Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000908730
Ethics application status
Approved
Date submitted
16/06/2022
Date registered
27/06/2022
Date last updated
28/01/2024
Date data sharing statement initially provided
27/06/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Effects of brain training in Huntington’s disease
Scientific title
Efficacy and neural mechanisms of computerised cognitive training in Huntington’s disease: A randomised controlled trial
Secondary ID [1] 307230 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Huntington's disease 326477 0
Cognitive impairment 326478 0
Dementia 326479 0
Condition category
Condition code
Neurological 323749 323749 0 0
Neurodegenerative diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention consists of computerised cognitive training, using the BrainHQ platform. BrainHQ involves a suite of online exercises targeting various cognitive functions, including processing speed, attention, working memory and executive functions. The training will be adaptive, i.e., the difficulty level will be adjusted according to participant performance and progress. Exercises will involve short games requiring a response using mouse or keyboard, such as reproducing a sequence of digits presented in moving circles.

Training will be administered on the participants’ personal computer, within their own homes. Participants will access the training via the BrainHQ website. Participants will be required to complete two 1-hour sessions of training per week, over 12 weeks. One session each week will be completed individually, without supervision, while another session will be supervised using a video conference software, and in a group format if scheduling allows. Supervision will be conducted by a student researcher trained in administering the cognitive training.

Participant adherence will be assessed according to the activity logs in BrainHQ, which automatically records the number of hours of training completed. Fidelity will be maintained through weekly phone calls by the student researcher to provide feedback on progress and increase motivation to complete the training. Barriers to adherence will be discussed and troubleshooted.
Intervention code [1] 323672 0
Treatment: Other
Comparator / control treatment
Control group participants will receive lifestyle education, through newsletters that contain information on lifestyle factors associated with cognitive function, such as physical exercise, diet, and social and cognitive activity. They will receive one newsletter each month, totalling three newsletters over the 12 weeks. Newsletters are designed specifically for this study and will be delivered via email (or physical mail if email is not available). Participants will be asked to read the newsletters, which will take approximately 5 minutes each to read. Participants will be given one 5-10 minute phone call each month, where they can confirm whether they have read the newsletter, and discuss any lifestyle changes following the newsletter (although they won’t be asked to make any lifestyle changes).

Control group participants will also receive a three-month subscription to the BrainHQ program after the study period (i.e., when they have completed their follow-up assessment). However, they will not be receiving a structured intervention with supervised group training, and can complete the training in their own time.
Control group
Active

Outcomes
Primary outcome [1] 331501 0
Change in processing speed, measured by number of correct substitutions on Symbol Digits Modalities Test (SDMT)
Timepoint [1] 331501 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [1] 410094 0
Change in functional connectivity of a frontoparietal network during performance of a task-switching paradigm, assessed by MRI
Timepoint [1] 410094 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [2] 410095 0
Change in functional connectivity of a frontoparietal, occipital and cerebellar network during performance of the modified SDMT, assessed by MRI
Timepoint [2] 410095 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [3] 410096 0
Change in functional connectivity of default mode network during resting state, assessed by MRI
Timepoint [3] 410096 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [4] 410097 0
Change in functional connectivity of frontoparietal resting state network, assessed by MRI
Timepoint [4] 410097 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [5] 410098 0
Change in subjective cognition, measured by total score on Cognitive Difficulties Scale
Timepoint [5] 410098 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [6] 410099 0
Change in neuropsychiatric symptoms, measured by total score on Hospital Anxiety and Depression Scale
Timepoint [6] 410099 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [7] 410100 0
Change in health-related quality of life, measured by total score on HD-PRO-TRIAD
Timepoint [7] 410100 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [8] 411203 0
Change in processing speed, measured by time to complete Trails A
Timepoint [8] 411203 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [9] 411204 0
Change in shifting ability, measured by time to complete Trails B
Timepoint [9] 411204 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [10] 411205 0
Change in short-term memory, measured by score on Digit Span forwards
Timepoint [10] 411205 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [11] 411207 0
Change in working memory, measured by score on Digit Span backwards
Timepoint [11] 411207 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [12] 411208 0
Change in short-term memory, measured by score on Spatial Span forwards
Timepoint [12] 411208 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [13] 411209 0
Change in working memory, measured by score on Spatial Span backwards
Timepoint [13] 411209 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [14] 411210 0
Change in processing speed, measured by score on Stroop colour condition
Timepoint [14] 411210 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [15] 411211 0
Change in processing speed, measured by score on Stroop word condition
Timepoint [15] 411211 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [16] 411212 0
Change in inhibition, measured by score on Stroop interference condition
Timepoint [16] 411212 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [17] 411213 0
Change in inhibition, measured by interference score on Stroop test
Timepoint [17] 411213 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [18] 411214 0
Change in processing speed, measured by reaction time on modified SDMT
Timepoint [18] 411214 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [19] 411215 0
Change in processing speed, measured by accuracy on modified SDMT
Timepoint [19] 411215 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [20] 411216 0
Change in shifting ability, measured by reaction time on switch trials in letter-number task switching paradigm
Timepoint [20] 411216 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [21] 411217 0
Change in shifting ability, measured by accuracy on switch trials in letter-number task switching paradigm
Timepoint [21] 411217 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [22] 411218 0
Change in shifting ability, measured by reaction time on repeat trials on letter-number task switching paradigm
Timepoint [22] 411218 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [23] 411219 0
Change in shifting ability, measured by accuracy on repeat trials on letter-number task switching paradigm
Timepoint [23] 411219 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [24] 411220 0
Change in shifting ability, measured by switch costs (reaction time) on letter-number task switching paradigm
Timepoint [24] 411220 0
Baseline and post-intervention (12 weeks after commencement)
Secondary outcome [25] 411221 0
Change in shifting ability, measured by switch costs (accuracy) on letter-number task switching paradigm
Timepoint [25] 411221 0
Baseline and post-intervention (12 weeks after commencement)

Eligibility
Key inclusion criteria
Inclusion criteria include:
(a) Genetically positive for Huntington’s disease (HD)
(b) Premanifest disease or early-stage manifest disease (total functional capacity [TFC] = 7-13)
(c) 18+ years of age
(d) Access to computer with Internet connection
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria include:
(a) Absence of known genetic confirmation for HD
(b) Late-stage disease (TFC < 7)
(c) Under 18 years of age
(d) Diagnosis of any major neurological or psychiatric condition other than HD (besides anxiety or depression), history of substance abuse or head injury
(e) Severe depression and anxiety symptoms (score > 14 on either HADS subscale)
(f) Unstable dose of medication for depression and anxiety in the last 6 months

Additional exclusion criteria if undergoing MRI:
(a) Left-handed
(b) Currently pregnant
(c) Other MRI contraindications

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The researcher responsible for enrolling a participant will contact a separate researcher off-site who is responsible for randomisation of the participants.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Minimisation will be used to randomise participants, and balance the following covariates between groups: Age, sex, years of education, disease stage, depression/anxiety symptoms, consent for MRI (to balance numbers of MRI outcomes between groups).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


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
All analyses will be carried out using intention-to-treat principles.

Analyses of cognitive and clinical measures:
Changes in cognitive and patient-reported outcomes will be analysed using a mixed model ANOVA to test for Group x Time interaction effects. Baseline variables which differ across groups will be included as covariates in an ANCOVA. If there is a significant amount of missing data (>5%), missing data will be imputed and complete-case analyses will be presented as supplementary analyses. Sensitivity analyses will be conducted using controlled multiple imputation to determine the robustness of estimates.

In line with meta-analyses of trials of computerised cognitive training in other populations, the estimated effect size on overall cognition is g = 0.4 (Gavelin et al., 2021). With a 2 x 2 ANOVA with 2 time-points (baseline and follow-up) and 2 groups (intervention and control), alpha set at 0.05, the sample size required for power of 80% to detect a significant interaction effect (Group x Time interaction) is 200 participants. As this is unfeasible for the given population as a rare genetically inherited disease, post hoc calculations of power were conducted. With a sample size of 50 participants, there is 23% power to detect an effect size of d = 0.4.

Pre-processing of MRI data:
BOLD-fMRI data will be pre-processed according to standardised pipelines.

Analyses of task-related functional connectivity:
Analysis of task-related effects will occur in two stages.
1. Identification of task-related ROIs. Two sets of ROIs will be examined in this study: A priori ROIs and exploratory ROIs. A priori ROIs for the task-switching paradigm include the dorsolateral prefrontal cortex, inferior parietal cortex, and anterior cingulate cortex. A priori ROIs for the modified SDMT include the lingual gyrus, cuneus, declive, superior parietal lobule, middle frontal gyrus and inferior frontal gyrus. ROIs will be identified by calculating group-level averages of task-related activity. For each individual, a general linear model (GLM) will be estimated for each task separately at baseline and follow-up. Group-level contrasts will be estimated and regions that are activated above threshold at baseline and follow-up, which are not in the list of a priori ROIs will be identified.
2. For a priori and exploratory ROIs, functional connectivity will be estimated at the individual level by correlating the timecourses between each ROI. These will then be averaged to form a group-level measure of connectivity. Changes in functional connectivity within this ‘task-related network’ between baseline and follow-up will be compared between groups.

Analyses of resting-state functional connectivity:
Resting state networks will be estimated; the default mode and frontoparietal networks will be identified based on prior literature. Changes in within-network connectivity between baseline and follow-up will be compared between groups.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
25/07/2022
Actual
19/07/2022
Date of last participant enrolment
Anticipated
1/09/2023
Actual
24/01/2024
Date of last data collection
Anticipated
24/04/2024
Actual
Sample size
Target
50
Accrual to date
Final
30
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 22445 0
Calvary Health Care Bethlehem Ltd - Caulfield
Recruitment hospital [2] 26121 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment postcode(s) [1] 37673 0
3162 - Caulfield
Recruitment postcode(s) [2] 41977 0
3050 - Parkville

Funding & Sponsors
Funding source category [1] 311528 0
University
Name [1] 311528 0
Monash University
Country [1] 311528 0
Australia
Funding source category [2] 311530 0
Charities/Societies/Foundations
Name [2] 311530 0
Huntington’s Victoria
Country [2] 311530 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Wellington Rd, Clayton, VIC 3800
Country
Australia
Secondary sponsor category [1] 313097 0
University
Name [1] 313097 0
University of Melbourne
Address [1] 313097 0
Grattan Street, Parkville, VIC 3010
Country [1] 313097 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310987 0
Monash University Human Research Ethics Committee
Ethics committee address [1] 310987 0
Ethics committee country [1] 310987 0
Australia
Date submitted for ethics approval [1] 310987 0
27/09/2018
Approval date [1] 310987 0
15/10/2018
Ethics approval number [1] 310987 0
16420

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

Contacts
Principal investigator
Name 119598 0
Prof Nellie Georgiou-Karistianis
Address 119598 0
18 Innovation Walk, Monash University, Clayton, VIC, 3800
Country 119598 0
Australia
Phone 119598 0
+61 3 9905 1575
Fax 119598 0
Email 119598 0
[email protected]
Contact person for public queries
Name 119599 0
Nellie Georgiou-Karistianis
Address 119599 0
18 Innovation Walk, Monash University, Clayton, VIC, 3800
Country 119599 0
Australia
Phone 119599 0
+61 3 9905 1575
Fax 119599 0
Email 119599 0
[email protected]
Contact person for scientific queries
Name 119600 0
Nellie Georgiou-Karistianis
Address 119600 0
18 Innovation Walk, Monash University, Clayton, VIC, 3800
Country 119600 0
Australia
Phone 119600 0
+61 3 9905 1575
Fax 119600 0
Email 119600 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
Data will not be shared in order to maintain participant confidentiality. Even though data will be anonymised by using participant identifier numbers, due to the rarity of the condition, there is a greater risk of participant identification.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
16220Study protocol    The study protocol will be published as a pre-prin... [More Details]



Results publications and other study-related documents

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