Sponsored by Keele University

1. www.active-trial.org.uk AutologousAutologousChondrocyteTransplantation/ImplantationVersusExisting treatmentsISCRCTN 48911177 A multicentre orthopaedic surgical RCT involving over 20 UK centres and 2 Norwegian centres Sponsored by Keele University Lead centre: Robert Jones & Agnes Hunt Orthopaedic Hospital NHS Trust in collaboration with the University of Birmingham

2. Overview • Aims of ACTIVE • Trial Design • Protocol requirements • Progress • Responsibilities of staff working on the trial

3. Collaborating Surgeons-UK & Norway Each centre has at least one surgeon and a study co-ordinator and independent assessor

4. Why the ACTIVE trial? • Lack of robust data on ACI vs non-ACI treatment over the long-term • Recommendations by NICE • Cost effectiveness

5. Primary Aim • Primary Aim • To determine whether ACI/MACI offers longer-term benefits than the ‘best alternative’ non-cell grafting treatment for repairing chondral defects in the knee that remain symptomatic following previous treatment

6. Secondary Aims • Secondary Aims: • To compare the use of periosteum with a manufactured membrane • To assess and compare the cost effectiveness of ACI vs non-ACI option and periosteum vs membrane

7. Trial Design • Patients randomised to: • Cell grafting (ACI/MACI) or Surgeons’ best non-ACI choice • further randomised to (this is optional) • periosteum or collagen membrane • patch patch

8. ‘Best alternative’ options • Debridement • Bone graft • Drilling • Microfracture • Mosaicplasty • AMIC

9. Patient Eligibility • Inclusion criteria • Isolated symptomatic chondral or osteochondral defect(s) in the femoral condyle, trochlea, or patella suitable for cell therapy and at least one other existing treatment • Previous failed treatment on same defect ≥ 6 months earlier (may include arthroscopic washout or ACI/MACI) • Meets the “uncertainty principle” • Willingness to comply with rehab & follow-up

10. Patient Eligibility • Exclusion criteria: • Bilateral defects both requiring surgery • kissing lesions • defects >12cm2 • total meniscectomy • Uncorrected patella malaligment • Generalised osteoarthritis

11. Information needed from referring surgeon before randomisation: * Patient details* Which knee* Date & type of previous surgery* Site of defect (medial/lateral FC; trochlea; patella)* Intended cell treatment (with optional sub- randomisation)* Intended control treatment option* Predicted size of chondral defect* If OCD, predicted depth of defect

12. Further requirements before randomisation • Patient invited to participate, given the information leaflet, and given at least 24 hours to decide • Patient given opportunity to ask questions before fully informed written consent is taken by the co-ordinator Sharon Quigley • Independent (blind) assessment with ACITVE physiotherapist Dean Muldoon • Patient questionnaire pack completed

13. Randomisation - externally by BCTU via internet • By minimisation with stratification variables: • Intended control treatment option • Size of chondral defect • Age • Pre-op Lysholm knee score • Femoral or patello-femoral defect • Important! • Once randomised, patients stay in trial as per ‘intention to treat’. Patients are not taken out of the trial if treatment didn’t go to plan as this introduces bias.

14. Treatment details • The ACTIVE Treatment Record to be completed by surgeon: • Page 1: Knee map - draw defect to scale • Page 2: Record actual findings & treatment • Defect size before & after debridement • Depth of defect (bone loss only in mm) • MACI/Chondron details – biopsy site; whether sutures used; self-score for stability • Page 3: Details on bone grafting if applicable • & explain if treatment didn’t go according to plan.

15. After ACTIVE Treatment • Independent blind assessments with Dean Muldoon at 2, 6 & 12 months; 3, 5 & 10 years. • Postal questionnaires at 2,4, 6-9 years • No biopsy/arthroscopy unless symptoms warrant further surgery • Additional assessment & surgery must be documented to help determine whether original ACTIVE treatment has failed

16. Independent Assessment

17. Outcome Measures“robust & relevant data” • Primary outcome measure: • Time to “cessation of benefit” • – Combination of questionnaires & independent blinded assessments over 10 years follow-up. Decision for further surgery may count as time of cessation of benefit so additional assessment forms should be completed • First planned analysis at 3-year follow-up. Then 5 & 10 years. • Secondary outcome measures: • – Health Economics: QALYs estimated for each arm • from a societal perspective • – Cininnati Sports Activity Scale • – IKDC Subjective Knee Evaluation Form

18. Funding / Support • MRC grant for research costs • e.g. trial manager, local co-ordinators, assessors, travel & training, materials • DoH funds excess treatment costs • - to meet cost difference bt. ACI vs. non ACI option • Qualifies for CLRN Support funding • - for clinic resources per patient formally registered • - per follow-up outpatient visit at 6 mts, 3, 5, & 10 yrs • Membrane donated by Geistlich for ACI • -any cell supplier can be used

19. Recruitment Progress (June ‘09) TotalPatients randomised = 294

20. Staff required to run the trial • Principal Investigator (overall responsibility for the trial at the hospital) • Recruiting surgeon(s) – the PI /other surgeons to follow the ACTIVE protocol • Co-ordinator (most important to make sure things happen according to protocol) • Independent blinded assessor (physio to do regular patient assessments, blind to treatment allocation). • Central ACTIVE trial office provides support.

21. www.active-trial.org.uk

22. Further Information • Prof. James Richardson, Chief Investigator – tel: 01691 404386 • Heather Smith, Trial Manager • Heatherj.smith@rjah.nhs.uktel: 01691 404142 Visit the website:www.active-trial.org.uk

23. Acknowledgements • Trial Steering Committee: • Prof. Neil Rushton (Orthopaedic Research Unit, Cambridge) • Dr Martin Landray (Clinical Trial Service Unit, Oxford) • Prof. Richard Gray (Birmingham Clinical Trials Unit) • Prof. James Richardson (RJAH Orthopaedic Hospital) • Prof. George Bentley (RNOH, Stanmore) • Prof. Marilyn James (Liverpool John Moores University) • Data Monitoring & Ethics Committee: • Prof. Hamish Simpson (Dept. Orthopaedics, Edinburgh Uni) • Dr Paresh Jobanputra (Dept. Rheumatology, B’ham Uni) • Dr Emma Hall (Institute of Cancer Research, Surrey)