (11): 3417-3423. 
https://doi.org/10.1007/s11999-014-3810-8. 
https://journals.lww.com/clinorthop/Fulltext/2014/11000/Does_Advanced_Cryotherapy_Reduce_Pain_an 
d_Narcotic.27.aspx.  
Waterman, B., J. J. Walker, C. Swaims, M. Shortt, M. S. Todd, S. M. Machen, and B. D. Owens. 2012. "The 
efficacy of combined cryotherapy and compression compared with cryotherapy alone following anterior 
cruciate ligament reconstruction." J Knee Surg 25 (2): 155-60. https://doi.org/10.1055/s-0031-1299650. 
https://www.ncbi.nlm.nih.gov/pubmed/22928433.  
Zeng, Y., W. Feng, X. Qi, J. Li, J. Chen, L. Lu, P. Deng, J. Zeng, and F. Li. 2016. "Differential knee skin 
temperature following total knee arthroplasty and its relationship with serum indices and outcome: A 
prospective study." J Int Med Res 44 (5): 1023-1033. https://doi.org/10.1177/0300060516655237.  
https://www.ncbi.nlm.nih.gov/pubmed/27596626.  
  
  
17. APPENDICES  
2. 
Subject Information Declaration of Consent  
3. 
Data collection form  
4. 
Copy of proof of insurance  
5. 
Advertisement  
6. 
Protocol Synopsis  
7. 
Employee  
8. 
CV's Investigator and Sponsor  
9. 
GCP Proof Investigator and Sponsor  
9. Operating manual and CE certification GR PRO 2.1