Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000767606
Ethics application status
Approved
Date submitted
17/06/2023
Date registered
13/07/2023
Date last updated
3/04/2024
Date data sharing statement initially provided
13/07/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Cognitive impairment in survivors of prostate cancer: combining cognitive and physical activity to target brain fog
Scientific title
Concurrent physical and cognitive training in prostate cancer survivors for cognitive function: a pilot and feasibility study
Secondary ID [1] 309254 0
None
Universal Trial Number (UTN)
U1111-1290-0189
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer related cognitive impairement 329409 0
Condition category
Condition code
Cancer 326355 326355 0 0
Prostate
Mental Health 327338 327338 0 0
Studies of normal psychology, cognitive function and behaviour

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The three training interventions will consist of 2 x 60-minute sessions per week for eight weeks, conducted on non-consecutive days. All training sessions will be supervised.

Arm 1: Concurrent training
For the concurrent physical and cognitive training intervention, participants will cycle on a recumbent cycle ergometer (CXP Target Training Cycle, Matrix Fitness, Australia) for 45 minutes (plus 15-min warm-up/cool-down) at a fixed intensity, relative to their cardiorespiratory fitness (peak oxygen consumption; VO2peak). During the initial week, participants will cycle at a power output corresponding to 65% VO2peak. For all subsequent weeks, the power output will be adjusted to achieve the same heart rate ±5 bpm . This approach will achieve a progressive adaptive overload (increase in the training stimulus as determined by power output) over the training period. While cycling, participants will complete a series of adaptive multi-domain cognitive tasks (including executive functions and working memory) using BrainHQ (Posit Science USA). The touchscreen and/or mouse utilised for responses (task-dependent) will be attached to the stationary bike utilising a customised desk attached immediately above the handlebar. The cognitive training tools from BrainHQ that have been selected:
* Double Decision - Visual processing speed, selective attention
* Target Tracker - Spatial attention
* Mind Bender - Task switching, cognitive flexibility
* Hawk Eye - Visual speed and attention
* Juggle Factor - Visuospatial memory, tracking
* Minds Eye - Visual memory, attention
* Scene Crasher - Visual working memory
* Eye for Detail - Visual processing speed, visual working memory

Arm 2: Physical-only training
For the physical-only training intervention, participants will undergo the same physical training as the concurrent intervention, except for completing the cognitive task. Participants will cycle on a recumbent cycle ergometer (CXP Target Training Cycle, Matrix Fitness, Australia) for 45 minutes (plus 15-min warm-up/cool-down) at a fixed intensity, relative to their cardiorespiratory fitness (peak oxygen consumption; VO2peak). During the initial week, participants will cycle at a power output corresponding to 65% VO2peak. For all subsequent weeks, the power output will be adjusted to achieve the same heart rate ±5 bpm . This approach will achieve a progressive adaptive overload (increase in the training stimulus as determined by power output) over the training period.

Arm 3: Cognitive-only training
For the cognitive-only group, participants will complete the same series of adaptive multi-domain cognitive tasks (including executive functions and working memory) using BrainHQ (Posit Science USA) as the concurrent training group. Participants will be seated at a desk to use the touchscreen and/or mouse utilised for responses (task-dependent). The cognitive training tools from BrainHQ that have been selected:
* Double Decision - Visual processing speed, selective attention
* Target Tracker - Spatial attention
* Mind Bender - Task switching, cognitive flexibility
* Hawk Eye - Visual speed and attention
* Juggle Factor - Visuospatial memory, tracking
* Minds Eye - Visual memory, attention
* Scene Crasher - Visual working memory
* Eye for Detail - Visual processing speed, visual working memory

Those completing the cognitive tasks (cognitive only and concurrent group) will be engaging in tasks that involve the participant:
-Responding to stimuli on the screen as quickly as possible
-Tracking moving objects to assess divided attention
-Challenging mental flexibility by processing changes in rules
-Training their field of view visual precision which translates to how much information they can quickly capture
-Keeping track of a sequence of moving objects and exercising intelligence by manipulating that sequence
-Remembering what they see while ignoring distraction on the screen
-Exercising visual memory by quickly taking in and remembering the details of a scene
-Transitioning information from working memory (ability to hold what you see in mind) long enough to move it to long-term memory for better recall later.

An Accredited Exercise Physiologist (AEP) will fully supervise physical activity assessments given the inherent potential for adverse events in the target population. Specifically, an AEP will monitor all assessments (including ECG surveillance during the aerobic fitness test), acting as an additional screening into the trial. An AEP/exercise scientist will supervise and oversee fidelity measures during the training interventions. Both roles are appropriately trained to monitor and handle adverse events (including first aid trained) with proximity to defibrillators (opposite our lab) and medical support (on-campus) if required. All participants will be recruited to this study under an ethical framework.

In terms of adherence, upon arrival for any type of training session, participants will physically sign and date on and attendance tracking sheet that allows manual tracking of the sessions. This will also be captured digitally through and attendance spreadsheet.
Intervention code [1] 325689 0
Rehabilitation
Comparator / control treatment
Wait-list control: participants in the wait-list control will be asked to maintain their current lifestyles. Participants in this group will be contacted on a fortnightly basis by the research team to discuss both their physical and cognitive activity in that period. Upon completion of the study, participants in this group will be offered to complete one of the interventions.
Control group
Active

Outcomes
Primary outcome [1] 334206 0
Objective cognitive performance Assessment 1
Specific computerised cognitive assessment for visuospatial skills and spatial memory:
* Visual search task (Divided attention) from Millisecond
Timepoint [1] 334206 0
1) Baseline (prior to group allocation).
2) Post- intervention (8-weeks following commencement of the intervention)
Primary outcome [2] 334207 0
Objective cognitive performance Assessment 2
Specific computerised cognitive assessment for visuospatial skills and spatial memory:
*Groton Maze test from Millisecond.
Timepoint [2] 334207 0
1) Baseline (prior to group allocation).
2) Post- intervention (8-weeks following commencement of the intervention)
Primary outcome [3] 334208 0
Objective cognitive performance Assessment 3
Specific computerised cognitive assessment for executive functioning, working memory and inhibition:
*Visual Simon task from Millisecond.
Timepoint [3] 334208 0
1) Baseline (prior to group allocation).
2) Post- intervention (8-weeks following commencement of the intervention)
Secondary outcome [1] 419835 0
*This is an additional primary measure*
Objective cognitive performance Assessment 4
Specific computerised cognitive assessment for executive functioning:
* Category Switch task from Millisecond.
Timepoint [1] 419835 0
1) Baseline (prior to group allocation).
2) Post- intervention (8-weeks following commencement of the intervention)
Secondary outcome [2] 419836 0
*This is an additional primary measure*
Objective cognitive performance Assessment 5
Specific computerised cognitive assessment for attention and response speed.:
*Psychomotor vigilance task (PVT) using Millisecond.
Timepoint [2] 419836 0
1) Baseline (prior to group allocation).
2) Post- intervention (8-weeks following commencement of the intervention)
Secondary outcome [3] 419837 0
*This is an additional primary measure*
Subjective Cognitive Function Assessment
Perceived cognitive functioning will be assessed through the Functional Assessment of Cancer Therapy - Cognitive Function Assessment Version 3.
Timepoint [3] 419837 0
1) Baseline (prior to group allocation).
2) Post- intervention (8-weeks following commencement of the intervention)
Secondary outcome [4] 423727 0

Feasibility and acceptability outcome 1
Adverse events
A possible adverse event is any that:
• is life-threatening (i.e., the subject was at risk of death at the time of the event; it does not refer to an event that hypothetically might have caused death if it were more severe)
• results in death;
• requires hospitalisation;
• results in persistent or significant disability or incapacity;
• results in a musculoskeletal injury/issue;
• is otherwise considered medically significant by the investigator.
Adverse events will be categorised as below in accordance with the Common Terminology Criteria for Adverse Events:
Grade 1 – Mild: asymptomatic or mild symptoms; clinical or diagnostic observation only; intervention not required.
Grade 2 – Moderate: minimal, local or non-invasive intervention indicated; limiting age-appropriate instrumental ADLs.
Grade 3 – Severe: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADLs.
Grade 4 – Life-threatening: Life-threatening consequences; urgent intervention indicated.
Grade 5 – Death: Death related to AE.
Serious adverse events
Serious adverse events will be classified as events graded 3, 4 or 5 as above. In this trial, any other serious adverse events that are related to the intervention are recorded. Events that are serious but are not related to the intervention will not be recorded as serious adverse events. In addition, all deaths (any cause) are also recorded as serious adverse events.

The Investigator will assess whether the serious adverse event is likely to be related to research procedures according to the following definitions:
• Related: resulted from the administration of an intervention session within the protocol
• Unrelated: where an event is not considered to have resulted from any of the research procedures.
Alternative causes such as the natural history of the underlying disease, other risk factors and the temporal relationship of the event to the intervention are considered.

The CI will report any serious adverse events (requiring medical or pharmaceutical intervention or hospital admission) to the University of Canberra Human Research Ethics Committee as per Therapeutic Goods Administration Good Clinical Practice procedures within 24 hours.

Timepoint [4] 423727 0
Weekly for the 8 week study period.
Secondary outcome [5] 423728 0
Feasibility and acceptability outcome 2
Recruitment Success: recruited participant numbers, relative to the number of invited participants and within the recruitment time frame, will be recorded. Specifically, we will assess our study recruitment record spreadsheets to identify success rate.
Timepoint [5] 423728 0
Every 6 months (ie. December of 2023, June 2024, December 2024 and upon completion of the study mid 2025).
Secondary outcome [6] 423729 0
Feasibility and acceptability outcome 3
Compliance:
Compliance metrics (e.g., drop-out, adherence) will be recorded throughout the study. Participants will be permitted to make up a "missed" session in the week that the session is missed if there is time to do so (that is reschedule a session within the same week). Intervention fidelity measures (e.g., heart rate, perceived effort, cycling metrics and cognitive performance metrics) will be recorded during training sessions to inform the feasibility of the desired training stimulus.
An adherence tracking sheet will be implemented whereby participants will 'sign in' upon attendance for any sessions so we can track compliance with the intervention.
Timepoint [6] 423729 0
Weekly for 8 study period. Drop-out rates will be assessed at the conclusion of the study.
Secondary outcome [7] 423730 0
Feasibility and acceptability outcome 4
Acceptability:
Intervention acceptability will be assessed through measures of satisfaction with treatment and compliance metrics, and participants’ attitudes towards the intervention. Specifically, in a study specific acceptability questionnaire, participants will be asked for perceptual responses in regard to the training interventions related to their level of enjoyment, interest, mental fatigue, and willingness to engage in future interventions. We will include an open-ended section that provides space for participants in the study to comment on their preferences for changes to the protocol that would encourage their adherence.
Timepoint [7] 423730 0
At the end of the 8 week study period per participant.
Secondary outcome [8] 423731 0
The Astrand-Rhyming is a single stage sub-maximal exercise assessment test lasting 6 minutes on a cycle ergometer. It was developed to estimate an individual’s maximal oxygen consumption from heart rates at submaximal workloads.
Timepoint [8] 423731 0
Pre and post intervention/ waitlist control period.
Secondary outcome [9] 423732 0
Fatigue Measurement 1
In this trial, the following event is common and anticipated and although is captured in accordance with the Common Terminology Criteria for Adverse Events, it will be reported as a secondary outcome rather than an adverse event or serious adverse event as categorised below:
o Grade 1: Fatigue relieved by rest;
o Grade 2: Fatigue not relieved by rest; limiting instrumental activities of daily living;
o Grade 3: Fatigue not relieved by rest; limiting self-care activities of daily living.

This fatigue measure articulates specifically how participants are coping with the intervention.
Timepoint [9] 423732 0
Before every intervention session using the Graded scale according to the Common Terminology Criteria for Adverse Events.
Secondary outcome [10] 423733 0
Fatigue Measurement 2
The Short-Form 12 (Ware et al., 1996), including the vitality subscale will capture fatigue levels.
This fatigue measure, on the other hand, captures participants general fatigue levels.
Timepoint [10] 423733 0
Pre intervention, mid intervention (Week 4) and post intervention.
Secondary outcome [11] 423735 0
Neurofilament light chains (NfLs)
NfLs are a novel biomarker of neural damage and are thought to relate to neurocognitive decline (Gaetani et al., 2019) and may provide a biomarker for the inverse association between cancers and neurodegenerative diseases (Liu et al., 2020). This will be collected from a plasma sample.
Timepoint [11] 423735 0
Pre-and post-intervention/waitlist control period per participant.
Secondary outcome [12] 424147 0
The following events are also common and expected and will therefore also be reported as secondary outcome measures rather than an adverse or serious adverse event. Furthermore, only notable results will be captured (ie. If they articulate a score above 0 for the following):

Muscle soreness (captured using a Likert scale from 0 being “A complete absence of soreness” to 6 being “A severe pain that limits my ability to move”.
Timepoint [12] 424147 0
At the start of every intervention session throughout the 8 week intervention period (16 time points).
Secondary outcome [13] 424148 0
Pain: This will be captured separate to the muscles soreness to articulate whether the participant is experiencing pain today, if so, where and what would the rating be using a visual analogue scale ranging from 0 implying no pain and 10 being worst possible pain.
Timepoint [13] 424148 0
At the start of every intervention session throughout the 8 week intervention period (16 time points).
Secondary outcome [14] 424149 0
Incontinence will be captured using the Expanded Prostate Cancer Index Composite which requests information around urinary and bowel function.
Timepoint [14] 424149 0
Assessed pre- and post-intervention period.
Secondary outcome [15] 433549 0
*This is an additional primary outcome measure*. Purdue Peg hole Test: This is a standardized, quantitative assessment used to measure finger dexterity and visuospatial capacity. It involves participant placing peg’s into a pegboard as quickly as possible with both their dominant and non-dominant hand separately and simultaneously in 30 seconds.
Timepoint [15] 433549 0
Secondary outcome [16] 433550 0
*This is an additional primary outcome measure*. Purdue Peg hole Test: This is a standardized, quantitative assessment used to measure finger dexterity and visuospatial capacity. It involves participant placing peg’s into a pegboard as quickly as possible with both their dominant and non-dominant hand separately and simultaneously in 30 seconds.
Timepoint [16] 433550 0
1)Baseline (prior to group allocation). 2) Post- intervention (8-weeks following commencement of the intervention).
Secondary outcome [17] 433551 0
Hip and waist circumference will be measured using an anthropometric tape measure as an indication of cardiovascular health in this population.
Timepoint [17] 433551 0
1)Baseline (prior to group allocation). 2) Post- intervention (8-weeks following commencement of the intervention).
Secondary outcome [18] 433552 0
Hip and waist circumference will be measured using an anthropometric tape measure as an indication of cardiovascular health in this population.
Timepoint [18] 433552 0
1) Baseline (prior to group allocation). 2) Post- intervention (8-weeks following commencement of the intervention).
Secondary outcome [19] 433553 0
Central blood pressure and arterial stiffness will be collected using the SphygmoCor XCEL system (SphygmoCor; At-Cor Medical Pty Ltd., Sydney, Australia), which provides a non-invasive measure of these parameters, including pulse wave velocity (ATCOR, 2020). Participants are required to rest supine for 10 minutes prior to the measurements being taken and continue to lie still while investigators use the external SphygmoCor XCEL system at both the carotid and femoral locations. A tonometer, shaped like a small, rounded pen, is placed on the skin over the carotid artery in the neck region to detect the underlying pulse with a leg cuff to capture blood pressure waveforms at the carotid and femoral sites. Physical distance measurements allow SphygmoCor software to perform the velocity and arterial stiffness calculations.
Timepoint [19] 433553 0
1) Baseline (prior to group allocation). 2) Post- intervention (8-weeks following commencement of the intervention).
Secondary outcome [20] 433554 0
Central blood pressure and arterial stiffness will be collected using the SphygmoCor XCEL system (SphygmoCor; At-Cor Medical Pty Ltd., Sydney, Australia), which provides a non-invasive measure of these parameters, including pulse wave velocity (ATCOR, 2020). Participants are required to rest supine for 10 minutes prior to the measurements being taken and continue to lie still while investigators use the external SphygmoCor XCEL system at both the carotid and femoral locations. A tonometer, shaped like a small, rounded pen, is placed on the skin over the carotid artery in the neck region to detect the underlying pulse with a leg cuff to capture blood pressure waveforms at the carotid and femoral sites. Physical distance measurements allow SphygmoCor software to perform the velocity and arterial stiffness calculations.
Timepoint [20] 433554 0
1) Baseline (prior to group allocation). 2) Post- intervention (8-weeks following commencement of the intervention).

Eligibility
Key inclusion criteria
Participants eligible to participate must meet the following inclusion criteria: male >18 years old, diagnosed with prostate cancer currently receiving primary ADT for both metastatic and non-metastatic hormone-sensitive prostate cancer. Further inclusion criteria includes having had at least one dose of ADT in the last six months prior to enrolment; self-assessed reading and writing English proficiency, able to provide written informed consent and who have expected life expectancy of more than 12 months.
-self-assessed reading and writing English proficiency, able to provide written informed consent and who have expected life expectancy of more than 12 months.
Minimum age
18 Years
Maximum age
No limit
Sex
Males
Can healthy volunteers participate?
No
Key exclusion criteria
Based on known interactions with the primary outcome measures, participants will be excluded if they have received chemotherapy or radiation within the last 3 months; they are on steroids equivalent to more than 10 mg of prednisolone a day; opioid-based analgesics within the last 28 days; previous neurological injury; major depression; or are unable to provide written informed consent.

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)
Allocations will be established by a researcher not directly involved in the study. After baseline testing, a sealed, opaque envelope with the group allocation will be delivered to the participant and training staff.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will use a computer-generated sequence of numbers in blocks of variable sizes in a 1:1:1:1 ratio, stratified by age.
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
Quantitative analysis will be conducted in the R statistical package. The mean and standard deviation of the outcome measures at baseline and follow-up will be calculated for each group. Group differences in baseline characteristics will be assessed with one-way ANOVA or Kruskal-Wallis test. Data related to the feasibility of the intervention (e.g., adherence, subjective reporting) will be reported as frequencies. To investigate intervention effects (i.e., cognitive and fatigue outcomes), General Linear Mixed Models with a random intercept fitted for subjects to take into account the repeated measures nature of the data and interindividual variability will be run using the lme4 package. As per our previous work, traditional hypothesis testing from pilot studies should be interpreted with caution as the small sample sizes can result in imprecise estimates and are unlikely to reach statistical significance (Northey et al., 2019). Therefore, we will calculate effect sizes for the pairwise changes in primary outcome measures between the experimental conditions. Effect sizes will be calculated as Cohen's d using the pooled standard deviation of the random effects to account for a Linear Mixed Model structure. Effect sizes will be interpreted as small, moderate, and large based on cut-off points of 0.2, 0.5 and 0.8, respectively. Estimates of sample size against these outcomes will be determined.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
17/07/2023
Actual
25/01/2024
Date of last participant enrolment
Anticipated
30/09/2024
Actual
Date of last data collection
Anticipated
29/11/2024
Actual
Sample size
Target
76
Accrual to date
8
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW
Recruitment hospital [1] 25076 0
The Canberra Hospital - Garran
Recruitment postcode(s) [1] 40741 0
2605 - Garran

Funding & Sponsors
Funding source category [1] 313443 0
Charities/Societies/Foundations
Name [1] 313443 0
World Cancer Research Fund
Country [1] 313443 0
United Kingdom
Funding source category [2] 313444 0
University
Name [2] 313444 0
University of Canberra
Country [2] 313444 0
Australia
Primary sponsor type
University
Name
University of Canberra
Address
11 Kirinari St, Bruce ACT 2617
Country
Australia
Secondary sponsor category [1] 315218 0
None
Name [1] 315218 0
Address [1] 315218 0
Country [1] 315218 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312650 0
University of Canberra Human Research Ethics Committee
Ethics committee address [1] 312650 0
11 Kirinari St, Bruce ACT 2617
Ethics committee country [1] 312650 0
Australia
Date submitted for ethics approval [1] 312650 0
08/11/2022
Approval date [1] 312650 0
10/03/2023
Ethics approval number [1] 312650 0
11955

Summary
Brief summary
This study is assessing a combined physical and cognitive intervention to improve the quality of life of men affected by prostate cancer receiving androgen deprivation therapy (ADT).

Who is it for?
You may be eligible for this study if you are are an adult male who has been diagnosed with prostate cancer currently receiving primary ADT for metastatic and nonmetastatic hormone-sensitive prostate cancer. Additionally, you commenced ADT at least six months prior to enrolment and are expected to receive for another 6 months.

Study details
Participants will be randomly allocated to one of four arms. Arm 1 will involve concurrent physical training (performed on a stationary bike) and cognitive training, Arm 2 will involve physical training only and Arm 3 will involve cognitive training only. These 3 treatment arms will be delivered as 2 x 60-minute sessions per week over 8 weeks. Arm 4 will be a waitlist control group, where participants will be able to select one of the treatment arms to participate in upon conclusion of the study period. All participants will be asked to complete questionnaires assessing their physical and cognitive performance at the start and end of the trial.

It is hoped that results from this study will help develop better treatment guidelines for brain fog and fatigue for men undergoing treatment for prostate cancer.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 125422 0
Prof Ben Rattray
Address 125422 0
University of Canberra, 11 Kirinari St, Bruce, ACT 2617
Country 125422 0
Australia
Phone 125422 0
+61 262015145
Fax 125422 0
Email 125422 0
ben.rattray@canberra.edu.au
Contact person for public queries
Name 125423 0
Prof Ben Rattray
Address 125423 0
University of Canberra, 11 Kirinari St, Bruce, ACT 2617
Country 125423 0
Australia
Phone 125423 0
+61 262015145
Fax 125423 0
Email 125423 0
ben.rattray@canberra.edu.au
Contact person for scientific queries
Name 125424 0
Prof Ben Rattray
Address 125424 0
University of Canberra, 11 Kirinari St, Bruce, ACT 2617
Country 125424 0
Australia
Phone 125424 0
+61 262015145
Fax 125424 0
Email 125424 0
ben.rattray@canberra.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data related to the primary and secondary outcomes, after deidentification.
When will data be available (start and end dates)?
Up to 15 years following the completion of the trial
Available to whom?
Proposals should be directed to the chief investigator. Data requestors must sign a data access agreement to gain access.
Available for what types of analyses?
Individual patient meta-analysis
How or where can data be obtained?
Proposals should be directed to the chief investigator via email on ben.rattray@canberra.edu.au.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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