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Trial registered on ANZCTR


Registration number
ACTRN12618001717246
Ethics application status
Approved
Date submitted
12/10/2018
Date registered
17/10/2018
Date last updated
17/10/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
Effect of multidisciplinary therapy in Huntington's disease
Scientific title
The effectiveness of a novel multidisciplinary therapy program on clinical and biological measures of disease progression in individuals with Huntington's disease.
Secondary ID [1] 295962 0
Nil
Universal Trial Number (UTN)
U1111-1219-7398
Trial acronym
Nil
Linked study record
Nil

Health condition
Health condition(s) or problem(s) studied:
Huntington's Disease 309471 0
Condition category
Condition code
Neurological 308306 308306 0 0
Other neurological disorders
Human Genetics and Inherited Disorders 308802 308802 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients in Perth were allocated to receive nine months of supervised outpatient multidisciplinary therapy in addition to their standard care. Patients in Melbourne were allocated to receive their standard care. Details of the multidisciplinary therapy intervention are provided below.

The intervention was designed by a highly experienced team of exercise physiologists, cognitive training specialists and strength and conditioning specialists. It consisted of nine months of three times weekly supervised exercise, cognitive training, dual task training, bilingual exercises, healthy lifestyle guidance and social activities. These rehabilitation methods were purposefully selected as they have been demonstrated to have positive effects on neural and clinical outcomes in HD individuals and other clinical populations.

To maximise physiological and clinical benefits the intervention was organised into distinct training blocks (mesocycles), which were designed to train different physiological systems and clinical function. Training blocks were six weeks in duration and consisted of a training phase (weeks 1-4), tapered phase (week 5) and rest phase (week 6). Training blocks were designed to train different physiological systems and clinical functions.

Exercise training

The exercise training program comprised individualised (ie, adjusted to baseline strength (1RM) and cardiorespiratory fitness (HRmax obtained via VO2max)), block periodised (ie, systematically organised exercise variation (volume, intensity and use of specific exercises) into mesocycles (six week blocks)), progressive and autoregulated (ie, adjustments to the volume and intensity of training based on the well-being of patients on training days (ie, soreness and motivation)) aerobic and resistance exercise training.

Autoregulated block periodization was used to maximise physiological and clinical benefits and to reduce the risk of injury for participants. Aerobic exercise training was undertaken on cycle ergometers and ellipticals. The intensity of aerobic exercise was prescribed using heart rate maximum and RPE values. The speed and resistance on aerobic machines was adjusted by exercise physiologists to ensure that participants reached their target heart rate and RPE. Resistance training was performed on resistance machine and targeted major upper, lower and core muscle groups. Resistance training intensity was prescribed using the repetition method (RM). The resistance training stimulus was adjusted by exercise physiologists as necessary in 1.25, 2.5 or 5kg increments to ensure muscular failure at the prescribed RM.

Cognitive training

The cognitive training program consisted of supervised computerised and manual cognitive training. Computerised cognitive training was undertaken using NeuroNation and Captain’s Log Mind Power Builder software three times per week for one hour. The prescription and dose of computerised cognitive training were informed by previous work (Lampit et al) and targeted a number of cognitive domains including, working memory, executive control, divided attention and response inhibition which are comprised early in HD. Training performance was automatically recorded by the computerised cognitive training software. Manual cognitive training was undertaken once per week for thirty minutes and consisted of performing response inhibition, working memory and sustained attention exercises.

Dual task training

Dual task training consisted of learning and memorising Spanish, Italian and German phrases whilst simultaneously performing aerobic exercise on an elliptical or cycle ergometer. The difficulty of phrases was increased throughout each mesocycle.

Healthy Lifestyle Guidance

Healthy lifestyle guidance consisted of educating participants on the importance of regular exercise and cognitive stimulation, sleep hygiene and a good nutrition. Recommendations on exercise were made according to American College of Sports Medicine Guidelines for adults. Recommendations on cognitive stimulation were made based on available evidence indicating that regular engagement in educational activities (learning new information, attending classes and seminars), reading books, playing cognitively stimulating games, playing musical instruments and learning a new language is beneficial for older adults and individuals with neurodegenerative diseases. Sleep hygiene recommendations outlined by Morton (2013) for individuals with HD were provided to participants throughout the intervention. Nutritional recommendations were made according to the Australian Dietary Guidelines (2013).

Socialisation

Socialisation was stimulated through group training sessions, group Facebook pages and tri-monthly social events including barbecues, picnics and restaurant outings.

Training adherence and compliance

Adherence and compliance to the interventions were recorded by exercise physiologists via training logs.
Intervention code [1] 312288 0
Rehabilitation
Comparator / control treatment
The control treatment is standard care.

Standard care consisted of the patients usual care received from clinicians.
Control group
Active

Outcomes
Primary outcome [1] 307709 0
Feasibility of supervised outpatient multidisciplinary therapy and usual care for individuals with premanifest Huntington's disease.

Feasibility was measured by evaluating the recruitment and retention of Huntington's disease (HD) patients during the trial, as well as the adherence of HD patients to supervised outpatient multidisciplinary therapy and usual care. The recruitment (number of patients recruited) and retention (number of patients retained at the conclusion of the study) of HD patients during the trial was recorded by the principle investigator. Adherence to the supervised outpatient multidisciplinary therapy intervention and usual care was recorded throughout the study by exercise physiologists.
Timepoint [1] 307709 0
The feasibility of supervised outpatient multidisciplinary therapy and usual care was be measured throughout the entirety of the trial.
Primary outcome [2] 307710 0
The safety of the supervised outpatient multidisciplinary therapy intervention was assessed by recording the incidence and severity of any adverse events throughout the intervention period. Adverse events was also assessed in the standard care group. In particular, musculoskeletal injuries, falls cardiovascular events, physical and mental fatigue were assessed.
Timepoint [2] 307710 0
The safety of the supervised outpatient multidisciplinary therapy intervention and standard care were assessed throughout the entirety of the intervention period.
Secondary outcome [1] 352595 0
Whole brain volume

Whole brain volume was calculated from T1-weighted images from MRI.
Timepoint [1] 352595 0
Whole brain volume was evaluated before and at the completion of the supervised outpatient multidisciplinary therapy intervention (9 months).
Secondary outcome [2] 352596 0
White matter microstructure

White matter microstructure was evaluated using diffusion weighted imaging sequences from MRI.
Timepoint [2] 352596 0
Changes in white and grey matter microstructure were evaluated before and at the completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [3] 352597 0
Regional changes in grey and white matter volume.

Regional changes in grey and white matter volume were evaluated using T1-weighted imaging sequences from MRI.
Timepoint [3] 352597 0
Regional changes in grey and white matter volume were evaluated before and at the completion of the supervised outpatient multidisciplinary therapy intervention (9 months).
Secondary outcome [4] 352598 0
Verbal learning and memory.

Verbal learning and memory were evaluated using the Hopkins Verbal Learning Test-Revised. This is a composite outcome.
Timepoint [4] 352598 0
Verbal learning and memory were evaluated before and at the completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [5] 352599 0
Information processing speed.

Information processing speed was evaluated using the Symbol Digits Modalities Test.
Timepoint [5] 352599 0
Information processing speed was evaluated before and at the completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [6] 352600 0
Problem solving and planning.

Problem solving and planning were evaluated using the One Touch Stockings of Cambridge Test. This is a composite outcome.
Timepoint [6] 352600 0
Problem solving and planning were evaluated before and at the completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [7] 352601 0
Attention and cognitive flexibility.

Attention and cognitive flexibility were measured using the Trail Making Test (Parts A and B).
Timepoint [7] 352601 0
Attention and cognitive flexibility were measured before and at the completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [8] 352602 0
Theory of mind.

Theory of mind was measured using the Reading the Mind in the Eyes Test, Cambridge Faces Test, Montreal Affective Voices Test, Musical Emotional Burst Test and Mini-Social Cognitive and Emotional Assessment.

This is a composite outcome.
Timepoint [8] 352602 0
Theory of mind was measured before and at the completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [9] 352603 0
Anxiety and depression symptomology

Anxiety and depression symptomology were evaluated with the Hospital Anxiety and Depression Scale.
Timepoint [9] 352603 0
Anxiety and depression symptomology was evaluated before and at the completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [10] 352604 0
Depression symptomology

Depression symptomology was evaluated with the Becks Depression Inventory.
Timepoint [10] 352604 0
Depression symptomology was evaluated before and at the completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [11] 352605 0
Aerobic Fitness

Aerobic fitness was evaluated using a graded exercise test (VO2max test).
Timepoint [11] 352605 0
Aerobic fitness was examined before and at the completion of the supervised outpatient multidisciplinary therapy.
Secondary outcome [12] 352606 0
Muscle strength

Muscle strength was evaluated using isokinetic dynamometry.
Timepoint [12] 352606 0
Muscle strength was evaluated before and at the completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [13] 352607 0
Muscle strength

Muscle strength in the upper and lower limbs was evaluated using 1 and 15 repetition maximum (RM) tests.
Timepoint [13] 352607 0
Muscle strength was evaluated before and at the completion of supervised outpatient multidisciplinary therapy.
Secondary outcome [14] 352608 0
Psychological stress

Psychological stress was evaluated using the Perceived Stress Scale.
Timepoint [14] 352608 0
Psychological stress was evaluated before and at the completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [15] 352609 0
Leisure time physical activity.

Leisure time physical activity was evaluated with the Minnesota Leisure Time Physical Activity Scale.
Timepoint [15] 352609 0
Leisure time physical activity was evaluated before and at the completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [16] 352610 0
Social Network Size and Complexity.

The Social Network Index (SNI) was used to examine social network size and complexity.
Timepoint [16] 352610 0
Social network size and complexity was evaluated before and at the completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [17] 352611 0
Premorbid Intelligence

Premorbid intelligence was evaluated with the National Adult Reading Test.
Timepoint [17] 352611 0
Premorbid intelligence was evaluated before and at the completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [18] 352701 0
Muscle Health

Whole-body, segmental (axial, appendicular) and regional (spinal, hip, femoral) scans was performed to examine lean mass using Dual-energy X-ray Absorptiometry (DXA; Discovery A, 1500 Hologic, Waltham, MA).

This is a composite outcome.
Timepoint [18] 352701 0
Muscle health was examined before and at the completion of the supervised outpatient multidisciplinary therapy intervention
Secondary outcome [19] 352702 0
Bone Health

Whole-body, segmental (axial, appendicular) and regional (spinal, hip, femoral) scans were performed to examine bone area (BA), bone mineral content (aBMC), bone mineral density (aBMD) using Dual-energy X-ray Absorptiometry (DXA; Discovery A, 1500 Hologic, Waltham, MA). Regional analyses (lumbar spine, total hip, femoral neck, femoral trochanter, Wards triangle) were performed in accordance with Hologic’s manufacturer specifications.

This is a composite secondary outcome.
Timepoint [19] 352702 0
Bone health were examined before and at the completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [20] 352703 0
Adiposity

Whole-body adipose tissue (fat mass) were measured using Dual-energy X-ray Absorptiometry (DXA; Discovery A, 1500 Hologic, Waltham, MA).
Timepoint [20] 352703 0
Adiposity was examined before and at the completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [21] 352704 0
Blood sampling

40mL of blood was drawn from study participants for the analysis of biological markers. This was an exploratory outcome.
Timepoint [21] 352704 0
Blood was sampled before and at the completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [22] 352705 0
Habitual Sleep

Habitual sleep was measured using the Pittsburgh Sleep Quality Index and the Consensus Sleep Diary.

Timepoint [22] 352705 0
Habitual sleep was examined with the Pittsburgh Sleep Quality Index and Consensus Sleep Diary before and at the completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [23] 352708 0
Habitual Sleep/Sleep Quality

The Epworth Sleepiness Scale was used to measure habitual sleep/sleep quality.

Timepoint [23] 352708 0
Habitual Sleep/Sleep Quality were examined with the Epworth Sleepiness Scale before and at the completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [24] 352710 0
Cognitive multitasking

Cognitive multitasking was measured using a novel cognitive dual-task proposed by Vallessi et al 2015.
Timepoint [24] 352710 0
Cognitive multitasking was evaluated before and at the completion of the supervised outpatient multidisciplinary therapy intervention using the cognitive dual-task proposed by Vallessi et al 2015.
Secondary outcome [25] 352711 0
Static and Dynamic Postural Stability

Static and dynamic postural stability was assessed using computerised dynamic posturography.

This is a composite outcome,
Timepoint [25] 352711 0
Static and dynamic postural stability was assessed before and at the completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [26] 352713 0
Limits of postural stability.

Limits of postural stability was assessed using a limits of stability test.
Timepoint [26] 352713 0
Limits of postural stability was assessed before and at the completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [27] 352714 0
Salivary cortisol.

Salivary cortisol was evaluated using an enzyme-linked immunosorbent assay.
Timepoint [27] 352714 0
Salivary cortisol was evaluated before and at the completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [28] 352715 0
Salivary Melatonin

Salivary melatonin was evaluated using an enzyme-linked immunosorbent assay.
Timepoint [28] 352715 0
Salivary melatonin was evaluated before and at completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [29] 352731 0
Cognitive-motor interference

Cognitive-motor interference was measured with serial threes and dual-cognitive tests and force steadiness and postural stability tests.
Timepoint [29] 352731 0
Cognitive-motor interference was be evaluated before and at the completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [30] 352732 0
Force steadiness in the plantarflexors

Force steadiness in the plantarflexors was evaluated using isokinetic dynamometry.
Timepoint [30] 352732 0
Force steadiness in the plantarflexors was evaluated before and at completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [31] 352749 0
Barriers and facilitators to supervised outpatient multidisciplinary therapy.

Barriers and facilitators to supervised outpatient multidisciplinary therapy were evaluated using a semi-structured interview.
Timepoint [31] 352749 0
Barriers and facilitators to supervised outpatient multidisciplinary therapy were evaluated following the completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [32] 352795 0
Hair cortisol

Hair cortisol concentrations were determined using enzyme-linked immunosorbent assays to evaluate chronic cortisol release.
Timepoint [32] 352795 0
Hair cortisol concentrations were measured before and at the completion of the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [33] 352796 0
Alexithymia

Alexithymia was evaluated using the Toronto Alexithymia Scale -20 (TAS-20).
Timepoint [33] 352796 0
Alexithymia was evaluated before and after the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [34] 352797 0
Empathy

Empathy was measured using the Interpersonal Reactivity Index (IRI).

Timepoint [34] 352797 0
Empathy was measured before and after the supervised outpatient multidisciplinary therapy intervention.
Secondary outcome [35] 352935 0
Tolerance to the cognitive training component of the intervention was recorded using a visual analog scale (0-10).

Timepoint [35] 352935 0
Tolerance to the cognitive training component of the intervention was recorded by participants using a visual analog scale (0-10) for each training session during the intervention period.
Secondary outcome [36] 352936 0
Tolerance to the exercise training component of the intervention was recorded by participants using a rate of perceived exertion scale (0-20).
Timepoint [36] 352936 0
Tolerance to the cognitive training component of the intervention was recorded by participants using a rate of perceived exertion scale (0-20) for each training session during the intervention period.
Secondary outcome [37] 352937 0
Tolerance to the dual-tasking component of the intervention was recorded by participants using a visual analog scale (0-10) for each training session during the intervention period.
Timepoint [37] 352937 0
Tolerance to the dual-tasking component of the intervention was recorded by participants using a visual analog scale (0-10) for each dual-task training session during the intervention period.

Eligibility
Key inclusion criteria
Inclusion criteria for premanifest HD individuals were a cytosine-adenine-guanine (CAG) repeat length > 39 and a diagnostic confidence score < 4 on the Unified Huntington’s Disease Rating Scale Total Motor Score (UHDRS-TMS) (Reilmann et al., 2014).
Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria were the presence of known musculoskeletal, metabolic, endocrine or cardiovascular disorders, recent or long-standing substance abuse, shift work other neurological conditions.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Non-randomised controlled trial
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Data from this trial will be assessed for normality using the Shapiro-Wilk test and through visual inspection of data distribution plots. Chi-squared tests (categorical data), independent t-tests (normal continuous data) and Mann-Whitney U tests (non-normal continuous data) will be used to examine differences in demographic characteristics between groups. Mixed-model ANOVAs with group and time as factors will be used to evaluate the therapeutic effects of multidisciplinary therapy on neurological and clinical outcomes. Effects sizes and minimally important differences will be calculated. Statistical analyses will be undertaken using STATA, SPSS and R statistical software packages.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA,VIC

Funding & Sponsors
Funding source category [1] 300560 0
Other
Name [1] 300560 0
Lotterywest
Address [1] 300560 0
38 Station St, Subiaco WA 6008
Country [1] 300560 0
Australia
Primary sponsor type
University
Name
Edith Cowan University
Address
270 Joondalup Drive, Joondalup, 6027, Perth, Western Australia, Australia
Country
Australia
Secondary sponsor category [1] 300042 0
University
Name [1] 300042 0
Deakin University
Address [1] 300042 0
221 Burwood Highway, 3025, VIC
Country [1] 300042 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301352 0
Edith Cowan University Human Research Ethics Committee
Ethics committee address [1] 301352 0
270 Joondalup Drive, Joondalup, 6027, WA
Ethics committee country [1] 301352 0
Australia
Date submitted for ethics approval [1] 301352 0
Approval date [1] 301352 0
27/10/2014
Ethics approval number [1] 301352 0
13145
Ethics committee name [2] 301669 0
Deakin University Human Research Ethics Committee
Ethics committee address [2] 301669 0
Melbourne Burwood Campus, 221 Burwood Highway, Burwood, VIC 3125
Ethics committee country [2] 301669 0
Australia
Date submitted for ethics approval [2] 301669 0
Approval date [2] 301669 0
05/05/2015
Ethics approval number [2] 301669 0
Ethics committee name [3] 301670 0
Monash University Human Research Ethics Commitee
Ethics committee address [3] 301670 0
Room 111, Chancellery Building E
24 Sports Walk
Clayton Campus
Wellington Rd
Clayton VIC 3800, Australia
Ethics committee country [3] 301670 0
Australia
Date submitted for ethics approval [3] 301670 0
Approval date [3] 301670 0
03/08/2015
Ethics approval number [3] 301670 0
CF15/117 - 2015000058

Summary
Brief summary
Study Aims
This study aims to assess the effects of a supervised outpatient multidisciplinary therapy program, compared to standard care, on neurological and clinical decline in individuals with premanifest Huntington's disease (HD).

Who is it for?
You may be eligible to participate in this study if you are 21 years or older and have been diagnosed as gene positive for the HD mutation (>39 CAG repeats).

Study Details
This study is a controlled exploratory study. Participants will be allocated to either the multidisciplinary therapy group (Perth) or standard care group (Melbourne). Participants in the multidisciplinary therapy group will be asked to undertake thrice-weekly training sessions for two hours per session for nine months. Training sessions comprise cognitive and exercise training, dual tasking and lifestyle guidance. The standard care group will receive their normal care throughout the study. Participants will be assessed with brain imaging, cognitive, movement, mood, sleep, physical and cognitive activity and biological tests and questionnaires.

Potential Study Outcomes
It is hoped that the finding of this research project will highlight the therapeutic utility of multidisciplinary therapy programs for people living with HD and provide much needed data to apply for funding for a randomised controlled trial across Australia.
Trial website
Nil
Trial related presentations / publications
Nil
Public notes
Nil

Contacts
Principal investigator
Name 86710 0
Prof Mel Ziman
Address 86710 0
Edith Cowan University, 270 Joondalup Drive, Joondalup, 6027, Perth, Western Australia, Australia
Country 86710 0
Australia
Phone 86710 0
+61 8 6304 3640
Fax 86710 0
Email 86710 0
m.ziman@ecu.edu.au
Contact person for public queries
Name 86711 0
Dr Travis Cruickshank
Address 86711 0
Edith Cowan University, 270 Joondalup Drive, Joondalup, 6027, Perth, Western Australia, Australia
Country 86711 0
Australia
Phone 86711 0
+61 8 6304 3416
Fax 86711 0
Email 86711 0
t.cruickshank@ecu.edu.au
Contact person for scientific queries
Name 86712 0
Dr Travis Cruickshank
Address 86712 0
Edith Cowan University, 270 Joondalup Drive, Joondalup, 6027, Perth, Western Australia, Australia
Country 86712 0
Australia
Phone 86712 0
+61 8 6304 3416
Fax 86712 0
Email 86712 0
t.cruickshank@ecu.edu.au

No data has been provided for results reporting
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary