1. Issues Concerning Clinical Outcomes in Long-Term Trials of Cellular Therapies for Cartilage Repair.May 15, 2009 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 Tromsø Bergen Trondheim Oslo Northern most University Hospital in the world Norwegian RCT ACI versus Microfracture Blinded histological evaluation: SR, Oswestry UK and VI Tromsø Norway 80 patients 40 patients in each group

3. Tromsø

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

5. RCTs Rare in orthopaedic surgery Rare in orthopaedic surgery Low methodological quality Low methodological quality What I have learned from our trial… What I have learned from our trial… Study design Study design Methods Methods Endpoints: Clinical benefit, Instruments of measurements. Endpoints: Clinical benefit, Instruments of measurements. Histology, MRI Histology, MRI Design a new trial… Design a new trial…

6. Methods ICRS ICRS Lysholm Lysholm SF-36 SF-36 Tegner Tegner Second-look arthroscopy Second-look arthroscopy Standing radiographs Standing radiographs Histology Histology Failures: Symptomatic non healing of defect and new cartilage operation Failures: Symptomatic non healing of defect and new cartilage operation Statistical M.: SPSS, level of sign. p<0.05 Statistical M.: SPSS, level of sign. p<0.05

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

8. ACIMicro LYSHOLM P=0.227 linear regression

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

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

11. 77.5%

12. 1. Hyaline predominantly 2. Fibrocartilage- hyaline mixture 3. Fibrocartilage 4. Inadequate biopsies or no repair tissue, predominantly bone d: polaraized light Arrow: may or may not be repair tissue

13. Histology 1234 p = 0.08

14. Histological Grade N No. of Failures 110 0 (0) 216 3 (18.8 ) 329 6 (20.7) 412 3 (25) Crosstabulation Histology P=0.118 P=0.001

15. Radiographic results at 5 yrs 25% reduced joint space (<4mm) 25% reduced joint space (<4mm) 33.9% at least Kellgren 2 at five years 33.9% at least Kellgren 2 at five years No significant difference between groups No significant difference between groups Significant association between OA and pain (Kellgren Lawrence and VAS) 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. 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) 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 ACI: two-step procedure including arthrotomy Microfracture: Cells have less protection 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 ACI and Microfracture resulted in similar clinical results Nine failures (22.5%) in both groups 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 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 Good quality repair-cartilage reduces risk of failure Microfracture: first line treatment for defects located on medial or lateral femoral condyle Microfracture: first line treatment for defects located on medial or lateral femoral condyle Younger and more active patients do better Younger and more active patients do better Improvements in surgical techniques needed as well as in the field of cellular and molecular biology Improvements in surgical techniques needed as well as in the field of cellular and molecular biology

20. Clinical scores KOOS: Patient –administered:10 minutes KOOS: Patient –administered:10 minutes Evaluates both short- and long-term consequences of knee injury 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 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) Includes WOMAC (24 items) OA Index (pain, function and stiffness)

21. KOOS Knee injury and Osteoarthritis Outcome Score Validated in several populations Validated in several populations ACL. Knee arthroscopy, Meniscectomy, TKR, ACI ACL. Knee arthroscopy, Meniscectomy, TKR, ACI Correlation with SF-36. +++ Correlation with SF-36. +++ KOOS is the recommended self-report measure of pain, function and QOL KOOS is the recommended self-report measure of pain, function and QOL KOOS responiseveness +++ indicating fewer subjects needed to get significance 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. Generally, the subscale QOL is the most responsive, followed by the subscale Pain and Sport and Recration function. Symptoms and function the last week Symptoms and function the last week 5 boxes (score 0-4) 5 boxes (score 0-4) 100 (normalized score) 100 (normalized score)

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

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

25. KOOS versus SF-36 KOOS includes also sport/recreation and knee related quality of life 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. 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- Physical Component Summaries PCS the only significant difference at 2 years in our study PCS the only significant difference at 2 years in our study MCS- Mental Component Summaries MCS- Mental Component Summaries

26. Outcomes Primary or secondary Primary or secondary “Soft”: Clinical outcomes: symptom reduction (incl pain) and function. Placebo, bias.. Patient based: KOOS best instrument in my opinion “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. Functional testing: One leg jumping…e.g. “Hard” –less bias: Failure, TKR (OA) “Hard” –less bias: Failure, TKR (OA) “Surrogate”: Histology, Arthroscopic evaluation/probing, MRI, ultrasound, X-rays, “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. Radiological evaluation Kellgren grade 3 Kellgren Lawrence 0-4

29. MRI Quantitative MRI Quantitative MRI Lozano et al JBJS (Am)2006;88:1349-1352. Non invasive MRI scoring systems Use of blinded readers Techniques improves.. Follow patients and evaluating repair site at different time points

30. RCT Power calculation Power calculation Multicenter Multicenter Randomization- difficult in surgery Randomization- difficult in surgery Standardization of procedure (Surgeons like to do it “my way”) Standardization of procedure (Surgeons like to do it “my way”) Clear Endpoints- we had too many and they could have been better defined Clear Endpoints- we had too many and they could have been better defined Blinding Blinding Rehabilitation Rehabilitation Control group: Non operative Control group: Non operative

31. Remember.. Evidence: On top: RCT Level 1 Evidence: On top: RCT Level 1 On bottom: Experts opinion Level 5 On bottom: Experts opinion Level 5 However, needing a surgeon- you would like to have an expert However, needing a surgeon- you would like to have an expert Skills- fingertip feeling-intuition are difficult to include in RCTs Skills- fingertip feeling-intuition are difficult to include in RCTs Surgery is complex Surgery is complex Standardization of techniques Standardization of techniques