INI-CRCT (Cardiovascular and Renal Clinical Trialists) Coord: Prof. P. Rossignol, Nancy Inserm 9501 CIC

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1 INI-CRCT (Cardiovascular and Renal Clinical Trialists) Coord: Prof. P. Rossignol, Nancy Inserm 9501 CIC CIC-INSERM, CHU de Nancy- Université de Lorraine UMR Inserm U 1116 Heart failure and Hypertension Unit Association Lorraine de Traitement de l Insuffisance Rénale DGOS

2 Chronic kidney disease (CKD) is associated with the epidemic burden of cardiovascular (CV) risk factors Many observational studies.but few RCTs Independent predictors of mortality: Multivariate Cox regression analysis. CV event-free survival Fosidial, n= 397 Fosinopril 0.8 Placebo The unacceptable mortality of patients with chronic kidney failure: what are we missing? Gansevoort et al, The Lancet, Zannad et al, Kidney Int Aortic % suffering Stiffness and CV Survival event Composite CV end-point in ESRD Aurora, n= 2776 Cano N et al. JASN 2007;18: % of CV event-free survival 1.00 SHARP, n= 9270 PWV <9.4 (1/3 m/s HD) < PWV <12.0 m/s Risk ratio PWV 0.83 >12.0 (0.74 m/s 0.94) Logrank 2P= Duration Years of of follow-up (months) Placebo Eze/simv Blacher.and London, Circulation 1999 Baigent, Massy et al, The Lancet ITT analysis: RR=0.929, P=0.35; Per protocol analysis, RR=0.795, P=0.09. Placebo Rosuvastatin HR, 0.96 P-value, 0.59 Years from randomization Felström and Zannad, NEJM 2009.

3 Alchemist ALdosterone antagonist Chronic HEModialysis Interventional Survival Trial P. Rossignol, L. Frimat, Z. Massy, G. London. F. Zannad granted by the French national PHRC DGOS Chronic hemodialysis LVH, or LVEF <40% or diabetes, or history of CV disease Mineralocorticoid receptor antagonist (MRA) RCTs RALES 1999 Placebo (n=375) EPHESUS 2003 EMPHASIS-HF 2011 Spironolactone 25 mg eod to 25 mg/d (n=375) MI, hospitalisation for HF, stroke, or CV death

4 LUNG WATER by Ultra-Sound GUIDED TREATMENT TO PREVENT DEATH AND CARDIOVASCULAR COMPLICATIONS IN HIGH RISK END STAGE RENAL DISEASE (ESRD) PATIENTS WITH CARDIOMYOPATHY Coord: C. Zoccali, EURECA-m ERA-EDTA working group Chronic hemodialysis history of MI or HF Usual care (n=250) Lung comets guided HD (n=250) MI, hospitalisation for HF or ACS, or death

5 Chronic kidney disease (CKD) is associated with the epidemic burden of cardiovascular (CV) risk factors and of heart failure (HF), since one third of HF patients display CKD. Metaanalysis 57 studies ( HF pts) CKD present in 32% of HF pts FIBROSIS RAAS activation FIBROSIS Zannad Damman et al. EPICAL, et al. Eur JACC H J , Am H J 2000 «Cardio-renal syndromes» Adapted from Ronco et al, JACC 2008

6 Cardiotrophin-1 (CT-1) as a cardio-vascular and renal fibrosis inducer (In vitro, Ex vivo, In vivo) CT-1 Myocardial fibrosis Renal fibrosis Vascular fibrosis v CARDIOVASCULAR and RENAL DYSFUNCTION Lopez-Andres..and P. Rossignol, J Hypertens, 2010 Lopez-Andrés.and P. Rossignol, Hypertension 2012, Hypertension 2013

7 PIIINP 7 6,5 6 5,5 5 4,5 4 3,5 3 A biomarkerapproachto assessthe cardiovascular and renal fibrosis in humans > median < median Placebo Aldactone Placebo Aldactone Overall PINP <med >med PICP <med >med PIIINP <med >med 2,5 baseline 6 months 0,00 0,50 1,00 1,50 2,00 Aldactone (better) Placebo (better) Zannad Circulation 2000 Iraqi, Rossignol.. and Zannad Circulation 2009 Eschalier Rossignol Circ Heart Fail 2013 Eschalier, Rossignol Zannad, Hypertension 2014

8 Subtyping HF and its comorbidities (CKD) New Concept Anti-fibrotic HF POPULATION therapy (MRAs) Active fibrogenesis Homogeneous Inherently progressive ~30-50% are at greatest risk of adverse outcome OTHER HF Heterogeneous etiology/pathology Not inherently progressive ~50-70% are at lower risk of adverse outcome

9 INI-CRCT members Demonstrativeoperativeexample(1-3) EU FP7 HOMAGE ( ) From large clinical databases and biobanks ( HF prone patients)..to a RCT

10 HOMAGE Trial Design Screened n ~ 6000 High-risk n ~ 1000 Risk of developing HF Low-risk n ~ 5000 Randomised PROBE Observational Usual care Spironolactone 9 months follow-up End point : Interaction between baseline BM fibrotic risk and change in PIIINP

11 PRIORITY Trial Design PI: P. Rossing(INI-CRCT advisor) Included n ~ 3500 High-risk n ~ 656 Randomised Double-blinded Placebo controlled Proteomic test Low-risk n ~ 2800 Observational Placebo Spironolactone Three years follow-up Decline in renal function/ proteinuria

12 Myocardial interstitial fibrosis: EU FP7 FIBROTARGETS TGF-βpro-fibrotic pathways TGF-β-related cytokines: Cardiotrophin-1 (CT-1), Apelin NADPH oxidases (NOX) Genetic and environmental factors MIF Other factors Aldosterone-related targets CT-1, NGAL, Galectin 3 Matricellular proteins SPARC Thrombosponin (TSP-2) Osteoglycin OGN Pro-fibrotic mirs mir-21, mir-21*, mir-24, mir-212/132

13 From our proof of concept to ongoing R&D 6000 pts, Survival study POC for self monitoring in HF patients EP (IT) Congestion: plasma volume Cardio Renal diagnostics Kidney function: egfr Heart-Kidney toxicity: Potassium TT : ACE-I, ARB, BB, ARM Diuretics Rossignol P, and Zannad F et al, Circulation 2012 Rossignol P., Ménard J., Fay R., Gustafsson F., Pitt B., Zannad F JACC 2011

14 1 UNE EQUIPE LEADER DANS L INSUFFISANCE CARDIAQUE MULTIDISCIPLINARY APPROACH S D Innovation POC devt CardioRenal diagnostics Coordination and marketing ISA- UCBL Sensors CRAN Signal IENSS Sensors DMP EDDH CIC-P Medical expertise LORIA INSTITUT ELIE CARTAN

15 main objective: to improve CV outcomes in CKD patients CLINICAL TRIALS BIOBANK COHORTS Validation of new biomarkers/biotargets (mechanistic phenotyping) New RCTs: Innovative experimental designs Personalized medicine approach

16 6 Cardiac and Renal Regional Patient Associations & Networks & DMPs basic researchers INI-CRCT Cardiovascular and Renal Clinical Trialists intensivists nephrologists methodologists cardiologists Nutrition in dialysis study group

17 Management structure within F-CRIN,for optimal efficiency F-CRIN «PARTNERS» platform C. Alberti & E. Vicaut

18 Conclusions INI-CRCT Will significantly advance the understanding of cardiovascular disease in CKD patients and of nephroprotection in CV diseases and of the underlying mechanisms. This scientific progress will in return enable the development of effective diagnostic tools based on identified biomarkers, of new therapies and, specifically, of more effective drugs INI-CRCT research results will contribute to combat the most important public health problem in Europe (and the world): CV diseases.

19 Beyonddeliverables, our main missions withinthe next5-years : To change medical practices To apply for and run new trials (EU Horizon 2020 ) Calls for personalizing health and care: ageing process, new diagnostic tools and technologies, clinical validation of biomarkers. new therapies for chronic diseases or rare diseases >>march 14: PHC1, PHC 10, PHC 17

20 PRME 2013 «ESTIM-rHTN» medicoeconomic evaluation of baroreceptor STIMulation for the treatment of Resistant HyperTensioN A multicenter randomized, open label trial

21 Comité scientifique: Investigateur coordonnateur: Patrick Rossignol, Nancy Investigateur co-coordonnateur: Michel Azizi, Paris Méthodologie: Gilles Chatellier, Paris Analyses médico-économiques : Karine Chevreul (URC-Eco, Paris) Dr Jean-Marc Alsac, Paris Pr Faiez Zannad, Nancy Conseiller : George Bakris, Chicago, USA Comité de surveillance : Pr Pascal Desgranges, Hôpital Henry Mondor, Créteil Pr Pascal Bousquet, cardiologue, pharmacologue, Université de Strasbourg. Dr Catherine Cornu, Centre d Investigations Cliniques, CHU de Lyon

22 EXPERIMENTAL DESIGN: PROBE N= 140 N= 64 N= 64