A trial of Nilvadipine in mild to moderate Alzheimer's disease
| ISRCTN | ISRCTN14485052 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN14485052 |
| EudraCT/CTIS number | 2012-002764-27 |
| ClinicalTrials.gov number | NCT02017340 |
| Secondary identifying numbers | 14541 |
- Submission date
- 22/07/2013
- Registration date
- 22/07/2013
- Last edited
- 19/08/2019
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Nervous System Diseases
Plain English Summary
Background and study aims
Alzheimers 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 Alzheimers disease, the patient is completely dependent upon caregivers.
With more than 15 million people affected worldwide (5 million in Europe), Alzheimers 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 Alzheimers 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 Alzheimers 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 Alzheimers disease. There is preliminary evidence for clinical benefit in individuals with cognitive impairment and strong scientific evidence based on animal model studies of Alzheimers disease.
Who can participate?
The study will recruit 500 people over 50 with mild to moderate Alzheimers 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 Alzheimers 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 Alzheimers 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
Contact information
Scientific
Institute Of Psychiatry
16 De Crespigny Park
London
SE5 8AF
United Kingdom
| Phone | +44 (0)207 848 0549 |
|---|---|
| Jessica.adams@kcl.ac.uk |
Study information
| Study design | Randomized double-blind placebo controlled parallel; Design type: Treatment |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | https://www.nilvad.eu/fileadmin/websites/nilvad/media/NILVAD_Brochure.pdf |
| Scientific title | A European multicenre double-blind placebo controlled phase III trial of nilvadipine in mild to moderate Alzheimer's disease |
| Study 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(s) | NRES Committee- North London Harrow, 06/02/2013, ref 12/LO/1903 |
| Condition | Topic: Dementias and Neurodegenerative Diseases Research Network; Subtopic: Dementia; Disease: Alzheimer's Disease |
| Intervention | A total of 500 subjects with Alzheimers 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 |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Nilvadipine |
| Primary outcome measure | Cognitive and non-cognitive symptoms of Alzheimer's disease are measured using the Alzheimers 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 study start date | 01/01/2012 |
| Overall study end date | 19/12/2016 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Sex | Both |
| Target number of participants | Planned Sample Size: 500; UK Sample Size: 60 |
| Participant inclusion criteria | 1. Age range: Adult subjects, males and females over age 50 years. 2. Subjects with a diagnosis of probable Alzheimers disease based on the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimers 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 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
- England
- France
- Germany
- Greece
- Hungary
- Ireland
- Italy
- Netherlands
- Sweden
- United Kingdom
Study participating centres
Dublin
8
Ireland
Ballinlough
Cork
-
Ireland
Lille
59037
France
Verquigneul
62131
France
Caen
14033
France
Lens
62300
France
Amiens
80000
United Kingdom
Calais
62107
France
Lille
59000
France
Ulm
89081
Germany
Thessaloniki
546 21
Greece
Papageorgiou
564 29
Greece
Chortiatis
570 10
Greece
Szeged
H-6720
Hungary
Castellanza
21053
Italy
Via Balbi, 5
Genova
16126
Italy
Milan
20148
Italy
Brescia
25125
Italy
Nijmegen
6525 GA
Netherlands
P. Debyelaan 25
Maastricht
6229 HX
Netherlands
Arnhem
6815 AD
Netherlands
Wallinsgatan 6
Mölndal
SE-43141
Sweden
Denmark Hill
Camberwell
London
SE5 8AZ
United Kingdom
Sponsor information
Hospital/treatment centre
James Street
Dublin
Dublin 8
Ireland
| Phone | +353 1 896 1000 |
|---|---|
| creggf@tcd.ie | |
| Website | http://www.stjames.ie/ |
"ROR" |
https://ror.org/04c6bry31 |
Funders
Funder type
Government
No information available
Results and Publications
| Intention to publish date | 31/07/2017 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| 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. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | protocol | 09/10/2014 | Yes | No | |
| Results article | results | 24/09/2018 | Yes | No | |
| Results article | results | 21/05/2019 | 19/08/2019 | Yes | No |
| Results article | results | 01/08/2019 | 19/08/2019 | Yes | No |
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
19/08/2019: ClinicalTrials.gov number added. Publication references added.
17/01/2019: Publication reference added.
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.
