Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616000501448
Ethics application status
Approved
Date submitted
22/03/2016
Date registered
18/04/2016
Date last updated
8/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Does Creatine Enhance the Effects of Cognitive Training in Older Adults with Mild Cognitive Impairment?
Scientific title
Does Creatine Enhance the Effects of Cognitive Training in Older Adults with Mild Cognitive Impairment?
Secondary ID [1] 288801 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Mild cognitive impairment 298068 0
Condition category
Condition code
Neurological 298231 298231 0 0
Neurodegenerative diseases
Physical Medicine / Rehabilitation 298260 298260 0 0
Other physical medicine / rehabilitation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention comprises daily oral creatine supplementation as an adjunctive treatment to a 12-week, twice-weekly cognitive training program. In this trial, all participants will complete the same cognitive training program; however the experimental condition refers to whether the adjunctive dietary supplement is active (i.e. creatine) or inactive (i.e. placebo). This will be randomly allocated.

In terms of the dietary supplements, participants will self-administer one daily oral dose, administered in 5g sachets. Participants will be instructed to dissolve the supplement in warm water and take one-hour before or after meals in order to maximise absorption. In both the active and inactive arms, an initial dose of 10g (5g twice daily) will be administered for 3 days to assess for tolerance. If the supplements are well tolerated, then a loading dose of 20g (10g twice daily) will be administered for the following 4 days. Subsequently, a maintenance dose of 10g (5g twice daily) will continue for a further 11 weeks, i.e. over the duration of the cognitive training period. Participants will be given written instructions for administration of all supplements.

Participants will be asked to return any unused medication for adherence checks and safety on a fortnightly basis, in line with the dispensing schedule. At each dispensation, the trial clinician will do a compliance check as well as check for side effects or any adverse events the participants might have experienced. Participants will also receive a medication tracking calendar to aid compliance and recording of any side effects.

The cognitive training program used in this trial is the computer-based Captains Log MindPower Builder software package, which targets multiple cognitive domains using an array of both auditory and visual exercises requiring responses via keyboard and mouse clicks. All participants will complete the same program of tasks; however graded difficulty is automatically adapted for each individual by the software program, with difficulty increasing as the participant improves their performance on each task. Each training session will last for 1 hour. The training will take place in a purpose-built cognitive training computer laboratory at the Brain and Mind Centre, Camperdown, Sydney. Each participant will work at their own computer and at their own pace; however multiple participants may attend the same training session simultaneously (based on availability). The training sessions will be run by trained facilitators comprising both Clinical Neuropsychologists, postdoctoral researchers and PhD students all of whom have received specialised training in these techniques and whom are experienced in facilitating cognitive training in over 400 older adults.
Intervention code [1] 294250 0
Treatment: Other
Intervention code [2] 294275 0
Rehabilitation
Comparator / control treatment
The control group will complete the same 12-week, twice-weekly computerized cognitive training program, but will take an adjunctive placebo (i.e. Maltodextrin) on a daily basis in place of the active dietary supplement.
Control group
Active

Outcomes
Primary outcome [1] 297732 0
The primary outcome is learning and memory, assessed using the Rey Auditory Verbal
Learning Test (RAVLT; see Lezak, 1995). This test was chosen for its sensitivity to improvements following cognitive training and has also been used in our previous clinical trials of cognitive training in Mild Cognitive Impairment.
Timepoint [1] 297732 0
This will be conducted at baseline and at post-intervention follow-up, which will be completed within four weeks of cessation of training. Alternate forms of this test will be administered at baseline and follow-up (counterbalanced) to ensure minimization of practice effects.
Secondary outcome [1] 322046 0
Neuropsychological: Working memory will be assessed using the Digit Span subtest from the 3rd Edition of the Weschsler Adult Intelligence Scale (See Wechsler, 1997).
Timepoint [1] 322046 0
This will be conducted at baseline and at post-intervention follow-up, which will be completed within four weeks of cessation of training.
Secondary outcome [2] 322047 0
Neuropsychological: Verbal learning and memory will be assessed using the Logical Memory subtest from the 3rd Edition of the Weschsler Memory Scale (See Wechsler, 1997).
Timepoint [2] 322047 0
This will be conducted at baseline and at post-intervention follow-up, which will be completed within four weeks of cessation of training.
Secondary outcome [3] 322048 0
Neuropsychological: Visual learning will also be assessed using the Rey Complex Figure Test (See Strauss, 2006).
Timepoint [3] 322048 0
This will be conducted at baseline and at post-intervention follow-up, which will be completed within four weeks of cessation of training. The Taylor Figure (Taylor, 1989) will be used as an alternate form and will be administered at either baseline or follow-up (counterbalanced) to ensure minimization of practice effects.
Secondary outcome [4] 322049 0
Neuropsychological: Processing speed will be assessed through part A of the Trail-making Test (See Reitan, 1979).
Timepoint [4] 322049 0
This will be conducted at baseline and at post-intervention follow-up, which will be completed within four weeks of cessation of training. Alternate forms of this test will be administered at baseline and follow-up (counterbalanced) to ensure minimization of practice effects.
Secondary outcome [5] 322311 0
Neuropsychological: Language will be assessed using the Boston Naming Test (See Kaplan et al., 1983)
Timepoint [5] 322311 0
This will be conducted at baseline and at post-intervention follow-up, which will be completed within four weeks of cessation of training.
Secondary outcome [6] 322312 0
Neuropsychological: Language will also be assessed using the Controlled Oral Word Association Test (See Strauss, 2006).
Timepoint [6] 322312 0
This will be conducted at baseline and at post-intervention follow-up, which will be completed within four weeks of cessation of training. Alternate forms of this test will be administered at baseline and follow-up (counterbalanced) to ensure minimization of practice effects.
Secondary outcome [7] 322313 0
Neuropsychological: Visuospatial abilities will be assessed by the Clock Drawing test (see Kitabayashi 2001)
Timepoint [7] 322313 0
This will be conducted at baseline and at post-intervention follow-up, which will be completed within four weeks of cessation of training. Alternate forms of this test will be administered at baseline and follow-up (counterbalanced) to ensure minimization of practice effects.
Secondary outcome [8] 322314 0
Neuropsychological: Executive functioning will be assessed using part B of the Trail-making Test (See Reitan, 1979).
Timepoint [8] 322314 0
This will be conducted at baseline and at post-intervention follow-up, which will be completed within four weeks of cessation of training. Alternate forms of this test will be administered at baseline and follow-up (counterbalanced) to ensure minimization of practice effects.
Secondary outcome [9] 322315 0
Neuropsychological: Executive Functioning will also be assessed using the Colour Word Interference Subtest of the Delis Kaplan Executive Functioning System (See Delis et al., 2001)

In addition, the Mini-Mental State Examination will be administered at baseline for general reporting purposes only.
Timepoint [9] 322315 0
This will be conducted at baseline and at post-intervention follow-up, which will be completed within four weeks of cessation of training.
Secondary outcome [10] 322316 0
Self-Report: To assess mood, the Geriatric Depression Scale will be used (See Yesavage, 1988)
Timepoint [10] 322316 0
This will be conducted at baseline and at post-intervention follow-up, which will be completed within four weeks of cessation of training.
Secondary outcome [11] 322317 0
Self-Report: To assess Sleep, the Pittsburgh Sleep Quality Index will be used (See Buysse et al., 1989)
Timepoint [11] 322317 0
This will be conducted at baseline and at post-intervention follow-up, which will be completed within four weeks of cessation of training.
Secondary outcome [12] 322318 0
Informant Report: With consent from participants, close informants (i.e., carers, family members or close friends) will be asked to complete the Revised Cambridge Behavioural Inventory to assess participant functioning (See Hodges, 2008)
Timepoint [12] 322318 0
This will be conducted at baseline and at post-intervention follow-up, which will be completed within four weeks of cessation of training.
Secondary outcome [13] 322319 0
Informant Report: With consent from participants, close informants (i.e., carers, family members or close friends) will be asked to complete the Bayer Activities of Daily Living Scale to assess participant functioning (See Hindmarch et al., 1998)
Timepoint [13] 322319 0
This will be conducted at baseline and at post-intervention follow-up, which will be completed within four weeks of cessation of training.

Eligibility
Key inclusion criteria
1. Aged 60 years or older;
2. Ability to read, write and communicate in English;
3. Ability to attend two sessions per week for 12 weeks at the training centre;
4. Sufficient physical abilities (motor, eyesight, hearing) to use a computer;
5. Cognitive impairment in memory or other cognitive domain (i.e., 1.5 SD below their
expected level of performance based on normative data), measured within the last 6 months;
6. MCI diagnosis: this will be determined by consensus of three independent clinician raters and will follow Winblad’s criteria.
Minimum age
60 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Bayler-ADL > 3.0
2. MMSE < 24
3. Geriatric Depression Scale > 7
4. Intellectual disability
5. Current diagnosis of:
- Dementia,
- Major Depressive Episode (within the last 6 months),
- Neurological illness (e.g. epilepsy, Parkinson’s Disease),
- Non-affective psychiatric illness (e.g. schizophrenia),
- Loss of consciousness >30-minutes in the past 12 months,
- Stroke,
- Diabetes and/or insulin resistance,
- Renal impairment (defined by serum creatinine-estimated Glomerular Filtration Rate <60mL/min)
- Gastrointestinal disease or food allergies (e.g. coeliac disease, corn starch allergy and/or irritable bowel syndrome).
6. Electroconvulsive Therapy
7. Current/past alcohol or substance dependence (other than nicotine)
8. Use of cholinesterase inhibitors or other cognitive enhancing drugs
9. Current treatment with diuretics, NSAIDS, Probenecid, Cimetidine, aminoglycoside
antibiotics and/or lansopraxolem
10. Clinical history of hepatic disease or chronic or acute renal impairment or failure
11. Presence of abnormal Liver Function Test results: abnormality defined on ANY of the
following as per local laboratory thresholds: albumin, alanine transaminase ALT,
aspartate transaminase AST, alkaline phosphatase ALP, bilirubin, gamma glutamyl
transpeptidase GGT).

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)
Allocation concealment will be conducted by contacting the holder of the allocation schedule located at a central administration site, who will then advise the trial substance dispenser directly whether to dispense treatment A or B. Supplements will be labelled only as A or B such that the trial dispenser, participants and assessors will not know whether they contain the active or inactive supplement.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants are randomly assigned to either cognitive training + creatine or cognitive training + placebo at a ratio based on a computer generated stratified randomisation sequence. Participants will be stratified according to MMSE score. For the purposes of stratification, MMSE scores ranging from 24-27 will be considered low and scores ranging from 28-30 will be considered high. Randomisation will be completed by a Clinical Trial Coordinator who is otherwise not involved with the trial, after screening and baseline assessment have been completed.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering 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
In order to assess the effects of 'computerized cognitive training + creatine' vs 'computerized cognitive training + placebo' at follow-up, we will conduct mixed-modelling repeated-measures (MMRM) analyses using SPSS version 21 (IBM Statistics). This model will include main effects for Group, Time and the main interaction of interest: Group X Time. Each primary and secondary outcome measure will be tested separately. MMRM incorporates a model for missing data values and so avoids discrete imputation or omission of cases. All results are therefore on an ITT basis. Covariates will only be included if there is evidence of systematic differences between the groups at baseline.

Additional analyses: linear regression modelling and Pearson’s correlations will be used to explore predictors of response to training based on baseline performance.

The sample size of 50 was determined based on expected relative effect size of 0.4 with alpha=0.05 and power 0.85.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
13/06/2016
Actual
Date of last participant enrolment
Anticipated
31/12/2017
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 5480 0
Brain and Mind Centre - University of Sydney - Camperdown
Recruitment postcode(s) [1] 12964 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 293179 0
Charities/Societies/Foundations
Name [1] 293179 0
J.O. & J.R. Wicking Trust
Country [1] 293179 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
Brain and Mind Centre, University of Sydney
100 Mallett Street
Camperdown,
NSW, 2050
Country
Australia
Secondary sponsor category [1] 291973 0
None
Name [1] 291973 0
None
Address [1] 291973 0
None
Country [1] 291973 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294658 0
University of Sydney Human Research Ethics Committee
Ethics committee address [1] 294658 0
Ethics committee country [1] 294658 0
Australia
Date submitted for ethics approval [1] 294658 0
24/06/2013
Approval date [1] 294658 0
04/07/2013
Ethics approval number [1] 294658 0
Project No. 2013/407

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

Contacts
Principal investigator
Name 64514 0
Prof Sharon Naismith
Address 64514 0
Healthy Brain Ageing Program
Brain and Mind Centre, University of Sydney
Level 2, 97 Church St,
Camperdown, NSW 2050
Country 64514 0
Australia
Phone 64514 0
+612 9114 4002
Fax 64514 0
+612 9351 0551
Email 64514 0
[email protected]
Contact person for public queries
Name 64515 0
Amelia English
Address 64515 0
Healthy Brain Ageing Program
Brain and Mind Centre, University of Sydney
Level 2, 97 Church St,
Camperdown, NSW 2050
Country 64515 0
Australia
Phone 64515 0
+612 9114 4002
Fax 64515 0
+612 9351 0551
Email 64515 0
[email protected]
Contact person for scientific queries
Name 64516 0
Loren Mowszowski
Address 64516 0
Healthy Brain Ageing Program
Brain and Mind Centre, University of Sydney
Level 2, 97 Church St,
Camperdown, NSW 2050
Country 64516 0
Australia
Phone 64516 0
+612 9114 4002
Fax 64516 0
+612 9351 0551
Email 64516 0
[email protected]

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