1. A A C T I V E Autologous Autologous Chondrocyte Transplantation/ Implantation Versus Existing treatments ISCRCTN 48911177 Sponsored by Keele University Lead centre: Robert Jones & Agnes Hunt Orthopaedic Hospital NHS Trust in collaboration with the University of Birmingham A multicentre orthopaedic surgical RCT involving over 20 UK centres and 2 Norwegian centres www.active-trial.org.uk

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 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

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 >12cm 2 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. Sample Size Based on 40% patients requiring additional procedure within 5 years -480 patients are needed to detect 30% reduction with 80% power at p=0.05 Statistical Analysis Cessation of benefit: standard log-rank & stratified analyses Continuous measures: change from baseline scores using standard multilevel mixed modelling

19. 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

20. Recruitment Progress (June ‘09) Total Patients randomised = 294

21. 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.

22. Main responsibilities for Co-ordinators: –Check patient eligibility –Explain the study to patients / staff –Take informed consent –Organise assessments with physiotherapist –Randomise patients –Give out rehabilitation advice leaflets –Organise the surgeon (form filling etc) –Help retain patients in trial Training and support provided by the central Trial Manager & Trial Assistant

23. Main responsibilities for assessors To assess patients through combination of questionnaires, functional tests and clinical examination To ensure assessments are done at pre-op, and 3, 6 12 months & 3, 5, 10 years follow-up. To be blind to treatment allocation To enter data using the ACTIVE online database or post questionnaires to ACTIVE office. To contact the ACTIVE office asap if a patient DNAs or cannot be contacted. Training and support provided by the central Trial Manager & Trial Assistant

24. www.active-trial.org.uk

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

26. 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)