Sterile Allogeneic Spongioflex® Allograft as Partial Meniscal Replacement After Incomplete Meniscal Loss, an Investigator-initiated Low Interventional Trial.
Phase: NA
Conditions: Meniscus Lesion
Sponsor: Sven Behrendt

 
Sterile allogeneic 
Spongioflex® allograft as 
partial meniscal replacement 
after incomplete meniscal 
loss, an investigator-initiated 
trial. 
Study protocol from  
January 5th 2024 
NCT06376422 

Protocol Spongioflex® Behrendt 
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Protocol Full Title:            Sterile allogeneic Spongioflex® allograft as partial meniscal 
replacement after incomplete meniscal loss, an investigator-initiated 
trial. 
Protocol Number:            EU-CT-2023-508271-36-00 
Version:                             Version 5 (Version 1-4 was an own template) 
Amendment Number:      Not Applicable 
Amendment Scope:          Not applicable 
Compound Number(s):  SUB184038 
Compounds Name(s):     Human Cancellous Bone (Spongioflex®)   
Trial Phase:                   Phase 4, Post-market authorization safety and efficacy study 
Short Title:                    Spongioflex® for partial meniscal replacement 
Sponsor Name and           Dr. Sven Behrendt 
                Address:       Praxis für Knie- und Schulterchirurgie 
                                   Hoher Wall 14 
                                   44137 Dortmund 
                                   Deutschland 
                                   Tel.: 0231 8626064 
Manufacturer Name  
and Address                     The Manufacturer of the substance is different from the sponsor 
                                          DIZG (Deutsches Institut für ZeII- und Gewebeersatz) 
                                          gemeinnützige GmbH 
                                          Haus 42 
                                          Köpenicker Str. 325 
                                          D-12555 Berlin 
                                          Deutschland
Regulatory Agency 
Identifier Number(s)        EU Trial Number: EU-CT-2023-508271-36-00    
Sponsor approval Date     Sponsor is identical with Investigator 
Sponsor/investigator Signatory 
 
Dr. Sven Behrendt 
 
 
 
 
 
05. Jan. 2024 
Principal Investigator and Sponsor 
 
Medical Monitor Name and Contact Information: 
Medical Monitor Institution will be selected dependent on availability after approval of the study. 
 
Report Serious Adverse Events within 24 hours via E-mail 
E-mail: s.behrendt@dokom.net 

Protocol Spongioflex® Behrendt 
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Table of Contents 
 
1 
PROTOCOL SUMMARY ................................................................................................................ 6 
1.1 
Protocol Synopsis ....................................................................................................................... 6 
1.2 
Trial Schema .............................................................................................................................. 7 
1.3 
Schedule of Activities ................................................................................................................ 8 
2 
INTRODUCTION ............................................................................................................................. 9 
2.1 
Purpose of Trial .......................................................................................................................... 9 
2.2 
Summary of Benefits and Risks ............................................................................................... 11 
3 
TRIAL OBJECTIVES, ENDPOINTS AND ESTIMANDS ........................................................... 14 
3.1 
Primary Objective + Associated Endpoint and Estimand ........................................................ 14 
3.2 
Secondary Objective + Associated Endpoint and Estimand .................................................... 14 
3.3 
Exploratory Objective + Associated Endpoint and Estimand.................................................. 15 
4 
TRIAL DESIGN .............................................................................................................................. 16 
4.1 
Description of Trial Design ...................................................................................................... 16 
4.2 
Rationale for Trial Design ....................................................................................................... 16 
4.2.1 
Rationale for Comparator ................................................................................................. 17 
4.2.2 
Rationale for Adaptive or Novel Trial Design ................................................................. 17 
4.2.3 
Other Trial Design Considerations ................................................................................... 17 
4.3 
Access to Trial Intervention After End of Trial ....................................................................... 17 
4.4 
Start of Trial and End of Trial .................................................................................................. 17 
5 
TRIAL POPULATION ................................................................................................................... 19 
5.1 
Selection of Trial Population ................................................................................................... 19 
5.2 
Rationale for Trial Population.................................................................................................. 19 
5.3 
Inclusion Criteria...................................................................................................................... 19 
5.4 
Exclusion Criteria .................................................................................................................... 19 
5.5 
Lifestyle Considerations .......................................................................................................... 20 
5.5.1 
Meals and Dietary Restrictions ......................................................................................... 20 
5.5.2 
Caffeine, Alcohol, Tobacco, and Other Habits ................................................................ 20 
5.5.3 
Physical Activity ............................................................................................................... 20 
5.5.4 
Other Activity ................................................................................................................... 20 
5.6 
Screen Failures ......................................................................................................................... 20 
6 
TRIAL INTERVENTION AND CONCOMITANT THERAPY ................................................... 21 
6.1 
Description of Trial Intervention ............................................................................................. 21 
6.2 
Rationale for Trial Intervention ............................................................................................... 22 

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6.3 
Dosing and Administration ...................................................................................................... 22 
6.3.1 
Trial Intervention Dose Modification ............................................................................... 22 
6.4 
Treatment of Overdose............................................................................................................. 22 
6.5 
Preparation, Handling, Storage and Accountability................................................................. 22 
6.5.1 
Preparation of Trial Intervention ...................................................................................... 22 
6.5.2 
Handling and Storage of Trial Intervention ...................................................................... 23 
6.5.3 
Accountability of Trial Intervention ................................................................................. 23 
6.6 
Participant Assignment, Randomisation and Blinding ............................................................ 23 
6.6.1 
Participant Assignment ..................................................................................................... 23 
6.6.2 
Randomisation .................................................................................................................. 23 
6.6.3 
Blinding and Unblinding .................................................................................................. 23 
6.7 
Trial Intervention Compliance ................................................................................................. 23 
6.8 
Concomitant Therapy ............................................................................................................... 23 
6.8.1 
Prohibited Concomitant Therapy ...................................................................................... 24 
6.8.2 
Permitted Concomitant Therapy ....................................................................................... 24 
Rescue Therapy ............................................................................................................................... 24 
6.8.4 
Other Therapy ................................................................................................................... 24 
7 
DISCONTINUATION OF TRIAL INTERVENTION AND PARTICIPANT WITHDRAWAL 
FROM TRIAL ................................................................................................................................. 25 
7.1 
Discontinuation of Trial Intervention ...................................................................................... 25 
7.1.1 
Criteria for Permanent Discontinuation of Trial Intervention .......................................... 25 
7.1.2 
Temporary Discontinuation or Interruption of Trial Intervention .................................... 25 
7.1.3 
Rechallenge ....................................................................................................................... 25 
7.2 
Participant Withdrawal from the Trial ..................................................................................... 26 
7.3 
Lost to Follow-Up .................................................................................................................... 26 
7.4 
Trial Stopping Rules ................................................................................................................ 26 
8 
TRIAL ASSESSMENTS AND PROCEDURES ............................................................................ 27 
8.1 
Screening/Baseline Assessments and Procedures .................................................................... 27 
8.2 
Efficacy Assessments and Procedures ..................................................................................... 27 
8.3. 
Safety Assessments and Procedures ........................................................................................ 27 
8.3.1 
Physical Examination ....................................................................................................... 28 
8.3.2 
Vital Signs ........................................................................................................................ 28 
8.3.3 
Electrocardiograms ........................................................................................................... 28 
8.3.4 
Clinical Laboratory Assessments ..................................................................................... 28 
8.3.5 
Suicidal Ideation and Behaviour Risk Monitoring ........................................................... 28 

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8.4 
Adverse Events and Serious Adverse Events .......................................................................... 28 
8.4.1 
Definitions of AE and SAE .............................................................................................. 28 
8.4.2 
Time Period and Frequency for Collecting AE and SAE Information ............................ 29 
8.4.3 
Identifying AEs and SAEs ................................................................................................ 29 
8.4.4 
Recording of AEs and SAEs ............................................................................................ 29 
8.4.5 
Follow-up of AEs and SAEs ............................................................................................. 29 
8.4.6 
Reporting of SAEs ............................................................................................................ 29 
8.4.7 
Regulatory Reporting Requirements for SAEs................................................................. 29 
8.4.8 
Serious and Unexpected Adverse Reaction Reporting ..................................................... 30 
8.4.9 
Adverse Events of Special Interest ................................................................................... 30 
8.4.10 
Disease-related Events or Outcomes Not Qualifying as AEs or SAEs ............................ 30 
8.5 
Pregnancy and Postpartum Information ................................................................................... 30 
8.5.1 
Participants Who Become Pregnant During the Trial ...................................................... 30 
8.5.2 
Participants Whose Partners Become Pregnant ................................................................ 30 
8.6 
Medical Device Product Complaints for Drug/Device Combination Products ....................... 30 
8.6.1 
Definition of Medical Device Product Complaints .......................................................... 30 
8.6.2 
Recording of Medical Device Product Complaints .......................................................... 30 
8.6.3 
Time Period and Frequency for Collecting Medical Device Product Complaints ........... 30 
8.6.4 
Follow-Up of Medical Device Product Complaints ......................................................... 31 
8.6.5 
Regulatory Reporting Requirements for Medical Device Product Complaints ............... 31 
8.7 
Pharmacokinetics ..................................................................................................................... 31 
8.8 
Genetics .................................................................................................................................... 31 
8.9 
Biomarkers ............................................................................................................................... 31 
8.10 Immunogenicity Assessments .................................................................................................. 31 
8.11 Medical Resource Utilisation and Health Economics ............................................................. 31 
9 STATISTICAL CONSIDERATIONS ................................................................................................ 32 
9.1 
Analysis Sets ............................................................................................................................ 32 
9.2 
Analyses Supporting Primary Objective(s).............................................................................. 32 
9.2.1 
Statistical Model, Hypothesis, and Method of Analysis .................................................. 33 
9.2.2 
Handling of Intercurrent Events of Primary Estimand(s) ................................................. 33 
9.2.4 
Sensitivity Analysis .......................................................................................................... 34 
9.2.5 
Supplementary Analysis ................................................................................................... 34 
9.3 
Analysis Supporting Secondary Objective(s) .......................................................................... 34 
9.4 
Analysis of Exploratory Objective(s) ...................................................................................... 34 
9.5 
Safety Analyses ........................................................................................................................ 34 

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9.6 
Other Analyses ......................................................................................................................... 35 
9.7 
Interim Analyses ...................................................................................................................... 35 
9.8 
Sample Size Determination ...................................................................................................... 35 
9.9 
Protocol Deviations .................................................................................................................. 35 
10 GENERAL CONSIDERATIONS: REGULATORY, ETHICAL, AND TRIAL OVERSIGHT ... 36 
10.1 Regulatory and Ethical Considerations .................................................................................... 36 
10.2 Committees .............................................................................................................................. 36 
10.3 Informed Consent Process ....................................................................................................... 36 
10.4 Data Protection ......................................................................................................................... 37 
10.5 Early Site Closure or Trial Termination .................................................................................. 37 
11 GENERAL CONSIDERATIONS: RISK MANAGEMENT AND QUALITY ASSURANCE..... 39 
11.1 Quality Tolerance Limits ......................................................................................................... 39 
11.2 Data Quality Assurance ........................................................................................................... 39 
11.3 Source Data .............................................................................................................................. 39 
12 APPENDIX: ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS – DEFINITIONS, 
SEVERITY, AND CAUSALITY.................................................................................................... 41 
12.1 Further Details and Clarifications on the AE Definition ............................................................ 41 
12.2 Further Details and Clarifications on the SAE Definition ....................................................... 41 
12.3 Severity .................................................................................................................................... 41 
12.4 Causality................................................................................................................................... 41 
13 APPENDIX: DEFINITIONS AND SUPPORTING OPERATIONAL DETAILS ........................ 43 
13.1 Contraception and Pregnancy Testing ..................................................................................... 43 
13.1.1 
Definitions Related to Childbearing Potential .................................................................. 43 
13.1.2 
Contraception .................................................................................................................... 43 
13.1.3 
Pregnancy Testing ............................................................................................................ 43 
13.2 Clinical Laboratory Tests ......................................................................................................... 43 
13.3 Country/Region-Specific Differences ...................................................................................... 43 
14 APPENDIX: GLOSSARY OF TERMS .......................................................................................... 44 
15 APPENDIX: REFERENCES .......................................................................................................... 45 
 
 
 

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1 
PROTOCOL SUMMARY 
1.1 
Protocol Synopsis 
Primary and Secondary Objectives and Endpoints 
Primary Objective 
Primary Endpoint 
To evaluate efficacy PROMs (KOOS, 
IKDC, VAS Pain Score) are evaluated 
Improvement of PROMs (KOOS, IKDC, VAS Pain Sore) 2 
and 5 years after surgery compared to scores of the non-
operated group and compared to pre-surgery scores 
 
Secondary Objective 
Secondary Endpoint 
Safety of the patient 
 
Efficacy of the procedure 
 
MRI image  
Patient satisfaction 
Type, frequency, and severity of treatment related to AEs and 
SAEs 
How many patients show a progression of osteoarthrosis up to 
TKA? 
2 and 5 years after inclusion in the study  
2 and 5 years after surgery 
 
Overall Design 
Several key aspects of the trial design are summarized below. 
Intervention Model: Parallel groups  
Population Type: 
Patients 
Control: 
Non-operated 
Population Diagnosis or 
Condition: 
Partial meniscal loss 
Active Comparator: N/A 
Population Age: 
Minimum: 
18 
Maximum: 
60 
Trial Intervention: 
Assignment Method 
Patient decides if 
operated or not 
Site Distribution 
Single site 
 
Number of Arms: 2 Arms  
 
Blinding: Not Applicable (No blinding)  
 
Number of Participants: 
Number: 30 patients in the operated group and 10 in the non-operated group. 
Arms and Duration 
2 arms: operated /non-operated. 
Duration: 
- 
Patients operated: 
 
- 
Enrollment, Surgery (is the treatment), Follow-up:5 years,  
- 
Patients not operated:  
 
- 
Enrollment, Follow-up:5 years, 

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Total duration of trial participation for each participant: Approximately 5 years 
Dose: This is an orthopedic trial and there is no dose. The substance used is human cancellous bone 
(Spongioflex®) which exists in varied sizes (22x10x10 mm, 30x10x10 mm and 42x10x10 mm) 
Rules/procedure: see Trial Schema 
 
Committees: 
N/A 
 
Independent Committees: 
N/A 
 
1.2 
Trial Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*The process: progression of osteoarthrosis is very slow. It will be very unlikely that more than 1 patient wants 
to change to the operated group within the 5 years of the trial. The same is true for progression to TKA. The 
possibility to change later in the operated group will take off the pressure from the patient to make the “wrong” 
decision now.   
See point 1.3 Schedule of activities for details. 
 
screening 
Patients not operated can decide at any time point to 
change to the operated group* 
Follow-up after 
At the end of hospital stay (U1) 
6 weeks after surgery (U2) 
6 months after surgery (U3 
12 months after surgery (U4) 
24 months after surgery (U5) 
5 years after surgery (U6) 
Follow-up after: 
6 months (U3 
12 months (U4) 
24 months (U5) 
5 years (U6) 
Enrollment ? 
Does not meet inclusion criteria 
Or meets exclusion criteria 
No 
Yes 
No written informed 
consent 
Written informed consent 
No 
Yes 
Surgery? 
Patient does not agree to 
surgery, but wants to be 
included in the study  
No 
Yes 
Surgery 
Follow-up 
Follow-up 

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1.3 
Schedule of Activities 
Observation parameter in detail: 
Parameter 
Screeni
ng  
Enrollment?
yes/no 
Surgery 
Follow-up 
(EU*) 
 
OP 
U1# 
U2 U3 U4 U5 U6 
date 
Ѵ 
 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
surgeon 
Ѵ 
 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Medical history (age, gender, 
working status, co-morbidities) 
Ѵ 
 
 
 
 
 
 
 
 
weight 
Ѵ 
 
 
 
 
 
 
 
Ѵ 
height 
Ѵ 
 
 
 
 
 
 
 
Ѵ 
BMI 
Ѵ 
 
 
 
 
 
 
 
Ѵ 
Nicotine 
Ѵ 
 
 
 
 
 
 
 
Ѵ 
Side 
Ѵ 
 
 
 
 
 
 
 
 
Previous knee treatment 
Ѵ 
 
 
 
 
 
 
 
 
Cartilage damage 
Ѵ 
 
 
 
 
 
 
 
 
Leg axis misalignment 
Ѵ 
 
 
 
 
 
 
 
 
Properties of the meniscus 
Ѵ 
 
 
 
 
 
 
 
 
Sport  
Ѵ 
 
 
 
 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Scores (KOOS, IKDC) 
Ѵ 
 
 
 
 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
VAS-pain Score 
Ѵ 
 
 
 
 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Diagnose 
Ѵ 
 
 
 
 
 
 
 
 
Inclusion criteria 
Ѵ 
Ѵ 
 
 
 
 
 
 
 
Exclusion criteria 
Ѵ 
Ѵ 
 
 
 
 
 
 
 
Written informed consent 
 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Pregnancy test 
 
 
Ѵ 
 
 
 
 
 
 
Surgeon 
 
 
Ѵ 
 
 
 
 
 
 
Time of surgery 
 
 
Ѵ 
 
 
 
 
 
 
Graduation after Outerbridge 
[1] 
 
 
Ѵ 
 
 
 
 
 
 
Way of Fixation 
 
 
Ѵ 
 
 
 
 
 
 
Spongioflex®-properties 
 
 
Ѵ 
 
 
 
 
 
 
Antibiotica 
 
 
Ѵ 
 
 
 
 
 
 
Additional Procedures 
 
 
Ѵ 
 
 
 
 
 
 
Complication 
 
 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
MR-image evaluation 
Ѵ  
 
 
 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Pain at rest 
 
 
 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Pain when walking 
 
 
 
 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Pain at sport 
 
 
 
 
 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Pain medication 
Ѵ 
 
 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Reoperation 
 
 
 
 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
Patient satisfaction 
 
 
 
 
 
Ѵ 
Ѵ 
Ѵ 
Ѵ 
*EU: screening visit; U1: at the end of hospital stay; U2: 6 weeks after surgery (± 4 days);  U3: 6 months after surgery (± 1 
months); U4: 12 months after surgery (± 1 months), U5: 24 months after surgery (± 1 months); U6: 5 years after surgery (± 3 
months); #grey shading: this parameter will only be evaluated when operated  
 

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2 
INTRODUCTION 
2.1 
Purpose of Trial 
The menisci consist of fibrocartilage. They are partially (laterally more than medially) mobile parts of the 
joint surfaces and compensate for the incongruence of the femur and tibia. They reduce the joint pressure on 
the tibial plateau and the femoral condyles and help to stabilize the joint.[2] Due to this biomechanical 
relevance, the partial loss of the meniscus leads to arthritic changes in the medium and long term.[3-7] 
Suturing the torn meniscus is increasingly becoming the focus of knee surgery.[8] Degenerative torn menisci 
have a significantly poorer prognosis with regard to healing than traumatically torn menisci (e.g. meniscus 
damage associated with a cruciate ligament tear).[9] 
Indications for partial meniscus replacement are symptomatic, degenerative, and irreparable damage to the 
inner and outer meniscus, possibly with early osteoarthritis of the compartments, as well as partial loss of 
the meniscus in the event of anterior knee instability in young, active patients, in which case simultaneous 
reconstruction of the anterior cruciate ligament should be performed. A prerequisite for a good clinical result 
after partial meniscus replacement is a stable knee without malalignment in the coronal plane. Partial 
meniscus replacement is not suitable in the case of axial deviation and knee instability, patients older than 
60 years, advanced chondromalacia and degenerative changes in the affected compartment, an extension 
deficit of more than 3° compared to the opposite side or a knee flexion of less than 125°. Inflammatory 
arthritis or synovial inflammation of the knee and a BMI greater than 30 kg/m² are additional exclusion 
criteria. 
Williams et al. 2007[10] could show, that 5 years after partial removal of the medial or lateral meniscus, 
despite an excellent functional result, 64% of patients showed medial and 33% lateral cartilage damage on 
MRI. This study highlights the considerable delay with which the symptoms occur despite already detectable 
arthritic changes. 
Englund et al.[11] were able to show in a study that patients developed osteoarthritis significantly more 
frequently over a period of 30 months if they had meniscus damage than if they did not. Englund et al. [12] 
detected tibiofemoral osteoarthritis in 27% of patients 15 years after partial meniscus removal compared to 
10% in a control group that had not undergone surgery. 
In the case of incomplete meniscus loss, where the peripheral rim is sufficiently intact, defect filling is the 
only way to restore the lost substance and function of the meniscus.[13,14] In the past, an implant made of 
bovine collagen (Collagen Meniscus Implant (CMI), Stryker) or an artificial meniscus made of polyurethane 
(Actifit, 2med) was often used. The CMI has been withdrawn from the market by the manufacturer, so that 
no biological treatment alternative exists. 
Schenk et al. [15] were able to show in a recent study for the CMI, consisting of bovine collagen that, despite 
a significant improvement in pain and function, the CMI is subject to a progressive shrinkage process over 
time. The studies mentioned above make it clear that partial replacement of the meniscus is necessary if 
preservation by meniscus suturing is no longer possible to prevent or postpone arthritic changes. 
In the investigator-initiated study on which this application is based, a novel implant made from 
demineralized allogenic human cancellous bone (Spongioflex®, DIZG gGmbH Berlin) is to be implanted 
into the meniscus defect of the recipient knee. This transplant has sponge-like properties and therefore 
facilitates the ingrowth of cells from the surrounding meniscus. The IMP (Spongioflex®) is de-calcified and 
demineralized, it is hard, when dry, but soft when wet. In the knee the conditions are wet, thus it stays soft. 
It is pliable (Fig1) and can be easily sutured.  

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Figure 1: Spongioflex® 
 
The manufacturer (DIZG gGmbH) did a study of cell ingrowth on Spongioflex®[16]. They describe that 
ingrowth of cells on Spongioflex® was observed after 28 days and these cells do not ossify[16].  
Scotti et al. [17] summarizes 2013 the knowledge in respect to meniscal repair as follows:  
“In the last decade, striving for optimal restoration of meniscal tissue, the orthopedic surgeon`s 
armamentarium has been enriched by the use of biocompatible meniscus scaffold and meniscal allograft 
transplantation”[17]. “However, despite promising short-term results, none of the current strategies have 
demonstrated regeneration of a functional, long-lasting meniscal tissue and re-establishment of a proper 
knee homeostasis in the meniscectomised knee”[17]. “The rationale for using a cell-free biomaterial to 
replace part of the meniscus is based on repopulation of the scaffold by the host cells recruited from the 
synovium and the meniscal remnants, and subsequent tissue ingrowth which renders this approach cell-
based after implantation. A mandatory prerequisite is the absence of both knee instability and 
malalignment”[17].  
This section of the paper of Scotti et al.[17] describes exactly the need for a restoration of the meniscus. 
Furthermore it [17] defines exactly the features of a scaffold: 
” A biomaterial used as scaffold for meniscus tissue engineering purposes should present many features. 
In particular, the ideal meniscal scaffold should be (i) “cell-instructive”, promoting cell differentiation 
and proliferation if cell-seeded, or cell migration if cell-free; (ii) “biomimetic”, mimicking architecture, 
tribology and mechanical features of the native meniscus; (iii) resilient and resistant to withstand 
mechanical forces acting in the joint while cells produce ECM; (iv) biocompatible, not evoking any 
foreign-body reaction also with its degradation products; (v) slowly biodegradable allowing to be 
gradually replaced by biologic tissue; (vi) open, with high porosity, allowing diffusion of nutrients and 
catabolic substances; and (vii) easy to handle, to be sutured and to be implanted by the surgeon”[17].  
Pereira et al. [18] describes that a meniscal implant, either for partial or total replacement should.  
“provide the biomechanical properties but also the biological features to replace the loss of native tissue. 
Moreover, these approaches include possibilities for patient-specific implants of correct size and 
shape”[18].  
Spongioflex® fulfils all these demands described by Scotti et al.[17] and Peirera et al.[18] and it can be adapted 
in size and shape and thus is in the moment the optimal choice for partial meniscal replacement.  
Dickerson et al. [19] describes that  
“the scaffold must have a high fluid conductance, concomitant with high porosity…. Porosity allows more 
rapid cell incorporation along the surface and through the thickness of the scaffold, promoting integration 
with the host tissue.”[19]. “The scaffold must guide cells to regenerate all four zones of the tissue 
structure”[19].  
This is the case of Spongioflex® it is porose and can guide cells. Scotti et al.[17] proposes 2013 to use CMI 
for partial meniscal regeneration, but this product is retracted from the market by now and they describe 
already the shrinking of the transplant[17]. Knee stability and an aligned knee are a requisite for the study 
proposed. Dickerson et al. [19] shows that new fibrocartilage tissue is formed on the demineralized end of the 
allograft. Results of Credille et al.[20] support these findings. It will not be ossified again[21]. Smith et al. [22] 
describes that  

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“demineralized cancellous bone sponges are Food and Drug Administration-approved and commercially 
available products that have the potential to provide biologic and biomechanical augments for rotator cuff 
healing. The sponge can act as a scaffold for cellular attachment and proliferation” [22].  
Credille et al. [20] showed in a recent publication that a biphasic interpositional cancellous allograft 
(BioEnthesis; Sparta BioPharma, Inc., Madison, NJ) can be used for rotator cuff repair. The allograft is 
 “a porous scaffold for endogenous biological factor migration and thus potentially address the lack of 
enthesis recapitulation at the rotator cuff repair interface… while the demineralized layer supports soft-
tissue ingrowth while acting as a “sponge” to hold bone marrow elements at the repair site”[1].  
The group around Prof. Moroder [21] from the Charité has used Spongioflex® for glenoid repair. They 
describe that the transplant does not calcify again.[21] The glenoid is also no bony structure. They got an 
ethic vote (EA1/039/18) for using the same product in non-bone structures and could show successful 
restoration of the glenoid.  
Sundar et al.[23] describes that the use demineralized bone matrix increased fibrocartilage when used for 
augmentation of rotator cuff repair. The used graft (Spongioflex®) provides a scaffold for cell migration of 
meniscal cells from neighbouring parts of the meniscus. The intended study will show that this kind of 
allograft is suitable for partial meniscal replacement because it allows cell migration and has enough porosity 
to allow fluid conductance [24]. As described by Wildemann et al. [25,26] sufficient growth factors are 
remaining in the demineralized bone matrix (Spongioflex®) to support new fibrocartilage formation. Scotti 
et al. [17] underlines the importance of growth factors for meniscal regeneration. 
 
In summary from the literature, it can be concluded, that Spongioflex® is an attractive scaffold for partial 
meniscal repair because it is fully biological, it still has fibrocartilage inductive factors, allows cell migration, 
fluid conductivity, resists biomechanical forces, does not provoke immunoreactivity, it is adaptable in size 
and can easily be sutured. Partial meniscus replacement is an established surgical treatment for patients who 
have undergone partial meniscus removal[13,15,27,28], to lead to the ingrowth of cells and the regeneration of 
meniscus-like tissue.[29] 
 
The purpose of this investigator-initiated trial is to evaluate whether the novel graft can prevent/reduce the 
disadvantages of the previously used replacement materials and shows better results than the group of 
patients, which were not operated. Since there is currently no alternative made of biological material to this 
product, this investigator-initiated trial is of great medical and economic importance. The otherwise 
following arthrosis [30] or knee prosthesis implantation (TKA ) could be prevented or at least postponed. 
Initial clinical results are promising [31]. 
This surgical method contributes to both pain relief and functional improvement of the knee joint. The aim 
of this investigator-initiated study is to assess whether the novel transplant can prevent/reduce the 
disadvantages of the replacement materials used to date. As there is currently no alternative made of 
biological material to this product, the realization of this investigator-initiated study is of great medical and 
economic importance.  
An important and sensitive parameter for assessing the postoperative function of the meniscus is the MRI 
image[32]. Genovese et al. 2007 were able to show in a categorization/classification which magnetic 
resonance image can be expected in the case of successful incorporation[32]. Several studies have shown that 
the known clinical knee scores (Lysholm, IKDC, KOOS, VAS pain) improve significantly after successful 
ingrowth of the meniscus implant [13,15,27,28,30].  
Refer to the Section 1.2, Trial Schema, and Section 1.3, Schedule of Activities, for more information about 
the trial design. 
 
2.2 
Summary of Benefits and Risks 

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The expected benefits of the surgery outweigh the expected risks. The benefit of the surgery is expected to 
be improved knee functionality. The risk in the operated group are the normal risks of every surgery, like 
pain and redness of the interventional side, side effects of anaesthesia. The patients not operated do not have 
the risks applying to any surgery. For this patient group, there is an extremely limited possibility that the 
knee functionality will improve. Another benefit for both groups is the close follow-up of the knee 
functionality. The non-operated patients can, at any time point, decide to be operated. 
 
Benefit Summary 
Since only patients with partial meniscal loss are included, only through allogeneic partial meniscal 
implantation with Spongioflex® the lost function of the corresponding meniscus can be improved, and the 
graft will convert into endogenous tissue without recalcification[5]. For the patient group, which will not be 
operated there is a limited possibility that the meniscal function will improve. The psychological benefit for 
the operated group will be that they can better perform for their daily life duties. 
The collagenous meniscus implant (CMI) has been withdrawn from the market. There is currently no 
alternative made of biological material. Spongioflex® does not affect the body's metabolism and does not 
influence the effect of medications the patient is taking. There are no restrictions for the patient for any 
medication. Allogeneic meniscal partial implantation is a standard orthopedic surgical technique that can be 
performed minimally invasively with arthroscopic support. Systemic side effects (e.g., transmission of 
infectious diseases) are not known after intra-articular application of freeze-preserved tissue grafts from the 
non-profit German Institute for Cell and Tissue Replacement (DIZG gGmbH). The grafts are sterilized using 
a validated sterilization procedure, and extensive donor screening is performed in accordance with regulatory 
requirements. 
A case report[31] shows that the procedure was performed with no complications. 
The benefit to society is that gonarthrosis will be postponed as well as TKA and thus the patient is able to 
work under better conditions, and longer before invalidity. 
The hospital, where the procedure was performed, is available 24h/7days a week when problems occur.  
 
Risk Summary and Mitigation Strategy 
 
Trial-specific Discussion of Intervention Risks and Mitigations 
 
There is a risk that even though the partial meniscal replacement is performed, the knee functionality will 
not improve. Strict inclusion and exclusion criteria should limit the number of cases without a benefit (see 
inclusion and exclusion criteria). The treatment would be the same, participating or not on the trial. Study 
specific is to fill the questionnaires at the planned visits (IKDC and KOOS, CRF). 
 
Trial-specific Discussion of Procedure Risks and Mitigations 
The procedure risks are the risk of any surgery for the operated group. The non-operated group does not have 
any surgical risk. They have the risk that the knee functionality will deteriorate. Due to the close follow-up, 
also for these patients, they can minimize this risk by deciding to change into the operated group.  
 
Trial-specific Discussion of Other Risks and Mitigations 
There are no other risks. There are no comparators, challenge agents or medical devices. 
 
Overall Benefit: Risk Conclusion 
The overall risk is very low, because partial meniscal replacement is an established operative procedure. 

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There are the normal risks applying to any surgical procedure. For the non-operated group, there are no 
surgical risks. 
The benefit for the surgical group is the possibility of improvement of knee functionality. The benefit for the 
non-operated group is the close follow up to monitor the properties of the meniscus. This will help to decide 
to switch to the surgery group. The risks are assessed at least once a year for up to 2 years. After this treatment 
related risks are not expected. The 5-year visit is scheduled to verify the properties of the meniscus and to 
evaluate the exploratory outcome of progression of osteoarthrosis up to TKA. 
 
 
 

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3 
TRIAL OBJECTIVES, ENDPOINTS AND ESTIMANDS 
 
3.1 
Primary Objective + Associated Endpoint and Estimand 
 
Primary Objective 
Primary Endpoint 
To evaluate efficacy of the procedure 
Improvement of PROMs (KOOS, IKDC, VAS Pain Score) 
2 and 5 years after surgery compared to scores of the non-
operated group and compared to pre-surgery scores. 
Primary Estimand (Variable): Difference in PROMs after 2 and 5 years 
Endpoint: 2 and 5 years after surgery/enrollment, or progression to TKA 
Treatment: varies with the group chosen by the patient (operated or not operated) 
Population: male and female patients between 18 and 60 years 
Intercurrent event: progression of osteoarthrosis up to TKA, lost to follow up, premature death, the patient 
wishes to change to the operated group after a certain time (The process: progression of osteoarthrosis is very 
slow. It will be very unlikely that more than 1 patient wants to change to the operated group within the 5 years of 
the trial. The same is true for progression to TKA. The possibility to change later in the operated group will take 
off the pressure from the patient to make the “wrong” decision now.) 
Population-level summary: The primary objective is to compare the PROM change from baseline between 
the operated and non-operated group after 2 and 5 years. The difference in obtained PROMS will be 
evaluated. 
 
Estimand Description: The Estimand are the Difference in PROMs. This includes specific knee scores 
(IKDC, KOOS) and the VAS-Pain Score. IKDC and KOOS have values between 0 and 100 and the higher 
they are as better the function of the knee. The VAS Pain Score has values between 0 and 10 and the higher 
the score the higher the pain. 
 
3.2 
Secondary Objective + Associated Endpoint and Estimand 
 
Secondary Objective 
Secondary Endpoint 
Safety of the patient 
 
Efficacy of the procedure 
 
MRI evaluation  
 
 
 
 
Patient satisfaction 
Type, frequency and severity of treatment-related AEs and 
SAEs . 
How many patients show a progression of osteoarthrosis up 
to TKA?  
Outerbridge graduation, size of meniscus, number of 
patients with extrusion, size of extrusion after 6 weeks, 6 
and 12 months (for operated patients) and after 2 and 5 
years, comparison between the operated and the non-
operated group   
very pleased, pleased, not pleased, very unsatisfied in the 
operated group after 2 and 5 years. 
 
Secondary Estimand(Variable): Safety of Patient: Number of AE and SAE, Efficacy of the procedure: 

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Number of patients with progression of osteoarthrosis up to TKA, MRI evaluation: Change in Outerbridge 
graduation from baseline and patient satisfaction.  
Endpoint: 2 and 5 years after surgery/enrollment, or progression to TKA 
Treatment: varies with the group chosen by the patient (operated or not operated) 
Population: male and female patients between 18 and 60 years 
Intercurrent event: progression of osteoarthrosis up to TKA; lost to follow up, premature death, the patient 
wishes to change to the operated group after a certain time (The process: progression of osteoarthrosis is very 
slow. It will be very unlikely that more than 1 patient wants to change to the operated group within the 5 years of 
the trial. The same is true for progression to TKA. The possibility to change later in the operated group will take 
off the pressure from the patient to make the “wrong” decision now.) 
Population-level summary: The secondary objective is safety of the patient, efficacy of the procedure, MRI 
evaluation and patient satisfaction. Type, frequency and severity of treatment-related AEs and SAEs will be 
evaluated and how many patients show a progression of osteoarthrosis up to TKA, to compare the MRI image 
from baseline and patient satisfaction after 2 and 5 years. 
 
Estimand Description 
Safety of the patient and efficacy of the procedure: if AE, SAE or SUSARs are reported, the benefit-risk 
balance evaluation will be renewed, and it will be decided if the study will be continued. 
MRI Image will be evaluated using the Outerbridge [1] graduation, the size of the meniscal defect and the 
meniscus itself, the MRI signal of the meniscus will be evaluated after a modified score after Genovese et 
al.[32] and if there is an extrusion and which size the extrusion has. Patient satisfaction will be categorized 
as: very pleased, pleased, not pleased, very unsatisfied and will be evaluated using the Chi-square test. 
 
3.3 
Exploratory Objective + Associated Endpoint and Estimand 
 
Exploratory Objective 
Exploratory Endpoint 
How many patients show a progression 
of osteoarthrosis up to TKA 
Progression of osteoarthrosis up to TKA 
 
Exploratory Estimand (Variable): Progression of osteoarthrosis up to TKA 
Endpoint: 2 and 5 years after surgery/enrollment  
Treatment: varies with the group chosen by the patient (operated or not operated) 
Population: male and female patients between 18 and 60 years 
Intercurrent event: lost to follow-up, premature death 
Population-level summary: the explorative objective is: how many patients have a progression of 
osteoarthrosis up to TKA, in the operated and non-operated group. 
 
Estimand Description:  
The number of patients with progressing of osteoarthrosis up to TKA will be evaluated using the Kaplan 
Meier estimator for time to event. 
 
 
 

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4 
TRIAL DESIGN 
 
4.1 
Description of Trial Design 
Description of Intervention Model 
This investigator initiated; low intervention trial is performed with 2 groups. The intervention group is the 
group of patients who will be operated. The control group are the patients not willing to be operated. Due 
to the incidence of patients with partial meniscal loss in the last years in the private praxis of the principal 
investigator 30 patients in the operated group and 10 patients in the non-operated group will be recruited 
within 2 years of recruitment. The study will be performed to prove patient safety and efficacy of the 
procedure. The process of progression of osteoarthrosis is very slow. It will be very unlikely that more than 1 
patient will be in this situation and wants to change to the operated group within the 5 years of the trial. The 
same is true for progression to TKA. The possibility to change later in the operated group will take off the 
pressure from the patient to make the “wrong” decision now. 
 
Description of Trial Duration 
The total trial duration will be 7 years. The recruitment period will be 2 years. Follow-up is 5 years. 
Depending on, if the patient will be operated or not, the time until surgery will add on these 5 years. The 
substance used (human cancellous bone) does not have a dose. It will be used in various dimensions.  
 
Method of Assignment to Trial Intervention 
This is a single centre trial. The initiator of the trial will perform the trail on its own. Due to the small 
number of patients included, the investigator will perform all visits on its own. There is no randomization. 
The patient decides if he/she will be operated or not. There is no blinding. A clinical monitor will perform 
data monitoring. There are no plans for a data monitoring committee due to the small number of patients 
and small number of data recorded. Bias is minimized by investigating the MRI images after a standardized 
protocol. The PROMs are filled in by the patient without the help of the investigator. The analysis will be 
performed by the investigator using statistical software. Patients from the non-operated group can transition 
to the operated group at any time. There are no rules for transition.  
An interim analysis is planned after 2 years. See details in section 9.7 
There will be no sample collection during the trial. In the moment there is no extension of the trial over the 
5 years planned. 
 
4.2 
Rationale for Trial Design 
Rationale for Intervention Model 
The comparison of the 2 groups (operated/non-operated) are chosen, because this gives an instant 
possibility to compare the knee functionality with and without surgical treatment.  
 
Rationale for Duration 
Only after 2 years the result can be evaluated. Biological processes in the meniscus are slow. Shrinkage of 
the transplant as described for CMI can occur later (up to 2 years). But normally after 2 years the 
remodelling process is finished. For this reason, close follow-up is performed for up to 2 years. 
 
Rationale for Endpoints 
The endpoints are the knee functionality after 2 and 5 years, the safety of the patient and the efficacy of the 
method. If the benefit-risk balance changes the investigator evaluates if the study will be continued. 

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Progression of osteoarthrosis up to TKA are additional end points for single participants. 
 
Interim Analysis 
An interim analysis will be performed in 2 years. If the benefit-risk balance changes or the safety of the 
patient or the efficacy of the procedure is not any mor given, the study will be stopped. 
 
4.2.1 Rationale for Comparator 
There is no comparator, the control group is the group of non-operated patients 
 
4.2.2 Rationale for Adaptive or Novel Trial Design 
There are no adaptive or novel trial design 
 
4.2.3 Other Trial Design Considerations 
There are no other trial design considerations. 
 
4.3 
Access to Trial Intervention After End of Trial 
If the trail shows benefit for the patient the procedure will be performed after the trial as standard 
procedure by the investigator. 
 
4.4 
Start of Trial and End of Trial 
The start date of the trial will be as soon as the approval for the study will be obtained. The end point will be 
the last visit of the last patient enrolled in the trial. 
Firs act of recruitment is the screening: 
The recruitment of patients for the investigator-initiated trial takes place during the consultation hours of the 
study centre. Since patients are specifically assigned for partial meniscus implantation, patients are already 
informed about the investigator-initiated trial at the time of appointment. During the first visit the inclusion 
and exclusion criteria are evaluated. If the patient qualifies for participation in the study based on the 
inclusion and exclusion criteria, he/she will be informed about the therapeutic procedure of partial meniscus 
implantation with Spongioflex® and the planned investigator-initiated trial (planned visits, data protection, 
etc.) will be explained. Patients also receive an information sheet explaining the surgical procedure, the 
advantages and disadvantages, the risks, and the follow-up treatment. After a sufficient reflection period, the 
patient must sign the consent form for participation in the investigator-initiated trial and the data protection 
declaration. Without these written consents, inclusion in the investigator-initiated trial cannot take place. 
After the signatures, the patient is included in the investigator-initiated trial. In accordance with standard 
clinical practice, the usual risk information for the surgical procedure is provided, for patients who decided 
to be operated. For the control group (not operated patients) the follow up visits are explained. This is 
conducted based on the information sheet customary in the respective hospital. In this form, patients are 
usually informed about the procedure, the treatment alternatives, the risks, and the aftercare. Woman are 
treated in the same way. Spongioflex® does not affect the body's metabolism and does not influence the 
effect of medications the patient is taking, thus there is no need for special female treatment option. There is 
no restriction for medication taken by the patient.  
Pregnant women are excluded from surgery but can join the non-operated group.  
Minor patients are not included.  
 

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The investigator-initiated trial may only be terminated prematurely for ethically relevant, i.e., medical/ 
scientific reasons. 
 
Premature exclusion of a patient from the study: 
- If, during the waiting period for the Spongioflex® graft, changes in the patient's state of health occur 
that constitute a contraindication for partial meniscal implantation (e.g., infection of the knee joint, tibial 
plateau fracture), the physician conducting the study must withdraw the patient from the investigator-
initiated trial if this appears reasonable and necessary for medical reasons. 
 
Premature termination of the entire study: Reasons for premature termination of the investigator-initiated 
trial include:  
- If the identifiable risks outweigh the expected benefits. 
- If an unreasonable risk to patients is apparent. 
- If unexpected serious adverse events (SAE); Suspected Adverse Drug Reaction (SADR) occur that are 
causally related to the insertion of the meniscal implant, they will be reported to the EudraVigilance 
database. Patients will be followed up until the SAE or SUSAR/SADR is solved, if necessary, in the 
hospital, otherwise as outpatient. 
- IF SUSARs are reported, a new benefit/risk balance evaluation will be performed and after the analysis 
it is decided if the study will be continued. 
 
If the investigator-initiated trial is terminated or suspended prematurely, the study director will inform the 
regulatory authority(ies) of the termination or suspension and provide a statement to that effect. The Ethics 
Committee will be promptly notified and provided with a detailed written explanation for the study director's 
termination or suspension of the investigator-initiated trial, as specified in the applicable regulatory 
requirements. If the investigator-initiated trial is terminated or suspended prematurely for any reason, study 
participants will be notified immediately. 
 
Patients can stop the participation of the study at any time, without giving the reason for it. 
 
The investigator and the sponsor are the same person, He has the right to decide if there will be an early site 
closure or if the study will be prematurely terminated. For further details see 10.5 (Early site closure or trial 
termination) for criteria and responsibilities related to early site closure or trial termination. 
In the event of premature termination or suspension of the investigator-initiated trial, irrespective of the 
reason, further follow-up of patients will continue according to standard clinical practice. 
 
 

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5 
TRIAL POPULATION 
5.1 
Selection of Trial Population 
This trial is performed on adult patients with a maximal age of 60 years. The enrollment criteria are carefully 
selected to increase patient safety and efficacy of the procedure. Patients must have a partial loss of the lateral 
or medial meniscus and a lateral or medial joint line pain. In this trial there are no drugs used. The human 
cancellous bone (SUB184038) is used in various dimensions to suite the defect. The progression of this 
partial loss ist the total loss of the meniscus, which is treated with total meniscal allograft replacement and 
when the cartilage is severely damaged a TKA is the only treatment option. The patients treated in this trial 
are mainly young active patients who want to continue their sport and daily life. Thus, to try to improve knee 
functionality is the goal of the partial meniscal replacement. 
 
5.2 
Rationale for Trial Population 
The rational for choosing this trial population is that this part of the population has this kind of diagnosis, 
and it must be treated as soon as possible. Additional measures are taken for leg axis misalignment and ACL 
rupture. For the efficacy of the procedure the leg must have a normal alignment and must be stable.  
No children or patients, who are unable to consent for themselves, or those that may respond to the trial 
intervention differently are included. There is no restriction on medicine taken by the patient because the 
allograft does not have systemic actions.  
Screening is performed via MRI. There must be a sufficient standing peripheral rim, so that the procedure 
can be performed. No laboratory tests or genetic tests are necessary for the screening. When the operation is 
decided later on, the usual laboratory tests are performed as for every surgery, not being a trial. Only after 
successful screening the patient will be enrolled. Subgroup possible will be sex (female versus male) and 
smoker versus non-smoker if enough power is generated to do statistical calculations. 
Individuals who do not meet criteria for trial eligibility will not be enrolled via protocol waivers. 
or exemptions. 
 
5.3 
Inclusion Criteria 
To be eligible to participate in this trial, an individual must meet all the following criteria: 
1. Patients (male and female) with: 
2. Partial loss of portions of the  
o lateral meniscus and lateral joint line pain 
OR 
o medial meniscus and medial joint line pain 
3. sufficient standing of the peripheral rim, so that the procedure can be performed 
4. Age: 18-60 years 
5. signed written informed consent to the study and to provide the scientific data in pseudonymized 
form 
 
5.4 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this trial: 
1. The presence of anterior cruciate ligament insufficiency which is not resolved by reconstruction of 
the anterior cruciate ligament within 16 weeks after partial meniscal implantation. 
2. Axial deviation (>2° varus or valgus) 
3. realignment osteotomy not performed within 12 weeks 

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4. advanced cartilage damage (grade III according to ICRS) and osteoarthrosis in the affected 
compartment (grade III according to Kellgren and Lawrence [33]) 
5. Extension deficit of more than 3° compared to the opposite side or a knee flexion of less than 125° 
6. inflammatory arthritis or synovitis on the treated knee  
7. BMI greater than 30 kg/m² 
8. <18 years, >60 years  
9. Chronic pain patients 
10. only for patients who will be operated: 
a. with increased anaesthesiologic risk, e.g., with known or predicted difficult airway  
b. with increased risk of bleeding  
c. with increased risk of infection 
d. with necrotic, infected, or poorly perfused host sides  
e. history of allergic reactions  
f. acute hypersensitivity reactions to the IMP or any of its excipients  
g. pregnant woman 
 
5.5 
Lifestyle Considerations 
5.5.1 Meals and Dietary Restrictions 
No meals and dietary restrictions. 
 
5.5.2 Caffeine, Alcohol, Tobacco, and Other Habits 
There are no restrictions to the intake of caffein, alcohol, or tobacco. 
 
5.5.3 Physical Activity 
Physical activity is restricted for the patients having an operation as follows: Rehabilitation consist of 5 
weeks partial weight bearing, range of motion will be restricted for the first 3 weeks to 30 °flexion, 4th 
week 60 °, 5th week 90 °, then full range of motion exercises were allowed. Jogging is not allowed for 4 
months and contact sport only after 6 months. 
 
5.5.4 Other Activity 
There are no restrictions to blood or tissue donation and sun exposure. 
Driving is not allowed for operated patients for 8 weeks with manual transmission and when the right leg is 
concerned also for automatic transmission. 
Heavy labour not for 3 months. 
 
5.6 
Screen Failures 
Screen failures will be left in the study. The study will be performed after the principle: full analysis set. 
The principal investigator is performing the screening himself, thus screening failures will be limited. 
 
 
 

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6 
TRIAL INTERVENTION AND CONCOMITANT THERAPY 
6.1 
Description of Trial Intervention 
The investigator-initiated trial is a "low-intervention clinical trial" according to Article 2(3)CTR. It will be 
conducted in accordance with the “FSA-Kodex” and the joint recommendations of the BfArM and PEI on 
the planning, conduct and analysis of investigator-initiated trials. The clinical trial will be conducted in 
compliance with the protocol, with the CTR regulation and with the principles of good clinical practice 
according to Annex I section D 17 (a) CTR 536/2014. 
 
The IMP is SUB184038, human cancellous bone, auxiliary medicinal product (NIMP) is Cephazolin, 2 gr. 
one shot just before surgery, IMP and NIMP for the surgical group only. 
 
 
Fig. 2 example of packaging and labelling.  
 
The IMP can be stored at room temperature (fig. 2). The transplant must be re-hydrated at least 30 min before 
implantation in physiological injectable solution (Fachinformation point 4.2).  
 
Intervention for the surgery group: As for any surgical procedure, the patient receives an antibiotic shot 
NIMP) just before surgery. The patient will be arthroscopically treated via the arthroscopic portal with 
implantation of a demineralized bone block (IMP: Spongioflex ®, appropriate size (DIZG gGmbH, Berlin, 
Germany)) as a partial meniscus substitute. The block will be adapted to the defect size and secured with 2-
4 inside-out sutures (Etibond 0, Ethicon, Somerville, NJ). No dosing, the IMP has no systemic effect. The 
surgery (Intervention) will last between 60-90 minutes. The hospital stay is between 2-3 days after surgery. 
Follow-up visits: at the end of the hospital stay, after 6 weeks, after 6, 12 and 24 months and after 5 years 
for the operated group. 
Non-operated group: no surgical treatment, no antibiotic shot, no visit at the end of the hospital stay, and no 
visit after 6 weeks. Follow-up visits after 6, 12 and 24 months and after 5 years. 
 
 
 
 
 
 

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Table 1: Trial interventions 
Trial intervention 
Operated group 
Non-operated group 
screening 
yes 
yes 
enrollment 
yes 
yes 
In-hospital surgery as summarized above  
with IMP and NIMP as defined above 
yes 
no 
Follow-up includes  
MRI evaluation and IKDC, KOOS and VAS-
pain-Score at each follow-up visit 
yes 
yes 
    at the end of hospital stay 
yes 
no 
   After 6 weeks 
yes 
no 
   After 6 months 
yes 
yes 
   After 12 months 
yes 
yes 
   After 24 months 
yes 
yes 
...After 5 years 
yes 
yes 
 
6.2 
Rationale for Trial Intervention 
Arthroscopy is an established method to treat meniscal lesions. This is the best way to protect the soft tissue 
and to minimize the risks for the patient. The IMP is a human cancellous bone block, which is hard when dry 
and has spongy soft properties when wet. It is sold in varied sizes. It can be sized in accordance with the 
defect size, it is pliable (important for shuttling through arthroscopic ports) and allows cell and fluid 
migration. The IMP has no systemic effect and thus does not have a dose. A case report [31] shows first 
promising results. The group around Prof. Moroder [21] from the Charité has used Spongioflex® for 
rebuilding the glenoid surface and were unable to demonstrate re-ossification on subsequent MRI scans up 
to 12 months and could show successful restoration of the glenoid. There are still sufficient growth factors 
in the IMP to initiate cell migration from surrounding tissue. Demineralized bone, as Spongioflex®, supports 
soft-tissue ingrowth [20]. See 2.1 purpose of trial for more details. 
There is no dose and no regime, thus there is no rational for dose and regime. 
 
6.3 Dosing and Administration 
The size of the IMP will be estimated by MRI evaluation and approved with the measuring rod during 
surgery by the operating surgeon. 
The IMP will only be handled by the orthopedic surgeon. The patient does not handle the IMP and not the 
NIMP, thus no instructions for the patients are needed.  
 
6.3.1 Trial Intervention Dose Modification 
There is no dose, thus there is no dose modification 
 
6.4 
Treatment of Overdose 
There is no dose, thus there is no overdose  
 
6.5 
Preparation, Handling, Storage and Accountability 
6.5.1 Preparation of Trial Intervention 
The preparation of the IMP is only handled by the investigator of the trial. The size of the IMP will be adapted 

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due to the defect size. The re-hydration of the IMP will be 30 min prior use in physiological injectable 
solution as explained in the “Fachinformation” (attached as separate document). The NIMP will be applied 
I.V. 
 
6.5.2 Handling and Storage of Trial Intervention 
The IMP can be stored at room temperature up to the date indicated on the package. Handling follows the 
instruction in the “Fachinformation” and as describe under 6.2 and 6.5.1. 
 
6.5.3 Accountability of Trial Intervention 
The IMP and NIMP will only be handled by the investigator. Each patient does get only 1 IMP. Because the 
size will be adapted during surgery, he is able to order the IMP before knowing the patient’s defect. He has 
a storage of the IMPs (in the operating tract) of the available sizes to treat several patients without the need 
to order. He orders via the hospital, where the treatment is performed from the manufacturer. The product is 
available on the market for orthopedic surgeons with a prescription. 
There is no return of unused products, the rest of the IMP, which is not implanted, will be disposed in the 
operating tract. One IMP is only allowed to use for 1 patient, even the remaining part would be big enough 
for treating another patient (Fachinformation point 6.6). 
 
6.6 
Participant Assignment, Randomisation and Blinding 
6.6.1 Participant Assignment 
The patient decides after screening on its own if he wants to be operated or not. For this reason, the patient 
decides to which group he will belong. 
 
6.6.2 Randomisation 
There is no randomization 
 
6.6.3 Blinding and Unblinding 
There is no blinding 
Emergency Unblinding: Because there is no blinding there is no need for emergency unblinding. 
 
6.7 
Trial Intervention Compliance 
Trial compliance is only for the follow-up-evaluation. It does not concern the IMP, because the IMP is placed 
at the surgery in the patient. The compliance is expected to be high with the restrictions regarding activity 
and the compliance with the visits. It is expected that maximal 20% of patients will be lost for follow up or 
withdraw their consent.  
 
6.8 
Concomitant Therapy 
There are no restrictions to concomitant therapy. There is no medication/supplement restriction for the trial. 
The IMP has no systemic effect. The patient can take all medications, which he has already, and which will 
be additionally during the trial period. There are only restrictions on activity as explained in 5.5.3 after 
surgery in the operated group. 
 

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6.8.1 Prohibited Concomitant Therapy 
There is no prohibited concomitant therapy. 
 
6.8.2 Permitted Concomitant Therapy 
Every other therapy is permitted during the trial. 
 
Rescue Therapy 
There is no rescue therapy. The patient who progress to osteoarthrosis or TKA would be excluded from 
data interpretation but would remain in the trial as the full analysis set principle is followed. This patient 
would be counted as failed treatment. 
A withdrawal from the trial by the patient (after surgery) will only affect the follow-up data. Withdrawal 
before surgery will not generate follow-up data, but patient will still be left in the study due to the full 
analysis set principle. This does not lead to temporary discontinuation of the study. 
 
6.8.4 Other Therapy 
There can be physiotherapy to improve the return to daily life and sport. 
 

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7 
DISCONTINUATION OF TRIAL INTERVENTION AND PARTICIPANT 
WITHDRAWAL FROM TRIAL 
 
7.1 Discontinuation of Trial Intervention 
7.1.1 Criteria for Permanent Discontinuation of Trial Intervention 
This is an orthopedic trial. The surgery is the start point and after the surgery there is no further treatment. 
There are only follow-up visits, which include an MRI (after 6 weeks, 6, 12, 24 months and 5 years in the 
operated group and after 24 months and 5 years in the non-operated group) and 3 questionnaires (IKDC 
and KOOS, CRF).  
Criteria for permanent discontinuation for single patients from the trial are the following: 
- 
Withdrawal of the informed consent 
- 
lost to follow-up,  
- 
premature death  
- 
progression of osteoarthrosis up to TKA  
- 
the patient wishes to change to the operated group after a certain time 
When withdrawal of the informed consent, premature death or lost to follow-up occurs, data up to the point 
will be used. If progression of osteoarthrosis up to TKA occurs, the treatment is counted as treatment 
failure. These patients cannot continue the trial. Data up to the point will be used. 
If the patient changes his decision and want to be operated at a later time point, the patient can continue the 
trial, but will be allocated to the other study arm. Data collected up to this point will be used in the first 
treatment group and then data will be generated in the second treatment group. 
 
7.1.2 Temporary Discontinuation or Interruption of Trial Intervention 
This is an orthopedic trial. The surgery is the start point and after the surgery there are no treatments. There 
are only follow-up visits, which include an MRI and 3 questionnaires (IKDC, KOOS, CRF)  
If the patient cannot attend a post-surgical visit at the time envisaged it is possible to do the visit 
later/earlier. For this there are time ranges given which is as follows: 
- 
U1: at the end of hospital stay (only for operated patients)  
- 
U2: 6 weeks after surgery (± 4 days, only for operated patients) 
- 
U3: 6 months after surgery (± 1 months, for operated patients, for non-operated patients only 
PROMs)  
- 
U4: 12 months after surgery (± 1 months, for operated patients, for non-operated patients only 
PROMs)  
- 
U5: 24 months after surgery (± 1 months)  
- 
U6: 5 years after surgery (± 3 months) 
If for any reason this time slots cannot be used by the patient e.g. because of a pandemic or another major 
event, then the next time slot will be used.  
Thus, a temporary discontinuation of the trial is not a problem, because no treatment occurs after surgery, 
but should be avoided. 
 
 
7.1.3 Rechallenge 
Because the treatment is finished after the surgery, there is no re-challenge possible for patients in the 
operated group. Patients from the non-operated group can change to the operated group, but this is than no 
rechallenge, but the start of the trial as described under 1.2 Trial Scheme.  

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7.2 Participant Withdrawal from the Trial 
This is an orthopedic trial. The surgery is the start point and after the surgery there is no further treatment. 
There are only follow-up visits, which include an MRI and 3 questionnaires (IKDC, KOOS, CRF). If a 
participant withdrawal his informed consent. If the patient is not compliant with the restrictions for 
rehabilitation after surgery (as described under 5.5.3), the investigator has the right to withdraw the patient 
from the trial. Data are used until the withdrawal. 
 
7.3 
Lost to Follow-Up 
This is an orthopedic trial. The surgery is the start point and after the surgery there are no treatments. There 
are only follow-up visits, which include an MRI and 3 questionnaires (IKDC, KOOS, CRF). Follow-up-
visits are at the end of the hospital stay, 6 weeks after surgery (both for operated patients only), and then for 
all patients: after 6, 12 and 24 months and after 5 years. 
Lost to follow-up will occur because the trial population are mainly young active people. They will move for 
work or private reasons and may not finish the visits. In the number of patients for the trial lost to follow-up 
is included in the statistical calculations. The investigator will explain, when the informed consent is 
discussed with the patient, the importance of attending the follow-up-visits. If the investigator has the 
impression that the patient will not be compliant regarding the follow-up-visits, he will not include the patient 
in the trial. 
When a patient is lost to follow up, the data up to the last visit attended will be used. 
 
7.4 
Trial Stopping Rules 
If AE, SAE and SUSARs change the benefit-risk balance, there will be a new benefit-risk balance evaluation 
and after this evaluation it will be decided if the trial will be stopped. 
If the safety of the patients is not any more given, the trial should be stopped.  
The investigator expects a maximal 20% failure rate of the procedure. If the failure rate is higher a new 
benefit-risk balance evaluation must be performed and after the evaluation it must be decided if the trial 
continues.  
The investigator also has the right to stop the trial. This could be because of the closure of the site. See 10.5 
for details. 
 

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8 TRIAL ASSESSMENTS AND PROCEDURES 
 
Assessment procedure is described in detail under 1.2 trial scheme and under 1.3 schedule of activities.  
 
8.1 Screening/Baseline Assessments and Procedures 
The recruitment of patients for the investigator-initiated trial takes place during the consultation hours of the 
study centre. Since patients are specifically assigned for partial meniscus implantation, patients are already 
informed about the investigator-initiated trial at the time of appointment.  
During the first visit (Screening) an MRI is done and evaluated, the inclusion and exclusion criteria are 
verified. If the patient qualifies for participation in the study based on the inclusion and exclusion criteria, 
he/she will be informed about the therapeutic procedure of partial meniscus implantation with Spongioflex® 
and the planned investigator-initiated trial (planned visits, data protection, etc.) will be explained. Patients 
also receive an information sheet explaining the surgical procedure, the advantages and disadvantages, the 
risks, and the follow-up treatment. After a sufficient reflection period, the patient must sign the informed 
consent form for participation in the investigator-initiated trial and the data protection declaration. Without 
these written consents, inclusion in the investigator-initiated trial cannot take place. After the signatures, the 
patient is included in the investigator-initiated trial. At this time point the patient must decide if he wants to 
be operated or not. In accordance with standard clinical practice, the usual risk information for the surgical 
procedure is provided for patients who decided to be operated. This is conducted based on the information 
sheet customary in the respective hospital. In this form, patients are usually informed about the procedure, 
the treatment alternatives, the risks, and the aftercare. Woman are treated in the same way. Spongioflex® 
does not affect the body's metabolism and does not influence the effect of medications the patient is taking, 
thus there is no need for special female treatment options. There is no restriction for medication taken by the 
patient. For the control group (not operated patients) the follow-up visits are explained. 
- Pregnant women are excluded from surgery  
- Minor patients are not included 
 
8.2 
Efficacy Assessments and Procedures 
The surgical procedure will be assessed at any time. The procedure should be successful in at least 80% of 
the patients. If there is a failure rate of more than 20 % the benefit-risk balance evaluation will be renewed. 
If the risk overweight’s the benefit of the surgical procedure, the trial will be prematurely terminated. For 
this reason, close meshed follow-up is scheduled to obtain sufficient information regarding the efficacy of 
the surgical procedure. 
 
8.3. 
Safety Assessments and Procedures 
This is a low intervention trial. This trial poses a minimal additional risk to subject safety compared to normal 
clinical practice (CTR, page 2 (11)). 
As described under 8.2 there is a close-meshed follow-up schedule, for operated patients, which will also 
evaluate the patient’s safety. The highest risk that safety issues occur is during surgery. But the surgery is an 
established method. All safety measures will be taken during surgery as for every surgery, not being a clinical 
trial. The first visit at the end of the hospital stay is one of the safety measures for the patient. Before the 
patient leaves the hospital, the patient will be checked, if there are no issues which may affect his/her safety. 
AE, SAE and SUSARs are recorded in the electronic patient chart and will be recorded in the CRF.  
AE will only be recorded in the electronic patient chart and in the CRF. When AEs affecting the conduct of 
the trial and/or increasing the risk to the subject, the IRB/IEC should be promptly informed by a written 

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report. 
SAE: because the investigator and sponsor is the same person in this trial, information to the sponsor is 
immediately. The SAE will be recorded in the electronic patient chart and in the CRF. Unless the protocol 
waives the notification, the investigator reports the SAE to the ethic committee and to the local authorities 
(Bundesoberbehörde) immediately but at least within 15 days, after becoming aware of it. If the investigator 
does not have all the information by then, the missing information must be submitted as soon as possible. 
SUSARs: The investigator/sponsor shall inform the competent higher federal authority, the lead ethics 
committee, and the competent authorities of other Member States immediately, but at the latest within 15 
days of becoming aware of a SUSAR. The deadline is reduced to 7 days if an unexpected serious adverse 
reaction is life-threatening or has led to death. 
There are no laboratory investigations part of the trial.  
There is no independent Data Monitoring Committee. Clinical monitoring will be performed from an 
independent clinical monitor for the safety of the patients. The extend and nature of the monitoring will be 
adapted due to Article 48 CTR.  
 
8.3.1 Physical Examination 
Physical examinations will be performed at each visit. Normal evaluations will not be recorded, only adverse 
events and complications.  
 
8.3.2 Vital Signs 
Vital signs are only recorded before and during surgery. The IMP has no systemic effect. For this reason, 
vital signs are recorded and not evaluated in the follow-up visits. 
 
8.3.3 Electrocardiograms 
Electrocardiograms are only recorded before and during surgery. The IMP has no systemic effect. For this 
reason, vital signs are not recorded and evaluated in the follow-up visits.  
 
8.3.4 Clinical Laboratory Assessments 
Clinical laboratory assessment will only be performed before surgery, due to normal medical praxis to prepare 
surgery. After the surgery, a laboratory assessment will only be performed, when AE (e.g. infections) are recorded 
or other events which need laboratory assessment. This will be due to routine practice of the hospital, where the 
patient is located or due to the practice of the investigator for such events and is not related to a special laboratory 
assessment due to the clinical trial 
 
8.3.5 Suicidal Ideation and Behaviour Risk Monitoring 
The diagnosis of partial meniscal defect is not life-threatening, thus suicidal ideation is not common for this 
kind of diagnosis. As described in 8.2, a close meshed follow-up is scheduled after surgery. The KOOS 
questionnaire includes questions about the quality of life. Discussion with the patient about the outcome of 
the KOOS questionnaire will point out possible suicidal ideation and will activate a closer follow up of the 
patient. 
 
8.4 
Adverse Events and Serious Adverse Events 
8.4.1 Definitions of AE and SAE 
AE definition: any untoward medical occurrence in a subject to whom a medicinal product is administered 
and which does not necessarily have a causal relationship with this treatment CTR article 2 (32). There are 

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4 grades of AE: mild AE; moderate AE; severe AE and life-threatening AE or disabling AE. 
 
SAE definition: any untoward medical occurrence that at any dose requires inpatient hospitalisation or 
prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, results in 
a congenital anomaly or birth defect, is life-threatening, or results in death 
Additional details and clarifications for AEs and SAEs are in Appendices 12.1 and 12.2 
 
8.4.2 Time Period and Frequency for Collecting AE and SAE Information 
At each follow-up (at the end of the hospital stay, after 6 weeks, after 6, 12 and 24 months and after 5 years, 
for the operated group and after 6, 12, 24 months and 5 years for the non-operated group) AE and SAE are 
collected regularly. Since the patient can inform the investigator about AE, or SAE at any time, collecting 
AE and SAE are performed as soon as known by the investigator. After finishing the trial, the investigator is 
still reachable for the patient to inform him about any AE or SAE. 
 
8.4.3 Identifying AEs and SAEs 
At each follow-up AE and SAE are collected regularly. Since the patient can inform the investigator about 
AE, or SAE at any time, collecting AE and SAE are performed as soon as known by the investigator. After 
finishing the trial, the investigator is still reachable for the patient to inform him about any AE or SAE 
 
8.4.4 Recording of AEs and SAEs 
AEs and SAEs will be recorded in the electronic patient chart and in the CRF and in the adverse event 
log/serious adverse event log. Severity and causality and final outcome will be recorded.  
Further details on assessing severity and causality of AEs and SAEs are in Appendix 12.3 and 12.4 
 
8.4.5 Follow-up of AEs and SAEs 
The adverse event log/serious adverse event log will follow-up all actions taken in respect to solving the 
adverse event or serious adverse event. Patient will be followed until the AE/SAE is solved either in the 
hospital or as an out-patient. 
 
8.4.6 Reporting of SAEs 
SAEs will be reported in the electronic patient chart, in the CRF and to follow-up in the SAE event log. All 
SAEs will be reported to the ethic committee and to local authorities (Bundesoberbehörde) at least 15 days 
after obtaining knowledge of the event. SAEs related to the IMP will be reported to the EudraVigilance Data 
base.  
On the Webpage of the PEI there is a document 
((https://www.pei.de/DE/arzneimittelsicherheit/gewebevigilanz/meldeformulare/meldeformulare-node.html 
Form G1a) to be filled in for :” Meldung des Verdachts einer schwerwiegenden unerwünschten 
Empfängerreaktion im Zusammenhang mit der Übertragung von Gewebe, Gewebezubereitungen oder 
Stammzellen gemäß § 63i AMG“ this form would be filled and send to the PEI. 
 
8.4.7 Regulatory Reporting Requirements for SAEs 
For this clinical trial, the sponsor and the investigator are the same person. The investigator/sponsor must 
report the following:  
SAEs should be reported to the ethic committee and to the authorities (Bundesoberbehörde) immediately 
after knowledge of the event, but not later than 15 calendar days. Life threatening SAEs must be reported 

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within 24 h but at least 7 days after being aware of the case. Follow-up-reports must be submitted if the 
information in the initial submission is incomplete. 
 
8.4.8 Serious and Unexpected Adverse Reaction Reporting 
SUSARs which are fatal or life threatening, the sponsor should report at least the minimum information as 
soon as possible and, in any case, not later than 7 days after being aware of the case to the ethic committee 
and to the local authorities (Bundesoberbehörde). SUSARs which are not fatal, or life threatening are to be 
reported within 15 days to the ethic committee and to the local authorities (Bundesoberbehörde). SUSARs 
must be reported to the EudraVigilance date base electronically and to the PEI using the specified form. 
 
8.4.9 Adverse Events of Special Interest 
There are no adverse events of special interest expected. 
 
8.4.10 Disease-related Events or Outcomes Not Qualifying as AEs or SAEs 
Disease related events and outcomes, which will be not reported as AE or SAE will be: progression of 
osteoarthrosis up to TKA. This will happen when the treatment failed.  
 
8.5 
Pregnancy and Postpartum Information 
8.5.1 Participants Who Become Pregnant During the Trial 
A pregnancy test must be performed before surgery for female patients, who are able to become pregnant. 
The patient group without surgery does not have to do the pregnancy test. Patients not able to become 
pregnant (male patients, female after menopause) do not have to have a pregnancy test. After surgery, the 
patient can become pregnant without any risk for her safety or for the efficacy of the study. If a patient 
wants to change to the surgery group, a pregnancy test must be performed before surgery. 
Pregnancy after surgery is not an AE. 
 
8.5.2 Participants Whose Partners Become Pregnant 
Participants, whose partners become pregnant is not an AE. The IMP has no systemic effect and thus does 
not affect reproductivity or child development. Pregnancy information of the partner will not be collected.  
 
8.6 
Medical Device Product Complaints for Drug/Device Combination Products 
There is no medical device included. 
 
8.6.1 Definition of Medical Device Product Complaints 
n/a 
 
8.6.2 Recording of Medical Device Product Complaints 
n/a 
 
8.6.3 Time Period and Frequency for Collecting Medical Device Product Complaints 
n/a 
 

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8.6.4 Follow-Up of Medical Device Product Complaints 
n/a 
 
8.6.5 Regulatory Reporting Requirements for Medical Device Product Complaints 
n/a 
 
8.7 Pharmacokinetics 
The IMP human cancellous bone has no pharmacokinetic action. It does not have systemic effects 
(Fachinformation point 5.1. 
 
8.8 Genetics 
No genetic information is recorded during the trial. 
 
8.9 Biomarkers 
No Biomarkers are collected during the trial. 
 
8.10 Immunogenicity Assessments 
There will be no immunogenicity assessment. The IMP is an authorized product and there are up to now no 
reports in respect to events regarding immunogenicity. 
 
8.11 Medical Resource Utilisation and Health Economics 
Medical resource utilization is minimal. The additional burden for the investigator is the explanation of the 
clinical trial to the patient and the filling of the documents related to the clinical trial. 
The burden for the patient is the extended explication regarding the trial and the filling of the forms (KOOS, 
IKDC, CRF) during the visit. The patient must be compliant with the visit schedule, this could be an 
additional burden. 
Regarding the health economics: Ther are no additional costs because of the trial. If the procedure shows 
efficacy and patient safety, the health system can save additional costs related to total meniscal 
transplantation or progression of osteoarthrosis up to TKA. Additionally, the patient can work longer and 
does not need or only needs later support from the government. 
 
 
 

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9 STATISTICAL CONSIDERATIONS 
 
Data analysis complies with ICH E9 Guideline and ICH E9(R1) Guideline. This clinical trial is to confirm 
patient safety and efficiency of the procedure.  
For this reason, as primary objective PROMs (IKDC, KOOS and VAS-pain score) will be evaluated before 
surgery/at the beginning of the trial and then starting at 6 months after surgery/beginning of the trial for the 
operated or non-operated group, respectively. The evaluation will be performed also after 12 and 24 months 
and after 5 years. A primary analysis will be performed 2 years after surgery/start of the trial.  
At the beginning of the trial and prior to operation demographic and baseline data will be collected and 
summarized for both groups. 
For safety, there will be an evaluation of complications, AE, SAE and SUSARs at each follow-up visit (at 
the end of the hospital stay, after 6 weeks, after 6, 12, 24, months and after 5 years, for the operated group). 
The number of AE, SAE and SUSARs will be recorded and evaluated at each visit. MRI evaluation starts at 
the follow-up visit 6 weeks after surgery for the operated group and 24 months after the start of the trial for 
the non-operated group. The evaluation of the MRI will be performed after a modified graduation of 
Genovese et al. [32]. Additionally, there will be the meniscal size evaluated and if there is an extrusion of the 
meniscus and how big the extrusion is. There will be a Kaplan-Meier-time to event curve for both groups 
regarding progression of osteoarthritis up to TKA. The analysis will be conducted on all participant data after 
2 years and after 5 years. 
 
9.1 
Analysis Sets 
Full analysis set will be performed. 
 
PROMs: 
Change from baseline for the PROMs (IKDC, KOOS, VAS-pain score) for the operated/non-operated group 
after 6, 12 and 24 months and 5 years and between groups.  
 
Complications, AE, SAE and SUSARs: 
The number of complications, AE, SAE and SUSARs will be evaluated at each time point and compared 
between the groups with Fishers exact test.  
 
MRI evaluation:  
Change in MRI evaluated using the Outerbridge [1] graduation, the size of the meniscal defect and the 
meniscus itself, the MRI signal of the meniscus will be evaluated after a modified score after Genovese et 
al.[32] and the number of patients with an extrusion and the size of the extrusion.  
 
Patient satisfaction: 
Patient satisfaction will be categorized as: very pleased, pleased, not pleased, very unsatisfied and will be 
evaluated using the Chi-square test.  
 
Progression of osteoarthrosis up to TKA: 
The number of patients with progression of osteoarthrosis up to TKA for both groups will be compared with 
a Kaplan-Meier time to event curve. 
 
9.2 
Analyses Supporting Primary Objective(s) 
The PROMs (IKDC, KOOS, VAS-pain score) may be considered as continuous numerical data. The PROMs 

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will be summarized by sample size N, mean, standard deviation (SD), minimum, first quartile Q1, median, 
third quartile and maximum. Box plots will be used to provide a graphical overview. If the numerical data 
are normally distributed an independent t-Test can be performed, if they are not normally distributed, a Mann-
Whitney-U-Test must be used. Statistically significant differences will be assigned when p<0.05. 
 
9.2.1 Statistical Model, Hypothesis, and Method of Analysis 
The change in PROMS from baseline in the operated and non-operated group will be compared by two-sided 
t-test for independent groups when data are normally distributed or with the Mann-Whitney-U-test. 
 
The Null-hypothesis is that partial meniscal replacement does not improve mean PROMs for knee function 
in comparison to the non-operated group after 2 and 5 years.  
 
The alternative hypothesis is that there that partial meniscal replacement does improve mean PROMs for 
knee function in comparison to the non-operated group after 2 and 5 years.  
 
The PROMS should improve (Mean KOOS and IKDC should increase by at least 20 points, and VAS-pain 
score should decrease by at least 3 points, or to near zero, depending on the pre-surgical value).  
Analysis of data will be performed by direct comparison of the groups at each time point and in comparison, 
to before surgery/start of the trial. Mean and standard deviation of the groups are compared. If there is a 
significant difference, the Null-Hypothesis will be rejected. Even when we have a loss of follow-up of 20% 
the power will still be 0.985. From our experience mean KOOS values presurgical are between 40-50 and 
between 50-60 for the IKDC, after treatment the expected improvement is to mean values between 80-90 for 
both scores. For the VAS-pain-score the presurgical mean value is around 4 and the post-surgical value is 
between 0 and 1. There is no risk of a type 1 error, because the values are measured several times over the 
follow-up period, thus there will be no false positive result. If the difference in the scores between pre- and 
post-surgery is lower than 18, the power is not big enough. Thus setting 20 as the difference for rejecting the 
Null-hypothesis is supported by enough power, even with only 8/24 patients in the respective group. The 
covariate could be smoking and sex. Smoking affects healing in general. It is not clear if there will be enough 
patients in each group to use these as confounders. Interactions will not be possible, because the treatment 
has no relation to any characteristic of the patient. There will be no adjustment made and no model fitting.  
 
9.2.2 Handling of Intercurrent Events of Primary Estimand(s) 
Intercurrent events are: progression of osteoarthrosis up to TKA, lost to follow up, premature death, the 
patient wishes to change to the operated group after a certain time. (as stated under point 3). 
Data obtained until the event will be included in the analysis, last observation will be included in the 
evaluation. In case of progression of osteoarthrosis up to TKA the procedure will be noted as fail. Premature 
death will be treated as lost to follow-up. Lost to follow-up and premature death can be unrelated to knee 
problems. If the patient wishes to change the treatment group, data are collected for this treatment up to the 
last treatment. If more than 20 % of patients fail, the benefit-risk balance will be re-evaluated, and it will be 
decided if the trial will be continued.  
 
9.2.3 Handling of Missing Data 
If the patient withdraws his consent, data up to this date will be used for the analysis. The last observation 
carried out will be the end point. Patient will be reported as withdrawn. 
Patients are not randomized and do not have therapy after surgery, they just have follow-up visits. There will 
be the full analysis set model for the analysis, thus all data from patients will be reported, which were 

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enrolled. If a patient is lost to follow up, the patient will be reported as this. 
For patients with progressing of osteoarthrosis up to TKA, they will be recorded as failed. Data up to the 
event will be analyzed.  
There will be no assumptions made for missing data. Data from last observation will be analysed. A drop-
out of 20% is accepted in orthopedic trials.  
 
9.2.4 Sensitivity Analysis 
The intercurrent events in this trial are progression of osteoarthrosis up to TKA, lost to follow-up, premature 
death and change to the other treatment group. Progression of osteoarthrosis up to TKA will be defined as 
procedure failure. Lost to follow-up and premature death can be unrelated to knee problems. Both will be 
defined as lost to follow up. Lost to follow-up will reduce the power of the result. A drop-out of 20 % is 
acceptable and will not bias the result. 
 
9.2.5 Supplementary Analysis 
Age, sex, and smoking may be subgroups. If there are enough patients for subgroups they will be analyzed. 
 
9.3 
Analysis Supporting Secondary Objective(s) 
Secondary objectives are: 
Safety of the patient, efficacy of the procedure, MRI image description and patient satisfaction.  
Patient safety will be analyzing the number of AE, SAE and SUSARs and will be compared for both groups. 
The numbers obtained will be compared in a Chi-Square test. SUSARs will only occur, if any, in the operated 
group and thus cannot be compared to any other value. For categorial variables. Efficacy of the procedure 
will be analyzed by counting the number of failed procedures in the operated group. Because this value will 
only be determined in the operated group, there is no statistical analysis. The efficacy of the procedure must 
be over 80%. If the failed procedures are higher than 20 % the benefit-risk balance will be re-evaluated. The 
MRI signal will be evaluated after a modified scheme of Genovese [32]. The size of the meniscus and the 
amount of extrusion of the meniscus will be measured and recorded in both groups. The obtained numbers 
will be compared to the other group at the same time point and to the value before surgery/at the beginning 
of the trial. This will be performed with an unpaired t-Test if the values are normally distributed or with the 
Mann-Whitney-U-test for not normally distributed values. Patient satisfaction is a categorial value and will 
be only evaluated in the operated group. The number of patients who are very pleased, pleased, not pleased, 
very unsatisfied will be described by means of frequency tables and plots. 
Intercurrent event are: progression of osteoarthrosis up to TKA, lost to follow-up, premature death, the 
patient wishes to change to the operated group after a certain time. If these events happen, the data will be 
available until the event. Last date recorded will be analyzed. Progression of osteoarthrosis up to TKA will 
be recorded as fail and will be reported as this. Patients changing to the operated group will be analyzed up 
to the date of change in the non-operated group. Missing data will not be estimated. A dop-out rate (lost to 
follow-up, premature death) of 20% is expected and accepted.  
 
9.4 
Analysis of Exploratory Objective(s) 
Exploratory Estimand (Variable): Progression of osteoarthrosis up to TKA. 
The number of patients with progressing osteoarthrosis up to TKA will be represented in a Kaplan-Meier-
survival curve for both groups. The equality of the curves will be assessed using logrank tests. 
 
9.5 
Safety Analyses 

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Patient safety will be analyzed by recording AE, SAE and SUSARs. The number of these events will be 
recorded and compared for both groups. SUSARs will only occur, if any, in the operated group. The 
frequencies obtained will be displayed in bar plots and tables with group comparisons based on Fisher´s exact 
test. Safety is a secondary outcome and is described in detail in 9.3. 
 
9.6 
Other Analyses 
The KOOS score has sub-scores: symptoms, pain, activity in daily live, sport and leisure, and quality of live. 
This sub-scores will be analyzed in detail for the 2 groups. There will be no adjusted analysis.  
 
9.7 
Interim Analyses 
Interim analysis will be performed 2 years after surgery/start of the trial. After knee surgery, the usual follow 
up is 2 years. Because long term results are important for the efficacy of the procedure, evaluations will be 
performed also after 5 years. The analysis will be performed by the investigator. The statistical methods used 
are described under 9.2 and 9.3. The outcome data will be seen only by the investigator while the trial is 
ongoing. The 2-years result will be published in an international orthopedic journal. There will be no group 
sequential test and no spending function. The number of patients is fixed at 30 in the operated group and at 
10 in the non-operated group. There will be no enrollment until an event occurs. There will be no trial 
adaptation or changes to the eligibility criteria. 
Stopping criteria are: If AE, SAE and SUSARs change the benefit-risk balance, there will be a new benefit-
risk balance evaluation and after this evaluation it will be decided if the trial will be stopped. The investigator 
expects a maximal 20% failure rate of the procedure. If the failure rate is higher a new benefit-risk balance 
evaluation must be performed and after the evaluation it must be decided if the trial continues. If the safety 
of the patients is not any more given, the trial should be stopped. 
The investigator also has the right to stop the trial. This could be because of the closure of the site. See 10.5 
for details. 
 
9.8 
Sample Size Determination 
The unpaired t-Test will be used for normally distributed PROMs. Values for the primary outcome are 
expected to be about 55/84 for the IKDC score and 46/86 for the KOOS pre/postsurgery, respectively. For 
this calculation, the program G-power was used. A sample size of 9 in the operated group and 3 in the non-
operated group would be sufficient to reach a power of 0.982.  When we include 10 non-operated patients 
and 30 operated patients the effect size is 2.0, α = 0.00655 and the power is than 0.993. If we have a 20% 
lost to follow-up, the numbers of patients will be 8/24 and α =0,014 and the power will be 0.985. The number 
of 30/10 is sufficient to reach a power of >0.8. 
 
9.9 
Protocol Deviations 
There will be no protocol deviations, because the surgery will be performed after a standardized procedure 
for each patient at the beginning of the trial and the follow-up visits will be performed after a predefined 
standardized protocol. There are no treatments planned after surgery. The tight follow-up plan will secure 
patient safety.  
 
 
 

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10 
GENERAL CONSIDERATIONS: REGULATORY, ETHICAL, AND TRIAL 
OVERSIGHT 
10.1 
Regulatory and Ethical Considerations 
The Investigator is also the sponsor. He is responsible for compliance with the below laws and regulations. 
The clinical trial will be conducted in compliance with the protocol, with the regulation and with the 
principles of good clinical practice according to Annex I section D 17 (a) CTR 536/2014, the declaration of 
Helsinki, the Council for International Organisations of Medical Sciences (CIOMS) International Ethical 
Guidelines, ICH Good Clinical Practice (GCP) Guidelines (the investigator holds the ICH-GCP-certificate). 
Additionally the German Bundesdatenschutzgesetz (BDSG) and the General Data protection Regulation 
(regulation (EU)2016/679), GDPR) will be followed. 
The study will only start after a positive ethic vote is obtained. 
The benefit-risk balance is in focus of the trial and will be evaluated when safety issues occur. The efficacy 
of the procedure is also in focus and only when the efficacy is over 80% the ethical balance is given. 
 
10.2 
Committees 
This is an investigator-initiated trial (Investigator=Sponsor). There will be no committee be involved in the 
trial. 
 
10.3 
Informed Consent Process 
The informed consent process starts with the first appointment. When patients are referred for partial 
meniscal replacement, they will be informed about the clinical trial. If the patient qualifies for participation 
in the study based on the inclusion and exclusion criteria, the investigator will explain the treatment 
procedure for partial meniscus replacement with Spongioflex® and the planned investigator-initiated trial 
(planned visits, data protection, etc.). Patients also receive an information sheet explaining the study and the 
surgical procedure, the advantages and disadvantages, the risks, and the follow-up treatment. The information 
sheet also provides information about the planned investigator-initiated study (planned visits, data protection, 
etc.). After a sufficient reflection period, the patient must sign the declaration of consent to participate in the 
investigator-initiated study and the data protection declaration. Without these written consents, the patient 
cannot be included in the investigator-initiated trial. After the signatures have been obtained, the patient is 
included in the investigator-initiated trial. The patient decides whether to undergo surgery. The operation is 
performed in accordance with standard clinical practice and the usual risk information for the surgical 
procedure. This is done using the standard information sheet used in the respective hospital. In this, patients 
are usually informed about the procedure, the treatment alternatives, the risks, and the follow-up treatment. 
Enrollment in the trial does NOT occur during an emergency in which the participant or their legally 
authorised representative is not able or available to give consent. 
 
Rescreening 
Rescreening can be performed when the patient did not meet the inclusion criteria (e.g. age) in the first 
attempt. If any exclusion criteria are not any more valid (e.g. BMI) rescreening can be performed. The 
screening will be performed even, when the patient does not agree to participate in the study, because than 
the patient will be treated/or not, but the data will not be collected for the study. The informed consent will 
be obtained after enrollment, when inclusion criteria are met and no exclusion criteria are met. Screen failure 
will be left in because the study model is full analysis set. When re-screening is performed informed consent 
is mandatory for participation in the study. 
There will be no collection of (biological) samples in the study.  
 

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10.4 
Data Protection 
All collected and stored data of the study participants are treated confidentially and are subject to medical 
confidentiality. The patient's right to respect his/her privacy and the protection of data concerning him/her is 
guaranteed in accordance with the General Data Protection Regulation (DSGVO) of 25.5.2018. The personal 
data are only accessible to the performing physician in the study center, who has included the patient, or to 
employees commissioned by him. The personal data will only be processed in pseudonymous form. For this 
purpose, the study center creates a pseudonymization list, which is only known to the authorized employees 
of the study center. The data are pseudonymized in ascending order for scientific analysis, so that third parties 
(biometricians) cannot establish a personal reference. In this study, the investigator and the sponsor are the 
same person. Therefore, no transfer of data between the investigator and the sponsor is necessary. 
Furthermore, it is intended that the investigator performs the analysis himself. If a biometrician (statistician) 
must be consulted for the evaluation, he will only receive the pseudonymized CRF, from which no 
conclusions can be drawn about the patient or the clinic in which the patient was treated. The 
pseudonymization will be performed by attributing numbers and special characters. Initials and birth dates 
are not used for pseudonymization and are omitted. For the patient, there is a right of access and objection at 
any time with the possibility to delete all collected data. Patients can withdraw their consent to participate in 
the study and to data collection at any time without giving reasons. This does not change medical treatment. 
The study is therefore a minimal interventional study, as the treatment is conducted in the same way with 
and without study participation. The only difference is that the data are only stored in the patient chart if the 
patient does not participate in the study and not transferred to the CRF after pseudonymization. If the patient's 
consent is withdrawn, the responsible bodies will immediately check the extent to which the stored data are 
still required. Data that are no longer required will be deleted immediately, unless statutory documentation 
and reporting obligations prevent this. However, the data processing conducted up to the point of withdrawal 
remains lawful. 
Safety of Data and patients is monitored by a CRA (clinical monitor).  
In case of a data security breach the patient will be informed about the breach without undue delay and at the 
latest within 7 days. Additionally, the data security breach will be reported to the EU portal and EU database 
(via the CTIS) without undue delay and at the latest within 7 days. The template provided at the CTIS should 
be filled in and all information which are described under 5 and appendix IIIb of the Guideline for the 
notification of serious breaches of Regulation (EU) No 536/2014 or the clinical trial protocol 
(EMA/698382/2021) from the 30th of June 2023. 
 
10.5 
Early Site Closure or Trial Termination 
Site closure: 
The Investigator and the Sponsor are the same person. The investigator has the right to close the site. This 
could be for physical or financial reasons. The ethic committee will be informed and a prompt notification 
of the patients will be performed. The treatment is the surgery and is terminated when the site is closed. The 
remaining follow-up’s will be performed by an orthopedic surgeon, who is familiar with the procedure and 
the follow-up. 
 
Termination or suspension: 
The investigator-initiated trial may only be terminated prematurely for ethically relevant, i.e., medical/ 
scientific reasons. 
Premature exclusion of a patient from the study: 
- 
If, during the waiting period for the Spongioflex® graft, changes in the patient's state of health occur 
that constitute a contraindication for partial meniscal implantation (e.g., infection of the knee joint, tibial 

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plateau fracture), the physician conducting the study must withdraw the patient from the investigator-
initiated trial if this appears reasonable and necessary for medical reasons. 
Premature termination of the entire study: Reasons for premature termination of the investigator-initiated 
trial include:  
- 
If the identifiable risks outweigh the expected benefits. 
- 
If an unreasonable risk to patients is apparent 
- 
If unexpected serious adverse events (SAE); Suspected Adverse Drug Reaction (SADR) occur that are 
causally related to the insertion of the meniscal implant they will be reported to the EudraVigilance 
database. A new benefit/risk balance evaluation is performed and after the analysis it is decided if the 
study will be continued. Patients will be followed up until the SAE or SADR is solved, if necessary, in 
the hospital, otherwise as outpatient. 
- 
IF SUSARs are reported, a new benefit/risk balance evaluation is performed and after the analysis it is 
decided if the study will be continued. 
If the investigator-initiated trial is terminated or suspended prematurely, the study director will inform the 
regulatory authority(ies) of the termination or suspension and provide a statement to that effect. The Ethic 
Committee will be promptly notified and provided with a detailed written explanation for the study director's 
termination or suspension of the investigator-initiated trial, as specified in the applicable regulatory 
requirements. If the investigator-initiated trial is terminated or suspended prematurely for any reason, study 
participants will be notified immediately. 
- In the event of premature termination or suspension of the investigator-initiated trial, further follow-
up of patients will continue according to standard clinical practice 
Patients can stop the participation of the study at any time, without giving the reason for it. 
 
 
 
 

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11 
GENERAL CONSIDERATIONS: RISK MANAGEMENT AND QUALITY 
ASSURANCE 
 
11.1 
Quality Tolerance Limits 
Quality tolerance limits are defined in the inclusion/exclusion criteria. The main criteria which may lead to 
exclusion of the patient from the trial are age (must be over 18 years and under 60 years) and BMI (must be 
<30 kg/m²). The investigator expects a 20% drop in total. If the drop-out will be higher, this could 
significantly impact the study results. Protocol deviations and violations will not occur, because the surgery 
is performed after a standardized procedure. The patient does not have any impact on this procedure. 
The percentage of withdrawal will be small, because the burden of the trial is very low (filling the 3 
questionnaires at the follow-up-visit). The investigator predicts a maximum of 5 % withdrawal, which is 
included in the 20% mentioned above. 
Incomplete data will occur due to lost to follow-up, withdrawal or due to progression of osteoarthrosis up to 
TKA. Progression of osteoarthritis is a very slow process; thus a 2.5% possibility would be defined by the 
investigator for incomplete data related to progression of osteoarthritis up to TK. 
AE and SAE occur at any time and may be not related to the IMP used. SAE not related to the investigational 
product do not impact study results. SADR/SUSAR’s do impact study results. Because human allogeneic 
cortical bone (in any supply form) was transplanted in different forms several thousand-fold, the 
manufacturer (DIZG gGmbH, Berlin, Germany) did not receive any information about and SADR or SUSAR 
up to now. 
The IMP is not a pharmacological drug and the administration is not over the trial period. The IMP will be 
implanted during surgery and remains in the body. It has no systemic effect and it is not a medical device. 
Patient follow-up will be the same for patients included in the trial or not, thus the lost to follow-up will be 
below 10 %, because the follow-up-visits are only a minimal burden. 
For ethical reasons, there is no randomization in the trial. The patient decides, if he will be operated, or not. 
Even if the patient will decide not to be operated in the first round, they have the possibility to change to the 
surgery group at any time. Thus, there is no pressure on the patient and there is no incorrectly randomized 
patient. 
All this Quality tolerance limits are monitored during the trial via a clinical monitor (CRA). 
 
11.2 
Data Quality Assurance 
This is an investigator-initiated trial. The private practice consists of an orthopedic surgeon and a part time 
medical assistant. The investigator is also the sponsor of the trial and is also responsible for quality assurance. 
A clinical monitor will verify the quality of the data. 
 
11.3 
Source Data 
Definition of Source Data:  
Source data includes all information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical investigation used for reconstructing and evaluating 
the investigation. 
The source data in this clinical trial are the electronic patient charts. They are attributable, legible, 
contemporaneous, original, and accurate and meet regulatory requirements. For this trial, this includes the 
MRI, the PROM’s, and the operative report (for the operated group). Data of patients who take part in the 
study will be transferred to the CRF in pseudonymized form. No date of birth or initials will be transferred. 
The pseudonymization list and the CRF will be only available to the orthopedic surgeon and the access is 
controlled and the hardcopy of the pseudonymization list and the CRF is saved in a safe. The investigator 

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permits trial-related monitoring, audits, IRB/IEC review and regulatory inspections providing direct access 
to source data/documents. The clinical monitor will regularly verify CRF-Data relative to source data. Safety 
of participants is protected and the conduct is in accordance with GCP.  
 
 
 

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12 
APPENDIX: ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS – 
DEFINITIONS, SEVERITY, AND CAUSALITY  
 
12.1 Further Details and Clarifications on the AE Definition 
There are no regional AE requirements. An adverse event log is filled to follow the adverse event until it is 
solved. 
A trial related adverse event is redness, haematoma, swelling, infection of the operated site and pain of the 
treated knee. This will be recorded in the electronic patient chart and in the CRF. 
Progression of osteoarthritis up to TKA does not meet AE definition; it is the normal progression of the 
disease and will be expected to be more observed in the non-operated group. 
The IMP of this clinical trial is human cancellous bone, there is no dose, there are only dimensions of the 
transplant. Thus, there is no overdose. 
Lack of efficacy of the procedure is provided when more than 20% of the procedures fail. 
 
12.2 
Further Details and Clarifications on the SAE Definition 
SAEs must be reported immediately to the IRB/IEC except for those SAEs that the protocol identifies as 
not needing immediate reporting. Additionally SAEs related to the IMP are reported to the EudraVigilance 
Data base and via the CTIS webpage. 
A trial related SAE is an allergic reaction against the IMP.  
Progression of osteoarthritis up to TKA does not meet SAE definition; it is the normal progression of the 
disease and will be expected to be more observed in the non-operated group. 
On the Webpage of the PEI there is a document 
(https://www.pei.de/DE/arzneimittelsicherheit/gewebevigilanz/meldeformulare/meldeformulare-node.html, 
Form G1a) to be filled in for :” Meldung des Verdachts einer schwerwiegenden unerwünschten 
Empfängerreaktion im Zusammenhang mit der Übertragung von Gewebe, Gewebezubereitungen oder 
Stammzellen gemäß § 63i AMG“ this form would be filled and send to the PEI. 
 
12.3 
Severity 
Definition Severity: 
Severity is the intensity of a specific event. The event itself can be of minor medical significance. 
- 
Grade 1: Mild — transient or mild discomfort (< 48 hours); no medical intervention/ therapy 
required. 
- 
Grade 2: Moderate — mild to moderate limitation in activity — some assistance may be needed; 
no or minimal medical intervention/ therapy required. 
- 
Grade 3: Severe — marked limitation in activity, some assistance usually required; medical 
intervention/ therapy required, hospitalization possible. 
- 
Grade 4: Life-Threatening — extreme limitation in activity; significant assistance required; 
significant medical intervention/therapy required, hospitalization, or hospice care probable. 
- 
Grade 5: Death. 
 
12.4 
Causality 
Definition Causality: Causality is an influence by which one event, process, state, or object (a cause) 
contributes to the production of another event, process, state, or object (an effect) where the cause is partly 
responsible for the effect, and the effect is partly dependent on the cause. It is an evaluation of the likelihood 
that a particular treatment is the cause of an observed adverse event (AE).  
 

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Causality Categories: 
- 
definitely related 
- 
probable 
- 
possible 
- 
unlikely 
- 
unclassified/unassessable 
- 
Causality ruled out/unrelated 
 
Procedure for assessing methodology: (WHO Methodology) 
- 
definitely related: good timing, no other cause, withdrawal response plausible, rechallenge, 
“definite” 
- 
probable: good timing, other cause unlikely, withdrawal 
- 
possible: good timing, other cause possible 
- 
unlikely: poor timing, other cause more likely 
- 
unassessable: insufficient or contradictory information 
 
 
 
 

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13 
APPENDIX: DEFINITIONS AND SUPPORTING OPERATIONAL DETAILS 
 
13.1 
Contraception and Pregnancy Testing 
13.1.1 Definitions Related to Childbearing Potential 
Participants of childbearing potential are females which can become pregnant. These patients can take part 
in the study, but when they decide for the operated group, they must make a pregnancy test before surgery. 
After surgery they can become pregnant. This does not influence study results.  
All patients with non-childbearing potentials are male or female after menopause. They can take part in the 
study without a pregnancy test. 
 
13.1.2 Contraception 
Contraception does not have to be taken. A pregnancy test before surgery is sufficient for childbearing 
potential patients who wish to be operated. 
 
13.1.3 Pregnancy Testing 
Pregnancy testing is only required for patients who will be operated and have childbearing potential. 
 
13.2 
Clinical Laboratory Tests 
Trial specific laboratory testing is not necessary and not planned. Only the normal laboratory testing will 
be performed for patients who will be operated. 
 
13.3 
Country/Region-Specific Differences 
The trial will be conducted only in Germany, there are no country/region specific differences to the above 
explained rules. 
 
13.4 
Prior Protocol Amendments 
This protocol has not been amended 
 
 
 

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14 
APPENDIX: GLOSSARY OF TERMS 
 
Abbreviations 
AE; 
 
 
 
Adverse event 
BfArM 
 
 
Bundesinstitut für Arzneimittel und Medizinprodukte 
CMI:  
 
 
Collagen Meniscus Implant   
FSA-Kodex: 
 
 
freiwillige Selbstkontrolle der Arzneimittelindustrie 
ICRS  
 
 
International Cartilage Repair Society 
IKDC:  
 
 
International Knee Documentation Committee Score 
IMP:  
 
 
investigational medicinal product 
IRB/IEC 
 
 
Institutional Review Board/Institutional Ethic Committee 
KOOS: 
 
 
Knee injury and Osteoarthritis Outcome Score 
PEI 
 
 
 
Paul Ehrlich Institut 
PROM: 
 
 
Patient Recorded Outcome Measures 
SADR: 
 
 
Serious adverse Drug reaction 
SAE:  
 
 
Serious adverse event 
SUSAR: 
 
 
Suspected Unexpected Serious Adverse Reaction 
TKA:   
 
 
total knee arthroplasty 
VAS Pain Score: 
 
Visual analogue pain scale 
 
 
 

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15 
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