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Issues Concerning Clinical Outcomes in Long-Term Trials of Cellular Therapies for Cartilage Repair. May 15, 2009

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Issues Concerning Clinical Outcomes in Long-Term Trials of Cellular Therapies for Cartilage Repair. May 15, 2009. Gunnar Knutsen MD, PhD University Hospital North Norway. Universities in Norway. Norwegian RCT ACI versus Microfracture. Northern most University Hospital in the world. Tromsø.

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slide1

Issues Concerning Clinical Outcomes in Long-Term Trials of Cellular Therapies for Cartilage Repair.May 15, 2009

Gunnar Knutsen MD, PhD

University Hospital North Norway

universities in norway
Universities in Norway

Norwegian RCT ACI versus Microfracture

Northern most University Hospital in the world

Tromsø

Trondheim

80 patients

40 patients in each group

Bergen

Oslo

Blinded histological evaluation: SR, Oswestry UK and VI Tromsø Norway

slide5
RCTs
  • Rare in orthopaedic surgery
  • Low methodological quality
  • What I have learned from our trial…
  • Study design
  • Methods
  • Endpoints: Clinical benefit, Instruments of measurements.
  • Histology, MRI
  • Design a new trial…
methods
Methods
  • ICRS
  • Lysholm
  • SF-36
  • Tegner
  • Second-look arthroscopy
  • Standing radiographs
  • Histology
  • Failures: Symptomatic non healing of defect and new cartilage operation
  • Statistical M.: SPSS, level of sign. p<0.05
slide7

Macroscopic evaluation ICRS 2 years

ICRS

Normal: 12p

nearly normal: 11-8p

abnormal: 7-4p

severely abnormal: 3-1p

p= 0,170

MACROSCOPIC REPAIR

slide8

LYSHOLM

P=0.227 linear regression

ACI

Micro

slide9

PCS- Physical component SF-36

ACI

Micro

P= 0.068

Lin.regression

slide10

VAS- Visual Analog pain Score

ACI

P=0.189

Linear regression

Micro

slide12

1. Hyaline predominantly

2. Fibrocartilage- hyaline mixture

3. Fibrocartilage

4. Inadequate biopsies or no repair tissue, predominantly bone

Arrow: may or may not be repair tissue

d: polaraized light

slide13

Histology

1

2

3

4

p = 0.08

radiographic results at 5 yrs
Radiographic results at 5 yrs
  • 25% reduced joint space (<4mm)
  • 33.9% at least Kellgren 2 at five years
  • No significant difference between groups
  • Significant association between OA and pain (Kellgren Lawrence and VAS)
age and activity
Age and activity
  • Younger patients (less than 30 yrs. old) in both groups have significant better results.
  • More active patients (Tegner) in both groups have also significantly better clinical scores (Lysholm, VAS and SF 36)
aci m
ACI-M
  • ACI: two-step procedure including arthrotomy
  • Microfracture: Cells have less protection

Cells from the bone-marrow my contribute to both repairs ?

conclusion 1
Conclusion 1
  • ACI and Microfracture resulted in similar clinical results
  • Nine failures (22.5%) in both groups
  • No significant difference in macroscopic or histological results and no correlation at this point between histology and clinical outcome
conclusion 2
Conclusion 2
  • Good quality repair-cartilage reduces risk of failure
  • Microfracture: first line treatment for defects located on medial or lateral femoral condyle
  • Younger and more active patients do better
  • Improvements in surgical techniques needed as well as in the field of cellular and molecular biology
clinical scores
Clinical scores
  • KOOS: Patient –administered:10 minutes
  • Evaluates both short- and long-term consequences of knee injury
  • 42 items in 5 separately scored domains; Pain, other symptoms, ADL, Function in Sport/Rec and knee related QOL
  • Includes WOMAC (24 items) OA Index (pain, function and stiffness)
koos knee injury and osteoarthritis outcome score
KOOS Knee injury and Osteoarthritis Outcome Score
  • Validated in several populations
  • ACL. Knee arthroscopy, Meniscectomy, TKR, ACI
  • Correlation with SF-36. +++
  • KOOS is the recommended self-report measure of pain, function and QOL
  • KOOS responiseveness +++ indicating fewer subjects needed to get significance
slide22
KOOS
  • Generally, the subscale QOL is the most responsive, followed by the subscale Pain and Sport and Recration function.
  • Symptoms and function the last week
  • 5 boxes (score 0-4)
  • 100 (normalized score)
slide23
IKDC
  • Demographic form
  • Current Health Asessment Form
  • Subjective Knee Evaluation Form
  • Knee History Form
  • Surgical Documentation Form
  • Knee Examination Form
subjective knee evaluation form ikdc
Subjective Knee Evaluation Form - IKDC
  • Symptoms
  • Sport
  • Function
  • 18 items
  • IKDC score max 100
koos versus sf 36
KOOS versus SF-36
  • KOOS includes also sport/recreation and knee related quality of life
  • SF-36 well accepted instrument in health research: 8 dimensions; role physical,bodily pain,general health,vitality, social functioning, role emotional and mental health.
  • PCS- Physical Component Summaries
  • PCS the only significant difference at 2 years in our study
  • MCS- Mental Component Summaries
outcomes
Outcomes
  • Primary or secondary
  • “Soft”: Clinical outcomes: symptom reduction (incl pain) and function. Placebo, bias.. Patient based: KOOS best instrument in my opinion
  • Functional testing: One leg jumping…e.g.
  • “Hard” –less bias: Failure, TKR (OA)
  • “Surrogate”: Histology, Arthroscopic evaluation/probing, MRI, ultrasound, X-rays,
fibrocartilage repair versus hyaline
Fibrocartilage repair versus hyaline

Bundles of collagen fibers, lying in random irregular manner. Cells more elongated and often more numerous.

Collagen type I

Homogenous matrix. Round or oval shape of the cells often surrounded by lacuna.

Collagen type II

Polarized light

slide29
MRI
  • Quantitative MRI

Non invasive

MRI scoring systems

Use of blinded readers

Techniques improves..

Follow patients and evaluating repair site at different time points

Lozano et al JBJS (Am)2006;88:1349-1352.

slide30
RCT
  • Power calculation
  • Multicenter
  • Randomization- difficult in surgery
  • Standardization of procedure (Surgeons like to do it “my way”)
  • Clear Endpoints- we had too many and they could have been better defined
  • Blinding
  • Rehabilitation
  • Control group: Non operative
remember
Remember..
  • Evidence: On top: RCT Level 1
  • On bottom: Experts opinion Level 5
  • However, needing a surgeon- you would like to have an expert
  • Skills- fingertip feeling-intuition are difficult to include in RCTs
  • Surgery is complex
  • Standardization of techniques
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