Community Research and Development Information Service - CORDIS


NILVAD Report Summary

Project ID: 279093
Funded under: FP7-HEALTH
Country: Ireland

Periodic Report Summary 3 - NILVAD (A European multicentre double-blind placebo-controlled phase III trial of nilvadIpine in mild to moderate Alzheimer’s disease)

Project Context and Objectives:
Project Context:
Alzheimer’s disease (AD) is an ever-increasing public health concern among the aging population and is the most common form of dementia affecting more than 15 million individuals worldwide and around 5 million Europeans. The direct and indirect costs of AD and other dementias amount to more than €440,000 million each year (, 2010). It is estimated that by 2050, 1 in 85 of the population worldwide will have AD and that approximately 40% of these cases will need the level of care equivalent to a nursing home. Even modest therapeutic advances that lead to small delays in Alzheimer’s onset and progression could significantly reduce the global and European burden of the disease and the level of care required by patients. While there are symptomatic-based drug therapies available for AD, these medications do not stop the disease process or prevent neuronal degeneration. There is therefore a clear unmet medical and public health need for the development of new treatments for AD that have disease modifying effects. NILVAD will investigate the efficacy of Nilvadipine to treat mild to moderate Alzheimer’s disease.

Project Objectives:
• To augment the initial studies of Nilvadipine as a treatment for AD by investigating its efficacy in a phase III double blind placebo-controlled study.
• To demonstrate the feasibility of a multi-site European clinical trial of a potential AD treatment with a demonstrated safety profile.
• To promote a European clinical trial network of AD clinicians and researchers.
• To expedite the availability of effective treatment to AD patients by advancing a promising, safe, anti-Alzheimer drug through Phase III clinical trials.
• To financially support the larger scale investigation of Nilvadipine in AD patients which the existing preclinical and clinical data strongly mandate.
• To investigate biomarkers of AD progression and response to nilvadipine.
• Ultimately, to improve treatment options and quality of life for people with AD in Europe.

Project Results:
Since the last reporting period major progress has been made in the NILVAD Project. The study has recruited the target number of patients, a low attrition rate has been maintained and there have been no significant safety concerns regarding the study drug. The work of the NILVAD project can be broken down into the following distinct phases: the set up phase, recruitment phase, follow up phase and the close out and analysis phase. The study is currently in the follow up phase and will shortly commence the close out and analysis phase.
Set up and recruitment phases; The NILVAD project has completed the first two phases namely set-up and recruitment. The set-up phase was completed on a phased basis across the sites. The larger lead sites were initiated first followed by the smaller sites. Site Initiations took place between May and November 2013. The set up phase consisted of the following key tasks:
• Regulatory Approval obtained for each of the partner countries
• Ethical approval obtained for each site in the partner countries
• Organisational approval (where relevant) obtained at each of the 23 recruiting sites
• Training of all staff in the relevant areas for the tasks that they are assigned in the study e.g. Good Clinical Practice (GCP), protocol, outcome assessment measure training for the assessors (ADAS, DAD, CDR, SMMSE)
• Manufacture of the Investigational Medicinal Product (IMP) and matching placebo and shipment to each of the partner sites
• Creation of a shared resource on the NILVAD website to make available to study staff all of the current and approved versions of the study documents
• Creation of the Source Data Worksheets and associated forms
• Creation of the Electronic case report form (eCRF) using a system called Macro and an online randomisation system
• Appropriate insurance cover obtained for each of the recruiting countries participating in the NILVAD study
• Set up of a 24 hour un-blinding service and provision of a dedicated local phone number for each country to access this service
• Set up of the Trial Master File (TMF) in the Sponsor’s Office in Dublin
• Set up of an Investigator Site File (ISF) in each of the recruiting sites
• Putting in place of all the relevant study documents; Standard Operating Procedures, Protocol, Investigators Brochure, Investigators Medicinal Product Dossier (IMPD) and monitoring documentation etc.
• Site initiation activities carried out at each of the study sites prior to the commencement of recruitment.
The recruitment phase began at the lead site, Dublin, in May 2013 with the first patient being recruited at the site on May 15th 2013. The remaining sites commenced recruitment between June 2013 and July 2014. Recruitment ceased in March 2015 with the final patient enrolled at the Dublin site bringing the total number of participants in the study to 511.
Follow-up phase: Once the last patient was recruited at the Dublin site in March 2015 the follow up phase commenced and will continue until the last patient last visit in Dublin on November 6th 2016. As of August 1st there were 430 patients who had completed the study.
The key tasks achieved to date in the follow-up phase include:
• Maintenance of a low attrition rate (lost to follow up and off IMP) which currently stands at 11.6%. This low attrition rate means that it is highly probable that we will be able to determine definitively whether nilvadipine has a disease modifying effect at 18 months compared to placebo.
• Monitoring for adverse events and serious adverse events. To-date (as of 25th August 2016) 116 serious adverse events have been reported, 16 of which are serious adverse reactions. There have been 5 confirmed suspected unexpected serious adverse events (SUSARs) reported. Three SUSARs were related to syncope, one was related to an overdose of Nilvadipine and circulatory collapse and another was related to cognitive deterioration and agitation. As a results of the SUSARs related to syncope, the Investigator’s Brochure and patient information leaflets were amended in 2015 via a substantial amendment to include syncope as an expected adverse reaction.
• A member of the Project Office attended Eudravigilance training at the European Medicines Agency (EMA). Therefore, the project office is now capable of reporting any SUSARs to the Eudravigilance database.
• Maintenance of IMP supply across the study sites. This has involved close monitoring of the IMP levels, ordering more IMP where necessary and redistributing IMP from low to high recruiting sites. A third batch of IMP was produced to ensure that there will be adequate levels of in date IMP across the study sites until the end of the study. Any used IMP is being returned to the IMP manufacturer on an ongoing basis where it will be destroyed at the end of the study.
• Regular monitoring visits conducted by the country monitors throughout the follow-up phase which is being overseen by the Project Office.
• Sponsor site inspections carried out by the Project Office staff. During the sponsor site inspection the ISF and Pharmacy file is inspected and approximately 20% of the patient files. To date, sponsor site inspections have been conducted at the sites in Chru-Lille, UULM, AUTH, KCL, UCC, SKU, Szeged and UGOT. There is a visit planned to the Italian sites in September 2016.
• Maintenance of a withdrawal log in the project office in Dublin. In total there are 117 patients who are off study medication, however half of these patient have agreed to follow up assessments and can therefore be included in the intention to treat analysis.
• Maintenance of a violation log in the project office. Currently there are 41 violations recorded for the study. The majority of these violations are related to concomitant medication of subjects. However, a substantial amendment was approved by the regulatory and ethics committees in 2014 for participants who are taking more than one blood pressure agent to be enrolled to the study. The vast majority of these violations were in relation to patients who were on more than one BP agent and were recorded prior to this amendment.
• Maintenance of the TMF in the sponsor site and ISF across the study sites. The TMF in the Project Office is being maintained on an ongoing basis and internal audits have been carried out on the files. The ISFs are reviewed by the monitors at the monitor visits.
• Successful recruitment to the four substudies. In total 467 patient were recruited to the Frailty Substudy, 336 to the Blood and Genetic substudy, 93 to the Cerebrospinal (CSF) substudy and 58 to the Cerebral blood flow (CBF) substudy. The Dutch team also intend to conduct a Blood Variability study and the proposal for this study has been approved by the NILVAD PIs.
• Data Management and Safety Board (DMSB) Meetingand reports. To date six DMSB meetings have taken place and 5 reports produced. This has ensured that the safety and progress of the study has been reviewed by the board regularly. The next DMSB meeting is due to take place after Data lock at the start of December 2016.
• Development Safety update reports (DSUR). Annual DSUR reports have been produced since recruitment commenced. These reports were submitted to the relevant regulatory authorities and ethics committees in the partner countries. The UK, Germany and Sweden now require that DSUR reports are submitted to their regulatory authorities via the Common European Submission Portal (CESP).
• Scientific Advisory Board, Steering Committee and General Assembly meetings have taken place as planned throughout the follow up period.
Close out and Analysis Phase: Once the last patient last visit has been conducted at each site the close out visit will be carried out by the country monitor. A close out SOP has been circulated to the country monitors. The visits will take place between September and November 2016. Once all of the closes out visits are complete the data will be cleaned and locked. Once the data is locked the Data Analysis phase can commence.
The statistical analysis plan has been written for the primary analysis and the code has been written. A Green paper has been produced in consultation with the NILVAD PI Group which outlines the plan for the secondary analysis. The Data Analysis phase will be conducted between December 2016 and the end of February 2017.
Other key achievements of the study to date:
Publications and Presentations at International Conferences
• To date, the NILVAD project has produced two publications in BMJ Open; the main NILVAD study protocol was published in 2014 and the substudy protocols were published in 2016.
• In addition, the coordinator is preparing a Key Learnings paper of the NILVAD study in which key management aspects of the trial will be described which we hope will inform future investigator-lead trials. It is anticipated that this paper will be published in early 2017.

• In July 2016 a poster on the NILVAD study was presented at the Alzheimer’s Association International Conference in Toronto. This poster contained information on patient status data, recruitment to the four sub-studies and information on serious adverse events.
• The NILVAD project will be represented at the upcoming Clinical Trials in Alzheimer’s Disease conference in San Diego in December 2016.
• In the period Jan 2015 – June 2016 baseline data of the CBF substudy was presented at two conferences; The 5th International Meeting on Cerebral Haemodynamic Regulation (CARNet), 13-15 July 2015 where a poster was presented and the 16th International Symposium on Intracranial Pressure and Neuromonitoring, in conjunction with the 6th Annual Meeting of the Cerebral Autoregulation Research Network, 28 June - 2 July 2016 where a poster was presented and an oral presentation was given.

Through the NILVAD study collaborative links have been forged between the NILVAD consortium and other projects:
• NILVAD will collaborate with the Fair Park II project (Conservative Iron Chelation as a disease modifying strategy in Parkinson’s disease: A multicentre, parallel group, placebo controlled, randomised control clinical trial of Deferiprone) which was funded under H2020. NILVAD will provide biobanked biosamples to Fair Park II which will be used to analyse the efficacy of Biomarkers for Parkinson’s disease
• The NILVAD consortium are currently in discussions with the EADB (A European DNA bank for deciphering the missing heritability of Alzheimer’s Disease) consortium. EADB is a JPND funded study and NILVAD may provide DNA extracts from the patients who participated in the Blood Biomarker substudy.
• The consortium is collaborating with Kaj Blennow’s Clinical Neurochemistry lab at Gothenburg University who will analyse the CSF samples for the CSF substudy.

Establishment of a biobank resource
A central biobank in Lille for biosamples from the NILVAD trial has been established. Currently there are almost 12,000 biosamples in this biobank. The remaining samples will be biobanked at LILLE by the end of the study. This will be an invaluable resource of Biobanked samples which may be used by future research groups. A Material Transfer Agreement has been drafted and a separate MTA will be drawn up for each institution that the NILVAD samples will be shipped to.

Leveraged Funding
Our Dutch partners at Radboud University (SKU) were granted funding from the Dutch Alzheimers Society to fund the Blood Flow substudy. SKU were also granted funding from the ADDF (Alzheimer’s Drug Discovery Foundation) for the Blood Flow Substudy but as they were also awarded funding from the Dutch Alzheimers Society for this work, the ADDF agreed that the funds can be used to fund the Blood Biomarker substudy.

Non-Interventional Study: People with dementia and caregiver experience of participating in the NILVAD clinical trial
An additional non-interventional study which will investigate the experience of patients and caregivers of participating in the NILVAD clinical trial will be conducted in Ireland, France and Greece. The study is comprised of a patient questionnaire and a face to face interview. The study was granted Ethics approval in Ireland on July 6th 2016 and Ethics approval is pending in France and Greece.

NILVAD Network
The NILVAD PIs hold regular calls to discuss the progress of the project, opportunities for additional funding and the future of the NILVAD consortium/network. There are plans to maintain a central resource at the Project office after the official NILVAD study ends in order to make the resources from the study available and to keep the network together. This will enable the network to make submissions for future funding calls or explore opportunities as they arise.

Potential Impact:
The NILVAD trial aims to establish the efficacy and safety of Nilvadipine as a treatment for mild to moderate Alzheimer’s disease (AD). If a positive result is achieved this would have a significant impact from a treatment and quality of life perspective for the 5 million Europeans who suffer from Alzheimer’s disease. If Nilvadipine was shown to slow the progression of the disease, this would also have a significant socio-economic impact in terms of costs of care for people with AD. Another expected final result of the NILVAD study will be the creation of a cross-national network in Europe which could be used to conduct future clinical trials in AD. The combined knowledge and experience of the network and the knowledge and expertise accumulated during the set-up framework of the NILVAD clinical trial will be extremely beneficial for future endeavours in this area and potentially speed up drug discovery and treatments for AD in Europe.
The NILVAD clinical trial will add to the existing body of information about AD and will be another step forward towards developing effective treatments for the disease. In addition, the wealth of information derived from the Frailty, Blood & Genetic Biomarker, Cerebral blood flow (CBF) and Cerebral Spinal Fluid (CSF) sub-studies will add to the existing scientific knowledge about the clinical and biological correlates of AD and may help to identify new biomarkers and indicators for the early detection of AD.
The Blood & Genetic Biomarkers and CSF samples which have been bio-banked will be an important bio-resource for ongoing scientific investigations into the development of novel biomarkers for AD after the NILVAD trial is concluded.
All blood and CSF samples collected during the NILVAD study will be shipped from the participating sites to the biobanking facility in Lille. NILVAD has developed a collaborative relationship with Dr. Patrick Gele, Lille Biobank and Dr. David Devos, PI on a H2020 phase 3 trial in Parkinson’s disease (Park II). Dr. Devos, as part of his successfully funded trial, will be able to carry out innovative biomarker analyses on the NILVAD samples. Furthermore, the partner site at Nijmegen, under the supervision of Dr. Olga Meulenbroek and Professor Marcel Ode-Rikkert are conducting a blood flow sub study and have been able to provide additional funding for the biomarker analyses on the NILVAD samples. This demonstrates the collaborative and synergistic opportunities for NILVAD as it builds up research linkages in clinical trials in AD across Europe. These collaborative efforts across FP7 and H2020 clinical trials increase the likelihood of scientific breakthroughs and the potential societal impact for NILVAD.

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