nstride aps clinical trial results · lr-prp vs lp-prp effects on chondrocytes proliferation… *...

Elizaveta Kon, M.D.

nSTRIDE® APS

Clinical Trial Results

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KNEE

POSITIVE BUT LACK OF HIGH LEVEL EVIDENCE

Sanchez et al, MSSE 2003

Sánchez et al, Clin Exp Rheumatol, 2008

Kon et al, KSSTA 2010 &2011

Wang-Saegusa et al, Arch Orthop 2010

Sampson et al, Am J PM&R 2010

Buda et al, JBJS Am 2010

Kon et al, Arthroscopy 2011

Filardo et al, KSSTA 2011

Gobbi et al, Sports Health 2012

Dhollander et al, KSSTA 2011

Spakova et al, AM J PM&R 2012

Sampson et al, Am J PM&R 2010

Torrero et al, J Biol Regul 2012

Napolitano et al, Blood Transf 2012

Siclari et al, KSSTA 2013

Halpern et al, Clin J Sport Med 2013

Jang et al, Eur J Orthop Surg 2013

Rayegani et al,Orthop Rev 2014

Gobbi et al, KSSTA 2014

Raeissadat et al, Clin Med Ins 2015

Forogh et al, J Sport Fit 2015

Duif et al, KSSTA 2015

Gormeli et al, KSSTA 2015

Katavar et al, J Phys Ther Sci 2016

Abate et al., KSSTA 2016

Smith et al, AJSM 2016

Paterson et al, BMC Musk. Disord. 2016

Kon E, Filardo G, Di Matteo B, et al. (Open Orthop J 2013)

PRP INTRA-ARTICULAR USE FOR OA:

A SUMMARY

2 RCTs AGAINST SALINE

7 RCTs AGAINST HA

1 RCT AGAINST CORTICOSTEROID

1 RCT AGAINST HA AND SALINE

1 RCT AGAINST PHYSICAL THERAPY

KNEE

SYNOPSIS

ANKLE

Mei-Dan et al, AJSM 2013

HIP Battaglia et al, Clin Exp Rheum 2011

Battaglia et al, Orthopedics 2013

Sanchez et al, Rheumatology 2012

Dallari et al, AJSM 2016

MORE THAN A DECADE HAS PASSED FROM THE

FIRST CLINICAL APPLICATIONS OF PLATELET

CONCENTRATE FOR CARTILAGE REPAIR…

STILL MANY QUESTIONS

UNANSWERED….

DIFFERENT PROCEDURES DIFFERENT PLATELETS

CONCENTRATES

DIFFERENT RESULTS

DIFFERENT PROPERTIES / DIFFERENT CLINICAL USE

(hemostasis, glue, scaffold, anti-inflammatory, analgesic, antibacterial,

enhancer of tissue healing potential…)

Blood volume harvested

Use of anticoagulant

No. of centrifugations

Speed of centrifugation

PRP volume obtained

Activation method

Integrity of platelets

Presence of leucocytes

Cryopreservation

PLATELET-RICH WHAT ???

Pure PRP (Cell separator PRP, Vivostat, Anitua’s PRGF)

PRP + leukocytes (Curasan, Regen,

Plateltex, SmartPReP, PCCS, Magellan,

GPS, Rizzoli’s PRP)

Platelet-rich fibrin (Fibrinet)

Platelet-rich fibrin + leucocytes (Choukroun’s PRF)

ACP (Arthrex)

MANY ATTEMPTS TO PROPOSE A

CLASSIFICATION FOR PRP PRODUCTS…..

NONE OF THEM HAS A REAL CLINICAL

CORRELATION

UP TO NOW, CLASSIFICATIONS ARE MORE USEFUL FOR

BIOLOGISTS THAN PHYISICIANS…

- P.A.W. SYSTEM

- Dohan Erhenfest Classification

-Mishra Classification

-Mautner Classification

….

THE CELL CONTENT QUARRELL…

HIGH PLATELET

CONCENTRATION -

LEUKOCYTE RICH

PRP

LOW PLATELET

CONCENTRATION -

LEUKOCYTE POOR

PRP

Fortier et al.: Growth Factor and Catabolic Cytokine Concentrations Are

Influenced by the Cellular Composition of Platelet-Rich Plasma, AJSM 2014

CATABOLIC EFFECTS CORRELATED WITH

LEUKOCYTES PRESENCE

LR-PRP & RBCs determined significantly higher cell death and pro-

inflammatory mediators production

LEUKOCYTES ARE DETRIMENTAL INTRA-ARTICULARLY

Dragoo et al.: The effect of platelet-rich plasma formulations and blood

products on human synoviocytes: implications for intra-articular injury and therapy, AJSM 2014

LR-PRP vs LP-PRP EFFECTS ON

CHONDROCYTES PROLIFERATION…

* *

PROLIFERATION

Cavallo, Filardo, Kon et al. JBJS

2014.

….. EFFECTS ON SYNOVIOCYTES

UP-REGULATION OF

PROINFLAMMATORY

FACTORS: IL-1b, IL-8 AND

FGF-2 BY L-PRP

DOWN MODULATION OF HGF

AND TIMP-4 EXPRESSION, ANTI-

CATABOLIC MEDIATORS IN

CARTILAGE, BY L-PRP

Assirelli , Filardo , Kon et al. KSSTA 2014

THE ROLE OF LEUKOCYTES…

38 PTS UNDERWENT SYNOVIAL FLUID AND BLOOD SAMPLING BEFORE

EACH WEEKLY L-PRP or HA INJECTION (3 INJ.)

PRO AND ANTI-INFLAMMATORY

CYTOKINES TESTED

NO DIFFERENCE IN ANY

SYNOVIAL FLUID IN

INFLAMMATORY

MOLECULES BETWEEN

L-PRP AND HA

THE LEUKOCYTE PRESENCE

DOES NOT UPREGULATE

INFLAMMATORY RESPONSE

ONE WEEK AFTER THE INJ.

TWICE CENTRIFUGED

20 ml of PRP produced divided into 4 units of 5 ml.

150-ml venous blood sample

PLATELET: 4.8x basal value

LEUKOCYTE: 1.1X basal value

OUR EXPERIENCE AT RIZZOLI:

LAB MADE PRP

INCLUSION CRITERIA • Monolateral symptomatic knee with history of chronic pain (at least

4 months) or swelling;

• Imaging findings of degenerative changes (Kellgren Lawrence 0 to

3 at X-ray or MRI evidence of degenerative chondropathy).

EXCLUSION CRITERIA •Age > 80 years;

•Kellgren-Lawrence score > 3;

•Major axial deviation;

•Focal chondral or osteochondral lesion;

•Presence of any concomitant knee lesion;

•Causing pain or swelling;

•Haematological diseases;

•Severe cardiovascular diseases;

•Infections.

192 PTS, 1Y F-UP

PRP vs HA

DOUBLE - BLINDED

Filardo G, Di Matteo B, Di Martino A, Merli ML, Cenacchi A,

Fornasari P, Marcacci M, Kon E. Am J Sports Med. 2015

ICRS 2015 AWARD CUM LAUDE

RANDOMIZED CONTROLLED TRIAL

IKDC SUBJ IMPROVEMENT at 12M F-UP

2 MONTHS PRP vs HA (n.s.)



RANDOMIZED CONTROLLED TRIAL

Kellgren < 3 Group

Comparison

NO STATISTICAL

DIFFERENCE

NOT THE BEST PRP PREPARATION FOR TREATING OA ???

PRP VARIABILITY

SEVERAL VARIABLES TO BE TAKEN INTO ACCOUNT

FURTHER STUDIES ARE NEEDED TO CLARIFY THE BEST PREPARATION

AND APPLICATIVE MODALITIES

DIFFERENT PREPARATION MIGHT BE EFFECTIVE IN DIFFERENT MSK

DISORDERS

STILL LOOKING FOR

THE RIGHT FORMULA

NOVEL SOLUTIONS

ANTI-INFLAMMATORY CYTOKINES AND

GROWTH FACTORS FROM WHOLE

BLOOD

White Blood

Cells

IL-1ra sTNF-RI sTNF-RII

Platelets

TGF-β PDGF FGF-2

VEGF EGF

Concentrated

Plasma

sIL-1R sTNF-RI sTNF-RII

IGF-1 HGF A2M

PROGRESS Autologous PROtein Solution Given via

intRa-articular injEction for knee oSteoarthritiS

Study Location

Status Tx N

F/U

(Mo) Safety WOMAC KOOS QoL

PGI

CGI

Cartilage

Imaging

Cytokine

Analysis

First-in-Human EU

Complete APS 11 6

US

Follow-up APS 10 12

EU

Long-Term

Follow-up

APS

Saline

31

15 12

EU Enrolling

APS 200 Until

Endpoint

US IDE Approved

APS

Saline

123

123 12

EU Development

APS

HA

120

120 12

PROGRESS I

PROGRESS II

PROGRESS IV

PROGRESS V

PROGRESS III

PROGRESS I (n=10; ongoing):

WOMAC pain subscale

Zimmer Biomet. Annual Report for A Pilot Study of a Single Intra-Articular Injection of Autologous

Protein Solution in Patients with Knee Osteoarthritis. 2016. Report No.: IDE-15978.

0

2

4

6

8

10

12

14

ScreeningN=10

ProcedureN=10

1 WeekN=10

1 MonthN=10

3 MonthN=10

6 MonthN=10

12 MonthN=5

WO

MA

C P

ain

Sco

re

Time Point

ENCOURAGING PRELIMINARY RESULTS

PROGRESS II: Study Design

DOUBLE BLIND RANDOMIZED TRIAL

31 patients treated with APS vs 15 treated with saline

Zimmer Biomet. A Multicenter, Double-Blind, Randomized, Placebo [Saline]-Controlled Pilot

Study of a Single, Intra-Articular Injection of Autologous Protein Solution in Patients with

Osteoarthritis of the Knee. 2016.

4 EUROPEAN CENTERS INVOLVED

Italy – Dr. Kon (Principal Investigator)

Norway – Prof. Engebretsen

Belgium – Prof. Verdonk

Austria – Prof. Nehrer

PROGRESS II: Study Design

Outcomes Efficacy – WOMAC LK 3.1(primary), KOOS,

VAS pain, and SF-36

MRI and X-ray

Safety – AEs, physical examinations, knee

examinations, and vital signs

APS characterization (Italian site only)

Follow-up time points 2 weeks, 1, 3, 6, 12 months for clinical

outcomes Long term follow up scheduled for 24, 36, 48, and

60 months

0, 3, and 12 months for MRI, 0 and 12 month

x-ray

Zimmer Biomet. A Multicenter, Double-Blind, Randomized, Placebo [Saline]-Controlled Pilot

Study of a Single, Intra-Articular Injection of Autologous Protein Solution in Patients with

Osteoarthritis of the Knee. 2016.

PROGRESS II:

CONSORT Flow diagram

Patients

enrolled

(n=59)

Screen Failures

(n=13)

Patients

randomized

(n=46)

Saline Group

(n=15)

APS Group

(n=31)

Completed

(n=30)

Completed

(n=15)

Early

Discontinuation

(n=1)

INCLUSION CRITERIA

Age ≥ 40 and ≤ 75

Body mass index ≤ 40

Unilateral knee OA with Kellgren-Lawrence

grade 2 or 3

Total mean WOMAC pain subscale

between 1.75 and 4 at baseline

EXCLUSION CRITERIA

Rheumatoid arthritis diagnosis

Symptomatic OA in non-study knee

Patellofemoral OA

Symptomatic meniscal injury

HA injection within 6 months or

steroid injection within 3 months

PROGRESS II: Treatment

SINGLE US-GUIDED BLIND INTRA-ARTICULAR INJECTION

2.5 cc APS or 2.5 cc SALINE

PROGRESS II: Demographics

APS Saline p-value

Number of patients 31 15 N/A

Age (Years) 57 (41 – 68) 54 (44 – 67) N.S.

Gender Male 18 9 N.S.

Female 13 6

Ethnicity Black 1 0 N.S.

White (non-Hispanic) 30 15

Kellgren-Lawrence Grade 2 (%) 48 52 N.S.

Grade 3 (%) 71 29

No differences in patient-reported outcome measures at baseline.

APS OUTPUT CHARACTERIZATION

(experiment performed at Rizzoli Orthopaedic Institute)

HIGH CONCENTRATION OF ANTI-INFLAMMATORY CYTOKINES

(IL-1RA, SIL-1RII, AND STNF-RII)

LOW CONCENTRATION OF INFLAMMATORY CYTOKINES

(IL-1Β AND TNFΑ)

PROGRESS II: APS Output

Concentration (pg/ml)

IL-1ra 33,482 ± 16,013

sIL-1RII 27,874 ± 12,087

IL-1β 23.4 ± 28.6

sTNF-RII 6,052 ± 1,643

TNFα 0.6 ± 1.3

1

Zimmer Biomet. A Multicenter, Double-Blind, Randomized, Placebo [Saline]-Controlled Pilot Study of a Single,

Intra-Articular Injection of Autologous Protein Solution in Patients with Osteoarthritis of the Knee. 2016.

• 48 total adverse events in the nSTRIDE APS group and 17 total

adverse events in the Saline group

1 event was likely related to device in nSTRIDE APS group

4 events definitely (3) or likely (1) related to procedure in nSTRIDE

APS group, 2 events definitely related to procedure in Saline group

No significant differences observed between groups in any AE

analysis

No serious adverse device events were reported

PROGRESS II: Adverse Events

PROGRESS II: WOMAC Pain Subscale*

0

10

20

30

40

50

60

70

80

Week 2 Month 1 Month 3 Month 6 Month 12

APS

Saline

% Im

pro

ve

me

nt



*Intent-to treat population

PROGRESS II: VAS Pain*

0

10

20

30

40

50

60

70

Week 2 Month 1 Month 3 Month 6 Month 12

APS

Saline

% Im

pro

ve

me

nt



*Per Protocol Analysis

26

MRI imaging analysis performed at

0, 3 and 12 months

• Joint Space Width/Narrowing

• Knee Osteoarthritis (Kellgren-

Lawrence)

• Magnetic Resonance Imaging

Osteoarthritis Knee Score (MOAKS)1

• Complications and Other Findings – Hemosiderotic Synovitis

– Chondrolysis

– Osteonecrosis

– Subchondral Fracture

PROGRESS II: Imaging

Zimmer Biomet. A Multicenter, Double-Blind, Randomized, Placebo [Saline]-Controlled Pilot Study of a Single, Intra-Articular Injection of

Autologous Protein Solution in Patients with Osteoarthritis of the Knee. 2016.

1. Hunter DJ, Guermazi A, Lo GH, et al. Evolution of semi-quantitative whole joint assessment of knee OA:

MOAKS (MRI Osteoarthritis Knee Score). Osteo & Cart 2011;19:990-1002

PROGRESS II: Imaging*

Medical Metrics. Autologous Protein Solution (APS) OUS (EU) Pilot Study (MMI Project #379) -12 Month Report. 06-Jul-2016

*Sample image does not represent the overall study population.

• Significant differences in size of bone marrow lesions (p=0.041; MOAKS scoring) and in

osteophytes (p=0.032; MOAKS scoring) in the central zone of the lateral femoral condyle

PROGRESS II: Imaging*

Medical Metrics. Autologous Protein Solution (APS) OUS (EU) Pilot Study (MMI Project #379) -12 Month Report. 06-Jul-2016

*Sample image does not represent the overall study population.

NO SIGNIFICANT DIFFERENCE OBSERVED

PROGRESS II demonstrated excellent safety profile for nSTRIDE APS

WOMAC and VAS for pain were significantly improved with APS

respect to saline

APS contains high concentrations of anti-inflammatory cytokines and

low concentrations of inflammatory cytokines

MRI imaging analysis suggest trends that may be detected in larger

clinical trials.

These study results are being used to power confirmatory trials in the

US and EU.

PROGESS II: CONCLUSIONS

Medical Metrics. Autologous Protein Solution (APS) OUS (EU) Pilot Study (MMI Project #379) -12 Month Report.

• FDA approval for PROGRESS IV (US pivotal IDE: APS vs. saline) – Study to begin enrolling Q4 2016

• PROGRESS V - European confirmatory trial (APS vs HA) – Ongoing protocol design

– Site identification

• Investigation of APS in patellofemoral OA (n=50; enrolling).

• PROGRESS III registry – enrolling

• ICRS registry

What is next?

THANK YOU !

THE TEAM Giuseppe Filardo

Alessandro Di Martino

Federica Balboni

Alessia Cavicchioli

Giulia Merli

Alice Roffi

Luca Andriolo

Sante Altamura

Roberto De Filippis

Berardo Di Matteo

Francesco Perdisa

Davide Reale

Filippo Selleri

Andrea Sessa

Francesco Tentoni

nstride aps clinical trial results · lr-prp vs lp-prp effects on chondrocytes proliferation… *...

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