Personalised Subject Specific HTO Versus Generic HTO Virtual Clinical Trial
Conditions: Osteoarthritis, Knee
Sponsor: University of Bath

Date and version No:     23 January 2018 v 0.3 Protocol number RG433_TVT_003 
 
 
Clinical Research Protocol Template version 1.0     
 
 
 
 
 
CONFIDENTIAL 
University of Bath 
 
 
 
 
 
 
 
 
Page 1 of 12 
Study Title:  ToKa HTO Virtual Clinical Trial 
IRAS project ID: 219877 
REC reference: 17/HRA/0033 
Date and Version No: 23 January 2018 v 0.3 
 
Chief Investigator: 
Professor Richie Gill, Dept. of Mechanical Engineering, University of 
Bath 
Investigators:  
Mr Andrew Toms, Royal Exeter & Devon NHS Trust 
Sponsor:  
Royal Exeter & Devon NHS Trust 
Funder: 
Arthritis Research UK 
Chief Investigator Signature:   
 
 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the 
Sponsor, the Investigator Team, host organisation, and members of the Research Ethics Committee, 
unless authorised to do so. 
 

Date and version No:     23 January 2018 v 0.3 Protocol number RG433_TVT_003 
 
 
Clinical Research Protocol Template version 1.0     
 
 
 
 
 
CONFIDENTIAL 
University of Bath 
 
 
 
 
 
 
 
 
Page 2 of 12 
TABLE OF CONTENTS 
 
1. 
SYNOPSIS ............................................................................................................................................... 4 
2. 
ABBREVIATIONS ..................................................................................................................................... 4 
3. 
BACKGROUND AND RATIONALE ............................................................................................................ 5 
4. 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS .......................................................................... 5 
5. 
STUDY DESIGN ....................................................................................................................................... 6 
6. 
PARTICIPANT IDENTIFICATION .............................................................................................................. 6 
6.1. 
Study Participants .......................................................................................................................... 6 
6.2. 
Inclusion Criteria ............................................................................................................................ 6 
6.3. 
Exclusion Criteria ........................................................................................................................... 6 
7. 
STUDY PROCEDURES ............................................................................................................................. 6 
7.1. 
Recruitment ................................................................................................................................... 7 
7.2. 
Informed Consent .......................................................................................................................... 7 
7.3. 
Screening and Eligibility Assessment ............................................................................................. 7 
7.4. 
Randomisation, blinding and code-breaking ................................................................................. 7 
7.5. 
Baseline Assessments .................................................................................................................... 7 
7.6. 
Subsequent Visits .......................................................................................................................... 7 
7.7. 
Discontinuation/Withdrawal of Participants from Study .............................................................. 7 
7.8. 
Definition of End of Study ............................................................................................................. 7 
8. 
INTERVENTIONS ..................................................................................................................................... 7 
9. 
SAFETY REPORTING ............................................................................................................................... 7 
10. 
STATISTICS AND ANALYSIS ................................................................................................................. 8 
10.1. 
Description of Statistical Methods ............................................................................................ 8 
10.2. 
The Number of Participants ...................................................................................................... 8 
10.3. 
Analysis of Outcome Measures/Endpoints ............................................................................... 8 
11. 
DATA MANAGEMENT ........................................................................................................................ 8 
11.1. 
Access to Data ........................................................................................................................... 8 
11.2. 
Data Recording and Record Keeping ......................................................................................... 9 
12. 
QUALITY ASSURANCE PROCEDURES ................................................................................................. 9 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................................. 9 
13.1. 
Declaration of Helsinki............................................................................................................... 9 
13.2. 
Approvals ................................................................................................................................... 9 
13.3. 
Reporting ................................................................................................................................... 9 

Date and version No:     23 January 2018 v 0.3 Protocol number RG433_TVT_003 
 
 
Clinical Research Protocol Template version 1.0     
 
 
 
 
 
CONFIDENTIAL 
University of Bath 
 
 
 
 
 
 
 
 
Page 3 of 12 
13.4. 
Participant Confidentiality ......................................................................................................... 9 
14. 
PUBLICATION POLICY ....................................................................................................................... 10 
15. 
REFERENCES .................................................................................................................................... 11 
16. 
APPENDIX C:  AMENDMENT HISTORY ............................................................................................. 12 
 
 
 

Date and version No:     23 January 2018 v 0.3 Protocol number RG433_TVT_003 
 
 
Clinical Research Protocol Template version 1.0     
 
 
 
 
 
CONFIDENTIAL 
University of Bath 
 
 
 
 
 
 
 
 
Page 4 of 12 
1. SYNOPSIS 
 
Study Title 
ToKa HTO Virtual Clinical Trial 
Internal ref. no. / short 
title 
NA 
Study Design 
Virtual comparative trial 
Study Participants 
Imaging data derived knee OA cohort 
Planned Sample Size 
20 
Planned Study Period 
12 months 
 
Objectives 
Endpoints 
Primary 
 
Safety comparison between existing 
HTO device (Tomofix) & ToKa 
Calculation of bone and device 
load environment using Finite 
Element Analysis (FEA) 
 
2. ABBREVIATIONS 
 
CI 
Chief Investigator 
CRF 
Case Report Form 
CTRG 
Clinical Trials & Research Governance, University of Oxford 
FEA 
Finite Element Analysis 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
HTO 
High Tibial Osteotomy 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonisation 
NHS 
National Health Service 
NRES 
National Research Ethics Service 
PI 
Principal Investigator 
PIL 
Participant/ Patient Information Leaflet 
R&D 
NHS Trust R&D Department 
REC 
Research Ethics Committee 
OA 
Osteoarthritis 
SOP 
Standard Operating Procedure 
TKR 
Total Knee Replacement 

Date and version No:     23 January 2018 v 0.3 Protocol number RG433_TVT_003 
 
 
Clinical Research Protocol Template version 1.0     
 
 
 
 
 
CONFIDENTIAL 
University of Bath 
 
 
 
 
 
 
 
 
Page 5 of 12 
UKR 
Unicompartmental Knee Replacement 
 
3. BACKGROUND AND RATIONALE 
High Tibial Osteotomy (HTO) is an alternative to knee replacement in suitable patients with early knee 
osteoarthritis (OA), it is particularly suited to patients with single compart disease who otherwise would 
be suitable for unicompartmental knee replacement (UKR)1. OA of the knee is very common and 
increasing driven by the ageing of the population2. The current limitations of HTO are related to the 
difficulty of achieving the desired correction due to a challenging surgical technique and soft tissue 
irritation due to the use of generic stabilisation plates3. This study will examine the safety equivalence of 
a new patient specific HTO process which has patient specific 3D printed plates, ToKa, with the existing 
most commonly used HTO procedure using the Tomofix plate. Importantly this study will be undertaken 
as a Virtual Trial, existing anonymised 3D imaging data will be used to create the virtual patient cohort. 
This cohort will receive both procedures, which for this type of procedure is only possible in a virtual 
scenario. 
The main question to be addressed is: “Is the ToKa procedure as safe as the most commonly used 
existing HTO procedure?”. In this context safety concerns the mechanical loads placed upon the tibia and 
the support plate. 
The interventions will all be made on computer models, the 3D imaging data will be used to create the 
intact (un-operated) models of the subject tibias. Each model will then be virtually operated upon, with 
both the ToKa and Tomofix procedures. The models will then be loaded with physiological loads 
experienced during function and the mechanical states compared4.  
In order to build the cohort of virtual patients existing anonymised CT data from patients with knee OA 
will be used. The exclusion criteria are: previous knee or osteotomy surgery, abnormal anatomy of the 
tibia, poor quality CT data. This study will use data from 20 patients, allowing paired comparison 
between each intervention in each virtual patient increasing the study power. There are no previous 
studies of this type to base a power analysis upon, thus the data will be critically evaluated and should 
increased numbers be required an extension to the ethics will be made. The study findings will be 
relevant to a knee OA population. 
4. OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
 
Objectives 
Outcome Measures/Endpoints  
Primary Objective 
To investigate whether the new ToKa HTO 
procedure is as safe as the currently widely used 
Tomofix HTO 
The key outcome measures are the mechanical 
load variables describing the mechanical loads 
present in the tibia and implanted devices during 
physiological loading as determined by FEA. 
 
 

Date and version No:     23 January 2018 v 0.3 Protocol number RG433_TVT_003 
 
 
Clinical Research Protocol Template version 1.0     
 
 
 
 
 
CONFIDENTIAL 
University of Bath 
 
 
 
 
 
 
 
 
Page 6 of 12 
5. STUDY DESIGN 
 
The study design is a virtual clinical trial in which BOTH interventions are applied to the virtual 
population. This is only possible in a virtual scenario. This allows powerful paired analysis. 
Flow diagram: 
 
6. PARTICIPANT IDENTIFICATION 
6.1. Study Participants 
Anonymised CT data sets from patients with moderate to severe knee OA. 
 
6.2. Inclusion Criteria 
 
 
Appropriate existing CT data of lower limb. 
 
Male or Female, aged 18 years or above. 
 
Diagnosed with moderate to severe OA of the knee. 
6.3. Exclusion Criteria 
 
The participant may not enter the study if ANY of the following apply: 
 
Abnormal anatomy of tibia or presence of pathology other than OA, e.g. bone tumour. 
 
Previous knee or osteotomy surgery. 
 
Presence of metal-work. 
7. STUDY PROCEDURES 
 

Date and version No:     23 January 2018 v 0.3 Protocol number RG433_TVT_003 
 
 
Clinical Research Protocol Template version 1.0     
 
 
 
 
 
CONFIDENTIAL 
University of Bath 
 
 
 
 
 
 
 
 
Page 7 of 12 
7.1. Recruitment 
Data obtained by querying hospital PACS systems for suitable patients with suitable radiological 
examinations, anonymised by hospital before transmitting to research team. 
7.2. Informed Consent 
We believe this is not required for anonymous use of existing imaging data. 
7.3. Screening and Eligibility Assessment 
CT data to be reviewed by surgical member of team to ensure subjects meet the inclusion criteria and 
that none of the exclusion criteria apply. 
7.4. Randomisation, blinding and code-breaking 
NA 
7.5. Baseline Assessments 
Intact tibia models will be loaded with physiological loads to establish a per subject baseline value for 
mechanical load variables. 
7.6. Subsequent Visits 
NA 
7.7. Discontinuation/Withdrawal of Participants from Study 
NA 
7.8. Definition of End of Study 
The end of study is the date of the final FEA analysis has been performed. 
8. INTERVENTIONS 
The interventions will all be made on computer models, the 3D imaging data will be used to create the 
intact (un-operated) models of the subject tibias. Each model will then be virtually operated upon, with 
both the ToKa and Tomofix procedures. The models will then be loaded with physiological loads 
experienced during function and the mechanical states compared4. The time point for the comparison 
will be 6 weeks simulated post-operation. 
9. SAFETY REPORTING  
NA 
 

Date and version No:     23 January 2018 v 0.3 Protocol number RG433_TVT_003 
 
 
Clinical Research Protocol Template version 1.0     
 
 
 
 
 
CONFIDENTIAL 
University of Bath 
 
 
 
 
 
 
 
 
Page 8 of 12 
10. STATISTICS AND ANALYSIS 
10.1. 
Description of Statistical Methods 
All study practices and statistical methods are based on the International Conference on Harmonization 
(IHC) document “Statistical Principles for Clinical Trials.” 
Data will be summarised by treatment group. Baseline characteristics, and safety outputs total overall 
columns will be included to summarise all subjects. 
For all baseline, demographic, safety and efficacy outputs data will be summarised by treatment group. 
In summary tables of continuous variables, the minimum and maximum statistics, the arithmetic mean 
and median, the 95% confidence interval, standard deviation, and standard error will be presented will 
to the same number of decimal places as the original data. 
In summary tables of categorical variables, counts and percentages will be used. The denominator for 
each percentage will be the number of subjects within the population treatment group unless otherwise 
specified. 
All hypothesis testing will be carried out at the 5% (2-sided) significance level unless otherwise specified. 
Two one-sided test (TOST) procedure will be used to test equivalence5. 
10.2. 
The Number of Participants 
This study will use data from 20 patients, allowing paired comparison between each intervention in each 
virtual patient increasing the study power. There are no previous studies of this type to base a power 
analysis upon, thus the data will be critically evaluated and should increased numbers be required an 
extension to the ethics will be made. In order to generate the virtual cohort we will request ethics for 
anonymous re-use of imaging records for 30 patients, allowing for drop out due to issues with images or 
patient anatomy. 
10.3. 
Analysis of Outcome Measures/Endpoints 
Two one-sided test (TOST) procedure on the mechanical load variables. The primary outcome measure 
will be maximum mechanical stress (von Mises stress) in the device under physiological loading 
experienced during gait and stair function at a simulated six weeks post-operatively. The secondary 
outcome measure will be the maximum mechanical strain (von Mises strain) in the bone around the 
screws holding the HTO plates. 
 
11. DATA MANAGEMENT 
11.1. 
Access to Data 

Date and version No:     23 January 2018 v 0.3 Protocol number RG433_TVT_003 
 
 
Clinical Research Protocol Template version 1.0     
 
 
 
 
 
CONFIDENTIAL 
University of Bath 
 
 
 
 
 
 
 
 
Page 9 of 12 
Direct access will be granted to authorised representatives from the Sponsor or host institution for 
monitoring and/or audit of the study to ensure compliance with regulations. 
Additionally, Renishaw plc. will be granted access to anonymised data for the purposes of pre-operative 
planning software development specifically for and only relating to the ToKa device.  
11.2. 
Data Recording and Record Keeping 
Data will stored according to University of Bath’s research data storage policy 
http://www.bath.ac.uk/research/data/policy/research-data-policy.html  
Anonymised data stored by Renishaw plc. will be stored according to their data storage policy: 
http://www.renishaw.com/en/data-protection-statement--7425 
12. QUALITY ASSURANCE PROCEDURES 
The study may be monitored, or audited in accordance with the current approved protocol, ICH GCP, 
relevant regulations and standard operating procedures. 
 
13. ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. 
Declaration of Helsinki 
The Investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki. 
13.2. 
Approvals 
The protocol will be submitted to an appropriate Research Ethics Committee (REC), and host 
institution(s) for written approval. 
The Investigator will submit and, where necessary, obtain approval from the above parties for all 
substantial amendments to the original approved documents. 
13.3. 
Reporting 
The CI shall submit once a year throughout the study, or on request, an Annual Progress report to the 
REC Committee, host organisation and Sponsor.  In addition, an End of Study notification and final report 
will be submitted to the same parties. 
13.4. 
Participant Confidentiality 
 
The study staff will ensure that the participants’ anonymity is maintained.  The participants will be 
identified only by initials and a participants ID number on the CRF and any electronic database.  All 

Date and version No:     23 January 2018 v 0.3 Protocol number RG433_TVT_003 
 
 
Clinical Research Protocol Template version 1.0     
 
 
 
 
 
CONFIDENTIAL 
University of Bath 
 
 
 
 
 
 
 
 
Page 10 of 12 
documents will be stored securely and only accessible by study staff and authorised personnel. The study 
will comply with the Data Protection Act, which requires data to be anonymised as soon as it is practical 
to do so. 
 
14. PUBLICATION POLICY 
The Investigators will be involved in reviewing drafts of the manuscripts, abstracts, press releases and 
any other publications arising from the study.  Authorship will be determined in accordance with the 
ICMJE guidelines and other contributors will be acknowledged. 
 
 

Date and version No:     23 January 2018 v 0.3 Protocol number RG433_TVT_003 
 
 
Clinical Research Protocol Template version 1.0     
 
 
 
 
 
CONFIDENTIAL 
University of Bath 
 
 
 
 
 
 
 
 
Page 11 of 12 
15. REFERENCES 
 
1. Harris JD, McNeilan R, Siston RA, Flanigan DC. Survival and clinical outcome of isolated high tibial 
osteotomy and combined biological knee reconstruction. Knee 2013;20-3:154-61. 
2. Arden N, Nevitt MC. Osteoarthritis: epidemiology. Best Pract Res Clin Rheumatol 2006;20-1:3-25. 
3. Niinimaki TT, Eskelinen A, Mann BS, Junnila M, Ohtonen P, Leppilahti J. Survivorship of high tibial 
osteotomy in the treatment of osteoarthritis of the knee: Finnish registry-based study of 3195 knees. J 
Bone Joint Surg Br 2012;94-11:1517-21. 
4. Bergmann G, Bender A, Graichen F, Dymke J, Rohlmann A, Trepczynski A, Heller MO, Kutzner I. 
Standardized loads acting in knee implants. PLoS One 2014;9-1:e86035. 
5. Walker E, Nowacki AS. Understanding equivalence and noninferiority testing. J Gen Intern Med 
2011;26-2:192-6. 
 
 

Date and version No:     23 January 2018 v 0.3 Protocol number RG433_TVT_003 
 
 
Clinical Research Protocol Template version 1.0     
 
 
 
 
 
CONFIDENTIAL 
University of Bath 
 
 
 
 
 
 
 
 
Page 12 of 12 
16. APPENDIX C:  AMENDMENT HISTORY 
 
Amendment 
No. 
Protocol Version 
No. 
Date issued Author(s) of changes 
Details of Changes 
made 
1 
Version_0_02_UoB 24/10/2017 Alisdair R. MacLeod, 
Richie Gill 
Anonymised data 
access will also be 
granted to Renishaw 
plc. who are now 
partners in 
developing ToKa 
software 
2 
Version_0_03_UoB 23/01/2018 Richie Gill 
Amended number of 
data sets access 
requested for