Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618001534279
Ethics application status
Approved
Date submitted
31/08/2018
Date registered
13/09/2018
Date last updated
2/03/2021
Date data sharing statement initially provided
19/09/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Aspirin, Cooling and Exercise in Multiple Sclerosis
Scientific title
The influence of aspirin and skin cooling on exercise capacity and postural sway in the heat in individuals with multiple sclerosis
Secondary ID [1] 295966 0
NIL
Universal Trial Number (UTN)
U1111-1219-7679
Trial acronym
ACEMS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Sclerosis 309476 0
Condition category
Condition code
Neurological 308309 308309 0 0
Multiple sclerosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Research Questions
The primary research questions guiding this project are:

1) Does oral ingestion of aspirin (650 mg in capsule form) 1 hour prior to exercise improve exercise capacity and reduce postural sway in the heat in a MS population?
2) Does spraying the skin with cold water during exercise improve exercise capacity and reduce postural sway in the heat in a MS population?

Research hypotheses:
The research hypotheses going into this study are:

1) Oral ingestion of aspirin (650 mg in capsule form) 1 hour prior to exercise will not improve exercise capacity or reduce postural sway in the heat in a MS population.
2) Spraying the skin with cold water during exercise will improve exercise capacity and reduce postural sway in the heat in a MS population.

Exercise and balance protocol (assessing exercise capacity and postural sway)
The exercise and balance protocol that will be used to test the participants exercise capacity and postural sway in the 3 familiarisation sessions and the 4 experimental trials (separated by at least 10 days for aspirin washout and delivered face-to-face by an Accredited Exercise Physiologist over a total time frame of approx. 2 months) is as follows:
1. 15-minute rest for baseline measures (experimental sessions only) and 15-minute postural sway testing on a low profile pressure-sensing mat
2. 20-minute pre-load cycling on an electronically braked semi-recumbent cycle ergometer at 50% pred. HRR
3. 20 minutes for rest and postural sway testing on a low profile pressure-sensing mat
4. 10-minute cycling time trial on an electronically braked semi-recumbent cycle ergometer
5. 20 minutes for postural sway testing on a low profile pressure-sensing mat and recovery

Experimental trials
The study will consist of four experimental trials which will take place in the climatic chamber with conditions set at 35ºC/40RH with participants completing the exercise and balance protocol (see details above) with:

1. Control - no intervention
2. Skin cooling using ~11mL of ~18 degree Celsius water sprayed onto the skin of the face, neck and arms every 5 minutes throughout the exercise protocol (COOL)
3. Oral ingestion of 650mg aspirin 1 hour prior to the exercise protocol (ASP)
4. Oral ingestion of one dose of 650mg non-active microcrystalline cellulose 1 hour prior to the exercise protocol (PLA)
Intervention code [1] 312292 0
Treatment: Other
Intervention code [2] 312293 0
Treatment: Drugs
Comparator / control treatment
This study remains a randomized, double blind, counterbalanced crossover, placebo-controlled clinical trial assessing the acute, independent influence of aspirin and cold water spray on exercise capacity and postural sway in the heat.
Control group
Placebo

Outcomes
Primary outcome [1] 307283 0
Composite primary outcome of exercise capacity measured via total work in a 10 minute cycling time trial on a semi-recumbent cycle ergometer.
Timepoint [1] 307283 0
Every one second through the 10-min time trial in each familiarisation session and each experimental trial
Primary outcome [2] 307284 0
Postural sway : Participants' postural sway will be assessed pre-trial, post pre-load and post time-trial. They will be asked to stand feet shoulder width apart which will be determined by the low-profile pressure-sensing mat (Tekscan, Inc.,Boston, MA) with eyes open (3 x 30 sec) and closed (3 x 30 sec) - together making up the composite primary outcome of "Postural Sway".
Timepoint [2] 307284 0
Pre-exercise protocol, post exercise pre-load and post-time trial
Primary outcome [3] 307285 0
Telemetric temperature sensor (pill): The core temperature sensor/pill will be used to assess gastrointestinal temperature. The sensor/pill will be swallowed the night prior to arriving at the laboratory so that the sensor/pill has progressed past the stomach by the time the experimental session begins.
Timepoint [3] 307285 0
Every 5 minutes throughout the 1 h 40 min experimental trials.
Secondary outcome [1] 351372 0
Skin temperature sensors: Four skin temperature sensors will be taped to the skin surface with hypoallergenic tape at the shoulder, chest, thigh and calf. These sensors give an indication of skin temperature and heat loss from the skin surface. Some hair may need to be shaved (by the use of disposable razors) in order to secure the sensors adequately to the skin surface. Using these four sites mean skin temperature will be estimated using a 4-point weighted mean making up the composite secondary outcome of "skin temperature". Skin temperature is the only outcome here.
Timepoint [1] 351372 0
Every 5 minutes throughout the 1 h 40 min experimental trials.
Secondary outcome [2] 351373 0
Heart rate: Heart rate will be recorded using a wireless 6 lead stress ECG system (Cosmed, Rome, Italy) for the composite secondary outcome of "heart rate".
Timepoint [2] 351373 0
Every 5 minutes throughout the 1 hr 25 min familiarisation sessions and 1 h 40 min experimental trials.
Secondary outcome [3] 351374 0
Blood Pressure: An automated blood pressure monitor will be strapped to the participants’ arm throughout the experimental trials and taken every five minutes during exercise using a Suntech Tango Monitoring system (Suntech Medical, Inc. USA).
Timepoint [3] 351374 0
Every 5 minutes throughout the 1 h 40 min experimental trials.
Secondary outcome [4] 351375 0
Heat-related fatigue symptoms: Participants will be asked to define their 3 most common heat-related fatigue symptoms (e.g. weakness, muscle stiffness) prior to their first experimental trial. They will then be asked, every 5-min, to rate their symptom sensations on a 100mm visual analogue scale that ranks from 0 (no symptom sensations whatsoever) to 10 (worst symptom sensation they have ever felt).
Timepoint [4] 351375 0
Every 5 minutes throughout the 1 hr 25 min familiarisation sessions and 1 h 40 min experimental trials and participants will be contacted at 6, 24 and 48 hours post familiarisation session and experimental trial and asked to rate these same symptoms and if any other symptoms have presented on the same 1-10 scale.
Secondary outcome [5] 351376 0
Rating of Perceived Exertion (RPE): Participants will be asked, every 5-min, to rate their perceived level of exertion on a 200mm visual analogue scale that ranks exertion on the Borg scale: from 6 (very very light) to 20 (very very hard).
Timepoint [5] 351376 0
Every 5 minutes throughout the 1 hr 25 min familiarisation sessions and 1 h 40 min experimental trials.
Secondary outcome [6] 351377 0
Whole-body thermal sensation (WBTS): During the trial participants will be asked, every 5-min, to rate their whole body thermal sensation on a 100mm visual analogue scale with 7 anchor points; 0 cm: cold, 16.7cm: cool, 33.3 cm: slightly cool, 50 cm: neutral, 66.7 com: slightly warm, 83.3 cm warm and 100 cm: hot.
Timepoint [6] 351377 0
Every 5 minutes throughout the 1 hr 25 min familiarisation sessions and 1 h 40 min experimental trials.
Secondary outcome [7] 351378 0
Whole-body sweat loss (WBSL): The participant will be weighed on a platform scale immediately before the start of exercise and immediately after exercise has stopped to measure whole-body sweat loss.
Timepoint [7] 351378 0
Pre and post-experimental trials.

Eligibility
Key inclusion criteria
1. Expanded Disability Severity score (EDSS) score between 0 (reflecting no disability or decrement to functional systems) and 5 (reflecting the ability to walk without an aid for 200 meters and mild impairment to functional systems).
2. Between the ages of 18-60 years.
3. Have clinically or laboratory-supported definite MS (clinically diagnosed MS by a neurologist experienced in the treatment of the disease using updated diagnostic criteria).
4. Able to understand the demands of the protocol, has had any questions answered and has voluntarily signed the participant consent form prior to any study procedures.
5. In otherwise good health, based on complete medical history and neurological/physical examination (completed Neurologist/General Practitioner Clearance form).
6. Self-reported sensitivities to the heat.
Minimum age
18 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Pregnant subjects (as determined by a urine pregnancy test)
2. Subjects with hypertension, cardiovascular, respiratory, and/or metabolic disorders.
3. Current smokers, as well as individuals who regularly smoked within the past 2 years.
4. Subjects with MS that experienced an exacerbation/relapse (within the past 3 months)
5. On study exacerbation/relapse
6. EDSS >5
7. Seizures
8. Peripheral neuropathy in the legs
9. Arthritis in the legs
10. Mood disorder (e.g. depression, bipolar, psychosis)
11. Allergy to aspirin
12. Peptic ulcer (ulcer in stomach/small intestine) or gastrointestinal bleeding
13. Anaemia (low red blood cell count)
14. Thrombocytopenia (low platelet count)
15. Bleeding diathesis e.g. haemophilia (decreased clotting)
16. Hepatic (liver) disease
17. Renal (kidney) disease
18. Hypothyroidism
19. Stroke
20. Recent major illness
21. Knee or Hip replacement if it causes any issues during exercise
22. Broken bone(s) in the last 5 years if it causes any issues during exercise
23. Any other condition if it causes any self-reported issues during exercise
24. Currently taking Tecfidera
25. Previous Lemtrada infusion
26. Currently has varicella-zoster (chickenpox) virus
27. Currently has Herpes-zoster (shingles)
28. Currently prescribed ongoing non-steroidal anti-inflammatory drug (NSAID) treatment

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 allocation of participants to the counterbalanced crossover order will be randomised and concealed from all those involved in the project. A person external to the thermal ergonomics laboratory and the research project will code the interventions and run a randomisation sequence for the counterbalanced crossover orders using a random number generator. When a new participant has given their consent this person external to the laboratory will be called and will assign the participant to a crossover order as per the randomisation sequence.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation sequence.
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
Crossover
Other design features
Randomized, double-blind, crossover, placebo-controlled clinical trial.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Control measures

Nutrition (24-h pre-carbohydrate intake), night before sleep quality and USG. Assessed using a one-way repeated measures analyses of variance (ANOVA) employing the independent variable of “condition” (4 levels: CON, COOL, ASP, PLA).

Total work in the 10-min time trial in the familiarisation sessions. Assessed using a one-way repeated measures ANOVA employing the independent variable of “condition” (3 levels: FAM2, FAM2 and FAM3). Coefficient of variation (CV) in total work between each familiarisation will also be calculated and reported.

Primary outcomes

1. Exercise capacity
1.1 Total work in the 10-min time trial in the experimental trials. Assessed using a one-way repeated measures ANOVA with the independent variables of condition (4 levels: CON, COOL, ASP and PLA). Total work in the 10-min time trial will also be assessed using two-tailed paired t-tests (1. CON vs COOL; 2. ASP vs PLA; 3. CON vs PLA; 4. CON vs familiarisation 3 (FAM3); 5. PLA vs FAM3). 3

1.2 Pacing (work per 2-min time block expressed as a percentage of block pace in FAM3) (5 levels: 2, 4, 6, 8 and 10 min of the 10 minute time-trial). Analysed using a two-way repeated measures ANOVA with the repeated factors of; CON, COOL, ASP, PLA.

2. Postural sway
Eyes open (3 levels: pre-trial, post pre-load, post time-trial), Eyes closed (3 levels: pre-trial, post pre-load, post time-trial). Analysed using a two-way repeated measures ANOVA with the repeated factors of FAM 3, CON, COOL, ASP, PLA.

3. Tcore (5 levels: 0, 5, 10, 15 and 20 min of the pre-load) and (4 levels: 0, 5, 10 and recovery). Analysed using a two-way repeated measures ANOVA with the repeated factors of CON, COOL, ASP, PLA.

Secondary outcomes

Tsk, HR, BP, HFS, RPE and WBTS (5 levels: 0, 5, 10, 15 and 20 min of the pre-load) and (4 levels: 0, 5, 10 and recovery). Post HFS (3 levels: 6, 24 and 48 hours post trial). Analysed using a two-way repeated measures ANOVA with the repeated factors of CON, COOL, ASP, PLA.
WBSL. Analysed using a one-way repeated measures ANOVA with the independent variables of condition ( 4 levels: CON, COOL, ASP, and PLA).

All analyses will include a Mauchly's test for sphericity and apply a Greenhouse-Geisser correction factor if required. If a significant main effect or interaction is observed, post-hoc comparisons will be conducted using a Sidak multiple comparisons test. A critical alpha level error of 0.05 will be maintained throughout. All data will be presented as mean ± standard deviation (SD). Statistical analyses will be conducted using GraphPad Prism “Latest Version” for Windows (Graphpad Software, La Jolla, CA, USA).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/04/2021
Actual
Date of last participant enrolment
Anticipated
1/04/2022
Actual
Date of last data collection
Anticipated
1/04/2022
Actual
Sample size
Target
16
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 11755 0
Brain and Mind Centre - University of Sydney - Camperdown
Recruitment hospital [2] 11756 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 23841 0
2050 - Camperdown
Recruitment postcode(s) [2] 23842 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 300562 0
Charities/Societies/Foundations
Name [1] 300562 0
MS Research Australia
Country [1] 300562 0
Australia
Primary sponsor type
Individual
Name
Ollie jay
Address
The University of Sydney
Faculty of Health Sciences
75 East St, Lidcombe, NSW 2141
Country
Australia
Secondary sponsor category [1] 300046 0
Individual
Name [1] 300046 0
Timothy English
Address [1] 300046 0
The University of Sydney
Faculty of Health Sciences
75 East St, Lidcombe, NSW 2141
Country [1] 300046 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301354 0
The University of Sydney Human Research Ethics Committee
Ethics committee address [1] 301354 0
Ethics committee country [1] 301354 0
Australia
Date submitted for ethics approval [1] 301354 0
27/08/2018
Approval date [1] 301354 0
06/05/2019
Ethics approval number [1] 301354 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 3071 3071 0 0
/AnzctrAttachments/375915-ACEMS_study_ethics_rationale.docx (Supplementary information)

Contacts
Principal investigator
Name 86718 0
A/Prof Ollie Jay
Address 86718 0
The University of Sydney
Faculty of Health Sciences
75 East St, Lidcombe, NSW 2141
Country 86718 0
Australia
Phone 86718 0
+61 2 935 19328
Fax 86718 0
+61 2 9351 9204
Email 86718 0
[email protected]
Contact person for public queries
Name 86719 0
Ollie Jay
Address 86719 0
The University of Sydney
Faculty of Health Sciences
75 East St, Lidcombe, NSW 2141
Country 86719 0
Australia
Phone 86719 0
+61 2 935 19328
Fax 86719 0
+61 2 9351 9204
Email 86719 0
[email protected]
Contact person for scientific queries
Name 86720 0
Ollie Jay
Address 86720 0
The University of Sydney
Faculty of Health Sciences
75 East St, Lidcombe, NSW 2141
Country 86720 0
Australia
Phone 86720 0
+61 2 935 19328
Fax 86720 0
+61 2 9351 9204
Email 86720 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Deindentified individual participant data for the three primary outcomes will be shared, i.e. exercise capacity (total work and pacing in the 10-min time trial), postural sway (eyes open and closed) and core temperature (absolute and change).
When will data be available (start and end dates)?
These data will be available when the manuscript is published - estimated June 2021 and will be available ongoing.
Available to whom?
These data will be made available to anyone wishing to access them.
Available for what types of analyses?
These data will be available for any purpose or analyses.
How or where can data be obtained?
A link to the data will be provided in the manuscript or as an appendix depending on the journal's requirements.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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