Folie 1 - HRB Trials Methodology Research Network |HRB-TMRN

Folie 1 - HRB Trials Methodology Research Network |HRB-TMRN

A European Multicentre Double-Blind controlled trial of Nilvadipine in Mild to Moderate Alzheimers Disease Investigators Perspective Professor Brian Lawlor, Coordinator, NILVAD This project has received funding from the European Unions Seventh Framework Programme for research, technological development and demonstration under grant agreement no 279093 Alzheimer's Disease 35 million people worldwide have Alzheimers disease Possible causes of AD: Tau, Amyloid, Inflammation Amyloid comes from a large protein which is found in the fatty membrane surrounding nerve cells. Amyloid is sticky and form plaques in the brain. Plaques block cell to cell signalling at synapses Amyloid can accumulate up to 2 decades before AD symptoms Main focus of therapeutics on amyloid with spectacular failures Alzheimer's Disease Current Medications 4 drugs available for AD 3 Cholinesterase Inhibitors, 1 glutamate antagonist Donepezil Rivastigmine Galantamine

Memantine Temporarily improve/stabilise memory & thinking skills None of these drugs halt the disease or slow progression Why Nilvadipine? Nilvadipine highly lipophilic- crosses the Blood Brain Barrier Compared to another calcium channel blocker Nifedipine-Nilvadipine is longer acting + less cardiac effects Nilvadipine has a known safety profile and is widely used in Japan & Asia for treatment of hypertension Nilvadipine increases cerebral blood flow more than other calcium channel blockers (x16 nifedipine) Nilvadipine shown to reduce amyloid accumulation in the brain by affecting amyloid production and clearance. Nilvadipines amyloid reducing affects appear to act via the inhibition of Spleen Tyrosine Kinsase (SYK) which is part of the inflammatory pathway

The journey so far... Animal models: Increased cerebral blood flow Increased blood levels of amyloid Decreased amyloid levels in the brain Safety Study 2008 (Phase 1a/II) Roskamp funded study at. St. Jamess Hospital 150 patients recruited Open label Nilvadipine 8mg for 6 weeks Nilvadipine at dose of 8mg deemed safe for AD patients NILVAD: Phase III Clinical Trial (2012 2016) NILVAD Clinical Trial NILVAD is an investigator led, non commercial clinical trial NILVAD is funded by the European Commission Framework 7 programme - 6 million St Jamess Hospital is the Sponsor for NILVAD NILVAD is a Phase III clinical trial NILVAD is a double blind trial with 2 arms (placebo/study drug) NILVAD: The facts 510 patients to be recruited to the study Treatment period: 18 months 10 visits in total, 4 involving outcome measure assessments

Outcome measures assessed: ADAS Cog (Alzheimer's Disease Assessment Scale) CDR (Clinical Dementia Rating) DAD (Disability Assessment for Dementia) Looking for change in outcome measure scores in treatment group Patients take the study drug once a day after breakfast Study drug (IMP) is over-encapsulated 8mg Nilvadipine or overencapsulated placebo (sugar pill) NILVAD Substudies 4 Substudies running in parallel to NILVAD study: 1. Frailty Substudy (Netherlands) 2. Cerebral Spinal Fluid Substudy (Sweden) 3. Blood Biomarker Substudy (Dublin/Archer US) 4. Cerebral Blood Flow Substudy (Netherlands) Samples from the CSF and Blood substudy will be analysed for Biomarkers (Tau, amyloid, inflammatory markers) at the end of the study. CSF and Blood substudy samples will be biobanked in LILLE, France Partners

Governance Scientific Advisory Board Oversight Data Safety & Monitoring Board Paul Aisen Suzanne Hendrix Maurice OConnell Robin Jacoby Martin ODonnell Bernadette McGuinness John Newell Peter Passmore ------------------------------------------------------------------------------------------------St. Jamess Hospital Sponsor Management Trial management committee PI, scientific project manager, statistician, data manager, programmer, administrative support Site teams, monitors Brian Lawlor

Fiona Cregg Sinead Larkin Cathal Walsh Leslie Daly Ricardo Segurado NILVAD: Collaborative Effort Country Target 1 Cork Ireland 100 2 Dublin UK 60 3

King College London 4 Papanikolaou Greece 100 Netherlands Hungary Italy Trial coordinated from Dublin (TCD & SJH) 9 EU countries recruiting patients 23 clinical trial sites 2 sites in Ireland (St Jamess, Dublin & St Finbarrs, Cork) Sweden Germany 80

30 50 Site Number Study Sites 5 Ahepa 6 Papageorgiou 7 Arnhem 8 Maastricht 9 Nijmegen

10 Szeged 11 Brescia 12 Castellanza 13 Genoa 14 Milan 15 15 UGOT 15

16 Ulm 17 Lille 18 GHICL 19 Lens 20 Bethune 21 Amiens 22 Caen

23 Calais France 60 NILVAD: Trial Phases Stage1: Set Up Stage 2: Recruitment January 2012-April 2013 May 2013-March 2015 Stage 3: Follow Up May 2013-September 2016 Stage 4: Analysis October2016-December 2016 Stage 1: Set Up - Approvals Regulatory Approval

Ethics Approval Local/Organisational Approval Start Clinical Trial Stage 1: Set Up Study documents: SOPs, forms IT systems: eCRF Randomisation Study Insurance Set up Trial Master File Commence Recruitment IMP Manufacture

24HR emergency unblinding service Train staff Online Document Repository Regulatory, Ethics, Org Approval Stage 1: Main Challenges Regulatory approval Not all countries agreed to take part in Voluntary Harmonisation Procedure Ethics approval No harmonised procedure IMP manufacture; Lengthy tender processed to identify best candidate for IMP manufactuer Expensive Separate company for drug supply & IMP manufacture New dissolution profile test established for overencapsulated IMP Ensuring IMP consistent supply of in date stock challenging Ensuring all study staff completed training (GCP, trial outcomes, trial operations) on time Initiating the sites in a timely manner

Pre-VHP Clinical Trials in the EU Sponsor National Competent Authority 1 GNA Local Clinical Trial Approval 1 National Competent Authority 2 GNA Local Clinical Trial Approval 2 Note: GNA = Grounds for Non Acceptance National Competent Authority 3

GNA Local Clinical Trial Approval 3 Sponsor to response to individual questions from each CA Different decisions (approvals/refusal s/conditional approval) Post VHP Clinical Trials in the EU Sponsor VHP-C National CA National CA

National CA Grounds for Non-Acceptance GNA Sponsor response National CA National CA Approval CA = Competent Authority VHP-C National CA Agreed Core CT National CA NILVAD: Trial Phases Stage1: Set Up Stage 2: Recruitment

Stage 3: Follow Up Stage 4: Analysis Stage 2: Recruitment Recruitment started in July 2013 Planned for 18 month recruitment period now extended to 21 month Recruitment period: July 2013 to March 2015 Currently 427 out of 510 recruited to the study End Now Start Jul 1 Aug 2 Sep Oct Nov Dec

Jan 3 4 5 6 7 2013 Feb Mar Apr May Jun Jul Aug

Sep Oct Nov 8 9 10 11 12 13 14 15 16 17 2014

Dec Jan 18 19 Feb Mar 20 21 2015 Stage 2: Recruitment Stage 2: Recruitment Country Target Recruited to Date Ireland 100

95 UK 60 54 Greece 100 78 Netherlands 80 51 Hungary 30 11 Italy

50 48 Sweden 15 18 Germany 15 8 France 60 44 Stage 2: Recruitment Main Challenges Exclusionary Medications - Beta blockers, calcium channel blockers, warfarin 3 Month stabilisiation required on Alzheimer Medication Availabilty of Patients with mild to moderate Alzheimers Disease Souvenaid The medical foodstuff is exclusionary

Shift patients from under to over recruiting sites (i.e. Hungary to Sweden, Italy, Dublin) Success of recruitment at individual sites dependent on commitment of Principal Investigator & Study staff NILVAD: Trial Phases Stage1: Set Up Stage 2: Recruitment Stage 3: Follow Up Stage 4: Analysis Stage 3 & 4 : Follow Up & Analysis Follow Up Phase: April 2015 until Sept 2016 Patients on study treatment for 18 months Analysis Phase Oct until December 2016 Data Analysis Phase Study Ends: End of December 2016 Stage 3 & 4 : Follow Up & Analysis Results of Trial Decision Tree ADAS Cog

CDR Not significant Conclusion Study not successful Significant Not significant Successful proof of concept study Significant Significant Evidence of delay in disability Dublin Office - Trial Management Duties Responsibilities to HPRA include: 1. Ensuring that we conduct the study according to the protocol which was approved by the HPRA 2. Submit any substantial

amendments to the HPRA for approval. 3. Ensure that we conduct the trial according to Good Clinical Practice. 4. Submit any SUSARs that occur in Irish patients to the HPRA 5. Submit a annual safety report (DSUR - Development Safety Update Report ) to the HPRA and each of the other NCAs 6. Submit a end of study report to the HPRA and each of the partner country NCAs Track patient withdrawals Maintain Trial Master File Maintain study documents (SOPs, Protocol) Track Protocol Violations Project Office Dublin

Manage Serious Adverse Event Reports Manage IMP supply for sites Respond to medical queries Remote Monitoring Oversee monitoring Legacy of NILVAD Pave the way for further multinational investigator led clinical trials Biobanked Blood & CSF samples for a large proportion of the patients Establish Alzheimers disease clinical trial Network across Europe from which further studies could be conducted Further collaborative reseach in Ireland and Europe Potentially offer a new disease modifying treatment for AD

Life Cycle of a Clinical Trial Grant Award and/or Parent contract established Protocol finalized Orientation or Initiation Meeting Model ICF finalized Sites selected Protocol Synopsis finalized Schedule of Activities finalized Operations Manual/MOP completed CRFs finalized Ethics & regulatory approvals obtained Site subcontracts/

payment schedule in place Finalize Contracts with third party vendors (labs, ECGs etc.) Database Locked Analysis Enroll subjects* Distribution of study drug to sites Answer Protocol/CRF questions Take incident calls SAEs Dosage Adjustments Premature Withdrawals Drug Disclosure Data query process Clean/Close database Transfer database to Biostatistics Perform primary/ secondary analysis Submit abstract Submit manuscript Submit CTR

Post results on Post-hoc analysis DSMB established Build database Finalize Study drug packaging/labeling* CONCEPTUAL PHASE PLANNING PHASE IMPLEMENTATION PHASE ANALYSIS/ PUBLICATION Thank you to the NILVAD Team & Partners Prof Brian Lawlor Coordinating Investigator Fiona Cregg, Scientific Project Manager Dr Sarah ODwyer - Study Clinician Lisa Crosby - Study Nurse Dr Sean Kennelly Medical Advisor

Sinead Larkin Project Assistant

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