Focal Cartilage Defects in the Knee -A Randomized Controlled Trial Comparing Autologous Chondrocyte Implantation With Arthroscopic Debridement
Phase: NA
Conditions: Knee Injury, Cartilage Injury
Sponsor: University Hospital, Akershus

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21.10.15 
 
Focal cartilage defects in the knee –A randomized 
controlled trial comparing autologous chondrocyte 
implantation with arthroscopic debridement  
NCP – Chondrocyte implantation 
 
 
 
 
 
Per-Henrik Randsborg 
Asbjørn Årøen 
 
 
Oslo 
Norway 2015 

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Table of contents 
 
1. STUDY SYNOPSIS 
2. SHORT SUMMARY 
3. INTRODUCTION  
3.1. Background 
3.2. Purpose of this study 
4. REASEARCH DESIGN 
4.1. Participants 
5. MATERIALS AND METHODS 
5.1. Participants 
5.2. Randomization  
5.3. Operative procedure 
5.4. Operative procedure – blood and tissue samples for parallel study 
5.5.Post-operative management 
5.6.Rehabilitation protocol 
6. VARIABLES 
6.1. Demographics 
6.2. Primary endpoint 
6.3. Secondary endpoint 
7. HYPOTHESIS, STATISTICAL ANALYSIS AND SAMPLE SIZE 
7.1. Hypothesis for the primary aim 
7.2. Statistical analysis   
7.3. Sample size  
8. SECONDARY PROJECTS 
8.1. Cost-effectiveness analysis  
8.2. Parallel study: “Healer-NonHealer” 
9. INSTITUTIONS AND RESPONSIBLE INVESTIGATORS 

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9.1. Institutions 
9.2. Responsible investigators  
10. ETHICS 
11. QUALITY-SECURITY CONTROL/SAFE STORAGE OF SENSITIVE DATA 
12. RISK ASSESSMENT  
13. COST AND FINANCING PLAN 
13.1. Cost 
13.2. Financing plan 
14. TIME SCHEDULE AND PUBLICATION PLAN 
14.1. Time schedule 
14.2 Publication plan 
15. STUDY ORGANIZATION 
16. REFERENCES  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. STUDY SYNOPSIS: NCP – Autologous Chondrocyte Implantation 
Topic  
Details  
Protocol Title:  
Focal cartilage defects in the knee – A 
randomized controlled trial comparing 
Autologous Chondrocyte Implantation with 
arthroscopic debridement  
Study Type:  
Clinical  
Indication:  
Compare the effect of Autologous 
Chondrocyte Implantation (ACI) with 
arthroscopic debridement (AD) in patients 
with symptomatic full thickness knee 
cartilage injuries larger than 2cm2.  
Hypothesis Statement  
Focal cartilage injuries in the knee might 
have devastating effect both in the short 
term and in the long term. Various surgical 
treatment options are available; with ACI 
established as a recognized treatment 
method for larger lesions. Meta-analysis 
and systematic reviews have required well-
designed, long-term, multicenter studies to 
evaluate clinical outcomes of ACI with the 
use of a “no treatment” group as a control 
group.  
H0: There is no difference in KOOS QoL 
after ACI or AD from baseline to 24 months 
after surgery.  
H1: There is a difference in KOOS QoL 
after ACI or AD from baseline to 24 months 
after surgery.  
Study Objectives:  
Questionnaires: KOOS, Tegner score, 
Lysholm score, EQ-5D, VAS.  
Physical examination: range of motion and 
hop test.  
Radiology: x-ray and MRI of the knee.  
Primary aim: KOOS quality of life (QoL) 
subscore.  
Study Design:  
Prospective, single-blinded parallel-group 
bicenter study with 2 treatment arms.  
Duration of Study Participation:  
Approx. 36 months inclusion and 24 months 
follow up. In total 5 years.  
Follow-up Period:  
24 months. All will be invited to participate 
in late controls after 5 and 10 years.  
Study Location:  
2 Norwegian hospitals: Akershus University 
Hospital and Oslo University Hospital – 
Ullevål.  
Number of Planned Subjects:  
82 patients  
Study Population:  
Inclusion: age 18-50 years old, single 
symptomatic cartilage defect on femoral 
condyle or trochlea, defect size larger than 2 

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cm2, defect ICRS grade 3-4, ligamentous 
stable knee, range of motion 5-105°, 
Lysholm score < 75 and informed consent.  
Exclusion: Osteoarthritis, rheumatoid or 
other systemic arthritis, malalignment > 5° 
measured on x-rays, BMI > 30, 
comorbidities that may influence surgery or 
rehabilitation, pregnancy, inability to 
complete questionnares or rehabilitation, 
serious alcohol or drug abuse, previous 
cartilage surgery to the chondral defect 
except OCD surgery.  
Treatment Groups:  
2 treatment groups with 41 patients in each 
group.  
Visit Schedule:  
3 months (± 2 weeks), 6 months (± 4 
weeks), 12 months (± 6 weeks) and 24 
months (± 8 weeks). All will be invited to 
participate in late controls after 5 and 10 
years.  
Safety Assessments:  
If any unforeseen complication outside 
normal clinical practice occurs, the sponsor 
representative will be contacted as soon as 
possible with a parallel message to the local 
coordinators at the involved hospitals. 
During each follow up, there will be a case 
report form (CRF) regarding complications 
and safety.  
Sample Collection:  
A 5 mL venous blood sample will be drawn 
on the day of operation. The blood sample 
will be centrifuged before serum is pipetted 
in a sterile tube. The serum will be analyzed 
at Oslo University Hospital – Rikshospitalet 
on the cartilage biomarker microRNA-140 
(miR-140).  
During the open chondrocyte implantation 
the excess cartilage debrided from the rim 
of the lesion will be sent for similar 
microRNA-140 (miR-140) analysis. 
(applicable for the 41 patients in the ACI 
arm only) 
Overview of Statistical Plan:  
If normal distribution, aims will be analyzed 
using linear mixed models (LMM), and the 
primary aim will be performed as a post hoc 
test for the LMM, similar to performing a 
two-sample t-test. If no normal distribution, 
analysis will be performed using Mann-
Whitney U-test.  
Sample Size Determination:  
Detecting a difference of 10 in primary aim 
with 80% power using a standard deviation 
of 15. A p < 0,05 is statistically significant. 

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This gives 37 patients in each group, adding 
10% drop out meaning 41 patients in each 
group and 82 in total.  
Interim Analysis:  
No interim analysis will be done.  
Ongoing Data Monitoring Plan:  
Monitor at Akershus University Hospital. 
Study Stopping Rules:  
Inclusion of 82 patients.  
End of Study:  
The end of this study is 24 months after the 
last included patient.  
Operational Risk Analysis:  
Inability to include 82 patients in 3 years. 
May prolong the inclusion period, or add 
other including hospitals in the study.  
Study Target Dates:  
See table below.  
 
Milestone  
Study Timeline: Target Date 
(Month/Year)  
IND Submitted (if appropriate)  
October 2015  
First Patient In (FPI)  
March 2016  
Last Patient In (LPI)  
March 2019 
Last Patient Out (LPO)  
March 2021 
Database Lock (DBL)  
April 2021 
First Look (FL)  
May 2021 
CSR Completed  
December 2021 
 
 
 
Tests and assessments 
Inclusion 
Surgery 
3 months
6 months
12 
months 
24 
months 
Medical History 
X 
 
X 
X 
X 
X 
Physical Examination 
X 
 
X 
X 
X 
X 
Questionnaires 
X 
 
X 
X 
X 
X 
X-ray 
X 
 
 
 
 
X 
Informed Consent 
X 
 
 
 
 
 
Randomization and surgery 
 
X 
 
 
 
 
Serum and cartilage sample 
 
X 
 
 
 
 
MRI 
 
 
 
 
 
X 
Adverse Events 
 
 
Monitor and record throughout the study 
Study Activities 

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2. SHORT SUMMARY 
Focal cartilage injuries in the knee might have devastating effect both in the short term and in 
the long term due to the predisposition of early onset osteoarthritis. To this date, various 
surgical treatment options are available. Since its introduction in the late 1980s, autologous 
chondrocyte implantation has become a recognized treatment option for larger cartilage 
lesions in the knee. In this study we want to increase clinical and economic knowledge about 
autologous chondrocyte implantation compared to arthroscopic debridement in the short and 
long run. 
3. INTRODUCTION 
3.1. Background 
The articular surfaces of joints are covered with hyaline cartilage, a unique tissue with 
extreme load shearing and low-friction properties. However, these characteristics come with a 
cost. It is aneural and avascular which explains its limited ability to self-repair[1-3]. Damage 
to the cartilage, which is common in young active adults, will therefore lead to permanent 
damage. These injuries are very common, with a reported prevalence of 12 % in the 
population [4]. Focal cartilage lesions predispose to development of early onset osteoarthritis, 
which in turn may lead to long rehabilitation periods and loss of function and time off work. 
Musculoskeletal problems are one of the major reasons for workers compensation and 
especially for younger patients this may lead to a significant reduced quality of life and loss of 
income [5-8]. Treatment of symptomatic cartilage injuries in the knee is therefore of 
particular interest and importance to the patient, the surgeon and the society [3, 9, 10]. 
The ideal treatment for isolated cartilage injuries aims at recreating a healthy hyaline-type 
tissue with similar strength and durability as the normal cartilage in the rest of the joint. 
Current surgical treatment options include debridement, microfracture, autologous 
osteochondral transplantation (mosaicplasty) and autologous chondrocyte implantation (ACI) 
[11-13]. Several studies conclude that microfracture is not effective for larger lesions [26, 27]. 
The purpose of arthroscopic debridement is to remove loose intraarticular tissue debris and 
inflammatory mediators down to the subchondral bone, but not through it [12]. ACI attempts 
to re-implant the patient’s own chondrocytes over the defect to permit the chondrocytes to 
heal back onto the bone and mature into a hyaline-like cartilage. ACI have been directly 
compared to microfracture and mosaicplasty in randomized controlled trials [20, 35, 36]. The 
results indicate improved knee function in (carefully selected) patients [14], but studies have 
been criticized for methodological weaknesses [15]. The Cochrane database reported that 
there is insufficient evidence to conclude that ACI is superior to other treatment strategies for 
treating full thickness cartilage defect of the knee [19].  
No statistically significant differences have been found between the different surgical 
treatments. This supports the suggestion that the improvement might be a result of the post-
operative rehabilitation rather than the surgery itself [16, 17]. Furthermore, inclusion in a 
clinical trial is known to improve symptoms by itself, known as the Hawthorne effect [18]. 

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All studies on cartilage reconstructive surgery have put the patients through a strict, careful, 
intensive and prolonged rehabilitation following the procedure, which could contribute to the 
clinical improvement observed. Wondrasch and co-workers implemented an active 
rehabilitation program in 48 patients with focal cartilage damage to a weight-bearing area of 
the knee [17]. None of the patients had any form of surgery to their injury. After three months 
there was a statistical significant and clinical meaningful improvement in KOOS score, load 
progression and hop score, to the point where 31 (65%) of the patients declined further 
surgery for their cartilage lesion. This indicates that good results can be achieve with 
physiotherapy alone. Dozin and coworkers compared ACI versus mosaicplasty, where all 
candidates where evaluated arthroscopically with debridement of the lesion 6 months prior to 
definitive treatment [20]. All candidates completed an intensive rehabilitation protocol 
following the debridement, but before the cartilage surgery. This included non-weight bearing 
for two weeks and immediate active and passive physiotherapy. After two weeks isometric 
and proprioception exercises were introduced, as well as gradually strengthening exercises.  
31 % of the candidates experienced substantial clinical improvement following the 
debridement and physiotherapy alone, and needed no further (surgical) treatment, questioning 
the need for cartilage treatment as a first port of call in such patients. The authors conclude 
that further randomized clinical trials are needed, where ACI should be compared to 
debridement alone. This is a missing link in our knowledge of cartilage reconstructive surgery 
and hampers further progression in cell therapy [20,33]. 
. 
 
3.2. Purpose of this study 
The purpose of this trial is to compare autologous chondrocyte implantation (ACI) with 
arthroscopic debridement (AD) in symptomatic cartilage injuries larger than 2 cm2 in patients 
aged 18-50 years old in regard to both subjective and objective variables at predefined times 
as described under “variables” in section 6.   
 
4. RESEARCH DESIGN  
The study is part of “The Norwegian Cartilage Project (NCP): A multidisciplinary Approach 
to Improve the Treatment of Injured Articular Cartilage”, which is a total of five studies 
regarding cartilage injuries in the knee, including clinical trials, register studies and basic 
research studies. 
This study is a prospective, randomized, controlled study with 2 treatment arms (ACI and 
AD). The study will be conducted at Akershus University Hospital and Oslo University 
Hospital with multicenter inclusion contribution from other Norwegian institutions which 
together form the NCP network of hospitals: These hospitals are in addition to Akershus and 
Oslo University Hospitals: Kristiansund Hospital, Haukeland University Hospital, Ålesund 
Hospital, Diakonhjemmet Hospital and Buskerud Hospital. 

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Because one treatment arm consists of a two stage surgery, with a mini-open arthrotomy, 
while the other treatment arm is a single stage arthroscopy, it will not be possible to blind the 
patients as to what treatment they have received.  
Inclusion and treatment will take place at Akershus University Hospital (Ahus) or Oslo 
University Hospital (Ullevål). .The follow up appointments will be performed at Ahus or at 
the local NCP affiliated hospital by an external reviewer connected to the NCP group. The 
follow up will be blinded so that the examinator is unaware of which treatment arm the 
patient belongs to. To achieve this, the patient is instructed not to reveal the nature of the 
treatment he/she has received, and an opaque elastic stocking is put over the knee to conceal 
the scars (which are different between the treatments).  Follow up is planned to 2 years, but 
each participant will also be invited to clinical and radiological follow ups after 5 and 10 
years. 
4.1. Participants 
The study will include a total of 82 patients, both men and non-pregnant women, with a full 
thickness or osteochondral defect in the weight bearing area of the femoral condyles or 
trochlea larger than 2 cm2. The lesion must be symptomatic, with a Lysholm score less than 
75 [34]. The inclusion criteria are based on the recommendations by Brittberg [22], and 
include patients aged 18 to 50 years old with a stable knee, good range of motion (ROM), 
normal alignment (less than 5° varus or valgus measured on hip-knee-ankle (HKA) angle 
images) and no sign of radiologically osteoarthritis classified after Kellgren-Lawrence [37]. 
The weight-bearing, fixed-flexion posteroanterior radiographs will be obtained with the 
SynaFlex X-ray positioning frame (Synarc) [38]. 
5. MATERIALS AND METHODS  
All patients will be assessed clinically as well as radiologically prior to inclusion to avoid 
peroperative exclusions. The full thickness or osteochondral defect will be verified 
arthroscopically as a grade 3 or 4 lesion according to the International Cartilage Repair 
Society (ICRS) [39]. Still, some patients might not be included peroperatively based on 
arthroscopic findings such as osteoarthritis, less than 50% normal meniscus or inappropriate 
size of the lesion [40]. The definitive inclusion of the patient will be performed by the 
operating surgeon during the diagnostic arthroscopy, prior to randomization. Patients who will 
be excluded based on peroperative findings will receive appropriate treatment according to 
the standard of care at the local hospitals.  
Exclusion criteria include general osteoarthritis, systemic arthritis, severe co-morbidities that 
may influence surgery or rehabilitation potential, significant alcohol or drug abuse, 
psychiatric disorders, language barriers, pregnancy, severe obesity (body mass index > 30) 
and previous surgery to the chondral defect such as previous microfracture (previous cruciate 
ligament reconstruction, fixation of osteochondritis dissecans lesions, alignment procedures 
(osteotomies) or meniscal surgeries are not exclusion criteria). Patients declining participation  
in the trial (and who fulfill the inclusion criteria) or withdrawing underway will receive 
appropriate treatment according to the standard of care at the local hospital. 

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RANDOMIZATION  
during diagnostic 
Autologous Chondrocyte Implantation
(Cartilage harvest during diagnostic arthroscopy) 

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The participants will also receive information about a parallel study (Healer Non-healer 
study) regarding obtaining venous blood samples, which also is part of the Norwegian 
Cartilage Project. For more information, see “Operative procedure – blood samples for 
parallel study” in section 5.4 and “Additional and secondary projects” in section 8.2. 
 
 
Inclusion criteria 
Exclusion criteria 
-Age 18-50 years old 
-Single symptomatic cartilage defect 
on medial or lateral femoral 
condyle or trochlea 
-Defect size larger than 2 cm2 
-Lesion graded ICRS 3-4 
->50% intact meniscus 
-Ligamentous stable knee  
-Acceptable range of motion  (5-105°) 
-Lysholm score < 75 
-Informed consent 
-Osteoarthritis, rheumatoid or other 
systemic arthritis 
-Malalignment >5° measured on HKA 
images 
-No radiological osteoarthritis 
-Obesity (Body mass index > 30) 
-Comorbidities that may influence 
surgery or rehabilitation 
-Pregnancy 
-Inability to complete questionnaires 
or rehabilitation 
-Serious alcohol or drug abuse 
-Previous surgery to the chondral 
defect except OCD surgery 
Inclusion and exclusion criteria  
 
5.2. Randomization 
The randomisation will be performed using an computer generator (randomization.org). 82 
patient will be block randomized in pairs of six-eight (1:1) to treatment allocations. Each 
patient receives a patient number (1 through 82) on inclusion. Randomization will be printed 
in faded text and concealed in opaque numerically marked envelopes. The printing and 
concealing will be done by a person working at Akershus University Hospital, but is not 
involved in the study, to secure blinding. The randomization process occurs in the operation 
theatre during the arthroscopy after the operating surgeon has measured and graded the lesion 
to fulfill the inclusion criteria (see section “4.3 Operative procedure”). 
 
5.3. Operative procedure 
In this study Autologous Chondrocyte Implantation (ACI) is compared with Arthroscopic 
Debridement (AD). All patients will undergo a diagnostic arthroscopy, and patients 
randomized to AD will have this procedure performed at the end of the diagnostic 
arthroscopy, while for the patients in the ACI group the chondrocyte implantation will take 
place two weeks later in a second stage operation as described below. The ACI technique is 
based on the technique described by Brittberg [23]. 

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Diagnostic arthroscopy: 
Three standard incisions are made (supralateral for the patella and medial and lateral for the 
patellar tendon). A thorough diagnostic arthroscopic examination is then done. Removal of 
loose bodies and other necessary intraarticular procedures are done first (meniscus, plica). 
The focal cartilage lesion is then measured using a standard 4-mm arthroscopic probe and 
ICRS graded [39, 40].  
Then either arthroscopic debridement (AD) or autologous chondrocyte implantation (ACI) is 
done, depending on randomization.  
 
Autologous Chondrocyte Implantation 
ACI is a three stage procedure taking place at Akershus University Hospital and Oslo 
University Hospital (Ex-Vivo Laboratory) over a two week period. 
Stage 1: Debridement and cartilage harvest.  
Stage 1 includes a diagnostic arthroscopy with full inspection of the knee joint to ensure the 
inclusion criteria are fulfilled. Loose bodies are removed, any meniscal pathology is 
addressed. Inflamed synovium is debrided. The lesion is stabilized by debridement around the 
edges and down to the subchondral bone using a ring curette, but not through it, as described 
above.  Cartilage biopsy is then taken from the non-weightbearing area of the medial aspect of 
the femoral notch. If this area does not contain enough healthy cartilage, the secondary donor 
site will be the non-weight bearing aspect of the lateral femoral condyle. Complications or 
donor site morbidity following arthroscopic harvesting of cartilage in this manner has not 
been described [22].   
Stage 2: Chondrocyte growth in Ex Vivo Laboratory Rikshospitalet, Oslo University Hospital 
The harvested cartilage is transported to the cell culture laboratory (Ex Vivo Laboratory at 
OUS, directed by Professor Jan Brinchmann) in a sterile tube containing 0.9 % NaCl.  The 
cells undergo mechanical mincing and antibiotic washing, and isolation of the chondrocytes 
by overnight collagenase digestion. The chondrocytes are then cultured for two weeks and 
resuspended to a treatment density of 30 million cells/ml. The cells are then transported back 
to Ahus for implantation. 
Stage 3: Implantation of chondrocytes two weeks after initial arthroscopy. 
The chondrocyte implantation is performed under general or spinal anesthesia, and a 
tourniquet inflated to 300 mmHg to achieve a blood-less field is applied to the upper thigh. A 
mini-open arthrotomy (medial or lateral depending of the location of the lesion) is performed 
and the lesion is assessed. The lesion is curetted down to subchondral bone, but care is taken 
to avoid bleeding. The surrounding cartilage is debrided to healthy tissue, exposing the lesion 
to bare bone. The lesion is measured and a template of sterile aluminum foil is used to model 
the exact shape of the lesion, overcorrecting with 1-2 millimeters. 

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The template is then used to cut out a matching piece of collagen sheet (ChondroGide® 
(Geistlich Pharma, Switzerland)) which is used to contain the cells in the defect.  The flap is 
sutured to the lesion with 6.0 resorbable stitches and sealed with fibrin glue, leaving and 
opening at the upper part for injection of the cells. Saline is injected to the cavity to check for 
leakage, then aspirated before the cells are slowly injected using a soft catheter. The last 
opening is then closed with a last stitch and fibrin glue. The knee is then closed in the 
standard manner, taking care to close the capsule with subcutaneous resorbable sutures, 
before closing the skin incision with nylon sutures. 
 Arthroscopic Debridement  
The AD group will be subjected to a diagnostic arthroscopy with a full inspection of the knee 
joint to ensure the inclusion criteria are fulfilled. Lose bodies are removed, any meniscal 
pathology is addressed. Inflamed synovium is debrided. The lesion is stabilized by 
debridement around the edges and down to the subchondral bone using a ring curette, but not 
through it. Microfracture or any other cartilage treatment will not be performed. 
No intra-articular local anesthetics will be used due to the possible harmful effect on cartilage 
[41-43].  
All the operating surgeons will receive proper training in the operative procedure before study 
start. 
 
5.4. Operative procedure – blood samples for parallel study  
On the day of surgery, all patients will have a 5 mL venous blood sample drawn through a 
standard puncture of vena cubuti in the elbow using a 22 gauge needle. The fasting blood 
sample will be taken after 30 minutes of bedrest, to limit the influence of preceding physical 
activity. The blood sample is part of the healer – nonhealer study by professor Jan 
Brinchmann at Oslo University Hospital – Rikshospitalet. For more information see Section 
“7.2. Parallel study: “Healer / NonHealer” 
 
5.5. Post-operative management 
The two treatment groups will receive identical postoperative care. The patients are usually 
admitted to the hospital for up to 4 days. No intravenous prophylactic antibiotics is given, 
anti-thrombotic prophylaxis is given only when there is a risk of thromboembolic disease 
(such as previous deep vein thrombosis or pulmonary embolus, protein C or S deficiency, 
Leiden V mutation and use of contraceptive pills). All patients will be given a sick leave up to 
2 weeks after the operation. 
If a patient experiences complications during treatment such as wound infections, catching or 
locking etc. the patient will receive medical attention and follow-up according to the problem.  

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5.6. Rehabilitation protocol 
The two treatment groups will receive identical rehabilitation protocol according to a modification of 
Wondrasch et al [17]. The study will have a designated study physiotherapist, Heidi A. Hanvold, 
leading the rehabilitation program along with the patients local physiotherapist. 
 
Rehabilitation 
phases 
Physiotherapy and 
activities 
Objectives 
Criteria for progression to next 
phase 
Phase1: 
Accomodation 
  
Education/coaching 
 
Ice, elevation and 
compression 
 
Isometric exercises 
 
Range of motion 
 
Gait training (no weight-
bearing for two weeks) 
Reduce pain and 
swelling 
 
Normalize range of 
motion 
 
Regain quadriceps 
control 
No pain & swelling during 
activities of daily living (ADL) 
 
Flexion 90° 
 
Normalized quadriceps activity 
while walking (clinical evaluation 
by the physical therapist) 
Phase2:  
Rehabilitation 
  
  
  
  
  
Stationary bike cycling 
 
Progressive knee and hip 
resistance training 
 
Neuromuscular training  
Recovery of full range 
of motion 
  
Normalize muscle 
strength 
  
Dynamic joint stability 
during ADL 
Full range of motion 
  
No pain or swelling during and 
after training sessions 
 
Equally distributed weight on the 
lower limbs during weight-
bearing exercises with no shift of 
the trunk (visually assessed by 
the physical therapist) 
  
Ability to stand on 1 limb on a 
flat surface for at lest 10 seconds
Phase 3: 
Return to 
activity 
Knee and hip resistance 
training 
 
Neuromuscular training 
 
Cardiovascular training 
Recovery of strength 
and neuromuscular 
control 
 
Return to activity/sport 
 
Return to sport  based on 
individual assessment 
 
Rehabilitation protocol (identical for both groups). 
 
The patients are admitted to the hospital for 2-4 days. The patients are seen by a 
physiotherapist and the surgeon day 1 after surgery to be instructed in range of motion 

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exercises and restrictions according to Phase 1. The patient is seen within two weeks by a 
local  physiotherapist who has received information about the rehabilitation program, and who 
will follow the patient through the program, supervised by the Project Physiotherapist (Heidi 
A Hanvold). 
 
The rehabilitation program is an active rehabilitation and education program divided into 3 
phases: accommodation (1), rehabilitation (2) and return to activity (3). During the 
rehabilitation program the physical therapist focuses on explaining why the exercises are 
important and how the exercises should be performed and adjusted based on pain response 
and other symptoms. The rehabilitation program consists primarily of cardiovascular and 
knee/hip progressive resistance and neuromuscular training, including balance and plyometric 
exercises. The local physical therapist receive information about the rehabilitation program, 
including what kind of exercises the patients should perform.  
 
To monitor the adherence to the rehabilitation program, all patients are asked to use training 
diaries to provide information about frequency, type of exercise, load progression and number 
of repetitions. In addition, the patients are asked to respond every second week to an online 
survey, with the questions; 1. Have you been to a supervised physical therapy session during 
the last two weeks?, 2. How many physical  therapy sessions did you attend during the last 
two weeks?, 3. What kind of training/exercises have you performed during the physical 
therapy sessions?, and 4. What kind of activities have you performed during the last two 
weeks? All questions are followed by several predefined answers (closed answers), but also 
open answers are included to make comments if required. The online survey will continue as 
long as the patient is under the care of a physiotherapist, while the training diary will be 
continued to the end of the project (24 months) to estimate the amount of home exercise 
performed by the patient.  
 
Phase 1 - accomodation:  
Inpatient rehabilitation consists of placing the leg in a Continuous Passive Motion (CPM) 
machine within the range as tolerated due to pain and swelling, aiming to achieve 30-70° day 
1 after surgery. The patients should use the machine for 6-8 hours every 24 hours. The 
physical therapist instructs the patients in exercises such as active dorsiflexion/ plantar flexion 
of the ankle to encourage lower extremity circulation and isometric contraction of the 
quadriceps, hamstrings, and gluteal musculature to maintain muscle tone and minimize 
muscle loss. This also includes abduction exercises for the hip. The patients remain non-weight 
bearing for two weeks, but are allowed touch-down weight-bearing (the foot or toes may 
touch the floor, but not support any weight) through the affected limb using crutches.  
 

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When discharged from the hospital, the patients are encouraged to continue range of motion 
exercises; flexion/extension of the knee 500 repetitions three times a day. In this phase, 2 to 3 
supervised physical therapy sessions are scheduled for each patient. Interventions such as ice, 
compression, electrical muscle stimulation, muscle activation of the quadriceps, hamstrings, 
gastrocnemius and gluteal muscles and gait training is included. Swimming is allowed when 
the wounds are healed. 
 
After two weeks, protected weight-bearing is carefully introduced within the pain threshold 
and gradually increased up to full weight-bearing (continues into phase 2). Crutches are used 
until the patient walks normal without limping. 
 
Phase 2 - Rehabilitation: 
The patients attends 2 or more supervised physical therapy sessions per week, in addition they 
perform 1 to 2 unsupervised training sessions per week. Cardiovascular training on a 
stationary bike and progressive knee and hip resistance training and neuromuscular training 
are performed in this phase. All strengthening exercises are performed with both the injured 
and uninjured limbs. When full weight-bearing is achieved, long distance walking with 
increasing distances is encouraged and cross-country skiing can be allowed. 
 
Phase 3 – Return to activity/sport: 
This phase is individualized according to the goals for each patient.  The patients attend 1 or 
more supervised sessions per week, in addition they perform resistance training for a 
minimum of 2 and a maximum of 4 sessions per week. Cardiovascular and neuromuscular 
training can be performed daily. Where a return to sport is planned, it is important that sport-
specific activities are included as functional progressions within the rehabilitation program.  
 
6. VARIABLES 
6.1. Demographics 
Demographics to be collected at inclusion is age, gender, height (cm), weight (kg), BMI, 
injury mechanism (if any), previous medical history, current medication, smoking, social 
status, work status and nationality. 
 
6.2. Primary endpoint 
The Knee Injury and Osteoarthritis Outcome Score (KOOS) is a patient reported outcome 
measure validated to use in cartilage research studies and will enable comparison of our 
results with other reports.  It assesses five domains; pain, symptoms, activity of daily living, 

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sport and recreational function and knee-related quality of life [44]. KOOS knee-related 
quality of life (QoL) subscore is the primary endpoint, where the primary aim is the difference 
in KOOS QoL subscore in the ACI group compared to the AD group at 2 years follow up. 
There will not be any interim analysis before 2 years follow up. 
 
6.3. Secondary endpoints 
A combination of self-explanatory questionnaires, clinical parameters, clinical hop tests and 
radiographs and Magnetic Resonance Imaging (MRI) will be used as secondary endpoints. 
The secondary aims will be the difference between the two treatment groups and within the 
group at predefined times as described below. The secondary aims are: 
• KOOS score: all subscores except the knee-related QoL subscore which is the primary 
aim. 
• Tegner score; To evaluate the level of physical activity. 
• Lysholm score; A condition-specific outcome score containing eight domains; limp, 
locking, pain, stair-climbing, use of support, instability, swelling and squatting. 
• EQ-5D; A generic measure of health status that provides a simple descriptive profile 
used in the clinical evaluation of health care. EQ-5D is also widely used by clinical 
researchers and recommended for use in cost-effectiveness analyses by the 
Washington Panel on Cost Effectiveness in Health and Medicine [45] and by the 
International Society for Pharmacoeconomics and Outcomes Research (ISPOR) task 
force on good clinical practices: Randomized Clinical Trial-Cost-Effectiveness 
Analysis (RCT-CEA) [46].  
• Visual analogue scale (VAS); A visual analogue scale for pain, where 0 represents no 
pain and 10 represents the worst pain imaginable. 
• Range of motion (ROM) will be measured with a goniometer  
• Costs; resource use related to the intervention, medication, rehabilitation, use of health 
care services and production loss. 
• The patients will also provide information about work (return to work) physical 
activity and return to sport.   
All outcome questionnaires will be completed by the patients before surgery (pre-operative or 
baseline values) and at the designated research follow-up appointments at 3 (±2 weeks), 6 (±4 
weeks), 12 (±6 weeks), and 24 (±8 weeks) months.  
At 24 months follow up, there will be 3 additional elements consisting of: 
• Standing x-rays to evaluate any development of osteoarthritis.  
• Magnetic Resonance Imaging (MRI); assessing the quality of the cartilage tissue, 
using a specific cartilageMRI technique, to assess the healing of the defect. 
• A hop test, validated and described previously by Noyes, to assess clinical function 
[47]. 

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We will also invite patients to attend a 5 year and 10 year follow up appointment. During 
these late controls, all the primary and secondary outcomes will be assessed for as described 
above.  
 
7. HYPOTHESIS, STATISTICS ANALYSIS AND SAMPLE SIZE 
7.1.Hypothesis for the primary aim 
Null hypothesis: There is no difference in KOOS subscore quality of life following ACI or 
AD treatment of a symptomatic cartilage defect (>2 cm2) in the weight bearing area of the 
knee 2 years after surgery.  
The alternative hypothesis claims that differences between ACI and AD in KOOS quality of 
life subscore exist. 
7.2.Statistical analysis 
Demographic and clinical characteristics will be presented as means and standard deviations 
(SD) or frequencies and percentages, as appropriate. The normality of continuous data will be 
assessed by examining the histograms. If necessary, a suitable transformation will be 
considered to symmetrize the data.  
Due to along follow-up period with 5 (7) measurement points, repeated observations will be 
available for each patient. A mixed model correctly adjusting for intra-patient correlations 
will be used to assess the trend in primary and secondary end-points. The model will contain 
random effects for intercepts and slopes, if significant. Fixed effects for time (likely non-
linear) and group will be included together with the interaction between the two. The 
interaction will quantify possible differences between arms regarding time profiles and serve 
as an omnibus test. For continuous end-points, linear mixed model will be estimated, while 
generalized linear model will be fitted to dichotomous end-points. Relevant pairwise 
comparisons will be performed by deriving individual time point contrasts within each study 
arm. The results will be presented as estimated means of odds ratios together with the 
corresponding 95% confidence intervals (CI) and p-values. The estimates will further be 
adjusted for possible confounders such as age of the patient and severity of the cartilage lesion 
in the multivariate regression models. 
The results with p-values below 0.05 will be considered statistically significant. Two-sided 
tests will be used. The data analysis will be conducted using SPSS v.22 (SPSS Inc, Chicago, 
Illinois) and SAS v 9.4. 
 
7.3.Sample size 
It has previously been shown that a change in subscore of 8-10 of KOOS QoL (quality of life) 
is clinically significant [48,49]. Therefore, for power analysis a difference in change of 10 

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between two treatment groups was assumed.  A SD for change of 15 [32] was used. With the 
power of 80% and significance level of 5% the estimated minimum number of patients was 37 
in each group. By adding 10% due to loss during follow-up, we therefore plan to include a 
total of 82 patients.  
 
8. SECONDARY PROJECTS 
8.1. Cost-effectiveness analysis 
In addition to the prospective randomized trial, we will also conduct a treatment-cost analysis. 
By recording the cost of each treatment, need of sick leaves, cost of additional doctor’s 
appointments and repeated surgery due to recurrence or complications, we will estimate the 
cost effectiveness and not only the functional results. This provides the necessary economic 
frame of reference from which to resolve treatment recommendations. 
To assess the cost-effectiveness of the two treatment we need to estimate both health outcome 
and costs. The health outcome will be measured by means of EQ-5D, while costs will include 
costs in the health care sector and production loss. To estimate costs, we will include the cost 
of the interventions, which includes the use of other health care services (home care services, 
rehabilitation and institution) which will be registered for both groups. Standard methods in 
economic evaluation will be applied, and cost-effectiveness will be calculated by means of the 
incremental cost-effectiveness ratio, defined by the cost per incremental QALY. Further 
uncertainty will be displayed by applying the bootstrap method with 1000 replications to 
illustrate the variation in the patient population with regard to incremental health gain and 
cost.  
  
8.2. Parallel study: “Healer-NonHealer”  
Patients accepting enrollment, will also be asked participation in the “Healer-NonHealer” 
project run by Professor J. Brinchmann at Oslo University Hospital – Rikshospitalet. Patients 
will have a 5 mL venous blood sample drawn as described in Section “5.4 Operative 
procedure – blood samples for parallel study”. The fasting blood sample will be taken after 30 
minutes of bedrest, to limit the influence of preceding physical activity.  
With this blood sample, we want to investigate the concentration of microRNA-140 (miR-
140). MicroRNAs (miRNAs) are a class of endogenous and non-coding single-strand RNAs, 
and have been associated with various diseases [50, 51]. MiR-140 is cartilage specific, is the 
most prevalent miR in normal human cartilage and have shown to regulate homeostasis and 
development ofcartilage[52]. It has been found to play a significant role in cartilage 
pathogenesis [50, 53, 54]. Deletion of miR-140 in mice predisposed to osteoarthritis (OA) like 
changes [55], and decreased expression of miR-140 in OA cartilage may contribute to the 
abnormal gene expression pattern characteristic of OA [53, 55, 56].  

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Since miR-140 will be found in serum and not whole blood, the peripheral venous blood 
sample will be collected in sterile tubes without any anticoagulant. The tubes will be in a 
standing position for 40 minutes for clotting, before centrifuged at 3700 rpm for 7 minutes at 
20 degrees Celsius. The serum will then be pipetted in sterile empty tubes and the remaining 
blood ingredients destroyed. The samples are frozen down using a slow freeze technique and 
stored at – 80 degrees at the biochemical department following the recommendations put 
forward by Chevillet et al [57]. All blood and serum sampling will be performed by a 
dedicated biochemist with study protocol training. The serum samples will within 3 weeks 
delivered to the Ex-Vivo Laboratory at Rikshospitalet,  Oslo, for analysis. All samples will be 
transported frozen at – 80 degrees Celsius in an upright position.   
Analysis will be performed at the Norwegian Center for Stem Cell Research, University of 
Oslo/Oslo University Hospital – Rikshospitalet. Total RNA and miRNA will be purified from 
serum using the miRNeasy mini kit following protocols from the manufacturer (Qiagen, 
Germantown, MD). cDNA synthesis and RT-qPCR will be performed following protocols 
from the manufacturer using the High Capacity cDNA Reverse Transcripton Kit (Applied 
Biosystems, Abingdon, U.K) [58]. Subsequently RT-qPCR will be performed using Taqman 
Gene or MicroRNA Expression assays and Taqman Universal PCR master mix with the 7300 
Real-Time RT PCR system (Applied Biosystems). After analysis of miR-140, the remaining 
serum will be destroyed. 
In addition, the patients randomized to the ACI group will be asked to donate the left over 
cartilage removed from the rim of the cartilage lesion during the preparation for the cartilage 
implantation (the second operation). Normally, this tissue is discarded, but in this case we will 
collect this (pathological) cartilage and send it to the Norwegian Center for Stem Cell 
Research for analysis similar to the one described above. The purpose is to detect biomarkers 
in the damaged cartilage that predicts good or poor outcome, as defined according to the 
primary and secondary outcome in this RCT. After analysis, the remaining cartilage will be 
destroyed.  
 
 
9. INSTITUTIONS AND RESPONSIBLE INVESTIGATORS 
9.1. Institutions 
Inclusion and operation will be conducted at: 
• Akershus University Hospital (Sykehusveien 25, 1478 Lørenskog) 
• Oslo University Hospital – Ullevål (Kirkeveien 166, 0450 Oslo) 
 
The postoperative follow-up will be performed at a designated research out-patient clinic at 
Akershus University Hospital. 
 

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Both hospitals will obtain venous blood samples from all included patients which is sent for 
analysis to Oslo University Hospital – Rikshospitalet (Sognsvannsveien 20, 0372 Oslo).For 
more see Section “7.2. Secondary Projects: Healer Non-healer“. 
 
 
9.2.Responsible investigators 
• Professor Asbjørn Årøen (Head supervisor, Akershus University Hospital) 
• Per-Henrik Randsborg, MD, PhD (local coordinator, Akershus University Hospital) 
• Sverre Løken, MD, PhD (local coordinator Oslo University Hospital – Ullevål) 
• Professor Jan Brinchmann (local coordinator  Oslo University Hospital – 
Rikshospitalet) 
• Heidi A. Hanvold (PT and NCP Research coordinator, Ahus). 
 
10. ETHICS 
The study will be conducted in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice and applicable 
regulatory requirements. Registration of patient data will be carried out in accordance with 
national personal data laws. 
The investigator is responsible for giving the patients full and adequate verbal and written 
information about the nature, purpose, possible risk and benefit of the study, includingthe 
parallel project Healer Non-healer, the surgical methods, the possible complications and the 
scheduled follow-ups. They will be informed as to the strict confidentiality of their patient 
data, but that their medical records may be reviewed for trial purposes by authorized 
individuals other than their treating physician.  
It will be emphasized that the participation is voluntary and that the patient is allowed to 
refuse further participation in the protocol whenever she/he wants. This will not prejudice the 
patient’s subsequent care. All patients will be given time to think between proposal and 
inclusion in the study. Documented informed consent must be obtained for all patients 
included in the study before they are registered in the study. This will be done in accordance 
with the national and local regulatory requirements. The investigator is responsible for 
obtaining signed informed consent. 
A copy of the patient information and consent will be given to the patients. The signed and 
dated patient consent forms will be filed in the Investigator Site File binder and also scanned 
to be part of the patient’s electronic medical record at the hospital. 
 
The patient will be informed as soon as possible, if new information becomes available that 

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may affect willingness to participate in the study. 
The study protocol, including the patient information and informed consent form to be used, 
must be approved by the regional ethics committee before enrolment of any patients into the 
study. 
The investigator is responsible for informing the ethics committee of any serious and 
unexpected adverse events and/or major amendments to the protocol as per national 
requirements. 
The trial will be registered on https://clinicaltrials.govand www.helseforsk.no before inclusion 
of the first patient, and the trial is subject to pre-approval by the regional ethical committee.   
11. QUALITY-SECURITY CONTROL/SAFE STORAGE OF SENSITIVE DATA 
The study will be monitored by an employee (N. Weldingh) with formal monitoring 
qualifications at Akershus University Hospital. Authorized representatives of a Competent 
Authority and Ethics Committee may visit the centre to perform inspections, including source 
data verification. Likewise the representatives from sponsor may visit the center to perform an 
audit. The purpose of an audit or inspection is to systematically and independently examine 
all study-related activities and documents to determine whether these activities were 
conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, Good Clinical Practice (ICH GCP), and any applicable regulatory requirements. The 
principal investigator will ensure that the inspectors and auditors will be provided with access 
to source data/documents. 
All data is primarily registered on paper in form of Clinical Research Forms (CRFs). These 
CRFs include the validated patient reported outcome measures scores (PROMS) such as 
KOOS, Lysholm Score, Tegner score and EQ5D, as well as baseline information such as age, 
sex, injury mechanism, work status and the VAS score for pain. They will also include 
inclusion and exclusion criteria. The CRFs are stored in a designated room that is locked in 
the department’s doctor’s office. This room is only available to the personal treating the 
patient. A designated research coordinator, H Hanvold, PT, will continuously follow up the 
patients to make sure the patients are completing their training diary. At the patient’s 
appointment, the treating doctor secures that the patient completes all the questionnaires. 
Objective measurements and any complications are recorded. The CRF data is then 
transferred digitally to a secure investigation server allocated at the University of Oslo 
(Services for Sensitive Data, SSD). Sensitive data will be anonymized and kept in a secure 
coded database and is traceable by a code that is kept safe and accessible only by the prime 
investigators. It will not be possible to identify patients in the results of the study when these 
are published, and data will be stored for 10 years after inclusion.  
 

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12. RISK ASSESSMENT 
Some patients may find it unpleasant when asked about demographic information. The 
treatment of choice in this patient population is not established, but standard clinical care 
include both arthroscopic debridement (AD) and autologous chondrocyte implantation (ACI). 
There are no additional risks of this study other than the potential risks of standard clinical 
practice.  
Potential risk of AD is rare with a frequency < 1% and include infection, deep vein 
thrombosis (DVT), arthralgia, headache, joint effusion/swelling, nasopharyngitis.  
Potential risk of ACI is rare, but slightly higher than for AD, as this treatment involves a 
second operation with a mini-opening of the knee.  Four major complications requiring 
surgery following ACI have been identified [25]:  
- 
Malfusion of the repair tissue to the bed of the lesion (3.8 %) 
- 
Delamination of healthy cartilage near lesion (2.8 %) 
- 
Hyperthrophy of the repair tissue (> 2 %) 
- 
Insufficient degenerative tissue (> 2 %) 
Other complications are rare and occurs in < 1 % of patients, such as wound break down, 
infection, DVT and joint stiffness . 
Both treatments have a risk of failure, meaning that the pain and stiffness in the knee does not 
improve despite surgery, and further surgery might be required. 
 
 
13. COST AND FINANCING PLAN 
13.1. Cost 
All follow ups up to 12 months are standard practice. Outside standard, the 24 month follow 
up will generate extra costs. X-ray and MRI will cost approximately 1000 Norwegian kroner 
(NOK) per patients in total. This gives a cost of 82 000 NOK outside standard clinical 
practice, in addition to the cost of running the research outpatient-clinic. The cost of 
chondrocyte production at Ex Vivo Laboratory is estimated at 35.000 NOK per patient. The 
ChondroGide® (Geistlich Pharma, Switzerland) membrane used during chondrocyte 
implantation costs 7500 NOK.  
 
 
 

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13.2. Financing plan 
The study is funded by research grants already awarded NCP from the  Regional Health 
Authority (Regionale Helseforetak, tverregionale midler).  
 
14. TIME SCHEDULE AND PUBLICATION PLAN 
14.1 Time Schedule 
The inclusion will start in the first quarter of 2016 and is expected due the first quarter of 
2019. Follow up is 2 years. Data collection is estimated to 6 months and data analysis is 
estimated to 6 months. Publication is expected 6 months after first submission. 
 
14.2 Publication plan 
The results will be published in peer reviewed orthopaedic journals, as well as presented to 
the orthopaedic community at national and international scientific meetings. They will also be 
actively communicated to the community by using the hospital web page with publication of 
the studies. 
Upon study completion and finalization of the study report the results of this study will be 
submitted for publication and/or posted in a publicly assessable database of clinical study 
results.  
The results of this study will also be submitted to the Competent Authority and the Ethics 
Committee according to EU and national regulations. 
All personnel who have contributed significantly with the planning and performance of the 
study (Vancouver convention 1988) may be included in the list of authors. 
The study will result in at least the following publications: 
1. Autologous Chondrocyte Implantation versus Arthroscopic Debridement for the 
treatment of focal cartilage lesions of the weight bearing area of the knee. A 
randomized controlled trial – results at 24 months. 
2. Cost related to Autologous Chondrocyte Implantation and Arthroscopic 
Debridement of cartilage lesions in the knee; considering the costs of surgery, 
hospitalization and follow-up, sick-leave and the need for secondary surgery. 
3. Autologous Chondrocyte Implantation versus Arthroscopic debridement for the 
treatment of focal cartilage lesions of the weight bearing area of the knee. A 
randomized controlled trial – results at 5 years.  
 

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15. STUDY ORGANIZATION 
 
Study organization 
 
 
 
 
 
 
 
 
 
 
 
 
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Project manager
PH Randsborg 
 
Akershus University 
Hospital
Healer-NonHealer 
study 
J Brinchmann 
Ex-Vivo Laboraory 
Rikshospitalet
Investigators
Akershus 
A Årøen 
PH Randsborg 
Investigators
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S Løken 
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H A Hanvold 

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