INHERITANCE – PRECARDIAINHERITANCE – PRECARDIAPavia Meeting

June 15, 2012

“INHERITANCE- PRECARDIA” Study or PRE clinical mutation CARriers from families with

Dilated cardiomyopathy and ACE inhibitors

• Aim.

- Study the impact of ACE inhibitors (ACEi) in relatives who carry a mutation but have not yet developed DCM through a double-blind randomized (parallel-group) multicenter trial.

- To extend the medical impact of predictive genetic testing in DCM (direct therapeutic impact).

• Hypothesis.

- ACEi may delay or prevent the occurence of DCM in these participants (preclinical stage).

“PRECARDIA” Study : Timetable • Submission to the sponsor (INSERM-ECRIN): Final approval obtained

the10th of January 2011

• Submission to the Competent Authorities via the Voluntary Harmonisation Procedure (to the Head of Medicines Agencies HMA – unified process): submitted June 2011, obtained 15 August 2011

• Submission to national competent authority in France (AFSSAPS): – Final agreement obtained in Paris 31 August 2011

• Submission to local ethical committees: submitted June 2011 for Pavia and Paris

– Final agreement obtained in Paris 05 October 2011

• Agreement / convention document : - with Servier: signed; with Brahms: underway - tripartite agreements between INSERM/ ECRIN partner or other CTU/ local

institution** : under way ** ECRIN partner or other CTU not part of the local institution

“PRECARDIA” Study :

inclusion in Paris

• First participant included: – 1st December 2011

• Total participants included by the 15th June 2012: – 3 participants – (all with a LMNA mutation, from 3 different families and 3 different mutations)– (2 with isolated LVED enlargement and 1 with isolated systolic dysfunction

(EF50%)

INHERITANCE – PRECARDIA 5

Update – Update – Submissions1/2

C10-44 PRECARDIANational Competent Authorities submissions

Country NCA Responsible of the submission Submission Date Autorization

France Afssaps Inserm Yes 31/08/2011 Yes

Italy (1) Agenzia italiana del farmaco - OsSC Cecilia Trovati Yes 23/08/2011 Yes

Denmark Lægemiddel Styrelsen Berit Grevstad Yes 14/10/2011 Yes

GermanyFederal Institute for Drugs and Medical Devices - BfArM

Regina Pribe/KKS Heidelberg In preparation     

Netherlands Central Committee on Research Involving Human Subjects - CCMO

Jacqueline van Dalen Waiting for the

signed agreement   

SpainAgencia Española de Medicamentos y Productos Sanitarios - AEMPS

Maria Sanchiz Yes 11/11/2011 Yes

UKMedicines and Healthcare products Regulatory Agency - MHRA

Waiting for a CTU & help of Eleanor Wicks

 IRAS portal not finalized

   

(1) Out of VHP

VHP Authorization 15/08/2011

15 June 2012

INHERITANCE – PRECARDIA 6

Update – Update – Submissions2/2

C10-44 PRECARDIAEthics Committees submission

Country EC Responsible of the submission Submission Date of session Opinion Date of opinion

France CPP Ile de France VI Inserm Yes 06/07/2011 Favorable 05/10/2011

ItalyComitato di Bioetica Fondazione IRCCS Policlinico San Matteo

Cecilia Trovati Yes 04/07/2011 Favorable 22/07/2011

Denmark (1)De Videnskabsetiske Komitéer for Region Midtjylland

Berit Grevstad Yes  January Favorable   25/01/2012

GermanyEthikkommission der Medizinischen Fakultät Heidelberg

Regina Pribe/KKS Heidelberg Waiting for the

signed agreement     

NetherlandsMedical Ethics CommitteeAcademic Medical Centre (AMC)

Jacqueline van Dalen  Waiting for the

signed agreement     

Spain (2)Comité Ético de Investigación Clínica de Galicia (CEIC)

Maria Sanchiz Yes  04/10/2011 Favorable 27/10/2011

UK NRES CommitteeWaiting for a CTU & help of Eleanor Wicks

 IRAS portal not finalized

     

(1) Translation into Danish of the Protocol(2) Translation into Spanish of the Protocol

15 June 2012

15 June 2012 INHERITANCE – PRECARDIA 7

Update - AgreementsUpdate - Agreements

C10-44 PRECARDIAAgreements

Countries Agreements between Inserm (Sponsor) and the hospital (local coordinator) +/- CTU

France NA

Italy Finalization

DenmarkComments sent by the Copenhagen Trial Unit.

Waiting for Arhus Hospital’s comments.

Germany= « R&D contract » Waiting for Heidelberg Hospital’s comments.

NetherlandsComments provided by AMC.

Waiting for sponsor’s legal department response.

Spain Comments provided by the CAIBER. Waiting for sponsor’s legal department response.

UK  Sent to Eleanor Wicks

First draft sent by the sponsor.

Submission to the VHP: 27/JUN/2011       

Authorization from the VHP: 15/AUG/2011

Competent Authority Ethics committee

Italy 23/AUG/2011 22/JUL/2011

France 31/AUG/2011 05/OCT/2011

Spain 11/NOV/2011 03/NOV/2011

Denmark 14/OCT/2011 25/JAN/2012

Germany Pending on the insurance Pending on the insurance

Netherlands Pending on the signature of the agreement

Pending on the signature of the agreement

United-Kingdom Pending Pending

Any comments?

PRECARDIA

“PRECARDIA” Study : Budget

• Cost related to drug/placebo production and distribution are covered by Servier company.

• Cost related to coordination, insurance and monitoring will be covered by Paris centre. Preparation/submission to Health Agencies and Ethical committees, was also covered by Paris.

• Cost related to SUSAR reporting, hospitals overcosts and clinical research associates (inclusion participants and entering data into DB) will be covered by local investigators.

• BUDGET:

– Each center received a budget for participating to several workpackages in FP7 / Inheritance network

– Total cost of PRECARDIA: 405,000 euros including 222,000 euros for Paris

“PRECARDIA” Study Budget ECRIN / local investigators: initial evaluation in 2010 (should be update, euros)

Denmark Sweden Spain Germany UK Italy Netherlands France Total

                   

Monitoring 4200 10450 5400 11625 14220 9000 8000 62,895

(covered by Paris)                  

Submission                  

Heatl Agency 935 3300 700 1700 6180 0 1600 14415

Ethical C 540 1600 700 5500 0 3000 1300 12640

sub total submission 1475 4900 1400 7200 6180 3000 2900 27,055

                   

CRA 17000 17000 17000 17000 17000 17000 17000 119,000

inclusion/entering data          

                   

Insurance 10000 10000 10000 10000 10000 10000 10000 10000 80,000

(covered by Paris)                

by Léa Stankovski, INSERM/ECRIN

Budget (update)

• Insurance:

– Paid by Paris (for France, Italy, Spain, Denmark, Netherlands) about 45,000 euros

– Pending for Germany and UK

25 Jan 2012 PRECARDIA 12

Budget (update evaluation)

Regulatory Submission Monitoring(based on the workload

estimated by the Sponsor)

Italy “absorbed” “absorbed”

France “absorbed” “absorbed”

Spain 2400 € (covered by the COSSEC grant)

5400 € for 25 patients

Denmark 6940 €(of which 6000 are covered by the COSSEC grant)

5850 € for 25 patients

Germany 6300 €(6291 covered by the COSSEC grant, still pending)

32,000 € (15 patients)

Netherlands 5000 €(covered by the COSSEC grant)

13,209 € for 25 patients

United-Kingdom Pending (3,000 €?) Pending (19,000 €?)

Budget for monitoring

• Final answer from Inserm/UE: not possible for Paris to pay other partners within the network

• Half of the required budget (~40 KE) however available from Paris-Inheritance budget through the use of indirect costs

• Half of the required budget? (~40 KE)

• Re-allocation directly from UE/Pavia?• Use of final part of UE funding?• Extra budget?