Condition category
Mental and Behavioural Disorders
Date applied
13/07/2016
Date assigned
28/07/2016
Last edited
02/04/2019
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Dementia is a common condition in the aging population. People with dementia have difficulties with mental processes such as memory, language, reasoning and identifying people and objects, which become progressively worst over time. There are a range of different types of dementia, but the most common is Alzheimer’s disease (AD). Agitation and aggression are common in people who suffer from dementia and can cause problems for the patients, families and the people caring for them. In many cases, agitation is persistent, with many still showing symptoms after six months. There are medicines available to treat agitation, but it is not clear which treatments work best for people with dementia. Current treatments include antipsychotic medication, but these only have limited positive effects and can cause harm. Non-drug treatments are recommended in the first instance, but there is a need for medicines to be available, if non-drug treatments fail. The aim of this study is to investigate the effectiveness of mirtazapine (a type of antidepressant), in the management of agitation in people with dementia.

Who can participate?
Adults with dementia who are also displaying agitated behaviours, and their carers (family or paid carer)

What does the study involve?
Participants are randomly allocated to one of two groups. The study is designed so that the participant, their carer, their doctors and the research team do not know which they are taking until the end. Those in the first group are given mirtazapine, those in the second group are given a placebo (dummy pill). All tablets are made in such a way that they look the same, although it is possible to find out which medicine is being taken, in the event of a medical emergency. In both groups, participants are asked to take one tablet for the first two weeks of treatment in the trial, two tablets in the next two weeks and three tablets for the remaining eight weeks of the treatment period (unless there are concerns about side effects resulting from them taking the medication). A blood and ECG (test to check the heart rhythm) test are taken before medication is given and after treatment stops, at 12 weeks. Participants will continue to receive care from their doctors and other health and social services in the usual way whilst they are taking part in the study, and are carefully monitored throughout. Participants and their carers complete a number of questionnaires at the start of the study and then after 6 and 12 weeks to measure agitation and quality of life. There is a long term follow up phone call, six months and one year after trial medication is first taken.

What are the possible benefits and risks of participating?
Benefits can’t be promised, but participation may lead to improved treatments for people with similar symptoms in future. It is however possible that participants may benefit from lower levels of agitation as a result of taking the medication in this study, and improved quality of life for them and their carers. Disadvantages include that the trial will take up time. Blood tests are being taken for participant safety but may cause some discomfort and/or inconvenience. Mirtazapine does have side effects but most are mild and resolve on their own. These may include: stomach upset, weight gain, feeling drowsy, dizzy, headaches and more rarely a rash and blood problems. A full summary is provided to participants and side effects are carefully monitored by the trial team.

Where is the study run from?
NHS trusts across the UK

When is the study starting and how long is it expected to run for?
December 2015 to October 2019

Who is funding the study?
National Institute for Health Research (UK)

Who is the main contact?
1. Miss Juliet High / Mr Nick Leavey (public)
symbad@uea.ac.uk
2. Prof. Sube Banerjee (scientific)
s.banerjee@bsms.ac.uk

Trial website

Contact information

Type

Public

Primary contact

Miss Juliet High

ORCID ID

Contact details

Norwich Clinical Trials Unit
Norwich Medical School
University of East Anglia
Norwich Research Park
Norwich
NR4 7TJ
United Kingdom
+44 1603 591708
symbad@uea.ac.uk

Type

Scientific

Additional contact

Prof Sube Banerjee

ORCID ID

Contact details

Brighton and Sussex Medical School
Centre for Dementia Studies
University of Sussex
Falmer
Brighton
BN1 9RY
United Kingdom
+44 1273 678472
s.banerjee@bsms.ac.uk

Type

Public

Additional contact

Mr Nick Leavey

ORCID ID

Contact details

Clinical Trial Manager
Room 2.17
Norwich Medical School
Faculty of Medicine and Health Sciences
University of East Anglia
Norwich
NR4 7TJ
United Kingdom
+44 (0)1603 59 3899
N.Leavey@uea.ac.uk

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

30474

Study information

Scientific title

A pragmatic, multi-centre, double-blind, placebo controlled randomised trial to assess the safety, clinical and cost effectiveness of mirtazapine in patients with Alzheimer's Disease (AD) and agitated behaviours

Acronym

Study hypothesis

Current study hypothesis:
The aim of this study is to assess the safety, clinical and cost effectiveness of mirtazapine in the management of agitation and/or aggression in people with dementia.

Previous study hypothesis:
The aim of this study is to assess the safety, clinical and cost effectiveness of mirtazapine or carbamazepine in the management of agitation and/or aggression in people with dementia.

Ethics approval

Committee: South Central – Hampshire A, 04/11/2015, ref: 15/SC/0606

Study design

Randomised; Interventional; Design type: Treatment, Drug

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Not specified

Trial type

Treatment

Patient information sheet

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

Condition

Dementia

Intervention

Current interventions as of 28/01/2019:
Patients will be randomised in a 1:1 ratio to mirtazapine or placebo, stratified by study region and independent living using permuted block randomisation via a web-based system.
Mirtazapine is a generic 15mg tablet, over encapsulated. IMP and placebo will be identically encapsulated to produce capsules.
Mirtazapine group: Participants receive 15mg starting dose increasing to 30mg after 2 weeks and up to 45 mg in total.
Placebo group: Participants receive 1 capsule starting dose increasing to 2 capsules after 2 weeks and up to 3 capsules in total.
IMP or placebo will be taken for 12 weeks in total. Patients/their carers will be contacted by phone 4 weeks after they stop taking IMP to ask how they are feeling and record any adverse events (AEs). Long term follow up will be at 26 and 52 weeks.

Previous interventions:
Patients will be randomised in a 1:1:1 ratio to mirtazapine, carbamazepine or placebo, stratified by study region and independent living using permuted block randomisation via a web-based system.
Mirtazapine is a generic 15mg tablet, over encapsulated. Carbamazepine is specifically Tegretol Extended Release 100mg tablet, over encapsulated. IMP and placebo will be identically encapsulated (15mg tablets for mirtazapine and 100mg tablets for carbamazepine) to produce capsules.
Mirtazapine group: Participants receive 15mg starting dose increasing to 30mg after 2 weeks and up to 45 mg in total.
Carbamazepine group: Participants receive 100mg starting dose increasing to 200mg after 2 weeks and up to 300mg in total.
Placebo group: Participants receive 1 capsule starting dose increasing to 2 capsules after 2 weeks and up to 3 capsules in total.
IMP or placebo will be taken for 12 weeks in total. Patients/their carers will be contacted by phone 4 weeks after they stop taking IMP to ask how they are feeling and record any adverse events (AEs). Long term follow up will be at 26 and 52 weeks.

Intervention type

Drug

Phase

Phase III

Drug names

Mirtazapine

Primary outcome measure

Agitation is measured using the Cohen Mansfield Agitation Inventory (CMAI) long version, at baseline and 12 weeks.

Secondary outcome measures

1. Cost effectiveness is assessed using a modified Client Service Receipt Inventory (CSRI), alongside information from DEMQOL and EQ-5D-5L interviews at baseline, 6 and 12 weeks
2. Agitation is measured using the CMAI score at 6 weeks (in addition to the primary outcome measure, as a secondary outcome measure)
3. Patient and carer quality of life is assessed via the Zarit carer burden, GHQ-12 and EQ-5D questionnaires at baseline, 6 and 12 weeks
4. Safety is assessed by looking at adverse events and adherence at 6 and 12 weeks. Adverse events are measured by face to face visits, follow up phone calls, review of medical records, notification by other health care professionals, blood and ECG test results and collection of a diary card which is completed by the patient/carer. Adherence is assessed by tablet counts, follow up phone calls and review of a diary card which is completed by the patient/carer, at week 2, 4, 6 and 12.

Long term follow up takes place at 26 and 52 weeks and is assessed via a phone call:
1. Agitation is measured using CMAI
2. Institutionalisation is assessed using a study specific questionnaire
3. Mortality is measured using a study specific questionnaire
4. Clinical management is assessed using a study specific questionnaire

Overall trial start date

01/12/2015

Overall trial end date

30/06/2020

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Aged 18 years and over
2. Clinical diagnosis of probable or possible Alzheimer’s Disease using National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS/ADRDA) criteria
3. A diagnosis of co-existing agitated behaviours
4. Evidence that the agitated behaviours have not responded to management according to the AS/DH algorithm
5. If receiving cholinesterase inhibitors or memantine, must be on a stable dose (defined as three months on current dose)
6. A Cohen Mansfield Agitation Inventory score of 45 or greater
7. Written informed consent to enter and be randomised into the trial or consultee agreement for those without capacity
8. Availability of a suitable informant (consenting identifiable family carer or paid carer) to provide information on carer-completed outcome measures and who consents to take part in the trial

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 262; UK Sample Size: 262

Participant exclusion criteria

Current exclusion criteria as of 28/01/2019:
1. Current treatment with antidepressants (including monoamine oxidase inhibitors (MAOIs)), anticonvulsants, antipsychotics. Patients must have completed treatment with these medications at least two weeks before trial drug administration
2. Contraindications to the administration of mirtazapine as per its current SmPCs
3. Patients with atrioventricular block, a history of bone marrow depression or history of hepatic porphyrias
4. Cases too critical for randomisation (ie where there is a suicide risk or where the patient presents a risk of harm to others)
5. Female subjects under the age of 55 of childbearing potential, defined as follows: postmenopausal females who have not had at least 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhoea with serum FSH>40mIU/ml or females who have not had a hysterectomy or bilateral oophorectomy at least 6 weeks prior to enrolment

Previous exclusion criteria:
1. Current treatment with antidepressants (including monoamine oxidase inhibitors (MAOIs)), anticonvulsants, antipsychotics. Patients must have completed treatment with these medications at least two weeks before trial drug administration
2. Contraindications to the administration of carbamazepine and mirtazapine as per their current SmPCs
3. Patients with atrioventricular block, a history of bone marrow depression or history of hepatic porphyrias
4. Cases too critical for randomisation (ie where there is a suicide risk or where the patient presents a risk of harm to others)
5. Female subjects under the age of 55 of childbearing potential, defined as follows: postmenopausal females who have not had at least 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhoea with serum FSH>40mIU/ml or females who have not had a hysterectomy or bilateral oophorectomy at least 6 weeks prior to enrolment

Recruitment start date

01/09/2016

Recruitment end date

31/03/2020

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Sussex Partnership NHS Foundation Trust
Grove House Southview Road
Crowborough
TN6 1HB
United Kingdom

Trial participating centre

Norfolk and Waveney Mental Health NHS Foundation Trust
Hellesdon Hospital Drayton High Road
Norwich
NR6 5BE
United Kingdom

Trial participating centre

Gateshead Health Foundation Trust
Clinical Trials Office Cheviot View Queen Elizabeth Hospital Queen Elizabeth Avenue Sheriff Hill
Gateshead
NE9 6SX
United Kingdom

Trial participating centre

Manchester Mental Health and Social Care Trust
Greater Manchester Central Manchester University Hospitals NHS Foundation Trust West Road Off North Road (Between Children’s and Adults A&E Departments)
Manchester
M13 9WL
United Kingdom

Trial participating centre

Camden and Islington NHS Foundation Trust and Barnet, Enfield and Haringey Mental Health Trust
St. Pancras Hospital 4 St. Pancras Way
London
NW1 3TH
United Kingdom

Trial participating centre

Birmingham and Solihull Mental Health NHS Foundation Trust
Barberry Centre 25 Vincent Drive
Edgbaston
B15 2FG
United Kingdom

Trial participating centre

Guy's and St Thomas' NHS Foundation Trust
Guys and St Thomas Hospital Great Maze Pond
London
SE1 9RT
United Kingdom

Trial participating centre

Surrey and Borders Partnership NHS Foundation Trust
Research and Development Department Abraham Cowley Unit St Peter’s Hospital Guildford Road
Chertsey
KT16 OPZ
United Kingdom

Trial participating centre

Barnet Enfield & Haringey Mental Health NHS Trust
St. Ann's Hospital
London
N15 3TH
United Kingdom

Trial participating centre

Bradford District Care Foundation Trust
Lynfield Mount Hospital
Bradford
BD9 6DP
United Kingdom

Trial participating centre

2gether Gloucestershire NHS Foundation Trust
Cheltenham
GL53 9DZ
United Kingdom

Sponsor information

Organisation

University of Sussex

Sponsor details

C/O Nigel Knight
Head of Contracts and IP
Falmer House
Falmer
Brighton
BN1 9QF
United Kingdom

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Government

Funder name

National Institute for Health Research

Alternative name(s)

NIHR

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

1. The dissemination plan will include facilitating the translation of findings of the research into practice. The plan will be developed during the trial, but the audience will include clinicians, people with dementia and their carers, other health care professionals and policy makers. All participants will have the option to request a copy of the results, all outputs will be tailored in style and content to the intended audience.
2. The data will be published in high impact, peer reviewed journals and open access to the papers will be enabled. Minimum publications will include: the trial protocol, a primary paper for publication of the results, a secondary clinical outcome paper, secondary economic evaluation paper, HTA publication of the final report and publication of the long term follow up data.
3. There will also be presentations at conferences and seminars, both locally, nationally and internationally.

Intention to publish date

30/06/2021

Participant level data

Other

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

02/04/2019: The condition has been changed from "Specialty: Dementias and neurodegeneration, Primary sub-specialty: Dementia; UKCRC code/ Disease: Neurological/ Other disorders of the nervous system" to "Dementia" following a request from the NIHR. 29/01/2019: Contact details updated. 28/01/2019: The following changes were made to the trial record as the trial has undergone a substantial amendment to remove the carbamazepine treatment arm: 1. The public and scientific titles, study hypothesis, interventions and exclusion criteria were updated to remove the references to carbamazepine. 2. The target number of participants was changed from 471 to 262. 3. Barnet Enfield & Haringey Mental Health NHS Trust, Bradford District Care Foundation Trust and 2gether Gloucestershire NHS Foundation Trust were added to the trial participating centres. 08/01/2019: The following changes have been made: 1. The recruitment end date has been updated from 31/12/2018 to 31/03/2020. 2. The overall trial end date has been updated from 31/10/2019 to 30/06/2020. 3. The intention to publish date has been updated from 31/10/2020 to 30/06/2021. 14/08/2018: The following changes have been made to the trial record: 1. The recruitment end date has been changed from 31/07/2018 to 31/12/2018. 2. South London and Maudsley NHS Foundation Trust has been removed as a trial participating centre.