Issues Concerning Clinical Outcomes in Long-Term Issues Concerning Clinical Outcomes in Long-Term Trials of Cellular Therapies for Cartilage Repair.Trials of Cellular Therapies for Cartilage Repair. May May 15, 200915, 2009 Gunnar Knutsen MD, PhDGunnar Knutsen MD, PhD

University Hospital North NorwayUniversity Hospital North Norway

Universities inUniversities in Norway 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

Tromsø

JBJS. March 2004 and Oct. 2007

Level 1 RCT

RCTsRCTs

Rare in orthopaedic surgeryRare in orthopaedic surgery Low methodological qualityLow methodological quality What I have learned from our trial…What I have learned from our trial… Study designStudy design MethodsMethods Endpoints: Clinical benefit, Instruments Endpoints: Clinical benefit, Instruments

of measurements. of measurements. Histology, MRIHistology, MRI Design a new trial…Design a new trial…

MethodsMethods

ICRSICRS LysholmLysholm SF-36SF-36 TegnerTegner Second-look arthroscopySecond-look arthroscopy Standing radiographsStanding radiographs HistologyHistology Failures: Symptomatic non healing of Failures: Symptomatic non healing of

defect and new cartilage operationdefect and new cartilage operation Statistical M.: SPSS, level of sign. p<0.05Statistical M.: SPSS, level of sign. p<0.05

Macroscopic evaluation ICRS 2 years

p= 0,170

Normal: 12p

nearly normal: 11-8p

abnormal: 7-4p

severely abnormal: 3-1p

ICRS

1,00

Treatment

0

20

40

60

80

100

Lyspre

Lys1

Lys2

Lys5

Treatment: 1,00

2,00

Treatment

0,00

20,00

40,00

60,00

80,00

100,00

49

Lyspre

Lys1

Lys2

Lys5

Treatment: 2,00

ACI Micro

LYSHOLM

P=0.227 linear regression

1,00

Treatment

20

30

40

50

60

70PCSpre

PCS1

PCS2

PCS5

Treatment: 1,00

2,00

Treatment

10

20

30

40

50

60

70

65 65

PCSpre

PCS1

PCS2

PCS5

Treatment: 2,00

ACI Micro

PCS- Physical component SF-36

P= 0.068

Lin.regression

1,00

Treatment

0,00

20,00

40,00

60,00

80,00

100,00VASpre

VAS1

VAS2

VAS5

Treatment: 1,00

2,00

Treatment

0,00

20,00

40,00

60,00

80,00

100,00VASpre

VAS1

VAS2

VAS5

Treatment: 2,00

ACI Micro

VAS- Visual Analog pain Score

P=0.189Linear regression

0 10 20 30 40 50 60

Failure month

0,0

0,2

0,4

0,6

0,8

1,0

Cu

m S

urv

ival

SURVIVAL

TreatmentACI

M

77.5%

ACI Microfracture

Group 1

Group 2

Group 3

Group 4

h i

a

gf

edc

b

1. Hyaline predominantly2. Fibrocartilage- hyaline mixture3. Fibrocartilage4. Inadequate biopsies or no repair tissue, predominantly bone

d: polaraized light

Arrow: may or may not be repair

tissue

0

2

4

6

8

10

12

14

16

18

ACIM

Histology

1 2 3 4

p = 0.08

Histological Histological GradeGrade

NN No. of No. of Failures Failures

11 1010 0 (0)0 (0)

22 1616 3 (18.8 )3 (18.8 )

33 2929 6 (20.7)6 (20.7)

44 1212 3 (25)3 (25)

Crosstabulation Crosstabulation HistologyHistology

P=0.118

P=0.001

Radiographic results Radiographic results at 5 yrsat 5 yrs 25% reduced joint space (<4mm)25% reduced joint space (<4mm) 33.9% at least Kellgren 2 at five 33.9% at least Kellgren 2 at five

yearsyears No significant difference between No significant difference between

groupsgroups Significant association between OA Significant association between OA

and pain (Kellgren Lawrence and and pain (Kellgren Lawrence and VAS)VAS)

Age and activityAge and activity

Younger patients (less than 30 Younger patients (less than 30 yrs. old) in both groups have yrs. old) in both groups have significant better results.significant better results.

More active patients (Tegner) More active patients (Tegner) in both groups have also in both groups have also significantly better clinical significantly better clinical scores (Lysholm, VAS and SF scores (Lysholm, VAS and SF 36)36)

ACI-MACI-M

ACI: two-step procedure including ACI: two-step procedure including arthrotomyarthrotomy

Microfracture: Cells have less Microfracture: Cells have less protectionprotection

Cells from the bone-marrow my contribute to both repairs ?

Conclusion 1Conclusion 1

ACI and Microfracture resulted ACI and Microfracture resulted in similar clinical results in similar clinical results

Nine failures (22.5%) in both Nine failures (22.5%) in both groupsgroups

No significant difference in No significant difference in macroscopic or histological macroscopic or histological results and no correlation at this results and no correlation at this point between histology and point between histology and clinical outcomeclinical outcome

Conclusion 2Conclusion 2 Good quality repair-cartilage reduces risk Good quality repair-cartilage reduces risk

of failureof failure Microfracture: first line treatment for Microfracture: first line treatment for

defects located on medial or lateral defects located on medial or lateral femoral condylefemoral condyle

Younger and more active patients do Younger and more active patients do betterbetter

Improvements in surgical techniques Improvements in surgical techniques needed as well as in the field of cellular needed as well as in the field of cellular and molecular biologyand molecular biology

Clinical scoresClinical scores

KOOS: Patient –administered:10 minutesKOOS: Patient –administered:10 minutes Evaluates both short- and long-term Evaluates both short- and long-term

consequences of knee injuryconsequences of knee injury 42 items in 5 separately scored domains; 42 items in 5 separately scored domains;

Pain, other symptoms, ADL, Function in Pain, other symptoms, ADL, Function in Sport/Rec and knee related QOLSport/Rec and knee related QOL

Includes WOMAC (24 items) OA Index Includes WOMAC (24 items) OA Index (pain, function and stiffness)(pain, function and stiffness)

KOOS KOOS Knee injury and Osteoarthritis Outcome ScoreKnee injury and Osteoarthritis Outcome Score

Validated in several populationsValidated in several populations ACL. Knee arthroscopy, Meniscectomy, ACL. Knee arthroscopy, Meniscectomy,

TKR, ACITKR, ACI Correlation with SF-36. +++Correlation with SF-36. +++ KOOS is the recommended self-report KOOS is the recommended self-report

measure of pain, function and QOLmeasure of pain, function and QOL KOOS responiseveness +++ indicating KOOS responiseveness +++ indicating

fewer subjects needed to get fewer subjects needed to get significancesignificance

KOOSKOOS

Generally, the subscale QOL is the Generally, the subscale QOL is the most responsive, followed by the most responsive, followed by the subscale Pain and Sport and subscale Pain and Sport and Recration function.Recration function.

Symptoms and function the last Symptoms and function the last weekweek

5 boxes (score 0-4)5 boxes (score 0-4) 100 (normalized score)100 (normalized score)

IKDCIKDC

Demographic formDemographic form Current Health Asessment FormCurrent Health Asessment Form Subjective Knee Evaluation FormSubjective Knee Evaluation Form Knee History FormKnee History Form Surgical Documentation FormSurgical Documentation Form Knee Examination FormKnee Examination Form

Subjective Knee Evaluation Form - IKDCSubjective Knee Evaluation Form - IKDC

SymptomsSymptoms SportSport FunctionFunction

18 items18 items IKDC score max 100IKDC score max 100

KOOS versus SF-36KOOS versus SF-36

KOOS includes also sport/recreation and knee KOOS includes also sport/recreation and knee related quality of liferelated quality of life

SF-36 well accepted instrument in health SF-36 well accepted instrument in health research: 8 dimensions; role physical,bodily research: 8 dimensions; role physical,bodily pain,general health,vitality, social pain,general health,vitality, social functioning, role emotional and mental functioning, role emotional and mental health.health.

PCS- Physical Component SummariesPCS- Physical Component Summaries PCS the only significant difference at 2 years PCS the only significant difference at 2 years

in our studyin our study MCS- Mental Component Summaries MCS- Mental Component Summaries

OutcomesOutcomes

Primary or secondaryPrimary or secondary ““Soft”: Clinical outcomes: symptom Soft”: Clinical outcomes: symptom

reduction (incl pain) and function. reduction (incl pain) and function. Placebo, bias.. Patient based: KOOS best Placebo, bias.. Patient based: KOOS best instrument in my opinioninstrument 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 Surrogate”: Histology, Arthroscopic

evaluation/probing, MRI, ultrasound, X-evaluation/probing, MRI, ultrasound, X-rays, rays,

Fibrocartilage repair Fibrocartilage repair versus hyalineversus hyalineBundles 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

Radiological Radiological evaluationevaluation

Kellgren grade 3

Kellgren Lawrence 0-4

MRIMRI

Quantitative MRIQuantitative 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

RCTRCT

Power calculationPower calculation MulticenterMulticenter Randomization- difficult in surgeryRandomization- difficult in surgery Standardization of procedure Standardization of procedure

(Surgeons like to do it “my way”)(Surgeons like to do it “my way”) Clear Endpoints- we had too many and Clear Endpoints- we had too many and

they could have been better definedthey could have been better defined BlindingBlinding RehabilitationRehabilitation Control group: Non operativeControl group: Non operative

Remember..Remember..

Evidence: On top: RCT Level 1Evidence: On top: RCT Level 1 On bottom: Experts opinion Level 5On bottom: Experts opinion Level 5 However, needing a surgeon- you However, needing a surgeon- you

would like to have an expertwould like to have an expert Skills- fingertip feeling-intuition are Skills- fingertip feeling-intuition are

difficult to include in RCTsdifficult to include in RCTs Surgery is complexSurgery is complex Standardization of techniquesStandardization of techniques