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Trial registered on ANZCTR


Registration number
ACTRN12616000487415
Ethics application status
Approved
Date submitted
6/04/2016
Date registered
13/04/2016
Date last updated
21/09/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
The influence of modafinil on the post-exercise exacerbation of symptoms in patients with chronic fatigue syndrome
Scientific title
Double-blinded placebo-controlled study of modafinil to relieve the post-exertional exacerbation of fatigue in patients with chronic fatigue syndrome undertaking exercise.
Secondary ID [1] 288898 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
chronic fatigue syndrome 298234 0
Condition category
Condition code
Other 298369 298369 0 0
Conditions of unknown or disputed aetiology (such as chronic fatigue syndrome/myalgic encephalomyelitis)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A post-exertional exacerbation of fatigue (and other symptoms) is a characteristic feature of chronic fatigue syndrome (CFS) following a relatively small amount of physical or cognitive activity. We aim to explore how this post-exertional exacerbation of fatigue following a continuous exercise bout differs with modafinil treatment. The exercise bout will consist of moderate-intensity cycling for generally 20 minutes and each participants’ reaction to the exercise bout will be recorded by monitoring worsened fatigue and accompanying symptoms when undertaken in conjunction with modafinil or placebo.

After an overnight fast and abstaining from caffeine 12 hours before each test the participants will report to the laboratory and ingest opaque gelatin capsules containing either placebo or 400mg modafinil. Following the capsule ingestion participants will be given an identical meal (e.g. muffin and orange juice) and two hours following they will complete the exercise test.

Assessment of symptoms and function will be conducted via self-report questionnaires conducted twice daily (morning and afternoon) 48 hours prior to exercise and for 96 hours following the exercise. Additionally symptoms and function will be assessed immediately prior to exercise (pre-0), and immediately following exercise (post-0). Actigraphy will be recorded for the 24 hours before and 24 hours following the exercise challenge. Algometry (pressure pain threshold) will be assessed immediately before and immediately after the exercise tests.

Each participant will be asked to complete two exercise sessions (one with modafinil and one with placebo) separated by at least two weeks (or until the subject feels their exacerbated symptoms have returned to ‘baseline’). Participants will undertake 20 minutes of moderate intensity stationary-cycling exercise, preceded by a 5-minute warm-up (at low intensity approx. 40 Watts) and followed by a 2-minute cool down period (at low intensity approx. 40 Watts). In the event of recruiting people of lower capacity for whom the 20 minute exercise dose would result in too great an exacerbation in symptoms, a shorter duration of exercise, as low as 10mins, will be applied. This group will also complete an abbreviated warm up e.g. 2.5 - 4 minutes.

Workload will be adjusted to require 70% of the individual’s age-predicted heart rate maximum (APHRM) for the high capacity group. Intensity will be determined using a standard equation for predicting maximal heart rate (= 208 – 0.7 x age) (Tanaka, Monahan et al. 2001). Resistance will be incrementally augmented during the first 5 minutes of exercise until the target heart rate is reached. The workload will then remain relatively constant throughout the duration of the bout, with minor adjustments to the applied resistance to continually keep the actual heart rate within 3 beats per minute of the target heart rate. The duration of each exercise bout will vary depending based on each participant being able to regularly undertake 10-20 minutes walking at a gentle pace without producing a post-exertional exacerbation of symptoms (as per inclusion criteria).

The total and average work from the first exercise bout will be calculated. The second exercise bout will be conducted will be conducted with the same target heart rate along with information on the anticipated workload. With the goal being to match both total workload and mean heart rate between the exercise bouts.

These data will provide preliminary information regarding the possible use of modafinil to augment the existing standard of care for patients with CFS (i.e. cognitive behavioural therapy and graded exercise therapy). Hence, this is a physiological investigation of the response to exercise in conjunction with medication to identify possible avenues for future
Intervention code [1] 294355 0
Treatment: Drugs
Comparator / control treatment
Placebo tablets (lactose)
Control group
Placebo

Outcomes
Primary outcome [1] 297841 0
The rating of perceived exertion (RPE) (6 - 20).
Timepoint [1] 297841 0
The RPE will be measured at the end of the warm-up and at 4 times during the exercise (e.g. 5, 10, 15, 20 minutes) and at the end of the cool-down phase.
Primary outcome [2] 297860 0
Fatigue and Energy Scale (FES) global score (0 - 10)
Timepoint [2] 297860 0
The fatigue (FES) change score will be calculated from five reports before each exercise challenge (baseline) and five reports following an exercise challenge; with the latter being five consecutive time points that best captured the exacerbation of symptoms for each individual (24-96 hours post-exercise). To capture the latter time points a moving average (with a window of five time points) is calculated and the window with the highest average is used. The start of the window is initially at the time point immediately post-exercise and is incremented up to two-days post exercise, such that the window ends from as early as 2 days post exercise to as late as 4 days after exercise. This analysis procedure accommodates the different onset of symptom exacerbation between patients whilst also capturing the period of greatest symptom change for a clinically meaningful period.
Secondary outcome [1] 322411 0
Objectively measured physical activity levels (Equivital chest monitor),
Timepoint [1] 322411 0
Continuous monitoring for 24 hours prior to and following each exercise bout
Secondary outcome [2] 322470 0
Sleep self report questionnaire (PSQI -Pittsburgh Sleep Quality Index)
Timepoint [2] 322470 0
Two nights before and two nights after each exercise bout.
Secondary outcome [3] 322471 0
Heart rate response to exercise using Polar heart rate monitor worn during exercise around the chest.
Timepoint [3] 322471 0
The heart rate measurement is recorded only for the active exercise period e.g. 20 minutes and excluding the warm-up and cool-down. For the majority of participants a 20 minute bout will be used where the recording will be made following the 5 minute warm-up until the end of the 20 minutes of the active exercise bout. For any participants performing less than 20 minutes of active exercise, the workload will still be calculated for the period after warm-up before cool-down.
Secondary outcome [4] 322472 0
Workload data are recorded using the Monark 839E cycle ergometer and accompanying software (Monark Exercise AB, Vansbro, Sweden) and analysed in a spreadsheet. The Watts are sampled every second and these are converted to Joules and summed.
Timepoint [4] 322472 0
The workload outcome measurement is recorded only for the active exercise period e.g. 20 minutes and excluding the warm-up and cool-down. For the majority of participants a 20 minute bout will be used where the recording will be made following the 5 minute warm-up until the end of the 20 minutes of the active exercise bout. For any participants performing less than 20 minutes of active exercise, the workload will still be calculated for the period after warm up before cool-down.
Secondary outcome [5] 322473 0
Pressure pain threshold (algometry) of exercise and unexercised limbs
Timepoint [5] 322473 0
Immediately before and after each exercise bout

Eligibility
Key inclusion criteria
i) meeting international diagnostic criteria for chronic fatigue syndrome (Fukuda, 1994)
ii) have their treating exercise physiologist and clinical psychologist resolve that they have a stable pattern of symptom severity, as well as having optimized and stable sleep patterns and well-managed mood disturbance
iii) undertaking regular of 10-20 minutes walking at a gentle pace without producing a post-exertional exacerbation of symptoms (that is an hour or more of worsened fatigue and other symptoms).
Minimum age
18 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
i) currently use beta-blockers or other agents known to affect heart rate response to exercise; or
ii) have any medical (e.g. lower limb injury) condition which may preclude reliable participation in exercise testing
iii) currently use central nervous system medications (e.g. Benzodiazepines and other sedative-hyponotics (e.g. stilnox), anti-epileptics, high-dose antidepressants (low-dose allowed),
iv) are pregnant or breastfeeding
v) have hepatic impairment
vi) are hypersensitive to modafinil
vii) have a history of left ventricular hypertrophy or ischaemic heart disease, or other clinically significant cardiac disease;
viii) uncontrolled anxiety disorder,
ix) have previously taken modafinil and experienced an adverse reaction.
x) taking anti-hypertensives/beta blockers
xi) taking corticosteroids
xii) taking major analgesics (e.g. oxycodone)

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)
This is a randomised cross-over study - each participant will receive modafinil and placebo, but the order of these will be randomised and concealed (by numbered containers) to the participant and study coordinator.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
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
The random order in which the capsules are administered was counter balanced between drug and placebo
Phase
Phase 3 / Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
The effects of modafinil will be monitored via two key variables: 1) the rating of perceived exertion (RPE) during the exercise bout, and 2) the post-exertional exacerbation of fatigue that is measured across several days with the Fatigue and Energy Scale (FES).

A previous study (Jacobs and Bell, 2004) examining the effects of acute modafinl ingestion (4mg/kg ~300 mg) on exercise time to exhaustion showed a statistically significant difference (P < 0.05) of 0.6 (SD 1.9) in the rate of perceived exertion (RPE) score (1 – 10 scale) between placebo and modafinil with a sample of 15 subjects. A study by our research group detected a statistically significant difference (P < 0.05) in RPE (6 – 20 scale) of 3.8 (SD 1.7) between people with CFS and age-matched healthy controls during the 20 minute cycling protocol using 10 subjects in each group. Using a single dose of modafinil (400 mg) and 20 participants we will be able to detect a difference of 1 point or more (SD 1.5) in RPE (6 – 20 scale) during exercise (80% power, alpha of 0.05, paired sample t-test, drug versus placebo). This difference corresponds to that previously demonstrated in healthy volunteers taking modafinil and represents a change of potential clinical significance for patients with CFS.

With regard to the post-exertional exacerbation of fatigue a sample of 20 participants would be sufficient to detect a difference in FES global change score (from baseline to post exercise) of 1.0 (10 point scale, anticipated standard deviation of 1.5) between the modafinil and placebo conditions (80% power, alpha of 0.05, paired sample t-test, drug versus placebo). Two previous studies by the research group reliably detected a change in the FES score from baseline to between 24 and 72 hours post exercise using the same 20-minute cycling protocol to be used in the current study (e.g. study 1: Keech et al. 2015, 10 patients with CFS, mean FES change: 1.7 (SD 1.6); study 2: Sandler et al. 2016, 14 patients with CFS, mean FES change: 1.5 (SD 0.7). Hence, a sample of 20 participants will be sufficient to detect a clinically meaningful change in the post-exertional exacerbation of fatigue and the RPE during the exercise bout.

Data will be analysed using the Statistical Package for Social Sciences (SPSS) Version 22. Paired sample t-tests will be conducted to compare baseline levels of fatigue, symptoms and function before each exercise bout. Differences between and within exercise bouts will be examined using paired sample t-tests. The fatigue (FES) change score will be calculated from five reports before each exercise challenge and five reports following an exercise challenge; with the latter being five consecutive time points that best capture the exacerbation of symptoms for each individual. A Pearson correlation test between the differences in FES change scores between drug and placebo and the difference in RPE between drug and placebo will be performed. Alpha is set at P < 0.05.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
18/04/2016
Actual
19/04/2017
Date of last participant enrolment
Anticipated
22/12/2017
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
20
Accrual to date
16
Final
Recruitment in Australia
Recruitment state(s)
NSW

Funding & Sponsors
Funding source category [1] 293252 0
Charities/Societies/Foundations
Name [1] 293252 0
Judith Jane Mason and Harold Stannett Williams Memorial Foundation
Country [1] 293252 0
Australia
Primary sponsor type
University
Name
University of New South Wales
Address
University of New South Wales, Sydney, NSW 2052 Australia
Country
Australia
Secondary sponsor category [1] 292106 0
None
Name [1] 292106 0
Address [1] 292106 0
Country [1] 292106 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294730 0
University of NSW Human Research Ethics Commitee
Ethics committee address [1] 294730 0
UNSW Research Ethics & Compliance Support
The University of New South Wales
Sydney NSW 2052 Australia
Ethics committee country [1] 294730 0
Australia
Date submitted for ethics approval [1] 294730 0
26/11/2013
Approval date [1] 294730 0
04/02/2014
Ethics approval number [1] 294730 0
HC13367

Summary
Brief summary
A post-exertional exacerbation of fatigue and other symptoms is a characteristic feature of chronic fatigue syndrome (CFS) following a relatively small amount of physical or cognitive activity. Although it is well established that graded exercise therapy (GET) is beneficial for the management of CFS, this intervention, which uses cautious, symptom-limited increases in gentle aerobic exercise, has only modest effectiveness. The key limiting factor is the delayed exacerbation of symptoms that follows exercise. This post-exertional exacerbation has been well characterized in exercise challenge studies.

Modafinil, a psycho-stimulant drug, has been licensed in Australia and internationally and used clinically for some time. Additionally, it has demonstrated some benefit in reducing fatigue in multiple sclerosis, and daytime sleepiness in Parkinson’s disease. In healthy subjects, the effect of a single dose of modafinil on exercise time has been examined and showed a prolonged time to exhaustion of 22% for high intensity exercise (Jacobs and Bell, 2004). Interestingly, the rate of perceived exertion (RPE) reported by participants was statistically significantly lower in the modafinil exercise trial compared to the placebo exercise trial.

Since the symptom of fatigue is the limiting factor in the progression of GET, it is appealing to test the possibility that modafinil may attenuate the exacerbation of fatigue following exercise for patients with CFS. This opens up the possibility of greater progression in GET and, therefore, potentially further increases in physical function. However, before a training study is undertaken a systematic evaluation of the acute response of the post-exertional exacerbation of fatigue and symptoms following modafinil is warranted.

It is hypothesized that for modafinil compared to placebo, patients will report a lower RPE during exercise and less post-exertional exacerbation of fatigue. The protocol will involve two sessions of a six-day assessment period, each including a 48 hour pre-exercise baseline assessment and 96 hour post-exercise assessment. Each participant (n=20) will be asked to complete two exercise sessions (one with modafinil and one with placebo) separated by at least two weeks. The order of the treatment trial (placebo or modafinil) will be randomised and counter-balanced as well as double-blinded. The exercise bout will consist of moderate-intensity cycling for generally 20 minutes.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 64834 0
Ms Carolina Sandler
Address 64834 0
School of Medical Sciences
UNSW Medicine
Wallace Wurth Building, High Street
UNSW AUSTRALIA NSW 2052
Country 64834 0
Australia
Phone 64834 0
+61293858709
Fax 64834 0
Email 64834 0
[email protected]
Contact person for public queries
Name 64835 0
Matthew Jones
Address 64835 0
School of Medical Sciences
UNSW Medicine
Wallace Wurth Building, High Street
UNSW AUSTRALIA NSW 2052
Country 64835 0
Australia
Phone 64835 0
+61293858272
Fax 64835 0
Email 64835 0
[email protected]
Contact person for scientific queries
Name 64836 0
Carolina Sandler
Address 64836 0
School of Medical Sciences
UNSW Medicine
Wallace Wurth Building, High Street
UNSW AUSTRALIA NSW 2052
Country 64836 0
Australia
Phone 64836 0
+61293858709
Fax 64836 0
Email 64836 0
[email protected]

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