AAutologous

AAutologousCChondrocyte TTransplantation/ IImplantation VVersus EExisting treatmentsISCRCTN 48911177

Sponsored by Keele UniversityLead 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

Overview

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

Collaborating Surgeons-UK & Norway

Each centre has at least one surgeon and a study co-ordinator and independent assessor

Why the ACTIVE trial?

• Lack of robust data on ACI vs non-ACI treatment over the long-term

• Recommendations by NICE

• Cost effectiveness

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

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

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

‘Best alternative’ options

• Debridement

• Bone graft

• Drilling

• Microfracture

• Mosaicplasty

• AMIC

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

Patient Eligibility

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

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

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

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.

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.

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

Independent Assessment

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

Funding / Support

MRC grant for research costse.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 yrsMembrane donated by Geistlich for ACI-any cell supplier can be used

Recruitment Progress (June ‘09)

Total Patients randomised = 294

11

22

33

45

56

66

77

910

1012

1618

1820

2022

23

58

0 10 20 30 40 50 60 70

OxfordYork

FairfieldBirmingham

NorthallertonCapio West

DudleyIpswichFrimley

WorthingSt. Mary'sHillingdon

Manchester GenStockport

WestonWrightington

WarringtonMiddlesbrough

PaisleyStanmoreSwindon

PeterboroughStoke

TromsøTrondheim

Oswestry

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.

www.active-trial.org.uk

Further Information

• Prof. James Richardson, Chief Investigator – tel: 01691 404386

• Heather Smith, Trial Manager– Heatherj.smith@rjah.nhs.uk tel: 01691 404142

Visit the website: www.active-trial.org.uk

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)