Condition category
Mental and Behavioural Disorders
Date applied
07/03/2014
Date assigned
15/04/2014
Last edited
21/07/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Stopped
Recruitment status
Stopped

Plain English Summary

Background and study aims
Vascular dementia is the second most common form of dementia, affecting an estimated 20% of people with dementia and accounting for approximately 7 million people worldwide. It is caused by problems with the blood supply to the brain, for example following a stroke or due to damage to the tiny blood vessel network in the brain. The resulting damage causes cells to be lost, leading to the development of dementia. The most common form of vascular dementia is subcortical ischemic vascular dementia (SIVD), affecting up to 67% of people with vascular dementia. To date there has been minimal investment in treatments for people with vascular dementia despite the large number of people affected by the condition. As a result there are no drugs licensed for the treatment of vascular dementia and no ongoing clinical trials. The aim of this study is to investigate whether treatment with the calcium channel blocker medication amlodipine can improve outcomes for people with SIVD. The study will compare amlodipine treatment with a control to see if there is any difference compared to the care people usually receive.

Who can participate?
We aims to recruit 588 patients aged 50 years or over with SIVD.

What does the study involve?
Patients will be randomly allocated to one of two groups and neither the patients nor the clinicians will know which group someone has been allocated to: usual care + amlodipine or usual care + dummy drug (placebo). Patients will be required to take either amlodipine or placebo: 5 mg once daily for 2 weeks followed by 10 mg once daily for 50 weeks. Patients will be enrolled in the study for 2 years; 1 year on treatment and a follow up telephone call at the end of year 2. Patients will undergo an MRI brain scan at the screening stage of the study to confirm diagnosis and also after 1 year to monitor progress. During the study, patients with an informant (friend, relative or professional carer) will be asked to attend the clinic at various intervals and both will be asked to complete questionnaires with the help of an assessor. The study will measure changes in mental speed and executive function (overall cognition), detect changes in ability to perform everyday tasks, further symptoms of dementia and caregiver burden. Tools will also be used to measure the cost-effectiveness of the treatments.

What are the possible benefits and risks of participating?
Participants may see an improvement in their dementia symptoms.
This will be the first large scale treatment study in people with vascular dementia. There have been no study of this size and there are no studies currently registered. Amlodipine is already licensed for use in the UK; therefore if the results of this trial are successful amlodipine could quickly be made available as a treatment for vascular dementia. Amlodipine is a licensed drug but, as with all drugs, there are side effects associated. The most common side effects include headache, oedema, flushing, dizziness, ankle swelling, fatigue, nausea, and rash. Side effects will be monitored by the study team throughout the trial.

Where is the study run from?
The study will take place across sites in the UK. The trial co-ordinating centre is the Northern Ireland Clinical Trials Unit (NICTU) and the lead centre will be The Belfast Health and Social Care Trust (UK).

When is the study starting and how long is it expected to run for?
Recruitment is expected to start in October 2014 and will run for 2 years.

Who is funding the study?
Funding has been provided equally by the Alzheimer's Society and the British Heart Foundation (UK).

Who is the main contact?
Professor Peter Passmore
P.Passmore@qub.ac.uk

Trial website

http://www.nictu.hscni.net/affect/

Contact information

Type

Scientific

Primary contact

Prof Peter Passmore

ORCID ID

Contact details

Institute of Clinical Sciences
Queen's University Belfast
Royal Hospitals
Grosvenor Road
Belfast
BT12 6BA
United Kingdom

Additional identifiers

EudraCT number

2014-000926-39

ClinicalTrials.gov number

Protocol/serial number

13154PP-SP

Study information

Scientific title

A randomised controlled trial of calcium channel blockade with Amlodipine For the treatment oF subcortical ischaEmic vasCular demenTia.

Acronym

AFFECT

Study hypothesis

1. To determine whether amlodipine will confer significant benefit with respect to change in cognitive outcome in people with subcortical ischaemic vascular dementia (SIVD) in comparison to placebo over 52 weeks.
2. To determine whether amlodipine will confer additional benefits on the following secondary outcomes; global impression, activities of daily living, neuropsychiatric symptoms and carer burden, in comparison to placebo.
3. To determine if amlodipine will be a cost effective treatment for SIVD compared to placebo.

On 07/10/2014 the anticipated end date was changed from to 13/01/2018 to 01/10/2018.

Ethics approval

Office for Research Ethics Committees in Northern Ireland (ORECNI), 23/06/2014, Ref: 14/NI/0069

Study design

Multi-centre randomised double-blind placebo-controlled parallel arm phase IIb trial

Primary study design

Interventional

Secondary study design

Randomised parallel trial

Trial setting

Other

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request patient information sheet

Condition

Subcortical ischaemic vascular dementia

Intervention

Patients will be randomised to either amlodipine or placebo: 5 mg once daily for 2 weeks followed by 10 mg once daily for 50 weeks

Intervention type

Drug

Phase

Phase II

Drug names

Amlodipine

Primary outcome measures

Current primary outcome measures as of 09/11/2015:
A change from baseline to 12 months in Vascular Dementia Assessment Scale cognitive subscale (VADAS-cog) score. The VADAS-cog is a more detailed cognitive assessment designed to be more sensitive to the cognitive outcomes in people with vascular dementia. This assessment should be completed face to face by an assessor who will be blinded to the intervention.

Previous primary outcome measures:
An improvement of 2.5 points in mean Vascular Dementia Assessment Scale cognitive subscale (VADAS-cog) from baseline to 12 months. The VADAS-cog is a more detailed cognitive assessment designed to be more sensitive to the cognitive outcomes in people with vascular dementia. This assessment should be completed face to face by an assessor who will be blinded to the intervention.

Secondary outcome measures

Current secondary outcome measures as of 09/11/2015:
1. Change in cognitive function measured with the Standardised Mini-Mental State Examination (sMMSE) from baseline to 12 months.
2. Change in the Trail Making test B from baseline to 12 months. The Trail Making test B is a timed measure of executive function.
3. Change in cognitive function from baseline to 12 months with a follow up at 24 months measured by Modified Telephone Interview for Cognitive Status (TICS-M).
4. Change in Clinical Global Impression of Change (CGIC) from baseline to 12 months. CGIC is a simple standardised rating of overall clinical outcome, rated by a clinician blind to treatment allocation.
5. Change in blood pressure from baseline to 12 months.
6. Change in lesion accrual from baseline to 12 months. This will be based on quantitation of lacunar lesions and diffuse white matter lesions measured quantitatively by MRI.
7. Change in health-related quality of life from baseline to 12 months measured with the EuroQol Group EQ-5D Health Questionnaire (EQ-5D-5L) and the Dementia Quality of Life-Proxy (DEMQOL-Proxy), a carer-rated and disease-specific measure of quality of life in dementia.
8. Change in activities of daily living from baseline to 12 months measured using the Disability Assessment in Dementia (DAD).
9. Change in non-cognitive dementia symptoms from baseline to 12 months measured with the Neuropsychiatric Inventory Caregiver Distress (NPI-D).
10. Change in care-giver burden from baseline to 12 months measured with the 12 item General Health Questionnaire (GHQ-12), and care-giver health-related quality of life measured with the EQ-5D-5L.
11. Cost-effectiveness measured as the combination of costs generated from the Client Service Receipt Inventory (CSRI).
12. Institutionalisation defined as permanent transition from living in an independent household to a care home, nursing home, NHS continuing care unit or hospital and measured with questions taken from the CSRI.

Previous secondary outcome measures:
1. Change in cognitive function measured with the Standardised Mini-Mental State Examination (sMMSE) from baseline to 12 months.
2. Change in the Trail Making test B from baseline to 12 months. The Trail Making test B is a timed measure of executive function.
3. Change in cognitive function from baseline to 12 months measured by Telephone Interview for Cognitive Status (TICS). There will also be a follow up at 24 months.
4. Clinical Global Impression of Change (CGIC) from baseline to 12 months. CGIC is a simple standardised rating of overall clinical outcome, rated by a clinician blind to treatment allocation.
5. Change in blood pressure from baseline to 12 months.
6. Change in lesion accrual from baseline to 12 months. This will be based on quantitation of lacunar lesions and diffuse white matter lesions measured quantitatively by MRI.
7. Change in health-related quality of life from baseline to 12 months measured with the EuroQol Group EQ-5D Health Questionnaire (EQ-5D-5L) and the Dementia Quality of Life-Proxy (DEMQOL-Proxy), a carer-rated and disease-specific measure of quality of life in dementia.
8. Change in activities of daily living from baseline to 12 months measured using the Disability Assessment in Dementia (DAD).
9. Change in non-cognitive dementia symptoms from baseline to 12 months measured with the Neuropsychiatric Inventory (NPI).
10. Change in care-giver burden from baseline to 12 months measured with the 12 item General Health Questionnaire (GHQ-12), and care-giver health-related quality of life measured with the EQ-5D-5L.
11. Cost-effectiveness measured as the combination of costs generated from the Client Service Receipt Inventory (CSRI).
12. Institutionalisation defined as permanent transition from living in an independent household to a care home, NHS continuing care unit or hospital and measured with questions taken from the CSRI.

Overall trial start date

01/10/2014

Overall trial end date

01/10/2018

Reason abandoned

Participant recruitment issue

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 09/11/2015:
1. Dementia syndrome according to the criteria a, b & d from code 290.4 of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).
2. Evidence of one or more clinical features in support of SIVD such as executive dysfunction, mood or gait disturbance or focal neurological signs
3. Multiple lacunae (>2) or diffuse lesions reaching a mean score of 2-3 across brain regions identified on baseline MRI scan.
4. sMMSE score between 15 and 26 (inclusive).
5. Age ≥ 50
6. If patients taking a cholinesterase inhibitor or memantine, dose stable for at least three months.
7. If patients taking antidepressants, dose stable for at least four weeks.
8. CT or MRI scan consistent with the probable diagnosis of SIVD providing there has been no significant clinical change since the scan.
9. Patient has resident family or professional carer or is visited at least twice a week by carer.
10. Fluency in English is essential as the study requires questionnaires to be completed.
11. Likely to be able to participate in all scheduled evaluations and complete all required tests.
12. Provision of appropriate consent.
13. Presence of an informant, aged 18 years or over who is willing to participate in the study.

Previous inclusion criteria:
1. Dementia syndrome according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)
2. Evidence of one or more clinical features in support of SIVD such as executive dysfunction, mood or gait disturbance or focal neurological signs
3. Multiple lacunae (>2) or diffuse lesions reaching a mean score of 2-3 across brain regions identified on baseline MRI scan
4. sMMSE score between 20 and 26 (inclusive)
5. Age 50 years or older
6. If patients taking a cholinesterase inhibitor or memantine, dose stable for at least three months
7. If patients taking antidepressants, dose stable for at least four weeks
8. Diagnosis of probable SIVD with supportive imaging (CT or MRI) within last 24 months
9. Patient has resident family or professional carer or is visited at least twice a week by carer
10. Fluency in English and evidence of adequate premorbid intellectual functioning
11. Likely to be able to participate in all scheduled evaluations and complete all required tests
12. Provision of appropriate consent
13. Presence of an informant who is willing to participate in the study

Participant type

Patient

Age group

Senior

Gender

Both

Target number of participants

588

Participant exclusion criteria

Current exclusion criteria as of 09/11/2015:
1. Severe, unstable or poorly controlled medical conditions apparent from physical examination or clinical history.
2. Moderate/severe heart disease or severe hepatic disease.
3. Significant renal insufficiency; estimated glomerular filtration rate (eGFR) <30ml/min.
4. Blood pressure (sitting) exceeds 160 mmHg systolic and/or 110 mmHg diastolic.
5. Systolic blood pressure (sitting) is less than 110mmHg.
6. Infarction involving the cortex on MRI scan.
7. Cerebrovascular event within the last six months.
8. Myocardial infarction within the last three months.
9. Already taking any calcium channel blocker.
10. Contraindications to a calcium channel blocker as per Summary of Product Characteristics (SPC)
11. Patient is unable to take trial medications.
12. Pregnant women or women who may possibly become pregnant (pre-menopausal). Females must be postmenopausal (no menses for ≥ 12 months without an alternative medical cause) to participate in the study.
13. Female patients who are breastfeeding will be excluded.
14. AD is considered to be the primary diagnosis: i.e. a predominantly amnestic presentation or evidence of an amnestic (pre-dementia) phase or strong biomarker evidence to support a diagnosis of AD. Patients with severe hippocampal atrophy on MRI (Scheltens GR 3 and 4 on both sides (i.e. a total score (left plus right) of 6 or more) will be excluded.
15. Significant neurological disease that may affect cognition other than SIVD or AD as a concurrent pathology.
16. Current presence of a clinically significant major psychiatric disorder (e.g. Major Depressive Disorder) according to the criteria of the DSM-IV.
17. Current clinically significant systemic illness that is likely to result in deterioration of the patient’s condition or affect the patient’s safety during the study.
18. Treatment with immunosuppressive medications (e.g. systemic corticosteroids) within the last 90 days (topical and nasal corticosteroids and inhaled corticosteroids for asthma are permitted) or chemotherapeutic agents for malignancy within the last three years.
19. Other clinically significant abnormality on physical, neurological, laboratory, examination that could compromise the study or be significantly detrimental to the patient (e.g. postural hypotension diagnosed within the last year which in the opinion of the PI would exclude the patient).
20. Alcohol or drug dependence or abuse within the last two years.
21. Treated with any other investigational medication or device within 60 days.
22. Patient taking simvastatin 40 mg or greater. A patient may be switched to an alternative statin and on stable dose for three months to meet inclusion criteria. A reduction in simvastatin dose solely for the purposes of eligibility is not permitted.

Previous exclusion criteria:
1. Severe, unstable or poorly controlled medical conditions apparent from physical examination or clinical history.
2. Moderate/severe heart disease or severe hepatic disease.
3. Significant renal insufficiency; estimated glomerular filtration rate (eGFR) <30ml/min.
4. Blood pressure exceeds 160 mmHg systolic and/or 110 mmHg diastolic.
5. Systolic blood pressure is less than 110mmHg.
6. Infarction involving the cortex on MRI scans.
7. Cerebrovascular event within the last six months.
8. Myocardial infarction within the last three months.
9. Already taking any calcium channel blocker.
10. Contraindications to a calcium channel blocker as per Summary of Product Characteristics (SPC)
11. Patient is unable to take trial medications.
12. Pregnant women, women who have not yet reached the menopause (no menses for over 12 months without an alternative medical cause) who test positive for pregnancy, are unwilling to take a pregnancy test prior to trial entry or are unwilling to undertake adequate precautions to prevent pregnancy for the duration of the trial.
13. Female patients who are breastfeeding will be excluded.
14. AD is considered to be the primary diagnosis: i.e. a predominantly amnestic presentation or evidence of an amnestic (pre-dementia) phase or strong biomarker evidence to support a diagnosis of AD. Patients with severe hippocampal atrophy on MRI (Scheltens GR 3 and 4 on both sides (i.e. a total score (left plus right) of 6 or more) will be excluded.
15. Significant neurological disease that may affect cognition other than SIVD or AD as a concurrent pathology.
16. Current presence of a clinically significant major psychiatric disorder (e.g. Major Depressive Disorder) according to the criteria of the DSM-IV.
17. Current clinically significant systemic illness that is likely to result in deterioration of the patient's condition or affect the patient's safety during the study.
18. Treatment with immunosuppressive medications (e.g. systemic corticosteroids) within the last 90 days (topical and nasal corticosteroids and inhaled corticosteroids for asthma are permitted) or chemotherapeutic agents for malignancy within the last three years.
19. Other clinically significant abnormality on physical, neurological, laboratory, examination that could compromise the study or be significantly detrimental to the patient.
20. Alcohol or drug dependence or abuse within the last two years.
21. Treated with any other investigational medication or device within 60 days.

Recruitment start date

01/10/2014

Recruitment end date

30/09/2016

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Royal Victoria Hospital
NICTU 1st Floor Elliott Dynes Building Grosvenor Road
Belfast
BT12 6BA
United Kingdom

Sponsor information

Organisation

Belfast Health and Social Care Trust (UK)

Sponsor details

Research Office
2nd Floor King Edward Building
The Royal Hospitals
Grosvenor Road
Belfast
BT12 6BA
United Kingdom
+44 (0)28 9063 6349
alison.murphy@belfasttrust.hscni.net

Sponsor type

Hospital/treatment centre

Website

http://www.belfasttrust.hscni.net/

Funders

Funder type

Charity

Funder name

Alzheimer's Society (UK) - Grant Number: 184

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

professional associations and societies

Location

United Kingdom

Funder name

British Heart Foundation (UK)

Alternative name(s)

BHF

Funding Body Type

private sector organisation

Funding Body Subtype

foundation

Location

United Kingdom

Results and Publications

Publication and dissemination plan

To be confirmed at a later date.

Following any publication of the primary and secondary study outcomes, there may be scope for additional analyses on the data collected. In such instances, formal requests for data will need to be made in writing to the AFFECT CI upon which there will be agreement with TMG and TSC.

Intention to publish date

Participant level data

Available on request

Results - basic reporting

Publication summary

2016 protocol in http://www.ncbi.nlm.nih.gov/pubmed/27430267

Publication citations

Additional files

Editorial Notes

21/07/2016: Publication reference added. 18/02/2016: The trial was stopped due to low recruitment and subsequent withdrawal of funder support.