Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616000886482
Ethics application status
Approved
Date submitted
4/07/2016
Date registered
6/07/2016
Date last updated
1/07/2021
Date data sharing statement initially provided
1/07/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Randomised trial aiming to prevent development of depression and improve quality of life in individuals with dementia (Alzheimer’s disease)
Scientific title
Randomised trial aiming to prevent development of depression and improve quality of life in individuals with dementia (Alzheimer’s disease) through a novel Cognitive Bias Modification intervention.
Secondary ID [1] 289605 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Depression 299385 0
Alzheimer's disease 299386 0
Condition category
Condition code
Mental Health 299369 299369 0 0
Depression
Neurological 299370 299370 0 0
Alzheimer's disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Cognitive bias modification (CBM) is a novel, simple, and safe computer-based intervention that requires behavioural responses from participants (i.e., pressing one of two buttons). CBM specifically targets attentional and interpretative biases associated with anxiety, dysphoria, and depression. CBM operates through implicit learning systems.

In this trial two forms of CBM will comprise the intervention, CBM-A (attentional modification) and CBM-I (interpretive modification).During CBM-A participants will be repeatedly exposed to pairs of emotional faces. Each face pair includes one face displaying a negative emotion, and one face portraying a non-negative emotion. The presentation of each face pair lasts 500 ms. After each face pair has been presented, a probe is presented in the same spatial position where one of the faces was located. Participants are asked to indicate the shape of each probe by pressing a square or a circle on a response box. The time taken for participants to discriminate the identity of the probe is recorded. In the active CBM-A condition, designed to reduce attention to negative information, and expected to result in subsequent reduction in symptoms of depression, probes always appear in the position of non-negative faces.

During CBM-I, participants will be repeatedly exposed to single ambiguous words (e.g. 'cane') for 1000 ms on the computer screen, followed by a pair of words. In each word pair, one word will be semantically related to either a negative or benign meaning (e.g. 'hit' or 'furniture') of the cue word, and one semantically unrelated word (e.g. 'cloud'). Participants will be asked to indicate whether the semantically related word appeared on the left or right side of the computer screen by pressing the left or right button on a response box. The time taken for participants to discriminate the location of the semantically related word is recorded. In the active CBM-I condition, designed to reduce negative interpretation of ambiguous information, and expected to result in subsequent reduction in symptoms of depression, the semantically related word will always present a benign meaning.

In this trial, each CBM session will last approximately 30 minutes: 15 minutes each for CBM-A and CBM-I, Over the course of the trial 35 CBM sessions will take place during office hours as follows: Week 1 - daily (5 sessions), Week 2 - 3 sessions, Weeks 3 to 4 - Twice a week (4 sessions), Week 5 to 25 months - Monthly (23 sessions).
The CBM sessions will be delivered on a local PC station at the study centre, under supervision of a trained research officer. The first session will also comprise initial baseline assessment of primary and secondary outcomes. Adherence to the trial will be monitored via registration of participant attendance at each session.
Intervention code [1] 295216 0
Treatment: Other
Intervention code [2] 295217 0
Behaviour
Comparator / control treatment
The control condition will follow the same procedure as described for the active intervention group, except for the following minor changes. During the CBM-A control condition probes will appear with equal frequency in the location of non-negative and negative faces. During the CBM-I control condition, the semantically related words will portray a benign or negative meaning with equal frequency.
Control group
Placebo

Outcomes
Primary outcome [1] 298837 0
A primary outcome is the incidence of clinically significant depressive symptoms in patients with Alzheimer's disease (AD) across the duration of the trial.

The Neuropsychiatric Inventory (NPI) will be used to establish the presence of clinically significant depression.
Timepoint [1] 298837 0
This primary outcome will be assessed at multiple time points across the duration of the trial. These time points are; baseline, 4 weeks, 6 months, 12 months, and 24 months.
Primary outcome [2] 298838 0
A primary outcome is the severity of clinically significant depressive symptoms in patients with Alzheimer's disease (AD) across the duration of the trial.

The Cornell Scale for Depression in Dementia (CSDD) will be used to measure severity of depressive symptoms.
Timepoint [2] 298838 0
This primary outcome will be assessed at multiple time points across the duration of the trial. These time points are; baseline, 4 weeks, 6 months, 12 months, and 24 months.
Secondary outcome [1] 325377 0
A secondary outcome is the change in quality of life of patients with Alzheimer's disease across the duration of the trial.

The Quality of Life - Alzheimer's Dementia Scale (QoL-AD) will be used to measure quality of life.
Timepoint [1] 325377 0
This secondary outcome will be assessed at multiple time points across the duration of the trial. These time points are; baseline, 4 weeks, 6 months, 12 months, and 24 months.
Secondary outcome [2] 325378 0
A secondary outcome is the change in dementia-related behavioural symptoms in patients with Alzheimer's disease across the duration of the trial.

The Neuropsychiatric Inventory will be used to measure dementia-related behavioural symptoms.
Timepoint [2] 325378 0
This secondary outcome will be assessed at multiple time points across the duration of the trial. These time points are; baseline, 4 weeks, 6 months, 12 months, and 24 months.
Secondary outcome [3] 325379 0
A secondary outcome is factors underlying the development of clinically significant depression in patients with Alzheimer's disease.

Investigators will collect demographic, lifestyle and clinical information via questionnaires and interview protocols designed specifically for this study.
Timepoint [3] 325379 0
This secondary outcome will be assessed at multiple time points across the duration of the trial. These time points are; baseline, 6 months, 12 months, and 24 months.
Secondary outcome [4] 325380 0
A secondary outcome will be change in burden of care as reported by carers of patients with Alzheimer disease.

Burden of care will be measured by the Zarit Burden Interview (ZBI).
Timepoint [4] 325380 0
This secondary outcome will be assessed at multiple time points across the duration of the trial. These time points are; baseline, 6 months, 12 months, and 24 months.
Secondary outcome [5] 325382 0
A secondary outcome is the change in the cognitive ability of patients with Alzheimer's disease across the duration of the trial.

The Mini-Mental State Examination (MMSE) will be used to assess cognitive ability.
Timepoint [5] 325382 0
This secondary outcome will be assessed at multiple time points across the duration of the trial. These time points are; baseline, 6 months, 12 months, and 24 months.
Secondary outcome [6] 325383 0
A secondary outcome is the assessment of neuroimaging predictors of clinically significant depression in patients with Alzheimer's disease. A random sample of up to 40 participants (20 in active CBM condition, 20 in control CBM condition) will undergo magnetic resonance scan (MRI).

Participants will undergo volumetric T1 and T2 weighted fluid-attenuated inversion recovery (FLAIR) imaging to assess for grey matter volume and cerebrovascular disease/white matter hyper-intensities. Images will be processes using SPM12 and MATLAB 7.14.
Timepoint [6] 325383 0
This secondary outcome will be assessed at multiple time points across the duration of the trial. These time points are; baseline, and 24 months.
Secondary outcome [7] 325406 0
A secondary outcome measure will be change, from baseline assessment, in level of attentional bias and interpretive bias across the duration of the trial. A baseline assessment of attentional bias and interpretive bias will be conducted prior to CBM intervention at the initial session, with assessments repeated throughout the duration of the trial. Attentional bias and interpretive bias will be assessed using computer tasks designed specifically for this study that will reflect methodologies typically employed for the assessment of such biases.
Timepoint [7] 325406 0
This secondary outcome will be assessed at multiple time points across the duration of the trial. These time points are; baseline, 4 weeks, and 24 months.

Eligibility
Key inclusion criteria
The inclusion criteria will be;
* Diagnosis of major neurocognitive disorder due to probable Alzheimer's disease according to DSM-5 criteria
* Mini-Mental State Examination (MMSE) score of greater than or equal to 15
* Neuropsychiatric Inventory (NPI) depression domain score of 1 (i.e. no depression)
* Availability of a close and reliable informant
* Fluent in written and spoken English
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
We will exclude individuals who;
* Have a medical condition that is likely to compromise their ability to complete the required activities of the study (e.g. severe sensory impairment)
* Consume alcohol in excess of 28 standard drinks per week
* Have no health practitioner who can provide ongoing clinical care
* Have a contra-indication to MRI (MRI sub-group only)
* Decline or are unable to provide informed consent.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Eligible participants will be automatically assigned to one of the two CBM conditions (active/control) by a computer. Allocation will be concealed from both the participant and the research team.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomly assigned to CBM conditions (active/control) according to a list of random numbers generated by a computer. Group allocation codes will then be linked to random ID numbers that will be assigned to each participant when they log on for their first CBM session. Neither the participant or research staff will be aware of the randomisation code
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Data from the longitudinal Maasbed study (Aalten, et al., 2005) showed that the 2-year cumulative incidence of depression from Alzheimer's disease is 33.4%. We estimate the CBM will result in an absolute risk reduction of around 15% (expected NNT=7). We therefore require 133 participants per group to declare as significant an absolute risk reduction of this magnitude given a power of 80%, and a two sided alpha of 0.05. Allowing for a 10-15% loss of participants to follow-up, we would therefore aim to recruit 300 participants in total (150 per group). The primary hypotheses (difference in the incidence of clinically significant depression between groups) will be tested using intention-to-treat analysis of panel data. This approach to the analysis of the data allows for the inclusion of all available information and for the investigation of interactions between terms (such as group and time).

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
1/08/2016
Actual
24/10/2016
Date of last participant enrolment
Anticipated
Actual
6/07/2018
Date of last data collection
Anticipated
Actual
3/01/2019
Sample size
Target
300
Accrual to date
Final
10
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 6105 0
Royal Perth Hospital - Perth
Recruitment hospital [2] 6106 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [3] 6107 0
Osborne Park Hospital - Stirling
Recruitment hospital [4] 6108 0
Bentley Health Service - Bentley
Recruitment hospital [5] 6109 0
Armadale Kelmscott Memorial Hospital - Armadale
Recruitment hospital [6] 6110 0
Fremantle Hospital and Health Service - Fremantle

Funding & Sponsors
Funding source category [1] 297776 0
Government body
Name [1] 297776 0
National Health and Medical Research Council
Country [1] 297776 0
Australia
Primary sponsor type
Other
Name
WA Centre for Health and Ageing
Address
Level 6
48 Murray St
Perth, WA, 6000
Country
Australia
Secondary sponsor category [1] 292809 0
None
Name [1] 292809 0
Address [1] 292809 0
Country [1] 292809 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295407 0
South Metropolitan Area Health Service Human Research Ethics Committee
Ethics committee address [1] 295407 0
Ethics committee country [1] 295407 0
Australia
Date submitted for ethics approval [1] 295407 0
21/04/2016
Approval date [1] 295407 0
14/07/2016
Ethics approval number [1] 295407 0
2016-071

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 67174 0
Dr Andrew Ford
Address 67174 0
WA Centre for Health & Ageing (M577)
University of Western Australia
35 Stirling Highway Perth WA 6009 Australia
Country 67174 0
Australia
Phone 67174 0
+61 8 9224 0295
Fax 67174 0
Email 67174 0
[email protected]
Contact person for public queries
Name 67175 0
Varsha Hirani
Address 67175 0
WA Centre for Health & Ageing (M577)
University of Western Australia
35 Stirling Highway Perth WA 6009 Australia
Country 67175 0
Australia
Phone 67175 0
+61 8 9224 0295
Fax 67175 0
Email 67175 0
varsha,[email protected]
Contact person for scientific queries
Name 67176 0
Andrew Ford
Address 67176 0
WA Centre for Health & Ageing (M577)
University of Western Australia
35 Stirling Highway Perth WA 6009 Australia
Country 67176 0
Australia
Phone 67176 0
+61 8 9224 0295
Fax 67176 0
Email 67176 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.