Condition category
Nervous System Diseases
Date applied
22/07/2013
Date assigned
22/07/2013
Last edited
30/01/2017
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Alzheimer’s disease (AD) is the most common form of dementia for which currently there is no cure available. Early symptoms include memory loss and mild cognitive impairment, often related to stress or aging. As the disease progresses, symptoms worsen to affect all areas of brain function, such as memory, behaviour, language and motor skills. In the final stages of Alzheimer’s disease, the patient is completely dependent upon caregivers.
With more than 15 million people affected worldwide (5 million in Europe), Alzheimer’s disease is an ever-increasing public health concern among the aging population, causing a great burden to patients and their caregivers. The economic costs of Alzheimer’s disease and other dementias are estimated at more than €180 billion in Europe each year.
Even small advances in treatment that delay the start of disease (onset) or its progression could significantly reduce the global burden of the disease and the level of care required by patients. While there are drug therapies available for AD that treat symptoms, these medications do not delay onset, slow progression or prevent the disease process itself. Therefore it is necessary to develop new treatments for AD that have disease-modifying effects.
The aim of this study is to investigate the effectiveness and safety of the drug nilvadipine in Alzheimer’s disease. Nilvadipine is a licensed blood pressure medication with a proven safety record in people with high blood pressure and more recently has been shown to be well tolerated and safe in older people with Alzheimer’s disease. There is preliminary evidence for clinical benefit in individuals with cognitive impairment and strong scientific evidence based on animal model studies of Alzheimer’s disease.

Who can participate?
The study will recruit 500 people over 50 with mild to moderate Alzheimer’s disease.

What does the study involve?
Participants will be randomly allocated to receive either nilvadipine or placebo (dummy) for 78 weeks.

What are the possible benefits and risks of participating?
This study tests whether nilvadipine has a disease-modifying effect in mild to moderate Alzheimer’s disease. If this is found to be correct, patients may benefit from this treatment.
In routine treatment, effects of medication are not monitored as regularly as in this study, so patients may benefit from the routine examinations during study participation.
Subjects administered the nilvadipine drug may experience adverse events, adverse drug reactions or other clinically significant complaints, symptoms or other abnormalities.
However, the risk associated with the trial is low. Nilvadipine is a licensed medication for high blood pressure in certain European countries with a reliable safety profile. A successful short-term safety study was carried out on Alzheimer’s patients in 2008 which showed very good tolerability in this patient population over the 6-week trial period.

Where is the study run from?
The study will be conducted across 23 study sites in nine partner countries (Ireland, UK, Netherlands, Sweden, Greece, Hungary, France, Italy, Germany) and is being coordinated by Prof Brian Lawlor from Trinity College Dublin, Ireland.

When is the study starting and how long is it expected to run for?
The study started in May 2013 and will be recruiting patients until December 2014. The study is expected to complete in July 2016.

Who is funding the study?
The study is funded by the European Commission's Framework 7 programme.

Who is the main contact?
Fiona Cregg
creggf@tcd.ie

Trial website

https://www.nilvad.eu/#

Contact information

Type

Scientific

Primary contact

Ms Jessica Adams

ORCID ID

Contact details

Institute Of Psychiatry
16 De Crespigny Park
London
SE5 8AF
United Kingdom
+44 (0)207 848 0549
Jessica.adams@kcl.ac.uk

Additional identifiers

EudraCT number

2012-002764-27

ClinicalTrials.gov number

Protocol/serial number

14541

Study information

Scientific title

A European multicenre double-blind placebo controlled phase III trial of nilvadipine in mild to moderate Alzheimer's disease

Acronym

NILVAD

Study hypothesis

The objective of this study is to investigate the efficacy of Nilvadipine as a disease course modifying treatment for mild to moderate AD in a phase III double-blind placebo-controlled study and to investigate the safety profile of Nilvadipine in patients with mild to moderate AD.

More details can be found at: http://www.nilvad.eu/fileadmin/websites/nilvad/media/NILVAD_Brochure.pdf

Ethics approval

NRES Committee- North London – Harrow, 06/02/2013, ref 12/LO/1903

Study design

Randomized double-blind placebo controlled parallel; Design type: Treatment

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

https://www.nilvad.eu/fileadmin/websites/nilvad/media/NILVAD_Brochure.pdf

Condition

Topic: Dementias and Neurodegenerative Diseases Research Network; Subtopic: Dementia; Disease: Alzheimer's Disease

Intervention

A total of 500 subjects with Alzheimer’s disease; 250 in the nilvadipine group and 250 in the placebo group recruited from 31 European centres.

Over encapsulated nilvadipine 8 mg, sustained release capsule, for the treatment group, taken once a day at lunchtime or, matching over encapsulated placebo for the control group, taken once a day at lunchtime.
The total study duration will be 82 weeks. Patients will receive study medication for 78 weeks.

Intervention type

Drug

Phase

Phase III

Drug names

Nilvadipine

Primary outcome measures

Cognitive and non-cognitive symptoms of Alzheimer's disease are measured using the Alzheimer’s Disease Assessment Scale (ADAS) at baseline, 13, 52 and 78 weeks

Secondary outcome measures

1. Involvement in activities of daily living are measured using the Disability Assessment for Dementia (DAD) at baseline, 13, 52 and 78 weeks
2. Severity of symptoms is measured using the Clinical Dementia Rating Scale (CDR) Assessments at baseline, 13, 52 and 78 weeks

Overall trial start date

01/01/2012

Overall trial end date

19/12/2016

Reason abandoned

Eligibility

Participant inclusion criteria

1. Age range: Adult subjects, males and females over age 50 years.
2. Subjects with a diagnosis of probable Alzheimer’s disease based on the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s disease and Related Disorders Association, Inc (NINCDS-ADRDA) criteria (McKhann et al, 1984)
3. Subjects with a Standardised Mini-Mental State Examination (SMMSE) (Standish & Molloy, 1991) score of greater than or equal to 12 and less than 27.
4.Subjects on a stable dose (>3 months) of cholinesterase inhibitor or memantine. The dose must be stabilised prior to randomisation. Patients due to begin these medications must not be enrolled until the dose is stabilised. Subjects who are not on cholinesterase inhibitors or memantine due to poor tolerability and/or who will not require treatment with these medications during the course of the study can be included.
5. Subjects who retain capacity will provide written informed consent for participation. The procedure for obtaining informed consent when the subject has reduced decision making capacity will follow national law and will be assessed by the relevant bodies in each of the participating countries.
6. Fluency in relevant language sufficient to reliably complete all study assessments.
7. Subjects with blood pressure values greater than 100/65 mmHg but less than 159/99 mmHg (Grade 1 hypertension, ECS guidelines 2007; escardio.org/guidelines) using an office based BP measurement will be included.
Subjects with blood pressure values greater than 105/70mmHg but less than 140/90 mmHg using an Ambulatory BP measurement will be included.

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 500; UK Sample Size: 60

Participant exclusion criteria

1. Subjects with co-morbid dementia due to other neurological disorders such as Parkinson's disease, vascular dementia, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, brain dementia, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, brain tumour, progressive supranuclear palsy, seizure disorder, subdural hematoma, or multiple sclerosis, as well as subjects with HIV disease, neurosyphilis, history of significant head trauma with loss of consciousness followed by persistent neurological deficits, known structural brain abnormalities, or any other condition known to interfere with cognitive function.
2. Subjects currently taking any calcium channel blocker or beta-blocker
3. Subjects who in the opinion of the investigator, have a medical condition that would preclude them from participating in the study (e.g.hemodynamically significant coronary artery disease, chronic heart failure, syncope within the past year, significant valvular heart disease i.e. severe aortic and mitral stenosis symptomatic orthostatic hypotension within the last year, subjects requiring more than one agent to control BP), or subjects who in the opinion of the investigator are unlikely to complete per protocol due to care issues etc.
4. Current Axis I diagnosis of schizophrenia, bipolar disorder, major depression. Subjects who are currently or who have within the past year met criteria for drug or alcohol abuse or dependence.
5. Pregnant women or women who may possibly become pregnant.
6. Female subjects who are breastfeeding will be excluded from the study
7. Subjects with a history of hypersensitivity to nilvadipine (Nivadil).
8. Subjects who have taken an investigational or other unapproved drug during the 30 days or five half-lives, whichever is longer, prior to baseline.
9. Subjects who are taking any medication listed in the list of exclusion medication for the study.
10. Subjects with abnormal ECG results which prevent participation in the study.
11. Standardised Mini-Mental State Examination (SMMSE) score of less than 12 or greater than 26.
12. Subjects who are participating in other clinical research studies.
13. Subjects with any clinically significant laboratory blood test abnormality on his/her screening test.
14.Subjects with blood pressure values less than 100/65 mmHg but greater than 159/99 mmHg (Grade 1 hypertension, ECS guidelines 2007; escardio.org/guidelines) using an office based BP measurement will be excluded. Subjects with blood pressure values less than 105/70mmHg but greater than 140/90 mmHg using an Ambulatory BP measurement will be excluded.
15.Subjects with clinically significant abnormalities in their CT/MRI results which would prevent inclusion in the study.
16. Patients with sigificant renal insuffiency (estimated glomerular filtration rate: eGFR <30ml/min) will be excluded .
17. Subjects with severly impaired hepatic function (liver cirrhosis) will be excluded.
18. The medical food stuff Souvenaid® is under exclusion from the study.

Recruitment start date

23/04/2013

Recruitment end date

10/04/2015

Locations

Countries of recruitment

France, Germany, Greece, Hungary, Ireland, Italy, Netherlands, Sweden, United Kingdom

Trial participating centre

St. James's Hospital
James Street
Dublin
8
Ireland

Trial participating centre

St Finbarrs Hospital
Douglas Road Ballinlough
Cork
-
Ireland

Trial participating centre

Centre Hospitalier Regionale et Universitaire de Lille
Avenue Oscar Lambret, 2
Lille
59037
France

Trial participating centre

Centre Hospitalier de Béthune
27 Rue Delbecque
Verquigneul
62131
France

Trial participating centre

Centre Hospitalier Universitaire de Caen
Avenue de la Côte de Nacre
Caen
14033
France

Trial participating centre

Hospital Center De Lens
99 Route de la Bassée
Lens
62300
France

Trial participating centre

CHU Amiens-Picardie
1 Place Victor Pauchet
Amiens
80000
United Kingdom

Trial participating centre

Centre Hospitalier de Calais
1601 Boulevard des Justes
Calais
62107
France

Trial participating centre

Centre de Recherche Clinique - DRM
53-55 rue Jean Jaurès
Lille
59000
France

Trial participating centre

Universität Ulm
Helmholtzstraße
Ulm
89081
Germany

Trial participating centre

AHEPA University Hospital
Kiriakidi 1
Thessaloniki
546 21
Greece

Trial participating centre

Papageorgiou General Hospital
Pavlos Melas
Papageorgiou
564 29
Greece

Trial participating centre

Papanikolaou Peripheral General Hospital
Epar.Od. Asvestochoriou
Chortiatis
570 10
Greece

Trial participating centre

University of Szeged
Dugonics square 13
Szeged
H-6720
Hungary

Trial participating centre

Ospedale MultiMedica Castellanza
Viale Piemonte, 70
Castellanza
21053
Italy

Trial participating centre

University of Genova
Department of Neuroscience, Ophthalmology and Genetics (DiNOG) Via Balbi, 5
Genova
16126
Italy

Trial participating centre

Fondazione Don Gnocchi - Centro IRCCS S. Maria Nascente
Via Alfonso Capecelatro, 66
Milan
20148
Italy

Trial participating centre

IRCSS-San Giovanni di Dio-Fatebenefratelli
Via Corsica, 339
Brescia
25125
Italy

Trial participating centre

Radboudumc
Geert Grooteplein Zuid 10
Nijmegen
6525 GA
Netherlands

Trial participating centre

Academisch Ziekenhuis Maastricht
ZiekenhuisapotheeK P. Debyelaan 25
Maastricht
6229 HX
Netherlands

Trial participating centre

Ziekenhuisapotheck Rijnstate
Wagnerlaan 55
Arnhem
6815 AD
Netherlands

Trial participating centre

Saghlgrenska Academy
Dept. of Psychiatry and Neurochemistry Wallinsgatan 6
Mölndal
SE-43141
Sweden

Trial participating centre

Maudsley Hospital
King's College London Denmark Hill Camberwell
London
SE5 8AZ
United Kingdom

Sponsor information

Organisation

St James Hospital (Ireland)

Sponsor details

James Street
Dublin
Dublin 8
Ireland
+353 1 896 1000
creggf@tcd.ie

Sponsor type

Hospital/treatment centre

Website

http://www.stjames.ie/

Funders

Funder type

Government

Funder name

European Commission Framework 7 programme; Grant Codes: 279093

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer reviewed journal in mid 2017.

IPD Sharing plan:
The current data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

31/07/2017

Participant level data

To be made available at a later date

Results - basic reporting

Publication summary

2014 protocol in https://www.ncbi.nlm.nih.gov/pubmed/25300460

Publication citations

Additional files

Editorial Notes

30/01/2017: The following changes have been made to the record: 1. The overall trial dates have been updated from 01/07/2013 - 31/03/2015 to 01/01/2012 - 19/12/2016 2. The recrutiment dates have been updated from 01/07/2013 - 31/03/2015 to 23/04/2013 - 10/04/2015] 3. The trial participating centres, IPD Sharing plan and publication and dissemination plan have been added. 18/01/2017: Publication reference added.