fact. - f-crin

A network dedicated to advancing clinical

research in the field of coronary artery

disease

FACT.French Alliance for Cardiovascular Clinical Trials

Alliance Francaise pour les Essais Cliniques Cardiovasculaires

Ph.Gabriel Steg for FACT

*DHU-FIRE, Hôpital Bichat, Assistance Publique – Hôpitaux de Paris,

Université Paris – Diderot, INSERM U-698, Paris, France,

and NHLI Imperial College, ICMS, Royal Brompton Hospital, London, UK

Why did we create FACT ?

• A « research gap » in CV trials in France

– Poor and slow enrolment of french sites in trials

– Poor perception of investigators and data quality

– Long implementation delays

– Fewer trials offered to french sites

– Poor representation of french academia in the leadership of international CV clinical trials

• Need for transverse collaborative structures

– Fair allocation of leadership and academic recognition

– Involvement of research groups inside and outside Paris

Main causes for the french CV clinical

research gap

• Lack of collective organisation of CV clinical research

• Lack of powerful academic research organizations

• « Cultural deficit »

– Of investigators

– Of the research organizations (INSERM/CNRS/Universities)

– Of hospitals (even among academic institutions)

• Lack of dedicated specialized research professionnals(research coordinators/nurses/bio-statisticians/computing/IT)

• Poor coordination between basic and clinical sciences

Our goals

FACT: a network of cardiology teams of excellence (private or public,

academic or not) with an interest in clinical trials, aiming to

1. Conduct high-quality cardiovascular clinical trials in the fields of coronaryartery disease and the cardiovascular complications of diabetes.

2. Emphasize academic value, quality, speed and efficiency throughout ourentire research program.

3. Push for the professionnalization of research (through training of researchpersonnel and investigators, recruitment and mutualization of skilledprofessionnals).

4. Provide single entry to a network of clinical sites for site selection, contracting, set-up and patient enrolment.

5. Provide fair access to academic leadership and recognition to itsmembers.

6. Enhance the profile and visibility of french CV clinical research at the European level.

7. Ultimately: create a spirit of collective endeavor at the national level.

Current projects

Academic trials

• TOTAL (PHRI, PG.Steg SC)

• COMPLETE (PHRI, L.Feldman SC)

• COMPASS (PHRI, V.Aboyans SC)

• Upcoming

– REALITY (submitted to PHRC & BHF PG.Steg EC Chair)

– RAHIM (Submitted to Fondation Cœur et Artères) Z.Mallat

– IL-2 in Acute MI

– MARINER (ATLAS/CPC, A.CohenSC)

Industry trials

• ODYSSEY Outcomes (Sanofi –PG.Steg Co-Chair EC)

• THEMIS (AZ – PG.Steg Co-Chair EC, T.Simon EC, N.Danchin SC)

• TIGRISS (AZ – T.Simon EC)

• Upcoming

– ENSURE (Daiichi, A.Cohen SC)

– CARDIC (Otsuka – PG.Steg Co-Chair EC)

– LATITUDE (GSK, PG.Steg EC)

– REGULATE (Regado, PG.Steg EC)

– Re-DUAL PCI (with ACTION)

Industry trials are only addressed when FACTmembers are scientifically involved in theinternational steering committees

In red: trials designed and led by theFACT leadership

4 examples of FACT studies

• An industry phase III trial: ODYSSEY Outcomes

GoF Mutations in PCSK9 cause autosomal dominant

hypercholesterolemia

Genetic analysis and mutation detection infamiiy HC60.(c) Pedigree and genetic analysis of family HC60.

Age (in years) at lipid measurement, totalcholesterol (TC) and low-density lipoproteincholesterol (LDL-C; in g/L; untreated values foraffected individuals) are given. (d) Sequenceanalysis in family HC60. The proband (HC60-II-2,indicated by an arrow) is heterozygous with respectto the 890T C substitution in exon 4, predicting theamino-acid substitution F216L.

Abifadel, et al. Nature Genetics 2003;34: 154 – 6. Abifadel, et al. Nature Genetics 2003;34: 154 – 6.

PCSK9 LoF mutations are associated with lower LDL cholesterol levels and incidence of CHD

Plasma LDL Cholesterol Levels (Panel A) and Incidence of Coronary Heart Disease (Panel B) among Black Subjects, According to the Presence or Absence of a 142X or 679X

Allele.

Cohen JC et al. N Engl J Med 2006;354:1264-1272.Cohen JC et al. N Engl J Med 2006;354:1264-1272.

The Role of PCSK9 in the Regulation of LDL Receptor Expression

For illustration purposes only

LDL lowering with alirocumab once every 2 weeks in primary hypercholesterolemia

Percent Change from Baseline in LDL Cholesterol

Roth EM et al. N Engl J Med 2012;367:1891-1900Roth EM et al. N Engl J Med 2012;367:1891-1900

18 000 Pts with recent ACS & LDL-C >70 g/dL on max toleratedstatin Rx

PI:GG.Schwartz & PG.Steg

Primary Endpoint: Time to first occurrence of one of the following CEC -adjudicated events: CHD death. Any non-fatal MI. Fatal and non-fatal stroke.

Hospitalization for unstable angina.

randomization

Alirocumab sq Q2W Placebo sq Q2W

ODYSSEY Outcomes

FACT.French Alliance for

Cardiovascular Trials

FACT.French Alliance for

Cardiovascular Trials



• An academic comparative effectiveness trial:

REALITY

1078 Pts with acute MI and 7 < Hb ≤ 10 g/dL within 24 h of admission

Chair: PG.Steg

Primary Endpoint: 30-day all-cause mortality

Secondary endpoint: Major cardiac events at 30-days: all-cause death, reinfarction, stroke, heart failure and emergency revascularization.

randomization

Liberal RBC transfusion strategy

Restrictive RBC transfusion strategy

REALITY

Power calculations: 80% power, 5% alpha, Absolute ∆: 4.25%. Mortality rate 8% in liberal group. Drop out rate: 2.5%

66 sites have agreed to participate in France and the UK

Planned enrolment: 0.54 pt/site/month over 30 months

Funding applications: PHRC & BHF




REALITY

• A translational research PoC trial: RAHIM

Sept 15, 2013, online pub.

Blood levels of BAFF predict outcome after AMI

(FAST MI registry)

The RAHIM Trial

Anterior STEMI patients

& successful PCI

within 24 hours of symptoms onset

< 48hrs

after PCI

Cardiac MRI

Blood Samples

Randomization Pre-Medication (30 min prior) : Methyl-prednisolone IV/or Placebo )

One single infusion of Rituximab or PL (IV),

Monitored in CCU

Cardiac MRI

FDG-PET

Blood Samples

4 months Follow up

Visit

Co-primary endpoints: clinical safety and the variation of circulating B cell count with Rituximab compared to placebo, at day 1 and month 4 after treatment.

Secondary endpoints:

-Variations of Infarct size and LVEF variations (M4-D1) by cardiac resonance magnetic imaging (CMR).

- Myocardial viability evaluated by FDG-PET.

- Relationship between

B cell depletion and systemic immune response

B cell depletion and occurrence of CV events (Death, arrhythmias, recurrent MI, stroke, re-intervention in infarct-related artery, re-hospitalization for cardiovascular disease).




REALITY

• A translational research PoC trial: RAHIM

• An idea turned into a phase 3 trial: THEMIS

Aspirin for primary prevention of cardiovascular events in people with

diabetes: meta-analysis of randomised controlled trials

19JPAD=Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes; POPADAD=Prevention Of Progression of Arterial Disease And Diabetes; WHS=Women’s Health Study; PPP=Primary Prevention Project; ETDRS=Early Treatment

Diabetic Retinopathy Study

De Berardis et al. BMJ 2009;339:b4531

Aspirin significantly reduced the risk of myocardial infarction in men (0.57, 0.34 to 0.94) but not in women (1.08, 0.71 to 1.65;

P for interaction=0.056)

Capodanno D et al. Circ Cardiovasc Interv 2011;4:180-187Capodanno D et al. Circ Cardiovasc Interv 2011;4:180-187

Value of bid dosing of aspirin in diabeticsResidual collagen-induced aggregation - Luminometry

Residual thromboxane B2 level

The THEMIS trial: Prevention of CV Events In

Patients With Type 2 Diabetes and CAD

Primary efficacy endpoint: :Composite of CV death, MI or stroke

Secondary endpoint: Composite of all-cause death, MI or stroke; CV death; all-cause death

Primary safety endpoint: TIMI Major bleeding

Event-driven study; 750 CV events required. 2 years mean follow-up (n=17,000)

Ticagrelor Placebo

Type 2 diabetes; treatmentType 2 diabetes; men and women ≥50 years; ≥6 months glucose-lowering drug treatment

Prior PCI or Prior CABG or ≥50% coronary stenosis

No previous MI or stroke, No planned use of ADP receptor antagonist

Optimal background therapy including aspirin

Co-chair: P.G.Steg & D.L.Bhatt, EC: T.Simon; SC: N.Danchin

Strategy for running european trials

• Links with academics and Academic Research Organizations in Europe

– Cambridge University (Z.Mallat)

– Imperial College (P.G.Steg)

– Uppsala Clinical Research – Uppsala University

– Leuven Coordinating Center – KUL

• Experience in running european and international trials and registries

– Clinical trials: TAO, EUROMAX,

– Registries: GRACE, REACH, CLARIFY

• Tools for trial coordination

– Methodological and statistical resources within the network (statisticians, healtheconomist), with experience in designing large trials and analysing large datasets

– Site management

– Outsourcing IVRS/monitoring (including through the PARTNERS F-CRIN platform)

– Investigator-initiated studies (with unrestricted grants from industry) or Publicly fundedstudies (EU-wide support)

• Need to get to the next level and get EU-funding (HORIZONS-2020)

FACT trial sites

Site Investigators

Centre Hospitalier de la Région d’Annecy - ANNECY BELLE Loïc

CH BOURGES - BOURGES TABONE Xavier

CH St Joseph St Luc - LYON DUBREUIL Olivier

CHU A. MICHALLON - GRENOBLE VANZETTO Gerald / MACHECOURT Jacques

CHU de Toulouse - Rangueil - TOULOUSE CARRIÉ Didier

CHU Dupuytren - LIMOGES ABOYANS Victor

CHU Haut Lévêque - PESSAC COSTE Pierre

CHU Hopital Nord - MARSEILLE PAGANELLI Franck /BONELLO Laurent

CHU Hôpital Saint-Jacques - BESANCON SCHIELE François

CHU Le Bocage - DIJON COTTIN Yves / ZELLER Marianne

CHU Nice - Hôpital Pasteur - NICE FERRARI Emile

CHU Saint Antoine - PARIS BOCCARA Franck

Clinique Pasteur - TOULOUSE FARAH Bruno / TCHETCHE Didier

Groupe Hospitalier Intercommunal MONTFERMEIL CATTAN Simon

H. MONDOR - CRETEIL TEIGER Emmanuel

HEGP - PARIS DANCHIN Nicolas

Hôpital Bichat-Claude Bernard - PARIS STEG Philippe Gabriel

Currently, 17 trial sites. Aiming to recruit 4 more sites in the coming months

- Lille

- Corbeil Essonne

- CHU Cochin, Paris

- Roubaix

-All sites agree to sign and abide by the FACT charter

Nice

MarseilleToulouse

Grenoble

AnnecyLyon

BesançonDijonBourges

Limoges

Pessac

Paris-HEGP

Paris-Bichat

Montfermeil

Créteil

Paris-Cochin

Corbeille-EssonnesLille

Roubaix

FACT is more than a network of trial sites

- A multipurpose clinical research platform : PARTNERS, linked to F-CRIN

- A certified biobanking facility (CRB-HUEP-UMPC, located at Hôpital Saint Antoine, Paris)

- Computing, Statistical, Health economics and IT resources

- Links with basic science groups (Cambridge/PARCC, INSERM, CRNS)

- Links to academic institutions (French Universities, Imperial College, Cambridge University)

- Linked to the Multidisciplinary Département Hospitalo-Universitaire FIRE (Univ. Paris-Diderot)

- Links to AROs (DCRI, UCR, TIMI, HCRI, ECRI, PHRI, etc…)

- Contacts with the pharma and device industry

The FACT assets

• Sites of excellence

• A strategized scientific policy,

• Highly motivated investigators (improved enrolment rates)

• Availability of professional resources

• Above standard training and SOPs to « raise the bar » in terms

of quality and speed

• A collective spirit !

Thank you !

fact. - f-crin

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