Coordinator, H Decousus, CIC de St Etienne (INSERM CIC1408)

Co-coordinator, G Meyer, CIC de Paris HEGP (INSERM CIC 1418)

Investigation Networks Initiative

Venous ThromboEmbolism (VTE)

� Deep vein thrombosis (DVT), Superficial vein thrombosis (SVT) and Pulmonary embolism (PE)

� PE: 3rd cardiovascular cause of death after myocardial infarction and stroke

� Annual Incidence: 20-25 per 10,000 adults

� Chronic disease:� Long-term recurrence rate: 30 to 50 %

� Post-thrombotic syndrome: up to 30 % of patients with DVT

� Chronic thromboembolic pulmonary hypertension: 1% of PE

� Many questions remain unanswered

Clinical Investigation Centres (12 CIC)

Biological Resource Centre (1)

University Research Units (2)

Nice

Valenciennes

Paris

Brest

Montpellier

St Etienne Grenoble

Rouen

Lille

Toulouse

Besançon

Clermont

CaenNancy

Angers

Agen

Bordeaux

����

Dijon

Limoges Lyon

Nantes

Nîmes

Strasbourg

Orthez

Roanne

CréteilBichat

Vernon

Amiens

Arras

Toulon

Cannes

Annecy

LangresLe Mans

Quimper

Established in 2008 by the creation of a charter

Marseille

Clinical sites (56)

Network Results (2009-2013)

� 33 multicenter academic studies, 35,528 patients � 30 French Clinical Research Programs (PHRC) � 13 with international collaboration (PREP,TIH Score, ADJUST, PEITHO…)� 10 studies (recruitment completed, follow-up and/or analyses ongoing)

� 13 industry-sponsored studies, 8,125 patients

� 213 international publications� 57 with international cooperation� 198 academic (1 NEJM, 2 Lancet, 3 Ann Intern Med, 3 BMJ, 4 Blood,…)� 15 industry-sponsored:

� GIRC first author: 2 (1 NEJM, 1 Chest)� GIRC co-author: 8 (7 NEJM, 1 Ann Intern Med)

Day 7 Day 30

R

DOUBLE BLIND

Sec

onra

y O

utom

es, S

AE

Prim

ary

Out

com

e, S

econ

dary

Out

com

es

Confirmed acute symptomatic PE

Absence of hemodynamic

collapse

Confirmed RV dysfunction +

myocardial injury

UFH

TNK

Placebo<2 h

UFH

UFH, LMWH or Fondaparinux

VKA

Tw

o ye

ar f

ollo

w-u

p

2 years

Tenecteplase

(n=506)

Placebo

(n=499) P value

n (%) n (%)

All-cause mortality or hemodynamic

collapse within 7 days of randomization 13 (2.6) 28 (5.6) 0.015

All-cause mortality within 7 days 6 (1.2) 9 (1.8) 0.43

Major non-intracranial bleeding 32 (6.3) 6 (1.5) <0.001

Strokes by day 7 12 (2.4) 1 (0.2) 0.003

VKA

1,006 patients, 76 sites, 12 European CountriesData Management, E. Vicaut Meyer G et al. N Engl J Med; accepted for publication

� 2 main Goals:

� Develop Translational Research in VTE

� Facilitate more Large Scale European Clinical Trials

� A New Structure:

INvestigation Network On Venous ThromboEmbolism

• 3 Haemostasis / Genetic units:o P. Morange, UMRS1062, Marseille

o F. Dignat-George, UMRS1076, Marseille

o D. Tregouet, UMRS 937, Paris

• 2 Medical Imaging and InformationProcessing units:o E Stindel, La TIM, Inserm U1101, Brest

o Ph Cinquin, TIMC-IMAG, CNRS 5525, CIC-IT, Grenoble

• GIRC: a Clinical Research Network +

INNOVTE

Clinical Investigation Centres (12 CIC)

Biological Resource Centre (1)

University Research Units (2)

Nice

Valenciennes

Paris

Brest

Montpellier

St Etienne Grenoble

Rouen

Lille

Toulouse

Besançon

Clermont

CaenNancy

Angers

Agen

Bordeaux

����

Dijon

Limoges Lyon

Nantes

Nîmes

Strasbourg

Orthez

Roanne

CréteilBichat

Vernon

Amiens

Arras

Toulon

Cannes

Annecy

LangresLe Mans

Quimper

Marseille

Clinical sites (56)

Biological and imaging Units

Our European Network

� A. Perrier,Geneva

A. Cohen, London�

S. Motte, Brussels ����

� R. Bauersachs, Darmstadt

P. Prandoni, Padova �

���� H Büller, Amsterdam

M. Monreal, Barcelona �

� S. Konstantinides, Mainz

INNOVTE

G. Agnelli, Perugia �

A Greinacher, Greifswald �

� W. Ageno, Varese

� D. Jimenez, Madrid

Scientific Program

� Therapeutic approach of VTE� Primary prophylaxis of VTE in elderly medical patients (SYMPTOMS)

� Secondary prophylaxis of VTE during pregnancy (HIGHLOW)

� Statins in recurrent VTE prevention (VAN GOGH)

� Pharmaco-epidemiology of the treatment of PE (PEAGE and COOPER)

� Pathophysiologic approach of long-term complication s of VTE� Recurrent VTE using biomarkers (STRATOSPHERE)

� Post-thrombotic syndrome using imaging and biomarkers (PTS)

� Long term complications of pulmonary embolism (risk factors and mechanisms)

� Two rare aspects of VTE� Heparin-induced thrombocytopenia: a model for hypercoagulability (HIT)

� Large families with unexplained VTE: a genotypic model of thrombosis (FAMILY)

European Clinical studies

� SYMPTOMS: Primary prophylaxis in elderly acutely ill hospitalized medical patients (PHRC 2013 / PHC 17, 2014)

� Clinical outcomes (VTE and major bleeding)

� Population at risk (> 70 years)

� Randomization: Enoxaparin / placebo for 10 +/- 4 days

� 5,030 patients

� Coordination: D. Mottier (CIC 1412, Brest)

� 5 European countries + Canada

� Senior Project Manager European Affairs (A. Ottavi, Inserm Transfert)

� Methodology / Statistics / Adjudication Committee performed by CIE 1408 / EA 3065 (S.Laporte, P.Mismetti, A, Merah, St-Etienne),

� Data management performed by one of the FCRIN platforms (E.Vicaut, Paris)

� Biobank managed by a Biological Resource Center (K.Lacut, Brest)

European Clinical studies

� STRATOSPHERE: Prevention of Recurrent VTE using biomarkers (PHC 5, 2014)

� Step 1. Predictive value of single nucleotide variants (SNVs) for the risk of recurrent VTE using available studies of VTE genome-wide genotype and expression data.

� Step 2. A risk-stratification score combining SNVs selected at step 1, clinical data and biomarkers will be derived and validated in prospective cohorts of patients with VTE

� Step 3. The effectiveness of the score will be evaluated against current practice in a proof of concept randomized controlled trial.

� Coordination: G. Meyer (CIC 1418, Paris HEGP)

� 4 European partners ( F Rosendaal,Leiden; P Wild, Maintz; M Monreal, Barcelona; L Mantovani, Napoli)

� 3 INSERM Biological Units (F. Dignat-George, P. Morange, D. Tregouët)

� Diagnostica Stago (France)

� Senior Project Manager European Affairs (A. Ottavi, Inserm Transfert)

� Methodology / Statistics (CIE 1408 / EA 3065, S.Laporte, P.Mismetti, St-Etienne)

European Clinical studies

� HIGHLOW: Secondary prophylaxis of VTE during pregnancy

(S. Middeldorp, Netherlands / A. Buchmuller - C. Chauleur,

CIC 1408 - réseau GO-CIC / Horizon 2020, PHC 13, 2014)

� VAN GOGH: Secondary prophylaxis of VTE by statins

(H, Büller, Netherlands / H. Decousus, CIC 1408, Horizon 2020, PHC13, 2014)

� HIT: Randomized trial in Heparin-induced thrombocytopenia

(B. Tardy, CIC 1408, PHRC 2008 Score TIH / Aviesan 2013 / Organon ; Sanofi ; Stago ; LFB, Horizon 2020, 2015)

Other studies

� PEAGE / COOPER: Pharmaco-epidemiology of the treatment of PE

(P. Mismetti, PHRC 2012 and Investigator- Initiated Study, Bayer Health Care)

� PTS: Post-Thrombotic Syndrome

(J Ph. Galanaud, AO académique canadien 2014 + PHRC 2014)

� FAMILY: Large families with unexplained VTE: a genotypic model of thrombosis

(P. Morange, Fondation Maladies rares 2014)

� Bio-imaging of the venous thrombus:

(G. Pernod, Financement F-CRIN)

FAMILY: Large kindreds withunexplained VTE

� VTE, in some families, is transmitted under a familial inheritance model without known genetic factors

� Proposal for hypothesis-free genome-wide approach using whole-exomesequencing in Families with multiple affected individuals

� To evaluate the newly identified genetic variants in other cohorts of patients with VTE

� To functionally characterize these genetic variants

� To identify new therapeutic targets

� Coordination: P Morange (UMRS 1062)

� Partners

• GIRC network (F. Couturaud, Brest)

• UMRS 937 (DA Tregouet, Paris), INSERM UMRS 1076 (F Dignat-George, Marseille)

Bio -imaging of the venous thrombus

� To assess mechanical properties of the venous thrombus

� To predict the risk of PE in patients with DVT

� To predict the risk of developing post-thrombotic syndrome in patients with DVT

� To create innovative evaluation criteria for the assessment of new treatments for DVT

� Techniques: Elastography and Elastometry

� Pilot study: 100 patients with DVT (CIC Brest, Grenoble, Montpellier)

� Coordination: G. Pernod (CIC 1406, Grenoble)

� Partners

• GIRC Network (D Mottier, I Quere)

• La TIM INSERM U1101 (E Stindel, L Bressollette, Brest)

• La TIMC-IMAG CNRS 5525/CIC IT (P Cinquin, J Ohayon, Grenoble)

• Institute of Biomedical Engineering, University of Montreal (G Cloutier)

• Supersonic Imaging company,

• Siemens, General Electric, Phillips

PARTNER Platform

GIRC� 12 CIC

� 1 BRC

� 56 Clinical Sites

H Decousus, G Meyer,

F-Crin, BRC, Platform Partners,

GIRC Board members, Scientific Partners

• Quality assurance, training program, Europe

• PEAGE-COOPER, PTS, CTEPH, FAMILY, bio-

imaging,

• SYMPTOMS, STRATOSPHERE, HIGHLOW, HIT

SCIENTIFIC PARTNERS

•P Morange, Marseille

INSERM –UMRS 1062

•F Dignat-Georges, Marseille

INSERM -UMRS 1076

•DA Tregouet, ParisINSERM -

UMR_S937

•S Laporte, P Mismetti,

St-EtienneEA 3065

•D Mottier, BrestEA 3878

•E Stindel, Brest

La TIM INSERM - U

1101

•P Cinquin, Grenoble

TIMC-IMAG UMR-5525 /

CIC-IT

Conclusion

F-Crin: a unique opportunity to create a new investigation network in VTE:

� To launch new European clinical studies

� Previous experience of our group

� No existing European Academic Structure for VTE research

� To produce high standard translational research leading to the development of innovative diagnostic and therapeutic approaches.

Cellule de coordination INNOVTE Année 1 Année 2 Année 3 Année 4 Année 5 Total

PH Coordination 0,6 ETP 65 260 65 260 0,5 ETP 54 380 54 380 0,4 ETP 34 128 273 408

ARC coordination 0,8 ETP 34 000 34 000 0,6 ETP 25 500 25 500 0,5 ETP 21 250 140 250

Secrétaire 0,3 ETP 11 205 11 205 0,3 ETP 11 205 11 205 0,3 ETP 11 205 56 025

Total personnel 469 683

Partenaires

U 1011 20 000 10 000 10 000 5 000 0 45 000

CNRS 5525 20 000 10 000 10 000 5 000 0 45 000

SOUS-TOTAL 90 000

Autres

50 000 50 000 50 000 50 000 50 000 250 000

Total dotation F-CRIN à INNOVTE 809 683

Budget prévisionnel

Budget

� Funding for GIRC coordination and sites support (last 5 years) � INSERM 212.5 K€ (coordination); CeNGEPS 857.3 K€ (coordination and CRAs)

� Funding for GIRC studies and sites support (last 5 years)

� 29 PHRC, 1 INSERM, 1 ANR, 1 Fondation de France, 1 Fondation de l’avenir; e.g. for 2012: 4 PHRC (2, 150 K€) and 1 Investigator- Initiated Study (1,000 K€, COOPER / Bayer)

� Support requested for this INNOVTE bid (1,182 K€ for 5 years)

� Coordination Unit 702.5 K€: 1 Physician and 1 Clinical Research Associate (615 K€)

+ Travelling and meetings (87.5 K€)

� ½ time engineers for each Imaging Unit: 250 K€

� ¼ time engineers for each Biological Unit: 230 K€

� Financial INNOVTE Sustainability for the next 5 years� Coordination Unit: INSERM (42 K€/year); CeNGEPS (240 K€/ 2014-2015); 8 % from each

new funding obtained per INNOVTE project

� Funding per project: some already obtained (pharmacoepidemiology, PTS, HIT); for others: PHRC, HORIZON 2020, Industry, INSERM, ANR, different Foundations

� Sites support: ~ 10 to 30 % from each funding obtained (~ 1/4 time CR Tech per project)