Randomized Controlled Trial for the Use of an Osteoconductive Scaffold in ACL-Reconstruction
Phase: NA
Conditions: ACL - Anterior Cruciate Ligament Rupture, ACL, ACL Injury
Sponsor: Sandro Fucentese

 
ACLROCS/Fucentese 
 Page 1 of 55 
Version 2.0 of 6 June 2017 
 
 
 
 
Clinical Study Protocol 
 
Randomized Controlled Trial for the Use of an Osteoconductive Scaffold in ACL-
Reconstruction  
 
 
 
Study Type: 
Clinical trial with Investigational Medical Device (IMD)  
Study Categorization: 
Clinical Trial with IMD Category A 
Study Registration: 
SNCTP and clinical.trials.gov 
Sponsor-Investigator and 
Principal Investigator: 
PD Dr. med. Sandro F. Fucentese 
 
Investigational Medical 
Device: 
SmartBone (IBI S. A.) 
Investigation plan Version 
and Date: 
V2.0 / 06.06.2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is confidential and the property of University Hospital 
Balgrist. The information may not - in full or in part - be transmitted, reproduced, published, or 
disclosed to others than the applicable Independent Ethics Committee(s) and Competent 
Authority(ies) without prior written authorization University Hospital Balgrist, except to the extent 
necessary to obtain informed consent from those participants who will participate in the study. 

 
ACLROCS/Fucentese 
 Page 2 of 55 
Version 2.0 of 6 June 2017 
SIGNATURE PAGE 
Study number 
 
 
Study Title 
Randomized Controlled Trial for the Use of an 
Osteoconductive Scaffold in ACL-
Reconstruction  
 
 
Sponsor-Investigator (Principal Investigator): 
 
The Sponsor-Investigator has approved the investigation plan version 2.0 of 06.06.2017, and 
confirms hereby to conduct the study according to the investigation plan, current version of the 
World Medical Association Declaration of Helsinki, ISO 14155 norm and the local legally 
applicable requirements. 
 
 
PD Dr. med. Sandro F. Fucentese 
 
 
 
Place/Date 
 
Signature 
 

 
ACLROCS/Fucentese 
 Page 3 of 55 
Version 2.0 of 6 June 2017 
TABLE OF CONTENTS 
SIGNATURE PAGE ...............................................................................................................2 
STUDY SYNOPSIS ................................................................................................................7 
STUDY SUMMARY IN LOCAL LANGUAGE ........................................................................ 11 
ABBREVIATIONS ................................................................................................................ 12 
STUDY SCHEDULE ............................................................................................................. 13 
1 
STUDY ADMINISTRATIVE STRUCTURE .................................................................. 14 
1.1 
Sponsor - Principal investigator .......................................................................... 14 
1.2 
Statistician .......................................................................................................... 14 
1.3 
Monitoring .......................................................................................................... 14 
2 
ETHICAL AND REGULATORY ASPECTS .................................................................. 14 
2.1 
Study Registration .............................................................................................. 14 
2.2 
Categorization of Study ...................................................................................... 15 
2.3 
Competent Ethics Committee (CEC) .................................................................. 15 
2.4 
Competent authorities (CA) ................................................................................ 15 
2.5 
Ethical Conduct of the Study .............................................................................. 15 
2.6 
Declaration of Interest ........................................................................................ 15 
2.7 
Patient Information and Informed Consent ......................................................... 15 
2.8 
Participant Privacy and Confidentiality ............................................................... 16 
2.9 
Early Termination of the Study ........................................................................... 16 
2.10 Protocol Amendments ........................................................................................ 16 
3 
INTRODUCTION ......................................................................................................... 17 
3.1 
Background and Rationale ................................................................................. 17 
3.1.1 Bone Tunnel Widening following ACL-Reconstruction ............................ 18 
3.2 
Investigational Medical Device and Indication .................................................... 18 
3.3 
Clinical Evidence to Date ................................................................................... 19 
3.3.1 SmartBone .............................................................................................. 19 
3.3.2 Autograft Scaffolds for ACL-Graft Fixation .............................................. 20 
3.3.3 Xenograft Scaffolds for ACL-Graft Fixation ............................................. 21 
3.3.4 Adverse Device Effects ........................................................................... 21 
3.4 
Rationale for the Intended Purpose in Study ...................................................... 21 
3.5 
Explanation for Choice of Comparator ................................................................ 21 
3.6 
Risk / Benefits .................................................................................................... 21 
3.6.1 Radiological Assessment Related Risks ................................................. 22 
3.6.2 Anticipated Adverse Device Effects ........................................................ 23 
4 
STUDY OBJECTIVES ................................................................................................. 23 
4.1 
Overall Objective ................................................................................................ 23 
4.2 
Primary Objective ............................................................................................... 23 
4.3 
Secondary Objectives ........................................................................................ 23 
4.4 
Safety Objectives ............................................................................................... 23 
5 
STUDY OUTCOMES .................................................................................................. 24 
5.1 
Primary Outcome ............................................................................................... 24 
5.2 
Secondary Outcomes ......................................................................................... 24 
5.2.1 Patient Subjective Knee Function ........................................................... 24 

 
ACLROCS/Fucentese 
 Page 4 of 55 
Version 2.0 of 6 June 2017 
5.2.2 Objective Measures of Knee Stability ...................................................... 24 
5.3 
Other Outcomes of Interest ................................................................................ 25 
5.3.1 Patient History ........................................................................................ 25 
5.3.2 OCS-Bone Integration ............................................................................. 25 
5.3.3 Intra-Patient Comparison of Ossification ................................................. 25 
5.3.4 Plain Radiography assessed Bone Tunnel Widening .............................. 25 
5.4 
Safety Outcomes ................................................................................................ 25 
6 
STUDY DESIGN AND COURSE OF STUDY .............................................................. 26 
6.1 
General study design and justification of design ................................................. 26 
6.1.1 Time Frame of the Study ........................................................................ 26 
6.2 
Study Duration and Study Schedule ................................................................... 26 
6.3 
Methods of Minimizing Bias ................................................................................ 26 
6.3.1 Randomization ........................................................................................ 26 
6.3.2 Blinding Procedures ................................................................................ 26 
6.3.3 Other Methods of Minimizing Bias........................................................... 27 
6.4 
Unblinding Procedures ....................................................................................... 27 
7 
STUDY POPULATION ................................................................................................ 27 
7.1 
Eligibility criteria ................................................................................................. 27 
7.1.1 General Criteria for Eligibility ................................................................... 27 
7.1.2 Inclusion / Exclusion for Eligible Subjects ............................................... 27 
7.2 
Recruitment and Screening ................................................................................ 28 
7.3 
Assignment to Study Groups .............................................................................. 29 
7.4 
Criteria for Withdrawal/ Discontinuation of Participants ...................................... 29 
8 
STUDY INTERVENTION............................................................................................. 30 
8.1 
Femoral Fixation Construct ................................................................................ 30 
8.2 
Graft Preparation ................................................................................................ 30 
8.2.1 Semitendinosus Tendon-only Graft ......................................................... 30 
8.2.2 Doubled Semitendinosus – Doubled Gracilis Tendon Graft..................... 30 
8.2.3 Quadrupled Semitendinosus – Doubled Gracilis Tendon Graft ............... 30 
8.3 
Bone Tunnels ..................................................................................................... 30 
8.4 
Surgical Technique ............................................................................................ 31 
8.4.1 Interventional Product ............................................................................. 33 
8.4.2 Packaging, Labelling and Supply (Re-Supply) ........................................ 33 
8.4.3 Storage Conditions ................................................................................. 34 
8.5 
Modifications of Device Application .................................................................... 34 
8.6 
Compliance with Study Intervention ................................................................... 34 
8.7 
Data Collection and Follow-up for Withdrawn Participants ................................. 34 
8.8 
Trial Specific Preventive Measures .................................................................... 34 
8.9 
Concomitant Intervention(s) ............................................................................... 34 
8.10 Medical Device Accountability ............................................................................ 34 
8.11 Return or Destruction of Medical Device ............................................................ 34 
9 
STUDY ASSESSMENTS ............................................................................................ 36 
9.1 
Study Flow Chart ................................................................................................ 36 
36 

 
ACLROCS/Fucentese 
 Page 5 of 55 
Version 2.0 of 6 June 2017 
9.2 
Assessments of Outcomes ................................................................................. 37 
9.2.1 Assessment of Primary Outcome ............................................................ 37 
9.2.2 Assessment of Secondary Outcomes ..................................................... 37 
9.2.3 Plain Radiography assessed Bone Tunnel Widening .............................. 40 
9.2.4 Assessment of Other Outcomes of Interest ............................................. 40 
9.2.5 Assessment of Safety Outcomes ............................................................ 41 
9.2.6 Assessments in Participants Who Prematurely Stop the Study ............... 41 
9.3 
Procedures at Each Visit .................................................................................... 41 
9.3.1 Screening (Visit 1) .................................................................................. 41 
9.3.2 Baseline (Visit 2) ..................................................................................... 41 
9.3.3 Follow-up 1 (Visit 3) ................................................................................ 42 
9.3.4 Follow-up 2 (Visit 4) ................................................................................ 42 
9.3.5 Follow-up 3 (Visit 5) ................................................................................ 42 
9.3.6 Follow-up 4 (Visit 6) ................................................................................ 43 
9.3.7 Follow-up 5 (Visit 7) ................................................................................ 43 
10 
SAFETY ...................................................................................................................... 43 
10.1 Medical Device Category A studies .................................................................... 43 
10.1.1 Definition and Assessment of safety related events ................................ 43 
10.1.2 Reporting of Safety related events .......................................................... 43 
11 
STATISTICAL METHODS ........................................................................................... 44 
11.1 Hypothesis ......................................................................................................... 44 
11.2 Determination of Sample Size ............................................................................ 44 
11.2.1 Power calculation of secondary outcome variables ................................. 44 
11.3 Statistical Criteria of Termination of Trial ............................................................ 45 
11.4 Planned Analyses .............................................................................................. 45 
11.4.1 Datasets to be analyzed, analysis populations ........................................ 45 
11.4.2 Primary Analysis ..................................................................................... 45 
11.4.3 Other Outcomes of Interest ..................................................................... 46 
11.4.4 Plain Radiography assessed Bone Tunnel Widening .............................. 46 
11.4.5 Interim analysis ....................................................................................... 46 
11.4.6 Safety Analysis ....................................................................................... 46 
11.4.7 Deviation(s) from the Original Statistical Plan ......................................... 47 
11.5 Handling of Missing Data ................................................................................... 47 
11.6 Handling of Drop-Outs ........................................................................................ 47 
12 
DATA QUALITY ASSURANCE AND CONTROL ......................................................... 47 
12.1 Data Handling and Record Keeping / Archiving .................................................. 47 
12.1.1 Case Report Forms ................................................................................ 47 
12.1.2 Specification of Source Documents ........................................................ 47 
12.1.3 Record Keeping / Archiving..................................................................... 48 
12.2 Data Management .............................................................................................. 48 
12.2.1 Data Management System, access and back-up .................................... 48 
12.2.2 Analysis and Archiving ............................................................................ 48 
12.3 Monitoring .......................................................................................................... 49 
12.4 Confidentiality, Data Protection .......................................................................... 49 

 
ACLROCS/Fucentese 
 Page 6 of 55 
Version 2.0 of 6 June 2017 
12.5 Storage of Related Health Data .......................................................................... 49 
13 
PUBLICATION AND DISSEMINATION POLICY ......................................................... 49 
14 
FUNDING AND SUPPORT ......................................................................................... 49 
15 
INSURANCE ............................................................................................................... 50 
16 
REFERENCES ............................................................................................................ 51 
17 
APPENDICES ............................................................................................................. 55 
 
 

 
ACLROCS/Fucentese 
 Page 7 of 55 
Version 2.0 of 6 June 2017 
STUDY SYNOPSIS 
Sponsor-Investigator 
PD Dr. med. Sandro F. Fucentese 
Study Title: 
Randomized Controlled Trial for the Use of an Osteoconductive 
Scaffold in ACL-Reconstruction  
Short Title / Study ID: 
ACLROCS 
Protocol Version and 
Date: 
V2.0, 6 June 2017 
Trial registration: 
 
Swiss Federal National Clinical Trials Portal SNCTP  
 
International trial registry ClinicalTrials.gov 
Study category and 
Rationale 
Category A, as the device under study bears a conformity marking 
and is to be used in accordance with the instructions. 
Clinical Phase: 
Post-market efficacy trial using an implantable CE-marked medical 
device 
Background and 
Rationale: 
Reconstruction of the anterior cruciate ligament (ACL) using 
autograft tissue is currently recommended as the standard of care 
following an ACL tear or rupture, with the bone-tendon-bone (BTB) 
graft and hamstring tendon graft the most common. Although a BTB 
autograft is widely recognized to offer high mechanical performance 
and rapid graft healing, these advantages come at the cost of a 
longer surgery time and higher risk of severe patient discomfort at 
the graft harvest site. Use of a hamstring tendon autograft is less 
painful, but is generally slower to heal with higher risk of mechanical 
graft failure due to poor bone ingrowth. The aim of the current study 
is to augment graft-to-bone incorporation by use of an 
osteoconductive scaffold enlaced into the hamstring tendon 
autograft. This bovine derived composite bone substitute is inserted 
into the articular aperture of the femoral bone tunnel and should 
provide an osteoconductive / osteoinductive environment at a 
biomimetic attachment site leading to improved secondary graft-
fixation and a reduced incidence of tunnel widening.  
Objective(s): 
Primary objective of the study is to evaluate efficacy of the surgical 
technique for ACL reconstruction using an osteoconductive scaffold, 
enlaced into the hamstring tendon autograft, compared to the 
traditional technique. 
Secondary objectives aim to assess the clinical outcome of the 
interventional treatment including patient subjective knee function 
and objective measures of knee stability. 
Outcome(s): 
The primary efficacy outcome of this study will be the CT based 
relative change of the femoral bone tunnel volume. 
Secondary outcome measures for patient subjective knee function 
include International Knee Documentation Committee Subjective 
Knee Evaluation Form, Lysholm Knee Scoring Scale and Tegner 
Activity Scale. Knee stability will be assessed using the KT-1000 
Arthrometer Test, the Lachman Test and the Pivot Shift Test. 
Safety will be evaluated by the occurrence, frequency and severity 
of intra- and postoperative complications. 
Study design: 
Randomized patient-blinded two-group parallel comparison trial 
using an active comparator. 

 
ACLROCS/Fucentese 
 Page 8 of 55 
Version 2.0 of 6 June 2017 
Inclusion / Exclusion 
criteria: 
Inclusion Criteria: 
 
18 to 60 years of age. 
 
Males and females. 
 
Acute unilateral complete tear of the ACL that occurred 
within 18 weeks before planned surgery and requires 
reconstruction of the ACL. 
 
Informed consent as documented by signature 
 
Exclusion Criteria: 
 
Prior ACL reconstruction or other surgical procedure on the 
affected knee. 
 
Prior fracture of the affected leg. 
 
Multi-ligament reconstruction. 
 
Previous or current ACL injury on contra-lateral leg. 
 
Medical condition or comorbidity that would interfere with 
study participation. 
 
The patient is mentally compromised. 
 
Inability to follow the procedures of the study, e.g. due to 
language problems, psychological disorders, dementia, etc. 
of the participant. 
 
Other clinically significant concomitant disease states (e.g. 
renal failure, hepatic dysfunction, cardiovascular disease, 
etc.). 
More in- and exclusion criteria on page 28 

 
ACLROCS/Fucentese 
 Page 9 of 55 
Version 2.0 of 6 June 2017 
Measurements and 
procedures: 
Screening (Visit 1): 
 
Patient information 
Surgery (Visit 2): 
 
Informed consent completed and signed 
 
Check of inclusion and exclusion criteria 
 
Medical/surgical history 
 
Pregnancy test 
 
Randomization 
 
ACL-reconstruction (interventional/control) according to 
assigned group 
 
Recording of AE’s (if any) 
 
CT scanning 
 
Plain radiography 
 
Clinical examination 
 
Patient subjective knee function 
 
Knee stability assessment 
 
Tegner activity scale 
 
Patient demographics 
Follow-up 1 (Visit 3) 
 
Plain radiography/Pregnancy Test 
 
Patient subjective knee function 
 
Tegner activity scale 
 
Knee stability assessment 
 
Clinical examination 
 
Recording of AE’s (if any) 
Follow-up 2 + 3 (Visit 4 + 5): 
 
CT scanning/Pregnancy test 
 
Plain radiography 
 
Patient subjective knee function 
 
Tegner activity scale 
 
Knee stability assessment 
 
Clinical examination  
 
Recording of AE’s (if any) 
Follow-up 4 (Visit 6) 
 
Plain radiography/Pregnancy test 
 
Patient subjective knee function 
 
Tegner activity scale 
 
Knee stability assessment 
 
Clinical examination  
 
Recording of AE’s (if any) 
Final Follow-up (Visit 7): 
 
Patient subjective knee function 
 
Tegner activity scale 
 
Knee stability assessment 
 
Clinical examination  
 
Recording of AE’s (if any) 

 
ACLROCS/Fucentese 
 Page 10 of 55 
Version 2.0 of 6 June 2017 
Study Product / 
Intervention:  
The device under study is a composite bone substitute composed of 
a natural mineral matrix of bovine origin, reinforced with 
biodegradable synthetic polymers and natural collagen derivatives 
of bovine origin. Before graft insertion this osteoconductive scaffold 
is enlaced into the folded hamstring tendon-graft, tied off using 
surgical suture and connected to the cortical suspension device. 
During surgery the graft is inserted through the medial portal and 
pulled into the femoral socket so that the scaffold is positioned at the 
articular aperture of the femoral bone tunnel. 
Control Intervention: 
ACL-reconstruction using hamstring autograft with hybrid fixation in 
accordance with standard of care. 
Number of Participants 
with Rationale: 
A total of 56 patients are required to detect a minimal clinically 
important difference in relative change of bone tunnel volume after a 
2-year follow-up of 20% given an assumed standard deviation of 
25.2% with a power of 0.8 and an α-error of 0.05 and accounting for 
a drop-out rate of 10% for this equally sized two-group parallel 
design. 
Study Duration: 
Expected duration for patient acquisition: 22 months 
Expected time from first patient acquisition to the end of follow-up of 
the last patient: 82 months 
Statistic and Abstract: ca. 6 months 
Study Schedule: 
First-Patient-In: 07/2017 
Last-Patient-Out: 05/2024 
Statistics/Abstract: 12/2024 
Investigator(s): 
PD Dr. med. Sandro F. Fucentese 
University Hospital Balgrist 
Study Centre(s): 
University Hospital Balgrist 
Statistical 
Considerations: 
Intention-To-Treat analysis 
Independent t-test on the primary efficacy outcome comparing the 
two groups with a significance level of 0.05, 2-sided. 
GCP Statement: 
This study will be conducted in compliance with the protocol, the 
current version of the Declaration of Helsinki, the ICH-GCP or ISO 
EN 14155 (as far as applicable) as well as all national legal and 
regulatory requirements.  
 
 
 

 
ACLROCS/Fucentese 
 Page 11 of 55 
Version 2.0 of 6 June 2017 
STUDY SUMMARY IN LOCAL LANGUAGE  
Das vordere Kreuzband verläuft im Kniegelenk von der Oberschenkelrolle zum Schienbeindach 
und stabilisiert zusammen mit dem hinteren Kreuzband das Kniegelenk. Durch diese Führung 
werden andere Strukturen des Kniegelenks wie Menisken und Knorpel gegen eine Zerstörung 
geschützt. Rupturen des Kreuzbandes treten häufig in Sportarten die schnelle 
Richtungswechsel beinhalten (z.B. Fussball, Basketball) und im Bereich Ski Alpin auf. Zur 
Rekonstruktion des vorderen Kreuzbandes wird meist körpereigenes Material als Transplantat 
verwendet. Hierzu wird das mittlere Drittel des Kniescheibenbands (Patellarsehne) mit je einem 
kleinen Knochenblock aus der Kniescheibe und dem Unterschenkel entnommen. Alternativ 
können auch Beugesehnen an der Innenseite des Kniegelenks (Semitendinosus- oder 
Gracilissehne) als Transplantat verwendet werden. Das Transplantat wird mittels 
Kniegelenksspiegelung (arthroskopisch) in Bohrkanälen im Oberschenkel respektive im 
Unterschenkel mit Hilfe von Schrauben oder Stiften fixiert. Die Verwendung des 
Kniescheibenbands bietet hierbei den Vorteil eines beschleunigten Einwachsens des 
Transplantats in den Bohrkanal. Jedoch können an der Entnahmestelle Komplikationen wie 
Schmerzen und Kniescheibenfrakturen auftreten. Da bei der Verwendung einer Beugesehne 
kein Knochenblock entnommen wird, ist deren Entnahme unproblematischer, der 
Heilungsverlauf im Bohrkanal aber oft langwieriger. Das zu testende Medizinprodukt besteht 
aus einem knochenwachstumsinduzierenden Knochenersatz. Dieser soll das Einwachsen des 
Beugesehnentransplantats in den Bohrkanal beschleunigen. Der Knochenersatz wird in das 
Sehnentransplantat eingefädelt und kommt nach dessen Einziehen am gelenksnahen Ende des 
Bohrkanales im Oberschenkel zu liegen.  
 
Zweck dieser Studie ist es, bei insgesamt 56 Patienten den Heilungsverlauf nach 
Kreuzbandrekonstruktion mit der zu untersuchenden Technik, mit der herkömmlichen Methode 
zu vergleichen. Primär untersucht wird das Auftreten von etwaigen Komplikationen sowie die 
Verknöcherung des Bohrkanals, ermittelt durch radiologische Untersuchungen. Hierzu werden 
der Heilungsverlauf, sowie die Patientenzufriedenheit und die Kniestabilität über einen Zeitraum 
von 5 Jahren verfolgt. 

 
ACLROCS/Fucentese 
 Page 12 of 55 
Version 2.0 of 6 June 2017 
ABBREVIATIONS  
ACL 
Anterior cruciate ligament 
AE 
Adverse Event  
BPTB 
Bone patellar tendon bone 
BTW 
Bone tunnel widening 
CA 
CEC 
Competent authorities (Swissmedic) 
Competent Ethics Committee 
ClinO 
Clinical Trials Ordinance 
CRF 
Case Report Form  
CT 
Computed Tomography 
CTCAE 
Common terminology criteria for adverse events 
eCRF 
Electronic Case Report Form  
FMEA 
Failure Mode and Effects Analysis 
H0 
Null hypothesis 
H1 
Alternative hypothesis 
HA 
Hydroxyapatite 
IFU 
Instructions for use 
IKDC 
International Knee Documentation Commitee 
IKDC SKEF 
IKDC Subjective Knee Evaluation Form 
IMD  
Investigational Medical Device 
ISF 
Investigator Site File  
ITT 
Intention to Treat 
LHR 
Law on human research 
LKSS 
Lysholm Knee Scoring Scale 
MRI 
Magnetic resonance imaging 
PI 
Principal Investigator  
PLDLLA 
Poly(l-lactide-co-D,l-lactide) 
PLLA 
poly-l-lactic acid  
SAE 
Serious Adverse Event  
SDV 
Source Data Verification  
SN 
Study Nurse 
SNCTP 
Swiss National Clinical Trial Portal 
SOP 
Standard Operating Procedure 
TAS 
Tegner Activity Scale 
TMF 
Trial Master File  
WI 
Work Instruction 
β-TCP 
β-Tricalcium phosphate 

 
ACLROCS/Fucentese 
 Page 13 of 55 
Version 2.0 of 6 June 2017 
STUDY SCHEDULE 
Study Periods 
Screening 
Surgery 
Follow-up   
Visit 
1 
2 
3 
4 
5 
6* 
7* 
Time 
[days/weeks/months
/years] 
-3wk  
(±14d) 
0 
42d 
(±10d) 
4.5m 
(±1m) 
1 y 
(±2m) 
2 y 
(±2m) 
5 y 
(±4m) 
Patient Information 
and Informed 
Consent 
X* 
 
 
 
 
 
 
Demographics 
X* 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
In- /Exclusion Criteria 
X* 
X* 
 
 
 
 
 
Pregnancy Test 
 
X* 
X* 
X* 
X* 
X* 
 
Clinical Examination 
 
x 
x 
x 
x 
X* 
X* 
Randomization 
 
X* 
 
 
 
 
 
CT scanning 
 
X* 
 
X* 
X* 
 
 
Plain Radiography 
 
x 
x 
x 
x 
X* 
 
Tegner Activity Scale 
 
x 
x 
x 
x 
X* 
X* 
IKDC Subjective 
Knee Evaluation 
Form 
 
x 
x 
x 
x 
X* 
X* 
Lysholm Knee 
Scoring Scale 
 
x 
x 
x 
x 
X* 
X* 
KT-1000 Arthrometer 
Testing 
 
x 
x 
x 
x 
X* 
X* 
Lachmann Test 
 
x 
x 
x 
x 
X* 
X* 
Pivot Shift Test 
 
x 
x 
x 
x 
X* 
X* 
Primary variables 
 
x 
x 
x 
x 
 
 
Secondary variables 
 
x 
x 
x 
x 
X* 
X* 
Adverse Events 
 
X* 
X* 
X* 
X* 
X* 
X* 
 
X* / * Study specific 
 

 
ACLROCS/Fucentese 
 Page 14 of 55 
Version 2.0 of 6 June 2017 
1 
STUDY ADMINISTRATIVE STRUCTURE  
1.1 Sponsor - Principal investigator  
PD Dr. med. Sandro F. Fucentese 
Head of Knee Surgery 
University Hospital Balgrist 
Forchstrasse 340 
CH-8008 Zürich 
Sandro.fucentese@balgrist.ch  
1.2 Statistician 
Tobias Götschi  
Research Fellow 
University Hospital Balgrist 
Forchstrasse 340 
CH-8008 Zürich 
tobias.goetschi@gmail.com  
1.3 Monitoring 
Sabrina Catanzaro 
University Hospital Balgrist 
Research Nurse UCAR 
Forchstrasse 340 
CH-8008 Zürich 
Sabrina.catanzaro@balgrist.ch  
2 
ETHICAL AND REGULATORY ASPECTS 
Before this study will be conducted, the investigation plan, the proposed participant information 
and consent form as well as other study-specific documents will be submitted to a properly 
constituted Competent Ethics Committee (CEC) in agreement with local legal requirements, for 
formal approval. Any amendment to the investigation plan must as well be approved. 
The decision of the CEC concerning the conduct of the study will be made in writing to the 
Sponsor-Investigator before commencement of this study. The clinical study can only begin once 
approval from all required authorities has been received. Any additional requirements imposed 
by the authorities shall be implemented. 
2.1 Study Registration 
The study will be registered in the Swiss Federal National Clinical Trials Portal SNCTP and in the 
international trial registry ClinicalTrials.gov. 

 
ACLROCS/Fucentese 
 Page 15 of 55 
Version 2.0 of 6 June 2017 
2.2 Categorization of Study 
Category A study with medical device. The device under study bears a conformity marking and 
is used in accordance with the instructions. 
2.3 Competent Ethics Committee (CEC)  
Approval from the appropriate constituted Competent Ethics Committee is sought for the study 
site in the clinical trial. The reporting duties and allowed time frame are respected. No substantial 
changes are made to the investigation plan without prior CEC approval, except where necessary 
to eliminate apparent immediate hazards to study participants. 
Premature study end or interruption of the study is reported within 15 days. The regular end of 
the study is reported to the CEC within 90 days, the final study report shall be submitted within 
one year after study end. Amendments are reported according to chapter Investigation Plan 
Amendments.  
2.4 Competent authorities (CA) 
 
CA (swissmedic) approval is only necessary for category B and C studies. Category A studies 
do not require a CA approval. The CA is entitled to carry out inspections of all clinical trials. 
2.5 Ethical Conduct of the Study 
The study will be carried out in accordance with principles enunciated in the European Directive 
on medical devices 93/42/EEC and the ISO Norm 14155 and ISO 14971, the Swiss Law and 
Swiss regulatory authority’s requirements. CEC will receive annual safety and interim reports and 
be informed about study stop/end in agreement with local requirements. 
2.6 Declaration of Interest  
This study will mainly be financed by ZuriMED Technologies AG.  
 
PD Dr. Sandro F. Fucentese is co-inventor of a patent which is licensed to ZuriMED Technologies 
AG. 
Prof. Jess G. Snedeker is co-inventor of a patent which is licensed to ZuriMED Technologies AG. 
Also he is a shareholder of named company. 
Elias Bachmann is co-inventor of a patent which is licensed to ZuriMED Technologies AG. Also 
he is a shareholder and partially employed by named company. 
Tobias Götschi is partially employed by ZuriMED Technologies AG. 
2.7 Patient Information and Informed Consent 
The investigator will explain to each participant the nature of the study, its purpose, the 
procedures involved, the expected duration, the potential risks and benefits and any discomfort it 
may entail. Each participant must be informed that the participation in the study is voluntary and 
that he/she may withdraw from the study at any time and that withdrawal of consent will not affect 
his/her subsequent medical treatment.  

 
ACLROCS/Fucentese 
 Page 16 of 55 
Version 2.0 of 6 June 2017 
The participant will be informed that his/her medical records may be examined by authorized 
individuals other than their treating physician. 
All participants for this study will be provided a participant information sheet and a consent form 
describing this study and providing sufficient information for participants to make an informed 
decision about their participation in this study.   
The participant information sheet and the consent form will be submitted with the investigation 
plan for review and approval for the study by the CEC. The formal consent of a participant, using 
the approved consent form, must be obtained before that participant is submitted to any study 
procedure.   
The participant should read and consider the statement before signing and dating the informed 
consent form, and should be given a copy of the signed document. The consent form must also 
be signed and dated by the investigator (or his designee) and it will be retained as part of the 
study records. 
2.8 Participant Privacy and Confidentiality 
The investigator affirms and upholds the principle of the participant's right to privacy and that they 
shall comply with applicable privacy laws. Especially, anonymity of the participants 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 study is considered confidential 
and disclosure to third parties is prohibited. Subject confidentiality will be further ensured by 
utilizing subject identification code numbers to correspond to treatment data in the computer files. 
Such medical information may be given to the participant’s personal physician or to other 
appropriate medical personnel responsible for the participant’s welfare, if the patient has given 
his/her written consent to do so. 
For data verification purposes, authorized representatives of the Sponsor-Investigator and an 
ethics committee may require direct access to parts of the medical records relevant to the study, 
including participants’ medical history. 
2.9  Early Termination of the Study  
The Sponsor-Investigator may terminate the study prematurely according to certain 
circumstances, e.g.: 
 
ethical concerns, 
 
insufficient participant recruitment, 
 
when the safety of the participants is doubtful or at risk, respectively, 
 
alterations in accepted clinical practice that make the continuation of a clinical trial 
unwise,  
 
early evidence of harm of the experimental intervention  
2.10 Protocol Amendments 
Substantial amendments are only implemented after approval of the CEC respectively. 
Under emergency circumstances, deviations from the investigation plan to protect the rights, 
safety and well-being of human participants may proceed without prior approval of the CEC. 
Such deviations shall be documented and reported to the CEC as soon as possible. 

 
ACLROCS/Fucentese 
 Page 17 of 55 
Version 2.0 of 6 June 2017 
All Non-substantial amendments are communicated to the CEC within the Annual Safety Report 
(ASR).  
3 
INTRODUCTION  
3.1 Background and Rationale 
Anterior cruciate ligament (ACL) rupture is one of the most common and severe ligament injury 
[1], with around 250,000 to 400,000 patients per year diagnosed with ACL  disruption  in  the  
United  States [2-4]. Reconstruction of the ACL is currently recommended as the standard of care 
following an ACL tear or rupture [5]. There are a number of currently available graft choices for 
ACL reconstruction, including autografts, allografts, xenografts, and a variety of synthetic grafts 
[6-8]. Hamstring tendon autografts have emerged as the most widespread clinical choice, 
normally employed using either the semitendinosus tendon and/or gracilis tendon [9-11]. Despite 
the excellent mechanical characteristics of these ligament grafts, hamstring graft to bone healing 
is often poor, with tendon graft elongation or even pullout as common failure modes for hamstring 
graft reconstructions [12]. Additionally, hamstring tendon autografts have been associated with 
bone tunnel widening (BTW) [13-17]. Hamstring tendon autografts take a long time to be 
incorporated into the bone tunnel in order to provide sufficient mechanical strength [18]. To 
mitigate this poor graft-bone integration, many surgeons favor a bone patellar tendon bone 
(BPTB) autograft extracted from the middle third of the patellar tendon along with bone blocks in 
continuity at each end of the graft (blocks from tibial tubercle and the outer surface of the patella, 
respectively). Because the native bone-tendon interface in these grafts is quite strong, and bone-
bone healing is rapid, clinical outcomes using these grafts are widely viewed as superior [19, 20]. 
The BPTB graft has for decades thus been regarded as a 'Gold Standard' graft choice for ACL 
reconstruction, among some controversy [21-25]. Still the BPTB autograft is severely limited by 
graft source site morbidity, with occasionally severe pain lasting up to 12 months after surgery – 
a fact that has drastically limited the use of BPTB autograft in the clinic [19, 26]. From a tissue 
engineering perspective, the largest challenge in reducing failure rates of hamstring tendon 
autografts is the integration of the graft with the host bone [27] with the long-term performance of 
the ACL graft believed to mainly depend on successful regeneration of the tendon-bone interface 
[28]. Many approaches have been tried to enhance the integration of the tendon-graft to bone in 
order to achieve improved biological attachment. The major concern is to provide appropriate 
molecular and cellular cues that result in effective healing between graft and bone. To this end, 
tissue engineering approaches have employed bone marrow derived mesenchymal stem cells 
(BMSCs) as potential agents to enhance graft to bone healing [29, 30]. Similarly, osteoinductive 
bioceramics such as Hydroxyapatite (HA), β-tricalcium phosphate (β-TCP), brushite calcium 
phosphate cement (CPC) have also been adopted to augment graft to bone attachment [31-36]. 
In most approaches, classical fixation methods such as interference screws have been employed, 
despite their inherent limitations to providing osteogenic contact surfaces [35]. In the current 
approach, an osteoconductive scaffold (OCS) is enlaced into the quadrupled tendon graft and is 
intended to provide optimal contact between the hamstring tendon and osteoconductive surfaces 
(OCS or bone tunnel). The device under study is a composite material obtained using bovine 
bone-derived 
matrix 
reinforced 
with 
poly(L-lactide-co-ε-caprolactone) 
(PLCL) 
and 
polysaccharides [37]. It has been successfully used as a bone substitute for oral and maxillofacial 
reconstructive surgery. Its macro- and micro-porous structure similar to the structure of human 
bone promotes the formation and growth of new bone in the implant site. The combination of 
biopolymers and collagen derivatives facilitates blood retention and activates the cascade of 
regenerative signals in the defect site. Biopolymers and collagen derivatives are reabsorbed 
slowly over the course of several weeks while the substitute integrates with the receiving tissue 

 
ACLROCS/Fucentese 
 Page 18 of 55 
Version 2.0 of 6 June 2017 
[IFU SmartBone]. The resorption and substitution of the OSC by bone close to the articular end 
of the bone tunnel should provide long-term fixation at a biomimetic attachment site of the ACL 
graft. 
3.1.1 Bone Tunnel Widening following ACL-Reconstruction 
BTW is a well-documented phenomenon following ACL-reconstruction [16, 38-40]. In studies 
using hamstring grafts, it has occurred in 25-100% in the femoral tunnel and in 29-100% in the 
tibial tunnel [41-45]. Although it may not affect the clinical outcome in terms of an increase in laxity 
or failure rates [46], it severely complicates revision surgery [40]. Etiological factors for tunnel 
widening probably are of mechanical, as well as of biological nature. Mechanical factors include 
motion of the graft within the bone tunnel, stress shielding and improper graft placement. Synovial 
fluid propagation into the bone tunnel and increased cytokine levels inducing osteolysis are 
believed to be biological factors leading to this phenomenon [40]. Bone tunnel widening can be 
assessed on plain radiograph [47], MRI [48] and CT with CT being the most accurate [49, 50]. In 
an attempt to reduce tunnel widening following ACL-reconstruction, osteoconductive materials 
have been used with promising results. The use of a poly-L-lactic acid (PLLA)-HA blended 
interference screw reduced tunnel widening compared to plain PLLA interference screws at an 
average follow-up of 30.9 months and 26.5 months, respectively (29.9 vs. 46% BTW) [46]. 
Similarly, Barth et al. [51] showed a statistically significant reduction of BTW using a poly (l-lactide-
co-D,l-lactide) (PLDLLA)-HA/β-TCP composite screw compared to the polymer-only screw in the 
tibia, but not in the femur. PLLA/HA composite screws also outperformed metal interference 
screws for graft fixation in ACL-reconstruction in terms of BTW in a study conducted by Lind et 
al. [52]. Resorption of polymer-bioceramic interference screws however, is generally slow [53]. 
High mechanical loads during insertion do not allow the use of highly porous materials for 
interference screws. In the current application, the osteoconductive scaffold does not take primary 
fixation function. This allows the use of highly porous material. 
3.2 Investigational Medical Device and Indication 
The device under study is a bone substitute intended and specifically developed for bone 
regeneration applications [TechInfos SmartBone]. It is composed of a natural mineral matrix of 
bovine origin, reinforced with biodegradable synthetic polymers and natural collagen derivatives 
of bovine origin. It has a macro- and micro-porous structure similar to the structure of the human 
bone [IFU SmartBone]. 
Clinical studies were performed to assess osteointegration on a 4 months observation timeframe. 
Histological analysis confirmed osseous integration, with natural bone formation and cells and 
vessels colonizing pores within it during time. Summarizing, the main biological features are:   
 
high cell viability and proliferation support,  
 
high osteoinduction, conduction and integration. 
Its mechanical properties can be summarized as follows: 
 
composite mechanical behavior: both rigid and elastic  
 
adequately high elastic modulus  
 
extreme load bearing resistance  
 
dust and debris free shaping  
 
capability to withstand precise shaping  
 
tenacity to fixation screws  
 
hammering and heavy surgical maneuvering resistance 
 
 

 
ACLROCS/Fucentese 
 Page 19 of 55 
Version 2.0 of 6 June 2017 
3.3 Clinical Evidence to Date 
3.3.1 SmartBone 
Pre- and post-market clinical investigations to date using SmartBone were performed only in the 
field of oral, maxillofacial and cranial surgery. The rationale behind this focus was that findings 
regarding performance and safety of a bone graft in said fields can be transferred to the use of 
the device in all orthopedic applications, but that vice-versa conclusions are not possible. 
In the following, clinical study data regarding SmartBone are summarized. 
Study design 
No. 
of 
pat. 
Aim 
Setup 
Results 
Single-centre, 
non-
randomized, 
comparative 
clinical trial 
[37]. 
5 
Assessment of 
complete in vivo 
biocompatibility and 
efficacy. 
Comparison of the 
non-CE marked device 
with its CE marked raw 
material component 
Tutobone (Tutogen, 
Germany). 
Histological analyses 
confirmed 
osteointegration and 
remodeling capabilities.  
Post-market 
clinical follow-
up. 
Randomized, 
non-blinded, 
multi-centric 
clinical trial 
(not published 
yet). 
44 
Confirm clinical 
performance and 
safety throughout a 
meaningful 
observation period. 
17 investigators 
performed surgeries in 
oral, maxillofacial and 
cranial districts. 
Quantitative 
assessment of bone 
regeneration based on 
evaluation of grafted 
volume evident on 
radiographs.  
27 patients monitored 
over the entire time frame 
(1 year). Out of the total of 
44 patients:12 cases 
showed optimal 
regeneration.29 showed 
good regeneration. 3 
showed medium 
regeneration. No failures, 
no accidents, nor adverse 
events nor poor results 
were recorded. 
Monocentric 
cohort study 
[54]. 
62 
Confirm safety, 
performance and 
acceptability of 
identified residual 
risks 
Monitoring safety and 
performance outcome 
using quantitative 
assessment of bone 
regeneration based on 
evaluation of grafted 
volume evident on 
radiographs. 
60 patients monitored 
over the entire time frame 
(>1.5 years). 55 cases 
showed optimal 
regeneration. 1 case with 
good regeneration. 3 
cases with poor 
regeneration. 1 case with 
a reported failure for 
dehiscence. No further 
failures, no accidents, nor 
adverse events nor poor 
results were recorded. 
The clinical data 
confirmed safety and 
performance of the device 
and showed acceptability 
of residual risk.  

 
ACLROCS/Fucentese 
 Page 20 of 55 
Version 2.0 of 6 June 2017 
Histological 
investigation 
[55]. 
10 
Assess the 
mechanism of 
action of the device 
histologically. 
Collection of tissue 
biopsies from clinical 
cases allowing easy 
and precise sample 
collection. 
Histomorphometric 
analysis and bone-
particle conductivity 
index calculation. 
Based on the analysis of 6 
histological images it was 
concluded that the bone 
graft shows about 35 – 
40% substitution at about 
4 – 8 months and 
complete substitution after 
about 2 years. No 
inflammatory cells were 
detected, confirming full 
biocompatibility of the 
medical device.  
Multicenter 
prospective 
clinical trial 
(not published 
yet) 
58 
Evaluation of the 
newly-formed 
tissue, correlating 
clinical and 
histological results 
to the sinus cavity 
size and 
conformation. 
Transcrestal sinus floor 
elevation performed in 
atrophic ridges. Cone 
beam computed 
tomography 10 days 
and 6 months after 
surgery. After 6 months 
a bone-core biopsy 
was harvested. 
Histomorphometric 
analysis was 
conducted. 
56 cases showed good or 
optimal regeneration. 2 
cases with failure for 
dehiscence. No further 
failures, no accidents, nor 
adverse events nor poor 
results were recorded. 
Monocentric 
cohort study 
(not published 
yet) 
10 
Histomorphometric 
evaluation. 
Alveolar preservation 
after tooth-extraction. 
Collection of biopsies 4 
months after 
implantation. 
Comparison of 
histological images 
with known cases 
treated with with other 
commercially available 
bone substitutes. 
Biopsies collected at 4 
months post-implantation 
showed the 
contemporaneous 
presence of SmartBone, 
new bone and fibrous 
tissue wirh formation of 
new vessels. Bone ECM 
molecules were highly 
expressed in the newly 
formed bone and 
osteoblasts were visible 
on the device’s surfaces. 
No failures, no accidents, 
nor adverse events nor 
poor results were 
recorded. 
 
3.3.2 Autograft Scaffolds for ACL-Graft Fixation 
Kim et al. [56] prospectively reviewed 81 patients who had undergone ACL-reconstruction with 
an Achilles tendon allograft using a bioabsorbable interference screw (group I) or an 
autogenous bone plug harvested from the tibial bone tunnel (group P) for tibial graft fixation. 
Patients and outcome-assessors were blinded to group assignment. After an average follow-up 
of 7.5 years, complication rate in group P was significantly less frequent than in group I (6 vs. 
14) and tunnel widening, assessed as cross-sectional area on MRI, averaged 15% in group P 
and 38% in group I (p = 0.017). No significant changes for patient subjective outcome scores 

 
ACLROCS/Fucentese 
 Page 21 of 55 
Version 2.0 of 6 June 2017 
and stability were detected. The authors deemed the use of autograft bone plugs for graft-
fixation a reasonable option for ACL-reconstruction with Achilles tendon allograft. 
3.3.3 Xenograft Scaffolds for ACL-Graft Fixation 
The bovine bone matrix SmartBone consists of is a CE-marked product (Tutobone) by Tutogen, 
Germany. In a randomized controlled trial, Jagodzinski et al. [57] used Tutobone, shaped into a 
conical block, for tibial press-fit fixation of the hamstring autograft in ACL-reconstruction. This 
approach was compared to the traditional technique using bioresorbable interference screw 
fixation, in terms of clinical outcome and BTW. At the proximal section of the tibial bone tunnel, 
the tunnel diameter was significantly smaller for the press-fit group at 3, 6, 12 and 24 months 
follow-up. No significant differences were detected for IKDC-, Tegner-, Lysholm score and knee 
stability between the two groups. No intra- or postoperative complications were reported. 
3.3.4 Adverse Device Effects  
In 2008, Konan et al. [58] summarized the literature concerning adverse device effects 
associated with the use of bioabsorbable interference screws in ACL-reconstruction. Adverse 
device effects identified, related to composite screws containing a part bioceramic (β-TCP/HA), 
were:  
 
Screw breakage during insertion 
 
Subcutaneous cyst formation (cured within the following 3 months) 
Tecklenburg et al. [59] evaluated the clinical outcome of ACL-reconstruction using 
hydroxyapatite composite screws, β-TCP composite screws and allograft interference screws in 
a total of 60 patients. There was no inflammatory response noted in any patients. 
3.4 Rationale for the Intended Purpose in Study  
The clinical outcome of ACL-reconstruction depends on the successful integration of the tendon-
graft into the host bone close to the attachment site of the native ACL [60-62]. The OCS is enlaced 
into the tendon-suture construct and provides an osteoconductive / osteoinductive environment 
at the articular aperture of the bone tunnel. The design maximizes the contact area between 
tendon and osteoconductive surface (Bone/HA). Different to the application of interference 
screws, graft insertion exerts minimal stress on the insert and allows the use of highly porous 
material. Enhanced bone-tendon integration should reduce graft micromotion and increase the 
repair strength of the reconstructed ACL. This in turn should reduce the rate of graft failure and 
the incidence of tunnel widening. 
3.5 Explanation for Choice of Comparator  
The active comparator in the current study will be the standard ACL-reconstruction technique 
used at Balgrist University Hospital. 
3.6 Risk / Benefits 
Since the OCS is an approved, CE-marked device, product related risks like biocompatibility, 
shelf-live et cetera were excluded from the internally conducted risk assessment and possible 
adverse effects of the product can be seen in the instruction for use. 
However a careful and detailed risk assessment was performed according to EN ISO 
14971:2013-04 to also take overall - not only product related risks into account. 

 
ACLROCS/Fucentese 
 Page 22 of 55 
Version 2.0 of 6 June 2017 
To identify and evaluate the risks a Failure Mode and Effects Analysis (FMEA) was performed, 
based on EN ISO 14971:2013-04 Annex C informative guideline. 
The full FMEA can be delivered upon request. In the following the results of the investigation 
are summarized. Identified risks in italic. 
 
Clinical study related risks 
 
Surgical team (surgeons, staff) is not introduced to clinical study procedure (device is not 
used according to study protocol). This risk has been minimized by several pre-clinical 
cadaver tests, where the full intervention was carried out, documented and analyzed 
with the involved team. (KEK-ZH-Nr. 2015-0372, Developing a novel surgical procedure 
for improved ACL reconstruction). 
 
Logistical flow from producer to patient does not work. Involved staff is informed and 
used to handling and storage conditions of the different medical products used for this 
study (OCS, sutures). 
 
Soft tissue bridging during graft insertion. In performed cadaver tests a possible soft 
tissue bridging which can occur during graft insertion through the medial portal did not 
occur. Since the graft insertion is reversible until knots are fastened this issue can be 
solved intraoperatively. 
 
OCS breaks during graft insertion. In-vitro experiments were performed in order to 
assess device strength during surgical insertion. For femoral pull-in of the construct, a 
force of 250N was applied resembling maximal achievable voluntary one-handed force. 
Subsequently, the construct was extracted and inspected for damage. None of the 
samples showed damage to the OCS. 
 
ACL loads during rehabilitation lead to damage to OCS and to subsequent release of 
particles into the joint capsule. The laboratory of Orthopedic Biomechanics at ETH 
Zurich performed mechanical in-vitro testing on the construct under study in porcine 
knees. The experiment included high load – low cycle testing, simulating out of the 
ordinary situations such as stumbling or jumping, as well as low load – high cycle 
testing, simulating the long term mechanical environment during rehabilitation. The OCS 
performed well in all tests with no signs of abrasion particles being released from the 
construct. 
 
OCS inserted into the tendon-graft reduces the fatigue life of the graft-construct. The 
material properties of the OCS highly differ from the material properties of the 
surrounding tendon. The OCS might damage the tendon or the suspension suture and 
accelerate fatigue failure of the construct. Comparing the fatigue life of the construct with 
OCS and without OCS revealed no such effect. 
 
The overall risk of this study is therefore stated as very low and has been evaluated acceptable, 
the expected benefits overweigh the minimized residual risk. 
 
Expected Benefits: 
 
Faster healing of soft-tissue to bone (up to 3-times more tendon to bone surface area) 
 
Stronger secondary fixation by having a „bony bridge“ 
 
Reduced tunnel widening due to faster secondary fixation (bone to bone) and windshield 
wiper effect. 
 
A successful outcome of this study would have a big impact in an improved ACL 
reconstruction. Further studies for a tibial (femoral & tibial) solution could be carried out 
on the basis of this study. 
3.6.1 Radiological Assessment Related Risks 
The mean volume CT dose index and the dose-length product of one CT-scan of the knee are 
approximately 9.8 mGy and 189 mGy*cm respectively. Using an effective dose conversion 

 
ACLROCS/Fucentese 
 Page 23 of 55 
Version 2.0 of 6 June 2017 
coefficient of 0.0004 mSv/(mGy*cm) for the knee of an adult subject [63] yields an effective 
radiation dose of 0.0756 mSv per examination.  
According to the reference table provided by Swissethics, one plain radiography examination of 
the knee in anterior-posterior direction yields an effective radiation dose of 0.015 mSv [64]. 
 
The table below shows the calculation of the total effective radiation dose each participant is 
exposed to by the two measurement modalities used in the current study [65].  
Measurement 
modality 
Effective dose per 
examination 
[Millisievert] 
Number of 
examinations per 
subject 
Total effective 
radiation dose per 
subject [Millisievert] 
Computed 
Tomography 
0.0756 
3 
0.2268 
Plain Radiology 
0.015 
5 
0.075 
Total exposure 
 
 
0.3018 
3.6.2 Anticipated Adverse Device Effects 
Anticipated adverse device effects based in part on the literature search described above are 
the following. 
 
Subcutaneous cyst formation 
 
Intratunnel cyst formation [66] 
Subcutaneous cysts usually reside over time and are easily manageable surgically [66, 67]. 
Intratunnel cysts are related to the effect of BTW and are therefore subject of the current 
investigation. 
 
4 
STUDY OBJECTIVES  
4.1 Overall Objective 
The overall objective of this study is to evaluate the efficacy of the use of the OCS in ACL 
reconstruction. 
4.2 Primary Objective 
The study seeks primarily to determine the effect of the use of the OCS-autograft fixation 
construct on femoral bone tunnel widening compared to the traditional ACL-reconstruction 
technique using a hamstring autograft. 
4.3 Secondary Objectives 
Secondary objectives are to assess patient subjective measures of knee function and objective 
measures of knee stability of the interventional treatment compared to the control treatment. 
Also the success of return to pre-injury activity level will be assessed. Additionally OCS-bone 
integration will be investigated. 
4.4 Safety Objectives 
Safety will be evaluated by the occurrence, frequency and severity of intra- and postoperative 
complications. 

 
ACLROCS/Fucentese 
 Page 24 of 55 
Version 2.0 of 6 June 2017 
5 
STUDY OUTCOMES  
5.1 Primary Outcome 
The primary outcome variable of this study is the relative change of the CT evaluated femoral 
bone tunnel volume from baseline to follow-up at 12 months. 
As the primary objective of the use of the OCS is to reduce tunnel widening by promoting bony 
ingrowth into the bone tunnel, the relative change of bone tunnel volume over time is an 
appropriate measure to quantitatively assess this effect. Assessing relative changes as 
opposed to absolute values negates the potential for bias by different tunnel drill sizes used in 
the two treatment arms potentially influencing the absolute ossification/de-ossification. In 
quantifying bone tunnel size, CT measurements provide substantially more reliable means than 
plain radiography or magnetic resonance imaging [50, 68].  
5.2 Secondary Outcomes 
The secondary endpoints aim to assess the clinical outcome of the two treatment groups. These 
clinical outcome measures can be divided into two domains: Patient subjective knee function 
and objective measures of knee stability. 
5.2.1 Patient Subjective Knee Function 
Patient subjective knee function is assessed using the International Knee Documentation 
Committee (IKDC) Subjective Knee Evaluation Form (SKEF) and the Lysholm Knee Scoring 
Scale (LKSS) measured at baseline visit (surgery) and at each follow-up visit.  
5.2.1.1 IKDC Subjective Knee Evaluation Form 
IKDC SKEF is designed to detect improvement or deterioration in symptoms, function and 
sports activities due to knee impairment for patients with a variety of knee conditions including 
ligament injuries. It is a patient-completed questionnaire available in multiple languages 
including German with an ordinal scoring system ranging from 0 (highest level of symptoms or 
lowest level of function) to 100 (no limitation with daily or sporting activities and the absence of 
symptoms) [69].  
5.2.1.2 Lysholm Knee Scoring Scale 
LKSS is designed to evaluate outcomes of knee ligament surgery, particularly symptoms of 
instability [70]. It has an ordinal scoring system ranging from 0 to 100 (No symptoms or 
disability) [71]. A validated German version will be used [72].  
5.2.2 Objective Measures of Knee Stability 
Anterior laxity is evaluated using the KT-1000 Arthrometer Test and the Lachman Test. 
Rotational stability is assessed using the Pivot Shift Test. 
5.2.2.1 KT-1000 Arthrometer Test 
The KT-1000 Arthrometer Test measures anterior displacement of the tibial plateau on the 
femur at a specific force. Its output variable is defined as the difference in full millimeters 
between the tibial displacement of the ACL reconstructed knee and the normal contralateral 
side [73]. 
5.2.2.2 Lachman Test 
The Lachman test measures anterior displacement conducted manually by the clinician. It is 
graded as the difference from the normal contralateral side as 0 (<3 mm), 1 (3 to 5 mm), or 2 
(>5 mm) [74]. 

 
ACLROCS/Fucentese 
 Page 25 of 55 
Version 2.0 of 6 June 2017 
5.2.2.3  Pivot Shift Test 
The pivot shift test assesses the combined tibio-femoral rotation and anterior tibial translation. 
The pathologic motion elicited is graded as a glide (grade 1), clunk (grade 2), or gross clunk 
with locking (grade 3). A normal finding is graded as zero.  The grade of the pivot shift has been 
shown to correlate with patient-reported functional instability and clinical outcomes [75]. The 
outcome measure is calculated from the difference between affected (repaired) and intact knee. 
5.2.2.4 Tegner activity scale 
The Tegner activity scale (TAS) is used to measure the change in physical activity from pre-
injury to follow-up. It was designed to complement the functional outcome of the LKSS. Patient’s 
activity is scored on a scale with 11 levels from level 0 (on sick leave/disability) to level 10 
(participation in competitive sports such as soccer at a national or international elite level) [71]. 
Evaluated will be the difference in score from pre-injury (assessed at baseline visit) to follow-up.  
5.3 Other Outcomes of Interest 
5.3.1 Patient History 
Patient history will be assessed using an adapted version of the IKDC SKEF (German version). 
Assessed will be: 
 
Date of injury 
 
Affected knee 
 
Activity of injury 
 
Mechanism of injury 
5.3.2 OCS-Bone Integration 
For a quantitative analysis of OCS-bone integration, the mineral density profile along a 
predefined line will be examined. A slice showing the central portion of the OCS in the axial 
plane will be selected. A straight line of 2 cm length will be drawn perpendicular to the long axis 
of the OCS using image analysis software (Mimics). The CT-values along this line will be 
recorded and evaluated in the following way. Since the CT-values change according to the bone 
mineral density, the profile along the line will have a minimum at the interface of the tunnel wall 
and the OCS and a maximum on the OCS. The difference in Hounsfield units from the 
cancellous bone in the tunnel wall and the OCS-bone interface will be used as a measure for 
the degree of osseous integration of the implant [24]. 
5.3.3 Intra-Patient Comparison of Ossification 
The intervention group will be additionally assessed in an intra-patient comparison model [51]. 
Using the available CT data, the tibial bone tunnel volume will be calculated using the same 
method as for the femoral bone tunnel volume described below. The relative change of the two 
parameters will be compared. 
5.3.4 Plain Radiography assessed Bone Tunnel Widening 
BTW will additionally be assessed on plain radiograph. Standard posteroanterior radiographs of 
the knee in full extension will be used [76]. Bone tunnel width will be assessed at the widest part 
of the femoral bone tunnel. Assessed will be the relative change in femoral bone tunnel width.  
5.4 Safety Outcomes 
Any occurrence of intra-operative complications will be recorded on the eCRF. Post-operative 
(serious) adverse events will be recorded at each follow-up visit.  

 
ACLROCS/Fucentese 
 Page 26 of 55 
Version 2.0 of 6 June 2017 
6 
STUDY DESIGN AND COURSE OF STUDY 
6.1 General study design and justification of design  
The present study is designed as a randomized patient-blinded equally sized two-group parallel 
design superiority trial using an active comparator. ACL-reconstruction using the in-house 
standard of care will be compared to the method under investigation. In a two staged 
randomization, a total of 56 patients are assigned to either of the two treatment groups. 
6.1.1 Time Frame of the Study 
Currently, no precise time frame for the occurrence of BTW has been defined [41]. Chen et al. 
[77] investigated the incidence of BTW following ACL-reconstruction using hamstring tendon in 
58 patients at 1, 2, 3, 6, 12 and 24 months postoperatively. BTW was found to mainly occur 
during 3 to 6 months after surgery with no change in bone tunnel volume between 12 and 24 
months postoperatively. Similarly, Jo et al. [78] concluded, BTW to be maximal within the first 9 
months following surgery using patellar tendon grafts. For the current trial, BTW-assessment 
using CT-scanning 4.5 and 12 months after surgery seems therefore reasonable. The need of 
correlating BTW with long-term clinical results has also been pointed out [79]. 
6.2 Study Duration and Study Schedule 
Total duration of subject participation will be 5 years. Total duration of the study is expected to 
be 82 months. Duration of patient acquisition is hereby estimated to be 22 months. This 
estimate is based on the following assumptions: 
 
ACL-reconstruction surgeries performed monthly at the investigation site: 12 
 
Ratio of patients agreeing to participate: 60% (estimate based on internal data) 
 
Ratio of patients eligible for the study: 35% (estimate based on internal data) 
The estimated patient allocation rate is therefore: 
12/month * 0.6 * 0.35 = 2.52/month 
Estimated duration for the acquisition of 56 patients is 22.2 months. 
 
First-Patient-In: 07/2017 
Last-Patient-Out: 04/2024 
Statistics/Abstract: 12/2024 
6.3 Methods of Minimizing Bias  
6.3.1 Randomization  
A two-staged randomization method will be used. To ensure adequate treatment distribution for 
interim analysis, the first block will contain 10 interventional and 10 control treatments. In the 
following, a block for the remaining treatment allocations will be used.  
6.3.2 Blinding Procedures  
The current clinical trial is designed as a patient-blinded study.  
Group allocation cannot be blinded to the operateur nor can the group allocation be blinded to 
the practitioner evaluating the radiological images at regular postsurgical follow-up visit and for 
safety assessment.  
Concealment of group allocation to the patient is ensured.  During surgery, graft preparation 
and graft insertion is outside the patient’s field of view. 
No radiological images will be shown to the patient as to not reveal group allocation. 

 
ACLROCS/Fucentese 
 Page 27 of 55 
Version 2.0 of 6 June 2017 
6.3.3 Other Methods of Minimizing Bias  
Patient subjective knee function will be assessed using German versions of validated 
questionnaires [69, 72]. KT-1000 arthrometer testing provides the means to objectively measure 
anterior knee stability [80]. 
6.4 Unblinding Procedures 
At patient study end - planned or unplanned - the patient will be informed about his/her group 
allocation in the trial. 
7 
STUDY POPULATION 
7.1 Eligibility criteria  
7.1.1 General Criteria for Eligibility 
Participants fulfilling all of the following criteria are eligible for the study: 
 
18 to 60 years of age at entry. 
 
Males and females. 
 
An ACL insufficiency as determined by clinical examination (positive pivot shift and/or 
positive Lachman test). 
The presence of any of the following criteria will render the patient not eligible for the study: 
 
Contraindications to the class of drugs under study, e.g. known hypersensitivity or 
allergy to the investigational product, 
 
Women who are pregnant or breast feeding,  
 
Medical condition or comorbidity that would interfere with study participation. 
 
Other clinically significant concomitant disease states (e.g., renal failure, hepatic 
dysfunction, cardiovascular disease, etc.), 
 
Acute or chronic infections (i.e. osteomyelitis) in the surgical site, 
 
Uncontrolled metabolic diseases, such as diabetes, osteomalacia, thyroid dysfunctions, 
 
Long-term cortisone therapy, 
 
Autoimmune diseases, 
 
Radiotherapy, 
 
Heavy smokers, 
 
Motion disorder, 
 
Known or suspected non-compliance, drug or alcohol abuse, 
 
Inability to follow the procedures of the study, e.g. due to language problems, 
psychological disorders, dementia, etc. of the participant, 
 
Participation in another study with investigational drug within the 30 days preceding and 
during the present study, 
 
Previous enrolment into the current study, 
 
Enrolment of the investigator, his/her family members, employees and other dependent 
persons. 
7.1.2 Inclusion / Exclusion for Eligible Subjects 
Eligible patients fulfilling all of the following inclusion criteria will be included into the study: 
 
Patient has reached skeletal maturity 

 
ACLROCS/Fucentese 
 Page 28 of 55 
Version 2.0 of 6 June 2017 
 
A complete ACL tear to be reconstructed using hamstring tendon autograft. The ACL 
injury can either be isolated or combined with one or several of the following injuries: 
o A meniscus tear that is either left untreated or treated with partial resection, 
o A small, stable meniscus tear treated with fixation, but fixation not interfering with 
the rehabilitation protocol, 
o Cartilage changes verified on MRI with arthroscopically determined intact surface 
or fissuring on the surface that do not reach subchondral bone or exceed 1.5 cm 
in diameter (Outerbridge grade I-III [81]). 
 
Harvested folded tendon (unsutured) has a diameter between 8 and 8.5mm at the end to 
be inserted into the femoral bone tunnel determined using a tendon thickness tester 
(Karl Storz). 
 
Tendon graft construct consists of one of the following: 
o Semitendinosus tendon quadrupled 
o Semitendinosus tendon quadrupled plus gracilis tendon doubled 
o Semitendinosus tendon doubled plus gracilis tendon doubled 
 
A normal joint status possibly combined with either one of the following findings: 
o A small-avulsed fragment located laterally, usually described as a Segond 
fracture, 
o Joint space narrowing grade 1 or osteophytes grade 1 as determined by the 
OARSI atlas [82]. 
 
Informed Consent as documented by signature 
Eligible patients fulfilling any of the following criteria will be excluded from the study: 
 
Prior fracture of the affected leg, 
 
Earlier major knee injury to the index knee, 
 
Associated posterior cruciate ligament injury or medial collateral ligament injury grade III 
in index knee, 
 
Previous or current ACL injury on contra-lateral leg, 
 
One of the following injuries to the index knee as visualized on MRI and/or arthroscopy: 
o An unstable longitudinal meniscus tear that requires repair and where the 
following treatment interferes with the standard rehabilitation protocol, 
o Bi-compartmental extensive meniscus resections, 
o A cartilage injury representing a full thickness loss with exposed subchondral 
bone (Outerbridge classification grade IV), 
o A total rupture of the lateral collateral ligament. 
 
Diameter of the tendon graft does not allow the use of the OCS (Irrespective of group 
allocation). 
 
Poor bone quality / missing bone material requiring alternative / additional graft-fixation. 
7.2 Recruitment and Screening 
Patients who will undergo ACL-reconstruction at Balgrist University Hospital will be recruited for 
this trial. All patients will be informed about the purpose of the trial, the operation modalities, 
and their benefits as well as risks. Patients will be asked whether they are prepared to 
participate in the trial prior to their inclusion. The patients will be handed out the written patient 
information brochure and will be given a minimum of 7 days for consideration. Patients that 
gave written informed consent will be screened for the inclusion and exclusion criteria of the 
current trial. Patients who were screened but not enrolled in the trial (including patients unable 
to give informed consent due to any reason) will be documented in the screening log, recording 
the reason for exclusion.  
All travel expenses for study-visits outside of standard of care will be reimbursed in the following 
way: 
 
Public transportation ticket from domicile to study site and back (2. Class, no Halbtax), or 

 
ACLROCS/Fucentese 
 Page 29 of 55 
Version 2.0 of 6 June 2017 
 
In case of travel by car: 0.50 CHF per kilometer from domicile to study site and back. 
Study-visits outside of standard of care and therefore object of reimbursement are: Visit 6 and 
7. 
7.3 Assignment to Study Groups  
A two-staged randomization scheme will be used. The first block will contain a total of 20 
patients. The second block will contain a total of 36 patients. For each block, a container with 
sealed envelopes with paper cards for the group assignment (equally sized groups) will be 
prepared. At final inclusion of a patient, one sealed envelope will be drawn from the container 
and the patient will be assigned accordingly. After assignment, the paper cards are sealed 
again and stored in the patients case report file.  
7.4 Criteria for Withdrawal/ Discontinuation of Participants 
If during the course of the study, a participant meets an exclusion criterion, he will be withdrawn 
from the study. Specifically, a potential rerupture of the graft will lead to exclusion of the patient. 
In any case of premature discontinuation of a participant, the reason will be documented in the 
respective eCRF. 
 
 

 
ACLROCS/Fucentese 
 Page 30 of 55 
Version 2.0 of 6 June 2017 
8 
STUDY INTERVENTION 
The surgical intervention under study is described in detail in ACLROCS_ 
WI_InterventionalSurgicalTechniqueGuide. 
8.1 Femoral Fixation Construct 
Control Group: Doubled suture loop (Ethibond 6) at appropriate length determined intra-
operatively connected to the femoral cortical fixation button (Flipptack, Karl Storz). 
Intervention Group: Doubled suture loop (Ethibond 6) at appropriate length determined intra-
operatively connected to the femoral cortical fixation button (Flipptack, Karl Storz). This 
construct is additionally connected to the device under study according to the interventional 
surgical technique guide. 
8.2 Graft Preparation 
Tendon preparation is done according to the in-house standard technique [Zeichnung SemiT-G-
Transplantatvorbereitung Flipp-Endotack_Balgrist]. The following procedures apply for both 
groups under study. Three graft configurations are permitted for study inclusion. In the following, 
the specifics in graft preparation related to tendon configuration are outlined. 
8.2.1 Semitendinosus Tendon-only Graft 
The semitendinosus tendon is harvested intra-operatively as described in the following chapter. 
The harvested tendon is mounted on the tendon board (Karl Storz) and both tendon ends are 
sutured using baseball stitches (Fibre Wire 2). The tendon is folded around a doubled suture 
(Ethibond 6). The tendon is folded a second time and enlaced with the femoral fixation 
construct. The tibial fixation button (ENDOTACK®, Karl Storz) is inserted and the construct is 
mounted on the tendon board (Karl Storz). Three sutures are placed on the tibial side of the 
graft and three on the femoral side in order to create a self-reinforcing suture noose (Vicryl 2-0). 
8.2.2 Doubled Semitendinosus – Doubled Gracilis Tendon Graft 
The harvested semitendinosus tendon is combined with a doubled gracilis tendon due to 
insufficient tendon length. The tendon ends are sutured using baseball stitches and the tendons 
are enlaced with the femoral fixation construct. Final graft preparation is then performed 
equivalently to the technique using semitendinosus tendon only.  
8.2.3 Quadrupled Semitendinosus – Doubled Gracilis Tendon Graft 
The harvested semitendinosus tendon is combined with a doubled gracilis tendon due to 
insufficient tendon diameter. The tendon ends are sutured using baseball stitches and the 
semitendinosus tendon is folded once. The two tendons are then enlaced with the femoral 
fixation construct. Final graft preparation is then performed equivalently to the technique using 
semitendinosus tendon only.  
8.3 Bone Tunnels 
The harvested unsutured tendon-graft must measure between 8 and 8.5 mm in diameter at the 
end to be inserted into the femoral bone tunnel for subject inclusion (see chapter 7.1.2). 
Enlacing the OCS increases the graft diameter by 1 mm (Determined experimentally). 

 
ACLROCS/Fucentese 
 Page 31 of 55 
Version 2.0 of 6 June 2017 
Accordingly, the overdrilled socket of the femoral bone tunnel has the following diameter 
depending on the subject’s group assignment:  
 
Intervention group: 9 - 9.5 mm 
 
Control group: 8 – 8.5 mm 
The tibial bone tunnel is drilled at a diameter of 8 ± 1 mm as applicable. 
8.4 Surgical Technique 
The surgical technique under study uses a semitendinosus tendon autograft (combined with 
gracilis tendon if applicable) harvested from the index knee or the contralateral knee according to 
the standard in-house technique. The pes anserinus is visualized through a three centimeter 
incision anteromedially at the proximal tibia. The semitendinosus tendon is harvested with a 
tendon stripper and length and thickness is measured. For the intraarticular procedure, standard 
medial and lateral parapatellar arthroscopy portals are used. After overdrilling with a 4.5 mm drill, 
the final femoral graft tunnel is created by a cannulated drill. Afterwards the tibial tunnel is 
prepared by using a drillguide (Karl Storz, Tuttlingen, Germany) targeted at the center of the tibial 
ACL footprint. The tendon graft is inserted first into the femoral bone tunnel through the medial 
portal. In the femoral tunnel the graft is secured using a flipping device on the cortical bone 
(Flipptack, KarlStorz, Tuttlingen, Germany). Tibial graft-fixation is achieved using an interference 
screw (Megafix, Karl Storz, Tuttlingen, Germany) proximally, and a small plate (Endotack, Karl 
Storz, Tuttlingen, Germany) covering the bone tunnel distally. 
 
 

 
ACLROCS/Fucentese 
 Page 32 of 55 
Version 2.0 of 6 June 2017 
The table below shows a schematic of the surgical techniques for graft fixation under study and 
the material in use. 
Control Intervention 
Experimental Intervention 
1) Femoral cortical fixation: Flipptack (Karl 
Storz) 
2) Femoral Graft suspension: Ethibond 6 
(Ethicon Inc.) 
Suture bone tunnel; diameter: 4.5 mm 
3) Cannulated bone tunnel; diameter: 8 – 
8.5 mm 
Length: 27 mm 
4) Tendon graft 
5) Resorbable interference screw fixation 
(Megafix, Karl Storz) 
6) Tibial bone tunnel; Diameter: 8 – 8.5 mm 
Tibial Graft suspension: Fibre Wire 2 
(Ethicon Inc.) and Ethibond 6 
7) Tibial cortical fixation: Endotack (Karl 
Storz) 
1) Femoral cortical fixation: Flipptack (Karl 
Storz) 
2) Femoral Graft suspension: Ethibond 6 
(Ethicon Inc.) 
Suture bone tunnel; diameter: 4.5 mm 
3) Cannulated bone tunnel; diameter: 9 – 
9.5 mm 
Length: 27 mm 
4) Tendon graft 
5) Resorbable interference screw fixation 
(Megafix, Karl Storz) 
6) Tibial bone tunnel; Diameter: 8 – 8.5 mm 
Tibial Graft suspension: Fibre Wire 2 
(Ethicon Inc.) and Ethibond 6 
7) Tibial cortical fixation: Endotack (Karl 
Storz) 
Black Arrow: Medical device under study 
enlaced into tendon graft. 
 
 

 
ACLROCS/Fucentese 
 Page 33 of 55 
Version 2.0 of 6 June 2017 
8.4.1 Interventional Product 
Brand name 
SmartBone® 
Type 
Block BTB-Converter 
Dimensions 
8x11 mm 
Manufacturer 
Industrie Biomediche Insubri 
Description 
SmartBone® is a composite xeno-hybrid Class III CE marked Medical 
Device, composed of bovine-bone derived porous mineral matrix, 
reinforced with a blend of collagen fragments (in the form of hydrolysed 
gelatine) and biopolymers (i.e. resorbable aliphatic block-co-
polyesters), intended for use in bone regeneration applications in 
reconstructive surgeries. SmartBone® is a long-term implantable, 
resorbable, sterile medical device, which is supplied in different shapes 
and dimensions to best match surgical needs. From big (15 x 30 x 60 
mm3) solid blocks to granulates (1-2 mm and 2-4 mm) to fine microchips 
(0.25-1mm). 
Intended use 
(according to IFU) 
SmartBone® is recommended for reconstructing and filling bone 
defects and for bone augmentation.  
For example, SmartBone® is recommended for filling bone defects and 
for bone augmentation in the following cases: 
 
Augmentation/reconstruction of the alveolar ridge;  
 
Alveolar filling after extraction;  
 
Implants: preparation of the implant bed, filling of the bone 
dehiscences, augmentation of the sinus floor;  
 
Periodontology: filling of bone defects, providing support for the 
membrane in guided tissue regeneration (GTR). 
Intended user and 
patient population 
SmartBone is intended for professional use only. It should be used by 
trained surgeons, e.g. orthopedic surgeons, neurosurgeons, plastic 
surgeons, oral and maxillofacial surgeons and trained dentists. The 
patient population consist of adults (age 18+; skeletally mature 
subjects) with edentulous areas or bone defects. 
CE Declaration of 
Conformity 
Yes 
Device Materials 
Bovine derived matrix: 
 
Calcium hydroxyapatite (Ca5(PO4)3(OH)) 
 
Minor collagen residuals 
Coating: 
 
Poly(L-lactide-co-ε-caprolactone) 
 
Polysaccharides 
8.4.2 Packaging, Labelling and Supply (Re-Supply) 
Upon receipt of the study device supplies, an inventory must be performed and a device receipt 
log filled out and signed by the person accepting the shipment. It is important that the designated 
study staff counts and verifies that the shipment contains all the items noted in the shipment 
inventory. Any damaged or unusable study devices in a given shipment will be documented in the 
study files.  

 
ACLROCS/Fucentese 
 Page 34 of 55 
Version 2.0 of 6 June 2017 
Regular study device reconciliation will be performed to document assigned and used devices. 
This reconciliation will be logged on the device accountability form, and signed and dated by the 
study team. 
8.4.3 Storage Conditions  
The device under study is stored in a secure, limited access area under the recommended storage 
conditions. It is to be stored in its original package in a dry place and away from direct sources of 
light or heat at temperatures between 2 and 25°C. 
8.5 Modifications of Device Application 
Modifications of the device under study or of its application are not planned. 
8.6 Compliance with Study Intervention 
No postsurgical exclusion criteria related to patient compliance are defined. 
8.7 Data Collection and Follow-up for Withdrawn Participants 
For subjects who withdraw from the study prior to completion, the site will attempt to contact the 
subject in order to obtain safety information.  
8.8 Trial Specific Preventive Measures 
In case of complications during ACL-reconstruction using the investigational product, the standard 
technique will be applied. The patient will be excluded from further analysis, the reason for 
exclusion will be recorded. Before every CT-scan, female patients will undergo pregnancy testing. 
Female patients of child bearing potential will have agreed in the informed consent form, to use 
contraception during the first 24 months of the study. 
8.9 Concomitant Intervention(s) 
Allowed concomitant surgical interventions are defined in the inclusion/exclusion criteria and will 
be recorded in the eCRF. No specific postsurgical concomitant rehabilitation therapies are 
prohibited. The patient will be advised to inform the treating physician about the participation in 
the clinical trial in the case he receives treatment - related or unrelated to the intervention under 
study – outside of the study protocol. 
8.10 Medical Device Accountability 
The investigator will maintain records including date of receival, lot number and quantities of the 
medical device under study. 
8.11 Return or Destruction of Medical Device 
At completion of the study, there will be a final reconciliation of devices shipped and used. This 
reconciliation will be logged on the device accountability form, signed and dated. Any 

 
ACLROCS/Fucentese 
 Page 35 of 55 
Version 2.0 of 6 June 2017 
discrepancies noted will be investigated, resolved, and documented prior to return or destruction 
of study devices. Devices destroyed on site will be documented in the study files. 
 
 

 
ACLROCS/Fucentese 
 Page 36 of 55 
Version 2.0 of 6 June 2017 
9 
STUDY ASSESSMENTS 
9.1 Study Flow Chart 
 

 
ACLROCS/Fucentese 
 Page 37 of 55 
Version 2.0 of 6 June 2017 
9.2 Assessments of Outcomes  
9.2.1 Assessment of Primary Outcome  
Bone tunnel volume will be assessed on CT. CT-scanning will be overseen by an experienced 
radiologist. The procedure (including pregnancy testing) is described in more detail in 
ACLROCS_WI_CTScan. The DICOM (Digital Imaging and Communications in Medicine) series 
are converted into a single volume and cropped to include the distal femur. Subsequently, the 
follow-up volumes of each patient are volumetrically registered to the baseline volume by using 
a rigid affine mutual information algorithm [83]. An intensity-based mask of each volume is 
created and cropped to contain only the femoral bone tunnel. The voxel-based volume of each 
follow-up mask is determined and compared to the baseline volume. The procedure is 
described in detail in ACLROCS_WI_FemBoneTunVolCalc. 
9.2.2 Assessment of Secondary Outcomes 
9.2.2.1 Assessment of Patient Subjective Knee Function 
IKDC SKEF, LKSS and TAS are assessed with patient filled eCRFs using online surveys on a 
tablet computer. The procedure is conducted by the SN.  
9.2.2.1.1 IKDC Subjective Knee Evaluation Form 
IKDC SKEF contains a total of 16 items. The responses to each item are scored using an 
ordinal method such that a score of 0 is given to responses that represent the lowest level of 
function or highest level of symptoms. The IKDC SKEF score is calculated by summing the 
scores for the individual items and then transforming the score to a scale that ranges from 0 to 
100. The maximum possible item score is 87. IKDC SKEF score therefore is calculated as 
follows: 
IKDC SKEF Score = Sum of item scores
87
 × 100 
 
 

 
ACLROCS/Fucentese 
 Page 38 of 55 
Version 2.0 of 6 June 2017 
9.2.2.1.2 Lysholm Knee Scoring Scale 
LKSS contains a total of 8 items. Each item response is scored based on the table shown 
below. LKSS score is calculated by summing up all item scores. The range of possible total 
score is [0,100]. 
Symptoms 
Options 
Points 
Hinken 
kein 
5 
leicht oder gelegentlich 
3 
stark oder konstant 
0 
Hilfsmittel 
keine 
5 
Stock oder Unterarmgehstütze 
2 
Belastung unmöglich 
0 
Blockieren 
kein Blockieren und kein Gefühl des Einklemmens 
15 
Gefühl des Einklemmens aber kein Blockieren 
10 
gelegentilches Blockieren 
6 
regelmässiges Blockieren 
2 
blockiertes Gelenk bei der Untersuchung 
0 
Instabilität 
niemals "giving way" (=einknicken) 
25 
selten während des Sports oder anderer starker 
Anstrengung 
20 
regelmässig während des Sports oder anderer  
starker Anstrengung (oder Teilnahme unmöglich) 
15 
gelegentlich bei Alltagsaktivitäten 
10 
oft bei Alltagsaktivitäten 
5 
bei jedem Schritt 
0 
Schmerzen 
keine 
25 
nicht immer und leicht während starker Anstrengung 
20 
deutlich während starker Anstrengung 
15 
deutlich während oder nach mehr als 2 km gehen 
10 
deutlich während oder nach weniger als 2 km gehen 
5 
konstant 
0 
Schwellung 
keine 
10 
bei starker Anstrengung 
6 
bei gewöhnlicher Anstrengung 
2 
konstant 
0 
Treppensteigen 
keine Probleme 
10 
leicht eingeschränkt 
6 
Stufe für Stufe 
2 
unmöglich 
0 
Kniebeugen (in die Hocke 
gehen) 
kein Problem 
5 
leicht eingeschränkt 
4 
nicht mehr als 90° 
2 
unmöglich 
0 
 

 
ACLROCS/Fucentese 
 Page 39 of 55 
Version 2.0 of 6 June 2017 
9.2.2.1.3 Tegner Activity Scale 
TAS contains one item. It is scored based on the following table. At surgery visit (Visit 2), 
preinjury activity score will be assessed. 
Instructions 
Choice 
Score 
Die folgende Frage 
bezieht sich auf Ihr 
Aktivitätsniveau. Bitte 
lesen sie die 
nachfolgende 
Aufstellung durch und 
kreuzen das 
HÖCHSTE Level an, 
das auf Sie zutrifft. 
Fussball 
10 
Eishockey, Ringen, Turnen, Fussball (untere Ligen) 
9 
Skifahren, Badminton, Squash, Leichtathletik (Weitsprung) 
8 
Handball, Tennis, Basketball, Leichtathletik (laufen), 
Querfeldeinlauf / Eishockey, Fussball, Squash, 
Weitsprung, Querfeldeinlauf 
7 
Badminton, Tennis, Basketball, Skifahren, Joggen bis 5x 
die Woche 
6 
Radfahren, Skilanglauf / Joggen auf unebenem Boden 
mind. 2x/Woche / Schwerarbeit (Bauarbeiter) 
5 
Skilanglauf, Radfahren, Joggen auf ebenem Boden mind. 
2x die Woche / Zeitweise schwere Arbeit 
4 
Schwimmen / Schwimmen / Leichte körperliche Arbeiten / 
Gehen auf unebenem Boden 
3 
Kaum körperliche Arbeit / Gehen im Wald unmöglich 
2 
Überwiegend sitzend / Gehen nur auf ebenem Boden 
möglich 
1 
Arbeitsunfähigkeit aufgrund einer Knieverletzung / 
Normales Gehen nicht möglich 
0 
 
9.2.2.2 Assessment of Knee Stability 
KT-1000 Arthrometer-, Lachman- and Pivot-shift testing are performed by the PI. All tests are 
performed first on the involved and secondly on the normal contralateral side. 
 
KT-1000 Arthrometer testing is performed with the patient in supine position on a firm 
examination table. The knee is flexed to an angle between 20° and 35°. The thighs rest on a 
support platform. The KT-1000 Arthrometer testing device is then strapped to the anterior 
aspect of the tibia. After zeroing of the machine, tibial anterior displacement is measured. The 
measurement is performed once, and the results are noted in millimeters on the respective 
eCRF. 
 
Lachman testing is performed by manual anterior displacement of the tibia in 15° flexion. The 
calf is grasped with one hand and quickly pulled anteriorly, while the other hand constrains the 
movement of the thigh. The test is performed once. The results are noted in the respective 
eCRF using the grading system displayed below. 
 
Grade 
Displacement 
0 
<3 mm 
1 
3 - 5 mm 
2 
>5 mm 
 
 
 

 
ACLROCS/Fucentese 
 Page 40 of 55 
Version 2.0 of 6 June 2017 
For Pivot-shift testing, the anteriorly subluxated tibia head is repositioned manually. While a 
manual force is applied for internal rotation, valgisation and axial pressure, the knee is flexed 
manually from full extension. The rolling-gliding motion is assessed. The test is performed once. 
The results are noted in the respective eCRF using the grading system displayed below. 
 
Grade 
Finding 
0 
Normal 
1 
Glide 
2 
Clunk 
3 
Gross clunk with locking 
9.2.3 Plain Radiography assessed Bone Tunnel Widening 
BTW will additionally be assessed on plain radiograph. Bone tunnel width will be assessed at 
the widest part of the femoral bone tunnel. Bone tunnel width is defined as the largest distance 
between the opposing tunnel walls on a line orthogonal to the direction of the bone tunnel. 
Assessed will be the relative change in femoral bone tunnel width from baseline to respective 
follow-up. 
9.2.4 Assessment of Other Outcomes of Interest 
9.2.4.1 Clinical History 
The following information regarding the clinical history of the patient will be gathered using 
eCRF: 
 
Date of the injury 
 
Affected side 
 
Activity at which injury occurred 
 
Mechanism of injury 
 
Comorbidities (if any) 
9.2.4.2 Patient Demographics 
The following information regarding patient demographics will be gathered using eCRF: 
 
Age 
 
Sex 
 
Height 
 
Weight 
 
Body Mass Index 
 
Smoking habit 
9.2.4.3 Assessment during Surgery 
The following information will be gathered at surgery: 
 
Date of surgery 
 
Comorbidities (if any) determined arthroscopically 
 
Additional surgical procedures (if any) not leading to patient exclusion (e.g. partial 
meniscectomy, meniscus repair) 
 
Side of autograft harvest (ipsilateral/contralateral) 
 
Tendon used (semitendinosus tendon with/without Gracilis tendon) 
 
Diameter of the femoral bone tunnel 
 
Diameter of the tibial bone tunnel 
 
Duration of the surgical procedure 

 
ACLROCS/Fucentese 
 Page 41 of 55 
Version 2.0 of 6 June 2017 
9.2.5 Assessment of Safety Outcomes 
9.2.5.1 Adverse Events  
Intra-operative complications (if any) will be recorded on the eCRF. Self-reported AEs will be 
assessed by interviewing the patient. The following question will be used: 
“Hatten Sie im Zusammenhang mit Ihrer Knieoperation irgendwelche nennenswerten 
medizinischen Probleme?” 
Also any out of window visit or unexpected finding will be recorded. The following adverse event 
information will be recorded: 
 
Adverse event term 
 
Date of onset 
 
Date of resolution/Duration 
 
Severity (Subjective assessment by PI) 
 
Seriousness 
 
Relationship with surgical intervention 
 
Relationship with device under study 
 
Actions taken in response 
 
Outcome of the adverse event 
9.2.6 Assessments in Participants Who Prematurely Stop the Study 
Study subjects who withdraw consent to participate or who fail to appear to the scheduled visits 
will be contacted by telephone in order to obtain the interview for self-reported AEs. 
9.3 Procedures at Each Visit 
9.3.1 Screening (Visit 1) 
Eligible patients will be informed about the ongoing study by the PI or by an involved 
practitioner, and will be handed out study patient information including informed consent form. 
9.3.2 Baseline (Visit 2) 
9.3.2.1 Admission Interview 
Eligible Patients giving oral consent to study participation will be interviewed by the SN for 
detailed screening of inclusion/exclusion criteria. A patient information eCRF will be filled 
covering all necessary points for temporary admission of the patient into the study. Definite 
admission can only be acquired after the surgery. The signed informed consent form will be 
validated by signature by the PI and stored in the patient’s trial file. The patient will receive a 
copy of the signed informed consent form. For female patients of child bearing potential, a 
pregnancy test will be performed. The result of the pregnancy test will be photographed and the 
photograph will be signed by the PI and filed. The patient will be given the opportunity to clarify 
all uncertainties concerning the trial and the upcoming surgery with the PI. Also recorded will be 
the medical history and patient demographics. At this stage the preinjury activity level using 
Tegner activity scale will be assessed. 
9.3.2.2 Preoperative Clinical Examination 
Clinical examination will be conducted by the PI. The following information will be recorded in 
the eCRF: 
 
Date of examination. 
 
Intra/Extra-articular effusion. 

 
ACLROCS/Fucentese 
 Page 42 of 55 
Version 2.0 of 6 June 2017 
 
Knee mobility. 
 
Anterior displacement of the affected and of the healthy knee using the Lachman Test 
and the KT-1000 Arthrometer Test. 
 
Online survey for all patient-completed questionnaires (IKDC SKEF, LKSS and TAS) 
 
Rotational stability of both knees using the Pivot shift test. 
9.3.2.3 Surgical Intervention 
9.3.2.3.1 Surgery 
See chapter 8. 
9.3.2.3.2 Randomization 
Patient randomization is acquired intraoperatively only if all inclusion criteria and no exclusion 
criteria have been met. The folded tendon-graft (not sutured, without OCS) must measure 8 – 
8.5 mm in diameter at the end which is to be inserted into the femoral bone tunnel. If no 
intraoperatively assessed exclusion criteria are met (e.g. tendon-graft specifications, severe 
cartilage damage, extensive meniscus resection necessary) the subject is allocated to one of 
the two treatment groups. The envelope for the randomized group allocation of the subject is 
opened and the surgical procedure is carried out respectively. The envelope is sealed again 
afterwards and stored in the patient’s trial file. The randomization procedure is described in 
detail in ACLROCS_WI_Randomization. 
9.3.2.3.1 CT-Scan 
The CT-scan will be performed according to ACLROCS_WI_CTScan.  
9.3.2.3.2 Plain Radiography 
Standard posteroanterior radiographs of the knee in full extension will be performed 
[ACLROCS_WI_PlainRadiography].  
9.3.3 Follow-up 1 (Visit 3) 
Follow-up 1 will be performed 42 days after surgery. The patient will be asked to fill an online 
survey for all patient-completed questionnaires (IKDC SKEF, LKSS and TAS) in the clinic. 
Subsequently, the clinical examination is conducted by the PI recording the identical points as 
during the preoperative clinical examination and the occurrence of any potential AEs. Plain 
radiography measurement is performed according to ACLROCS_WI_PlainRadiography.  
9.3.4 Follow-up 2 (Visit 4) 
Follow-up 2 will be performed equivalently to Follow-up 1. Additionally, CT-scanning is 
performed according to ACLROCS_WI_CTScan. This WI includes pregnancy testing and its 
validation by signature by the PI before the CT-scan. Follow-up 2 will be performed 4.5 months 
after surgery. 
9.3.5 Follow-up 3 (Visit 5) 
Follow-up 3 will be performed equivalently to Follow-up 2. It will be performed 1 year after 
surgery. 

 
ACLROCS/Fucentese 
 Page 43 of 55 
Version 2.0 of 6 June 2017 
9.3.6 Follow-up 4 (Visit 6) 
At Follow-up 4 patient-completed questionnaires and clinical examination will be performed 
equivalently to Follow-up 2 and 3. A plain radiography measurement (pregnancy test) will be 
done. No CT-scan will be performed. It is scheduled 2 years after surgery. 
9.3.7 Follow-up 5 (Visit 7) 
At Follow-up 5 no CT-scan and no plain radiography will be performed. Patient-completed 
questionnaires and clinical examination will be done equivalently to Follow-up 2 and 3. 
Additionally, the study-end eCRF will be filled-out. It is scheduled 5 years after surgery. 
10 SAFETY  
10.1 Medical Device Category A studies 
10.1.1 Definition and Assessment of safety related events 
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury or any untoward clinical signs 
(including an abnormal laboratory finding) in participants, users or other persons whether or not 
related to the investigational medical device [ISO 14155: 3.2]. 
 
Serious Adverse Event (SAE) 
Adverse event that: 
 
results in death, or 
 
led to a serious deterioration in health that either: 
o results in a life-threatening illness or injury, or 
o results in a permanent impairment of a body structure or a body function, or 
o required in-patient or prolonged hospitalisation, or 
o results in medical or surgical intervention to prevent life threatening illness, or 
 
led to fetal distress, death or a congenital abnormality or birth defect. [ISO 14155: 3.37]. 
 
Health hazards that require measures 
Findings that may require additional action are: 
 
Persistent anterior knee pain 
 
Septic arthritis 
 
Arthrofibrosis 
 
Graft rupture 
 
Aseptic effusion 
 
Subcutaneous cyst 
10.1.2 Reporting of Safety related events 
Reporting to Authorities: 
In Category A studies it is the Investigator’s responsibility to report to the local Ethics Committee 
 
Health hazards that require measures within 2 days  

 
ACLROCS/Fucentese 
 Page 44 of 55 
Version 2.0 of 6 June 2017 
11 STATISTICAL METHODS  
11.1 Hypothesis 
Null hypothesis: Both treatments yield the same relative change in bone tunnel volume from 
baseline (Visit 2) to follow-up 3 (Visit 5). 
 
µControl = µIntervention 
 
Alternative hypothesis: The two treatments have a different effect on the primary endpoint after 
entire follow-up 
 
µControl ≠ µIntervention 
11.2 Determination of Sample Size  
For the power calculation a dedicated software (G*Power [84]) was used. It is aimed to detect a 
20% difference in relative change of bone tunnel volume between the two groups. Pooling the 
standard deviations of the percentage volume change of different bone tunnel sections 
(articular/outside third) and two different tunnels (anteromedial/posterolateral tunnel) from the 
study conducted by Araki et al. [85] yields an estimate for the overall standard deviation of 
±25.175%. With a type I error rate of α=0.05 and a power of 1-β = 0.8 and assuming both 
samples to be normally distributed and having equal variances, the required sample size per 
group is n = 25.  
Accounting for a drop-out rate of 10% the total number of subjects for equally sized groups to 
be acquired is N = 56. 
11.2.1 Power calculation of secondary outcome variables 
Based on the calculated sample size above (expected drop-out excluded), power calculations 
for the secondary variables to be used for statistical inference testing are conducted. The table 
below shows the results of the power calculation of primary and secondary outcome variables.  
 
 
Tunnel 
Enlargement 
IKDC 
Subjective 
Knee 
Evaluation 
Form 
Lysholm Knee 
Scoring Scale 
KT-1000 
Arthrometer 
Test 
Lachman 
Test 
Pivot 
Shift 
Test 
Test significance 
level, α 
0.05 
0.05 
0.05 
0.05 
0.05 
 
Assumption of 
distribution 
Normal  
Normal 
Normal 
Non-normal 
Non-
normal 
Non-
normal 
Difference in means 
to be detectable 
|µControl - µIntervention| 
20% [86] 
11.5 [87] 
10 [88] 
2 mm 
0.5 
0.8 
Common standard 
deviation, σ 
25.175% 
[85] 
10 [86] 
7 [86] 
1.7 mm [86] 
0.25 
0.71 
[86] 
Effect size,  
δ = |µControl - 
µIntervention| / σ 
0.7944 
1.15 
1.429 
0.88 
2 
1.13 
Power 
0.8 
0.98 
0.99 
0.84 
0.99 
0.97 
N per group 
(identically sized) 
25 
25 
25 
25 
25 
25 
 

 
ACLROCS/Fucentese 
 Page 45 of 55 
Version 2.0 of 6 June 2017 
11.3 Statistical Criteria of Termination of Trial  
Statistically significant inferiority (P ≤ 0.05) of the interventional treatment determined at 4.5 
months follow-up on the primary efficacy outcome with a total of 20 patients (10 interventional, 
10 control) will lead to premature termination of the study. 
11.4 Planned Analyses  
In all statistical analyses testing a significant difference in central tendency between the two 
groups, significance is set at α = 0.05. All statistical tests will be two-sided. The results of these 
tests will be reported in 95% confidence Interval and p-value for the Student’s t-test and in 
Mann-Whitney U and p-value for the Mann-Whitney U test. 
11.4.1 Datasets to be analyzed, analysis populations 
Statistical analysis is based on the intention-to-treat analysis. In the case of the current trial this 
means that patients not following the rehabilitation protocol will not be excluded from analysis. 
11.4.2 Primary Analysis 
Confirmatory analysis is performed on the null hypothesis of equal relative changes in bone 
tunnel volume from baseline to last CT follow-up (follow-up 3, Visit 5) between the two groups. 
To make appropriate assumptions on the distribution of the data, the Kolmogorov-Smirnov Test 
is used to test for significant departure from normality. Significance is set at α = 0.05. In case 
the assumption of normality holds, a Student’s t-test is performed to test for a significant 
difference in means between the two groups. In case the normality assumption is violated, a 
Mann-Whitney U test is applied. Mean values and standard deviations will be reported. The 
same procedure will be applied on the dataset of the first CT-follow-up (Visit 4) in the mode of a 
supportive analysis. 
11.4.2.1 
Confounder-Controlled Analysis 
Additionally to the analysis described above in a secondary analysis, group differences in 
relative change of bone tunnel volume from baseline to follow-up 2 and from baseline to follow-
up 3 are assessed in an analysis of covariance (ANCOVA)-model, controlling for confounding 
factors. The preliminary model contains the following confounding factors: 
 
Patient sex [89] 
 
Patient age [89] 
 
Preinjury Tegner activity score 
 
Associated bone/meniscus/cartilage-injury (Present/Not Present) 
In a univariate analysis each factor is tested for association with the dependent variable (relative 
change of bone tunnel volume). All factors with association p < 0.2 are then included in a 
preliminary ANCOVA. A stepwise modelling approach is then used where variables with 
association p > 0.05 are excluded. At each exclusion, the model is computed again. The order 
of exclusion of all factors not associated significantly with the dependent variable is opposite to 
the list shown above (i.e. from bottom to top) [90].  
 
11.4.2.2 
Secondary Analyses 
The procedures described hereafter will be applied on all follow-up datasets. Statistical 
significance testing is based on the Null hypothesis of both groups having an equal effect on the 
dependent variables. 

 
ACLROCS/Fucentese 
 Page 46 of 55 
Version 2.0 of 6 June 2017 
11.4.2.3 
Patient Subjective Knee Function 
Mean values and standard deviations of the two groups at the different follow-up assessments 
will be reported. Due to the large number of distinct possible outcome values, the outcome of 
IKDC SKEF and LKSS are treated as continuous data [91]. Group means and standard 
deviations will be reported. If normal distribution can be assumed – tested with the Kolmogorov-
Smirnov Test on an α = 0.05 level - an independent-samples Student’s t-test will be performed 
to detect significant differences between the group means. Otherwise – possibly due to a ceiling 
effect [87] - a Mann-Whitney U test is applied.  
11.4.2.4 
Assessment of Knee Stability 
The side-to-side difference of the KT-1000 Arthrometer Test will be reported in group mean and 
standard deviation. The two group means will be compared with the Mann-Whitney U test.  
The side-to-side difference [86] scores of the Lachman Test and the Pivot Shift Test will be 
reported in frequencies. Statistical inference testing will be done using the Mann-Whitney U test. 
11.4.2.5 
Tegner Activity Scale 
The difference in TAS scores from baseline (pre-injury state) to follow-up will be reported in 
group mean and standard deviation. The two groups will be compared using the Mann-Whitney 
U test. 
11.4.3 Other Outcomes of Interest 
11.4.3.1 
Intra-Patient Comparison of Ossification 
The within-subject differences in femoral vs. tibial relative change in bone tunnel volume will be 
assessed for the interventional patient group. For descriptive statistics, mean and standard 
deviation values will be reported. For statistical inference testing, the null hypothesis in this 
setup is a mean difference in femoral vs. tibial relative change in bone tunnel volume equal to 
zero. If the normality assumption holds (Kolmogorov-Smirnov Test), a paired t test is applied to 
test for a significant two-sided departure from zero. Otherwise, a Wilcoxon signed-rank test will 
be used. 
11.4.4 Plain Radiography assessed Bone Tunnel Widening 
Radiographically assessed relative change of femoral bone tunnel width will be reported in 
group-mean values and in group standard deviation. Inter-group comparison will be performed 
using Student’s t-test based on the relative change of femoral bone tunnel width at each 
assessed time point. 
11.4.5 Interim analysis 
An interim analysis will be conducted when the first 10 interventional patients have reached 4.5 
months follow-up (Visit 4). All available data will be assessed, analyzed and evaluated 
equivalently to the full data analysis. To mitigate the risk for type II error, stopping criteria only 
include the primary outcome variable. Statistically significant (P ≤ 0.05) inferiority of the 
interventional treatment in the primary outcome variable will lead to premature termination of the 
trial. 
11.4.6 Safety Analysis 
Safety will be evaluated by tabulations of AE’s and SAE‘s and will be presented with descriptive 
statistics at baseline and follow-up visits for each treatment group. Inferential analyses of 
(serious) adverse events are not done. 

 
ACLROCS/Fucentese 
 Page 47 of 55 
Version 2.0 of 6 June 2017 
11.4.7 Deviation(s) from the Original Statistical Plan  
All deviations from the original statistical analysis plan will be provided in the final clinical study 
report. 
11.5 Handling of Missing Data  
Missing data will be left missing, i.e. no imputation scheme will be used. All data from a subject 
will be used for analysis, irrespective of possibly missing values. 
11.6 Handling of Drop-Outs  
Drop-outs are accounted for in the sample size calculation. Therefore no additional replacement 
of drop-out is planned. 
12 DATA QUALITY ASSURANCE AND CONTROL 
The Sponsor-Investigator is implementing and maintaining quality assurance and quality control 
systems with written SOPs and Working Instructions to ensure that trials are conducted and 
data are generated, documented (record), and reported in compliance with the investigation 
plan, ISO EN 14155, and applicable regulatory requirement(s).  
Monitoring and Audits will be conducted during the course of the study for quality assurance 
purposes. 
12.1 Data Handling and Record Keeping / Archiving 
The study will strictly follow the investigation plan. If any changes become necessary, they must 
be laid down in an amendment to the investigation plan. All amendments of the investigation plan 
must be signed by the Sponsor-Investigator and submitted to CEC.  
12.1.1 Case Report Forms  
In the current study, eCRFs based on the data capture software REDCap [92] will be used. The 
software meets the requirements of good clinical practice. It is the responsibility of the PI to 
ensure correctness and completeness of the recorded data. After data recording, all data must 
be entered into eCRF as soon as possible. The name of the patient will not be visible in the 
eCRF. Personal data is encoded using a subject identifier. Study-related patient documentation 
and the signed informed consent form is to be stored in a patient specific folder. All data in the 
eCRF must be noted in the patient’s medical file. All essential documents of the trial must be 
stored for a minimal duration of 15 years starting from study close-out. Patient’s medical files 
must be stored for the maximum duration applicable at the clinic. The subject identifier key is 
stored in form of an enrolment-log on a different server than the eCRFs. Access is password 
restricted. 
12.1.2 Specification of Source Documents 
The following documents are considered source data, including but not limited to: 
• SAE worksheets 

 
ACLROCS/Fucentese 
 Page 48 of 55 
Version 2.0 of 6 June 2017 
• Nurse records, records of clinical coordinators, and  
• Medical records from other department(s), or other hospital(s), or discharge letters and 
correspondence with other departments/hospitals, if participant visited any during the study 
period and the post study period.  
Source data must be available at the site to document the existence of the study participants 
and substantiate the integrity of study data collected. Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
participant. 
The following information (at least but not limited to) should be included in the source 
documents: 
• Demographic data (age, sex) 
• Inclusion and Exclusion Criteria details  
• Participation in study and signed and dated Informed Consent Forms  
• Visit dates  
• Medical history and physical examination details  
• Key efficacy and safety data (as specified in the investigation plan)  
• AEs and concomitant medication  
• Results of relevant examinations  
• Laboratory printouts  
• Dispensing and return of study device details  
• Reason for premature discontinuation  
• Randomization number 
12.1.3 Record Keeping / Archiving  
All essential documents of the clinical trial will be stored for a duration of at least 15 years. 
Patient medical files and other source data will be stored for the maximal time allowed by the 
University Hospital Balgrist. Printed patient medical files will be archived in an access restricted 
area. The patient medical file software (KISIM) and the study data capture software (REDCap) 
are access restricted. 
12.2 Data Management  
12.2.1 Data Management System, access and back-up 
Subject-related data will be stored in the research electronic data capture software REDCap 
[92]. The PI is responsible for data recording. The PI will grant the relevant personnel user 
rights to view, edit or overwrite data entries by password as applicable. All edits will be 
automatically documented in the change history log.  
 
12.2.2 Analysis and Archiving 
For data analysis, subject-related data from REDCap will be exported and analyzed in statistics 
software (IBM - SPSS). Before data export, all patient identifiers will be removed. CT- and 
radiographic images will be analyzed using image analysis software (3D Slicer [83], MATLAB). 
All eCRF data will be stored for a minimum of 15 years in a safe storage facility at an external 
location. In-house archiving of research related data and responsibilities are outlined in the clinic’s 
WI: UCAR_WI_013_Archiving_01. 

 
ACLROCS/Fucentese 
 Page 49 of 55 
Version 2.0 of 6 June 2017 
12.3 Monitoring 
Regular monitoring visits at the investigator’s site prior to the start and during the course of the 
study will help to follow up the progress of the clinical study, to assure utmost accuracy of the 
data and to detect possible errors at an early time point. The Sponsor-Investigator organizes 
professional independent monitoring for the study.  
All original data including all patient files, progress notes and copies of laboratory and medical 
test results must be available for monitoring. The monitor will review all or a part of the eCRFs 
and written informed consents. The accuracy of the data will be verified by reviewing the above 
referenced documents.  
A quality assurance audit/inspection of this study may be conducted by the competent authority 
or CEC, respectively. The quality assurance auditor/inspector will have access to all medical 
records, the investigator's study related files and correspondence, and the informed consent 
documentation that is relevant to this clinical study. 
The investigator will allow the persons being responsible for the audit or the inspection to have 
access to the source data/documents and to answer any questions arising. All involved parties 
will keep the patient data strictly confidential. 
12.4 Confidentiality, Data Protection  
Direct access to source data may be granted in the case of monitoring, audit or inspections. All 
personnel must treat patient data as confidential. As far as possible, encoded data will be used. 
Only persons listed on the staff list have access to the source data. 
12.5 Storage of Related Health Data  
All health-related patient data will be stored and archived in the data capture software REDCap. 
Patient-source data will be registered using subject identifiers. After full data analysis, all subject 
identifiers will be erased. Patient-source data may still be saved in the patient’s medical record. 
Collection, disclosure, storage of patient-related data are carried out in accordance with Swiss 
data protection regulations and the Human Research Act. A requirement is the informed 
consent of every subject prior to inclusion in the clinical trial.  
13 PUBLICATION AND DISSEMINATION POLICY  
The sponsor-Investigator will make every effort to publish the data of the interim analysis, the 
primary endpoint analysis and the full data analysis in a peer-reviewed medical journal. No 
statistical codes or record IDs of study participants will be published. No trade secrets will be 
disclosed. 
14 FUNDING AND SUPPORT  
This study will mainly be financed by ZuriMED Technologies AG.  

 
ACLROCS/Fucentese 
 Page 50 of 55 
Version 2.0 of 6 June 2017 
15 INSURANCE 
The trial is covered by insurance by “Winterthur Versicherung” (Insurance number: 14.050.565). 
The insurance certificate is deposited at the cantonal ethics committee. For insurance coverage, 
patients must follow the instructions by the PI. The patient must report the occurrence of any 
health related complication to the PI. In such a case, as far as necessary, representatives of the 
insurance company may be granted access to the health-related patient data.  
 
 

 
ACLROCS/Fucentese 
 Page 51 of 55 
Version 2.0 of 6 June 2017 
16 REFERENCES 
1. 
Clayton, R.A. and C.M. Court-Brown, The epidemiology of musculoskeletal tendinous and 
ligamentous injuries. Injury, 2008. 39(12): p. 1338-44. 
2. 
freeman, J.W.K., A.L, Recent Advancements in Ligament Tissue Engineering: The Usw of 
Various Techniques and Materials for ACL Repair. Recent Pat. Biomed. Eng, 2008. 1: p. 6. 
3. 
Majewski, M., H. Susanne, and S. Klaus, Epidemiology of athletic knee injuries: A 10-year study. 
Knee, 2006. 13(3): p. 184-188. 
4. 
Junkin, D., et al., Knee ligament injuries. Orthopaedic knowledge update: sports medicine. 
Rosemont, IL: American Academy of Orthopaedic Surgeons. p, 2009. 136. 
5. 
Fithian, D.C., et al., Prospective trial of a treatment algorithm for the management of the anterior 
cruciate ligament-injured knee. Am J Sports Med, 2005. 33(3): p. 335-46. 
6. 
Samuelsson, K., et al., Trends in surgeon preferences on anterior cruciate ligament 
reconstructive techniques. Clinics in Sports Medicine, 2013. 32(1): p. 111-126. 
7. 
Nandra, R., et al., A review of anterior cruciate ligament injuries and reconstructive techniques. 
Part 1: Basic science. Trauma, 2013. 
8. 
Miller, S.L. and J.N. Gladstone, Graft selection in anterior cruciate ligament reconstruction. 
Orthopedic Clinics of North America, 2002. 33(4): p. 675-+. 
9. 
Lipscomb, A.B., Evaluation of hamstring strength following use of semitendinosus and gracilis 
tendons to reconstruct the anterior cruciate ligament. The American journal of sports medicine, 
1982. 10: p. 340-342. 
10. 
Karlsson, J., et al., Anatomic single- and double-bundle anterior cruciate ligament reconstruction, 
part 2: clinical application of surgical technique. Am J Sports Med, 2011. 39(9): p. 2016-26. 
11. 
Magnussen, R.A., et al., Cross-cultural comparison of patients undergoing ACL reconstruction in 
the United States and Norway. Knee Surg Sports Traumatol Arthrosc, 2010. 18(1): p. 98-105. 
12. 
Whitehead, T.S., Failure of anterior cruciate ligament reconstruction. Clin Sports Med, 2013. 
32(1): p. 177-204. 
13. 
Hollis, R., et al., Autologous bone effects on femoral tunnel widening in hamstring anterior 
cruciate ligament reconstruction. J Knee Surg, 2009. 22(2): p. 114-9. 
14. 
Choi, N.H., et al., Femoral tunnel widening after hamstring anterior cruciate ligament 
reconstruction with bioabsorbable transfix. Am J Sports Med, 2012. 40(2): p. 383-7. 
15. 
Nebelung, S., et al., High incidence of tunnel widening after anterior cruciate ligament 
reconstruction with transtibial femoral tunnel placement. Arch Orthop Trauma Surg, 2012. 
132(11): p. 1653-63. 
16. 
Iorio, R., et al., Bone tunnel enlargement after ACL reconstruction using autologous hamstring 
tendons: a CT study. Int Orthop, 2007. 31(1): p. 49-55. 
17. 
Baumfeld, J.A., et al., Tunnel widening following anterior cruciate ligament reconstruction using 
hamstring autograft: a comparison between double cross-pin and suspensory graft fixation. Knee 
Surg Sports Traumatol Arthrosc, 2008. 16(12): p. 1108-13. 
18. 
Nakase, J., et al., Grafted tendon healing in femoral and tibial tunnels after anterior cruciate 
ligament reconstruction. J Orthop Surg (Hong Kong), 2014. 22(1): p. 65-9. 
19. 
Freedman, K.B., et al., Arthroscopic anterior cruciate ligament reconstruction: A metaanalysis 
comparing patellar tendon and hamstring tendon autografts. American Journal of Sports 
Medicine, 2003. 31(1): p. 2-11. 
20. 
Goldblatt, J.P., et al., Reconstruction of the anterior cruciate ligament: Meta-analysis of patellar 
tendon versus hamstring tendon autograft. Arthroscopy-the Journal of Arthroscopic and Related 
Surgery, 2005. 21(7): p. 791-803. 
21. 
Hospodar, M.S.J. and M.D. Miller, Controversies in ACL reconstruction: bone-patellar tendon-
bone anterior cruciate ligament reconstruction remains the gold standard. Sports Medicine and 
Arthroscopy Review, 2009. 17(4): p. 242-246. 
22. 
Sherman, O.H. and M.B. Banffy, Anterior cruciate ligament reconstruction: which graft is best? 
Arthroscopy, 2004. 20(9): p. 974-80. 
23. 
Chambat, P., et al., The evolution of ACL reconstruction over the last fifty years. Int Orthop, 2013. 
37(2): p. 181-6. 
24. 
Suzuki, T., et al., Early integration of a bone plug in the femoral tunnel in rectangular tunnel ACL 
reconstruction with a bone-patellar tendon-bone graft: a prospective computed tomography 
analysis. Knee Surg Sports Traumatol Arthrosc, 2011. 19 Suppl 1: p. S29-35. 

 
ACLROCS/Fucentese 
 Page 52 of 55 
Version 2.0 of 6 June 2017 
25. 
Carmichael, J.R. and M.J. Cross, Why bone–patella tendon–bone grafts should still be 
considered the gold standard for anterior cruciate ligament reconstruction. British Journal of 
Sports Medicine, 2009. 43(5): p. 323-325. 
26. 
Foster, T.E., et al., Does the graft source really matter in the outcome of patients undergoing 
anterior cruciate ligament reconstruction? An evaluation of autograft versus allograft 
reconstruction results: a systematic review. Am J Sports Med, 2010. 38(1): p. 189-99. 
27. 
Lei, J. and J.S. Temenoff, Engineering Fibrous Tissues and Their Interfaces with Bone, in 
Structural Interfaces and Attachments in Biology. 2013, Springer. p. 323-349. 
28. 
He, P., et al., In Vitro Ligament–Bone Interface Regeneration Using a Trilineage Coculture 
System on a Hybrid Silk Scaffold. Biomacromolecules, 2012. 13(9): p. 2692-2703. 
29. 
Soon, M.Y.H., et al., An analysis of soft tissue allograft anterior cruciate ligament reconstruction 
in a rabbit model - A short-term study of the use of mesenchymal stem cells to enhance tendon 
osteointegration. American Journal of Sports Medicine, 2007. 35(6): p. 962-971. 
30. 
Lim, J.K., et al., Enhancement of tendon graft osteointegration using mesenchymal stem cells in 
a rabbit model of anterior cruciate ligament reconstruction. Arthroscopy-the Journal of 
Arthroscopic and Related Surgery, 2004. 20(9): p. 899-910. 
31. 
Wen, C.Y., et al., The Use of Brushite Calcium Phosphate Cement for Enhancement of Bone-
Tendon Integration in an Anterior Cruciate Ligament Reconstruction Rabbit Model. Journal of 
Biomedical Materials Research Part B-Applied Biomaterials, 2009. 89B(2): p. 466-474. 
32. 
Huangfu, X.Q. and J.Z. Zhao, Tendon-bone healing enhancement using injectable tricalcium 
phosphate in a dog anterior cruciate ligament reconstruction model. Arthroscopy-the Journal of 
Arthroscopic and Related Surgery, 2007. 23(5): p. 455-462. 
33. 
Swetha, M., et al., Biocomposites containing natural polymers and hydroxyapatite for bone tissue 
engineering. International Journal of Biological Macromolecules, 2010. 47(1): p. 1-4. 
34. 
Dorozhkin, S.V., Bioceramics of calcium orthophosphates. Biomaterials, 2010. 31(7): p. 1465-
1485. 
35. 
Farshad, M., et al., Embossing of a screw thread and TCP granules enhances the fixation 
strength of compressed ACL grafts with interference screws. Knee Surgery, Sports 
Traumatology, Arthroscopy, 2012. 20(2): p. 268-274. 
36. 
Shi, P., et al., Variation of the effect of calcium phosphate enhancement of implanted silk fibroin 
ligament bone integration. Biomaterials, 2013. 
37. 
Pertici, G., et al., Composite Polymer-Coated Mineral Scaffolds for Bone Regeneration: From 
Material Characterization to Human Studies. J Biol Regul Homeost Agents, 2015. 29(3 Suppl 1): 
p. 136-48. 
38. 
Webster, K.E., J.A. Feller, and K.A. Hameister, Bone tunnel enlargement following anterior 
cruciate ligament reconstruction: a randomised comparison of hamstring and patellar tendon 
grafts with 2-year follow-up. Knee Surg Sports Traumatol Arthrosc, 2001. 9(2): p. 86-91. 
39. 
Zysk, S.P., et al., Tunnel enlargement and changes in synovial fluid cytokine profile following 
anterior cruciate ligament reconstruction with patellar tendon and hamstring tendon autografts. 
Knee Surg Sports Traumatol Arthrosc, 2004. 12(2): p. 98-103. 
40. 
Wilson, T.C., et al., Tunnel enlargement after anterior cruciate ligament surgery. Am J Sports 
Med, 2004. 32(2): p. 543-9. 
41. 
Stolarz, M., et al., Bone tunnel enlargement following hamstring anterior cruciate ligament 
reconstruction: a comprehensive review. Phys Sportsmed, 2016: p. 1-10. 
42. 
Segawa, H., et al., Bone tunnel enlargement after anterior cruciate ligament reconstruction using 
hamstring tendons. Knee Surg Sports Traumatol Arthrosc, 2001. 9(4): p. 206-10. 
43. 
Nebelung, W., et al., Bone tunnel enlargement after anterior cruciate ligament reconstruction with 
semitendinosus tendon using Endobutton fixation on the femoral side. Arthroscopy, 1998. 14(8): 
p. 810-5. 
44. 
Singhal, M.C., et al., MRI evaluation of the tibial tunnel/screw/tendon interface after ACL 
reconstruction using a bioabsorbable interference screw. Orthopedics, 2008. 31(6): p. 575-9. 
45. 
Fules, P.J., et al., Evaluation of tibial bone tunnel enlargement using MRI scan cross-sectional 
area measurement after autologous hamstring tendon ACL replacement. Knee, 2003. 10(1): p. 
87-91. 
46. 
Robinson, J., et al., Reduced bone tunnel enlargement post hamstring ACL reconstruction with 
poly-L-lactic acid/hydroxyapatite bioabsorbable screws. Knee, 2006. 13(2): p. 127-31. 
47. 
Fahey, M. and P.A. Indelicato, Bone Tunnel Enlargement after Anterior Cruciate Ligament 
Replacement. American Journal of Sports Medicine, 1994. 22(3): p. 410-414. 
48. 
Jansson, K.A., et al., Bone tunnel enlargement after anterior cruciate ligament reconstruction with 
the hamstring autograft and endobutton fixation technique. A clinical, radiographic and magnetic 

 
ACLROCS/Fucentese 
 Page 53 of 55 
Version 2.0 of 6 June 2017 
resonance imaging study with 2 years follow-up. Knee Surg Sports Traumatol Arthrosc, 1999. 
7(5): p. 290-5. 
49. 
Marchant, M.H., Jr., et al., Comparison of plain radiography, computed tomography, and 
magnetic resonance imaging in the evaluation of bone tunnel widening after anterior cruciate 
ligament reconstruction. Knee Surg Sports Traumatol Arthrosc, 2010. 18(8): p. 1059-64. 
50. 
Webster, K.E., et al., A comparison of bone tunnel measurements made using computed 
tomography and digital plain radiography after anterior cruciate ligament reconstruction. 
Arthroscopy, 2004. 20(9): p. 946-50. 
51. 
Barth, J., et al., Efficacy of Osteoconductive Ceramics in Bioresorbable Screws for Anterior 
Cruciate Ligament Reconstruction: A Prospective Intrapatient Comparative Study. Orthop J 
Sports Med, 2016. 4(5): p. 2325967116647724. 
52. 
Lind, M., J. Feller, and K.E. Webster, Tibial bone tunnel widening is reduced by 
polylactate/hydroxyapatite interference screws compared to metal screws after ACL 
reconstruction with hamstring grafts. Knee, 2009. 16(6): p. 447-451. 
53. 
Cox, C.L., et al., Do Newer-Generation Bioabsorbable Screws Become Incorporated into Bone at 
Two Years After ACL Reconstruction with Patellar Tendon Graft? A Cohort Study. Journal of 
Bone and Joint Surgery-American Volume, 2014. 96a(3): p. 244-250. 
54. 
Carusi G. , S.M., Sclilla M., Tecnica MISE - Procedure Chirurgiche. 2016, Italy: EDRA Ed. 
55. 
D'Alessandro, D., et al., Bovine bone matrix/poly(l-lactic-co-epsilon-caprolactone)/gelatin hybrid 
scaffold (SmartBone(R)) for maxillary sinus augmentation: A histologic study on bone 
regeneration. Int J Pharm, 2016. 
56. 
Kim, S.J., et al., Bone tunnel widening with autogenous bone plugs versus bioabsorbable 
interference screws for secondary fixation in ACL reconstruction. J Bone Joint Surg Am, 2013. 
95(2): p. 103-8. 
57. 
Jagodzinski, M., et al., Biodegradable screw versus a press-fit bone plug fixation for hamstring 
anterior cruciate ligament reconstruction: a prospective randomized study. Am J Sports Med, 
2010. 38(3): p. 501-8. 
58. 
Konan, S. and F.S. Haddad, A clinical review of bioabsorbable interference screws and their 
adverse effects in anterior cruciate ligament reconstruction surgery. Knee, 2009. 16(1): p. 6-13. 
59. 
Tecklenburg, K., et al., Prospective evaluation of patellar tendon graft fixation in anterior cruciate 
ligament reconstruction comparing composite bioabsorbable and allograft interference screws. 
Arthroscopy-the Journal of Arthroscopic and Related Surgery, 2006. 22(9): p. 993-999. 
60. 
Dargel, J., et al., Biomechanics of the anterior cruciate ligament and implications for surgical 
reconstruction. Strategies Trauma Limb Reconstr, 2007. 2(1): p. 1-12. 
61. 
Chen, C.H., Graft healing in anterior cruciate ligament reconstruction. Sports Med Arthrosc 
Rehabil Ther Technol, 2009. 1(1): p. 21. 
62. 
Ekdahl, M., et al., Graft healing in anterior cruciate ligament reconstruction. Knee Surg Sports 
Traumatol Arthrosc, 2008. 16(10): p. 935-47. 
63. 
Saltybaeva, N., et al., Estimates of effective dose for CT scans of the lower extremities. 
Radiology, 2014. 273(1): p. 153-9. 
64. 
Swissethics. Table of effective radiation dose per radiological examination.  27.04.2017]; 
Available from: http://www.swissethics.ch/BASEC_assets/dose_table.xls. 
65. 
Cross, T., Diagnostic imaging: radiation exposure and safety considerations. Medicine Today, 
2012. 13(9): p. 72 - 76. 
66. 
Ghazikhanian, V., et al., Tibial tunnel and pretibial cysts following ACL graft reconstruction: MR 
imaging diagnosis. Skeletal Radiol, 2012. 41(11): p. 1375-9. 
67. 
Martinek, V. and N.F. Friederich, Tibial and pretibial cyst formation after anterior cruciate ligament 
reconstruction with bioabsorbable interference screw fixation. Arthroscopy, 1999. 15(3): p. 317-
20. 
68. 
Marchant, M.H., et al., Comparison of plain radiography, computed tomography, and magnetic 
resonance imaging in the evaluation of bone tunnel widening after anterior cruciate ligament 
reconstruction. Knee Surgery Sports Traumatology Arthroscopy, 2010. 18(8): p. 1059-1064. 
69. 
Rossi, M.J., J.H. Lubowitz, and D. Guttmann, Development and validation of the International 
Knee Documentation Committee Subjective Knee Form. Am J Sports Med, 2002. 30(1): p. 152. 
70. 
Lysholm, J. and J. Gillquist, Evaluation of knee ligament surgery results with special emphasis on 
use of a scoring scale. Am J Sports Med, 1982. 10(3): p. 150-4. 
71. 
Tegner, Y. and J. Lysholm, Rating systems in the evaluation of knee ligament injuries. Clin 
Orthop Relat Res, 1985(198): p. 43-9. 

 
ACLROCS/Fucentese 
 Page 54 of 55 
Version 2.0 of 6 June 2017 
72. 
Wirth, B., F. Liffert, and E.D. de Bruin, Development and evaluation of a German version of the 
Lysholm score for measuring outcome after anterior cruciate ligament injuries. Sportverletz 
Sportschaden, 2011. 25(1): p. 37-43. 
73. 
Kowalk, D.L., et al., Quantitative analysis of the measuring capabilities of the KT-1000 knee 
ligament arthrometer. Am J Sports Med, 1993. 21(5): p. 744-7. 
74. 
Torg, J.S., W. Conrad, and V. Kalen, Clinical diagnosis of anterior cruciate ligament instability in 
the athlete. Am J Sports Med, 1976. 4(2): p. 84-93. 
75. 
Ayeni, O.R., et al., Pivot shift as an outcome measure for ACL reconstruction: a systematic 
review. Knee Surg Sports Traumatol Arthrosc, 2012. 20(4): p. 767-77. 
76. 
Cheung, P., et al., Femoral tunnel widening after quadrupled hamstring anterior cruciate ligament 
reconstruction. J Orthop Surg (Hong Kong), 2010. 18(2): p. 198-202. 
77. 
Chen, B.C., et al., [The incidence and variation of tunnel enlargement after anterior cruciate 
ligament reconstruction]. Zhonghua Wai Ke Za Zhi, 2007. 45(2): p. 78-81. 
78. 
Jo, H., et al., Tibial tunnel area changes following arthroscopic anterior cruciate ligament 
reconstructions with autogenous patellar tendon graft. Knee Surg Sports Traumatol Arthrosc, 
2004. 12(4): p. 311-6. 
79. 
Buck, D.C., et al., Timeline of tibial tunnel expansion after single-incision hamstring anterior 
cruciate ligament reconstruction. Arthroscopy, 2004. 20(1): p. 34-6. 
80. 
Arneja, S. and J. Leith, Review article: Validity of the KT-1000 knee ligament arthrometer. J 
Orthop Surg (Hong Kong), 2009. 17(1): p. 77-9. 
81. 
Outerbridge, R.E., The etiology of chondromalacia patellae. 1961. Clin Orthop Relat Res, 
2001(389): p. 5-8. 
82. 
Altman, R.D. and G.E. Gold, Atlas of individual radiographic features in osteoarthritis, revised. 
Osteoarthritis Cartilage, 2007. 15 Suppl A: p. A1-56. 
83. 
Fedorov, A., et al., 3D Slicer as an image computing platform for the Quantitative Imaging 
Network. Magn Reson Imaging, 2012. 30(9): p. 1323-41. 
84. 
Faul, F., et al., G*Power 3: A flexible statistical power analysis program for the social, behavioral, 
and biomedical sciences. Behavior Research Methods, 2007. 39(2): p. 175-191. 
85. 
Araki, D., et al., Three-dimensional analysis of bone tunnel changes after anatomic double-
bundle anterior cruciate ligament reconstruction using multidetector-row computed tomography. 
Am J Sports Med, 2014. 42(9): p. 2234-41. 
86. 
Bourke, H.E., et al., Randomized controlled trial of osteoconductive fixation screws for anterior 
cruciate ligament reconstruction: a comparison of the Calaxo and Milagro screws. Arthroscopy, 
2013. 29(1): p. 74-82. 
87. 
Collins, N.J., et al., Measures of knee function: International Knee Documentation Committee 
(IKDC) Subjective Knee Evaluation Form, Knee Injury and Osteoarthritis Outcome Score 
(KOOS), Knee Injury and Osteoarthritis Outcome Score Physical Function Short Form (KOOS-
PS), Knee Outcome Survey Activities of Daily Living Scale (KOS-ADL), Lysholm Knee Scoring 
Scale, Oxford Knee Score (OKS), Western Ontario and McMaster Universities Osteoarthritis 
Index (WOMAC), Activity Rating Scale (ARS), and Tegner Activity Score (TAS). Arthritis Care 
Res (Hoboken), 2011. 63 Suppl 11: p. S208-28. 
88. 
Chuang, L.H., A. Garratt, and S. Brealey, Comparative responsiveness and minimal change of 
the Knee Quality of Life 26-item (KQoL-26) questionnaire. Qual Life Res, 2013. 22(9): p. 2461-75. 
89. 
Weber, A.E., et al., Tibial and Femoral Tunnel Changes After ACL Reconstruction A Prospective 
2-Year Longitudinal MRI Study. American Journal of Sports Medicine, 2015. 43(5): p. 1147-1156. 
90. 
Spencer, F.A., et al., Association of statin therapy with outcomes of acute coronary syndromes: 
the GRACE study. Ann Intern Med, 2004. 140(11): p. 857-66. 
91. 
Walters, S.J., Sample size and power estimation for studies with health related quality of life 
outcomes: a comparison of four methods using the SF-36. Health Qual Life Outcomes, 2004. 2: 
p. 26. 
92. 
Harris, P.A., et al., Research electronic data capture (REDCap)--a metadata-driven methodology 
and workflow process for providing translational research informatics support. J Biomed Inform, 
2009. 42(2): p. 377-81. 
 

 
ACLROCS/Fucentese 
 Page 55 of 55 
Version 2.0 of 6 June 2017 
17 APPENDICES 
 
Instructions for use SmartBone 
 
TechInfos SmartBone 
 
EC Certfificate SmartBone