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

1. 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

2. 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

3. Tromsø

4. JBJS. March 2004 and Oct. 2007 Level 1 RCT

5. 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…

6. 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

7. Macroscopic evaluation ICRS 2 years ICRS Normal: 12p nearly normal: 11-8p abnormal: 7-4p severely abnormal: 3-1p p= 0,170 MACROSCOPIC REPAIR

8. LYSHOLM P=0.227 linear regression ACI Micro

9. PCS- Physical component SF-36 ACI Micro P= 0.068 Lin.regression

10. VAS- Visual Analog pain Score ACI P=0.189 Linear regression Micro

11. 77.5%

12. 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

13. Histology 1 2 3 4 p = 0.08

14. Crosstabulation Histology P=0.001 P=0.118

15. 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)

16. 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)

17. ACI-M • ACI: two-step procedure including arthrotomy • Microfracture: Cells have less protection Cells from the bone-marrow my contribute to both repairs ?

18. 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

19. 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

20. 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)

21. 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

22. 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)

23. IKDC • Demographic form • Current Health Asessment Form • Subjective Knee Evaluation Form • Knee History Form • Surgical Documentation Form • Knee Examination Form

24. Subjective Knee Evaluation Form - IKDC • Symptoms • Sport • Function • 18 items • IKDC score max 100

25. 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

26. 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,

27. 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

28. Kellgren Lawrence 0-4 Radiological evaluation Kellgren grade 3

29. 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.

30. 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

31. 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

32. Thank you!