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Trial registered on ANZCTR


Registration number
ACTRN12618000602224
Ethics application status
Approved
Date submitted
28/03/2018
Date registered
18/04/2018
Date last updated
29/07/2019
Date data sharing statement initially provided
29/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Modafinil In Debilitating Fatigue After Stroke 2
(MIDAS 2)
Scientific title
A Phase III, Multicentre, Prospective, Randomised, Placebo-controlled, Double-blind,
Parallel group study to evaluate the effect of Modafinil on Debilitating Fatigue in Stroke Survivors
Secondary ID [1] 294462 0
Nil
Universal Trial Number (UTN)
Trial acronym
MIDAS 2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Post Stroke Fatigue 307219 0
Condition category
Condition code
Stroke 306333 306333 0 0
Haemorrhagic
Stroke 306480 306480 0 0
Ischaemic

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Study Drug: Modafinil
Dose: 200mg taken once a day for 56 days followed by open-label non-randomised
observational phase for 10 months.
Route: oral tablet
Time of administration; Modafinil is ideally to be taken with breakfast.
Treatment adherence will be monitored by drug tablet return.
Intervention code [1] 300756 0
Treatment: Drugs
Comparator / control treatment
Placebo: Physically identical to Modafinil (Microcrystalline Cellulose)
Dose: taken once a day for at least 56 days.
Route: oral tablet
Time of administration; ideally to be taken with breakfast
Treatment adherence will be monitored by drug tablet return.
Control group
Placebo

Outcomes
Primary outcome [1] 305344 0
Change in the Quality of life of participants on Modanifil compared to placebo assessed by an increase of 10 or more points on the self-reported quality of life using the 36-item Short Form Survey (SF-36).
Timepoint [1] 305344 0
Assessments will be completed at Baseline, Day 28, Day 56 (primary endpoint) and Month 12 (optional).
It is optional for the participants to participate in the open label sub study. Participants will be consented to this sub study. If consent is obtained and participant is recruited to the sub study, the month 12 follow-up will be completed.
Secondary outcome [1] 344924 0
Change in the Multidimensional Fatigue Inventory (MFI) compared between study groups _ Modafinil and Placebo





Timepoint [1] 344924 0
Assessments will be completed at Baseline, Day 28, Day 56 and Month 12 (optional)
Secondary outcome [2] 345089 0
Change in the Montreal Cognitive Assessment (MoCA) compared between study groups - Modafinil and Placebo

Timepoint [2] 345089 0
Assessments will be completed at Baseline, Day 28, Day 56 and Month 12 (optional)
Secondary outcome [3] 345090 0
Change in the Depressive Anxiety and Stress Scale (DASS 42) compared between study groups - Modafinil and Placebo
Timepoint [3] 345090 0
Assessments will be completed at Baseline, Day 28, Day 56 and Month 12 (optional)
Secondary outcome [4] 345091 0
Change in the EuroQol five dimensions questionnaire (EQ-5D) compared between study groups - Modafinil and placebo
Timepoint [4] 345091 0
Assessments will be completed at Baseline, Day 28, Day 56 and Month 12 (optional)
Secondary outcome [5] 345092 0
Change in the Trail Making A and B test compared between study groups- Modafinil and Placebo
Timepoint [5] 345092 0
Assessments will be completed at Baseline, Day 28, Day 56 and Month 12 (optional)
Secondary outcome [6] 345464 0
Change in the Modified Ranking Scale (mRS) compared between study groups- Modafinil and placebo (Tertiary Endpoint)
Timepoint [6] 345464 0
Assessments will be completed at Baseline, Day 28, Day 56 and Month 12 (optional)
Secondary outcome [7] 345465 0
Change in the Fatigue Severity Scale (FSS) compared between study groups- Modafinil and placebo (Tertiary Endpoint)
Timepoint [7] 345465 0
Assessments will be completed at Baseline, Day 28, Day 56 and Month 12 (optional)
Secondary outcome [8] 345466 0
Safety Endpoint 1: Number of severe adverse events between modafinil and placebo assessed by the Investigator and designated study personnel monitoring each subject for adverse events during the study.
Timepoint [8] 345466 0
Assessments will be completed at Baseline, Day 28, Day 56 and then in the open label phase at Month 3 , Month 6 and Month 12 (optional).
In clinical trials involving patients with narcolepsy, obstructive sleep apnoea, and shift-work sleep disorder, modafinil is generally reported to be well-tolerated. The most common adverse effect reported is headache, occurring in approximately one in six patients. Headaches were severe enough to require discontinuation of the drug in approximately 1% of patients. Nausea, dizziness, and insomnia are also reported, occurring in approximately 1 in 20 patients. Anxiety can be presented in up to 1 in 20 patients as well and requires medication cessation. Lastly severe rash can occur in less than 0.1% of patients, however this event requires urgent medical attention.
Secondary outcome [9] 345467 0
Safety Endpoint 2: Number of rash complications compared between study groups- Modafinil and Placebo assessed by adverse event review by the investigator and designated study personnel for each subject during the study.
Timepoint [9] 345467 0
Assessments will be completed at Baseline, Day 28, Day 56 and then in the open label phase at Month 3 , Month 6 and Month 12 (optional).

The key safety variables of serious adverse events such as hospitalisation during the study
and the occurrence of a rash are considered serious enough to warrant inclusion in the safety interim analysis. This analysis, to be performed when 100, 200 and 300 patients have
completed the Day 56 relevant assessments. If there are concerns about the safety of
participants, this Committee will make a recommendation to the trial Management Committee about continuing, stopping, or modifying the trial. The Haybittle-Peto procedure for generating early stopping boundaries will be used. To compare the safety of the modafinil therapy and placebo, safety parameters – the number of serious adverse events and the occurrence of rash will be tested independently. A recommendation of early termination due to safety reasons will be considered by the independent DSMB if the corresponding Haybittle-Peto boundary (p = 0.003, Z =3) at a given interim analysis is crossed.
Secondary outcome [10] 350599 0
Change in the Quality of life of participants on Modanifil compared to placebo assessed by an increase of 5 or more points on the self-reported quality of life using the 36-item Short Form Survey (SF-36).
Timepoint [10] 350599 0
Assessments will be completed at Baseline, Day 28, Day 56 and Month 12 (optional)
Secondary outcome [11] 350600 0
Change in carer burden on the Oberst Caregiving Burden Scale and Caregiver Strain Index.
Timepoint [11] 350600 0
Assessments will be completed at Baseline, Day 28, Day 56 and Month 12 (optional)

Eligibility
Key inclusion criteria
Participant:
• 18 years of age or older
• have suffered a stroke (ischaemic/ Haemorrhagic) at least 3 months ago
• have persistent self-reported fatigue with MFI score of 60 or more
• modified Rankin Score (mRS) of 3 or less
• can speak reasonable English, understand instructions and be able to complete tests and questionnaires on their own or with minimal support
• able to give informed consent to participate in the study, in accordance with the ICH GCP guidelines, and local regulations, before initiating any study related procedures

Caregiver:
• have the consent of the study participant for whom they care for, to take part in the research
• meets the definition of a ‘caregiver’ to participate in the research. They must be a reliable and capable person, who either lives in the same household with the participant or interacts with the participant at least 10 hours per week and will be available to attend all clinic visits with them in person.
• able to give informed consent to participate in the study, in accordance with the ICH GCP guidelines, and local regulations, before initiating any study related procedures
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
•an active, symptomatic or untreated anxiety disorder who,
based on the clinical judgement of the investigator, could be
prone to an exacerbation of anxiety with the use of modafinil
(Note: Subjects with well-controlled anxiety who are on
medication are eligible for consideration for inclusion in the trial)

• an active, symptomatic or untreated depression who, based on
the clinical judgement of the investigator could be prone to an
exacerbation of depression or the development of agitation
(Note: Subjects with well-controlled depression who are stable
and/or have been on antidepressant medication for at least 6
months are eligible for consideration for inclusion in the trial)

• pre-existing dementia or other neuropsychiatric disease

• other diagnoses with fatigue as a known symptom e.g. chronic
fatigue syndrome, multiple sclerosis, narcolepsy

• current or past drug abuse

• known contraindication to treatment with modafinil

• known active malignancy, intracranial tumour, subdural or
epidural hematoma

• severe renal or hepatic impairment (GFR <15mL/min)

• Unstable or poorly controlled epilepsy where the investigator is
concerned about the potential for drug interactions.

• benzodiazepines or other hypnosedative drugs which may
interact with modafinil as per specific medication guidance


• clinical suspicion of sleep apnoea. If the investigator suspects
on clinical grounds, that fatigue is related to sleep apnoea, an
Epworth Sleepiness Scale must be undertaken. If the score is
>10, overnight pulse oximetry monitoring or a sleep study must
be undertaken to exclude sleep apnoea.

• participant is receiving immunosuppressive therapy or has a
known immunodeficiency state, e.g., HIV.

• pregnant or breastfeeding women. Women of child bearing
potential will need to have a negative pregnancy test at
screening and should agree to using an acceptable barrier form
of birth control. The effectiveness of steroidal contraceptives
(contraceptive pill, implants, intrauterine devices (IUDs) or
patches, etc.) may be impaired due to induction of CYP3A4/5 by
modafinil. Alternative or concomitant methods of contraception
are recommended for patients treated with modafinil.
Acceptable methods of contraception should continue to be
used for at least two months after ingestion of the final study
dose.

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)
Randomisation will be based on a 1:1 allocation ratio and will be performed at the individual
subject-level using a centralised on-line eCRF system.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be stratified for baseline MFI score (dichotomized at 75 points) and time since stroke (dichotomized at 1 year). Central block randomisation with varied block sizes will be implemented using a centralised on-line eCRF system.
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
Multicentre, Prospective, Randomised, Placebo-controlled, Double-blind,
Parallel group, with an adaptive sample size re-estimation study in Stroke Survivors
Phase
Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Analysis will be performed on an intention-to-treat basis. The primary outcome will be analysed using a linear regression model with the treatment group (modafinil vs placebo) as an independent variable and baseline values of SF36, MFI and time since stroke as adjustment covariates. The adjusted treatment effects will be reported as a mean difference between groups with its 95% confidence interval and p-value.
All other analysis will be undertaken using appropriate generalised linear mixed models. Between groups differences in secondary outcomes (MFI, MoCA, FSS, EQ-5D, DASS 42) will
be assessed using the generalised linear mixed models (GLMM) approach, using a link
function as appropriate to the response outcome distribution.

Recruitment
Recruitment status
Recruiting
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)
NSW,SA,TAS,WA,VIC
Recruitment hospital [1] 10514 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 10515 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [3] 10518 0
John Hunter Hospital - New Lambton
Recruitment hospital [4] 14321 0
Box Hill Hospital - Box Hill
Recruitment hospital [5] 14322 0
Western Hospital - Footscray - Footscray
Recruitment hospital [6] 14323 0
Sunshine Hospital - St Albans
Recruitment hospital [7] 14324 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [8] 14325 0
Liverpool Hospital - Liverpool
Recruitment hospital [9] 14326 0
The Alfred - Prahran
Recruitment hospital [10] 14327 0
Caulfield Hospital - Caulfield
Recruitment hospital [11] 14328 0
Hornsby Ku-ring-gai Hospital - Hornsby
Recruitment hospital [12] 14329 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [13] 14330 0
Launceston General Hospital - Launceston
Recruitment hospital [14] 14331 0
Perron Institute for Neurological and Translational Science - Nedlands
Recruitment postcode(s) [1] 22228 0
5000 - Adelaide
Recruitment postcode(s) [2] 22229 0
3050 - Parkville
Recruitment postcode(s) [3] 22232 0
2305 - New Lambton
Recruitment postcode(s) [4] 27323 0
3128 - Box Hill
Recruitment postcode(s) [5] 27324 0
3011 - Footscray
Recruitment postcode(s) [6] 27325 0
3021 - St Albans
Recruitment postcode(s) [7] 27326 0
2050 - Camperdown
Recruitment postcode(s) [8] 27327 0
2170 - Liverpool
Recruitment postcode(s) [9] 27328 0
3004 - Prahran
Recruitment postcode(s) [10] 27329 0
3162 - Caulfield
Recruitment postcode(s) [11] 27330 0
2077 - Hornsby
Recruitment postcode(s) [12] 27331 0
3084 - Heidelberg
Recruitment postcode(s) [13] 27332 0
7250 - Launceston
Recruitment postcode(s) [14] 27333 0
6009 - Nedlands
Recruitment postcode(s) [15] 27334 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 299086 0
Charities/Societies/Foundations
Name [1] 299086 0
Greater Building Society
Address [1] 299086 0
Greater Charitable Foundation
103 Tudor Street
Hamilton NSW 2303
Country [1] 299086 0
Australia
Primary sponsor type
Other
Name
The Florey Institute of Neuroscience and Mental Health (The Florey)
Address
Melbourne Brain Centre – Austin Campus 245 Burgundy Street
Heidelberg, VIC 3084, AUSTRALIA
Country
Australia
Secondary sponsor category [1] 298334 0
None
Name [1] 298334 0
Address [1] 298334 0
Country [1] 298334 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300022 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 300022 0
Research Ethics and Governance Office
The Lodge, Rankin Park Campus
Lookout Road, New Lambton NSW 2305
Ethics committee country [1] 300022 0
Australia
Date submitted for ethics approval [1] 300022 0
27/02/2018
Approval date [1] 300022 0
12/04/2018
Ethics approval number [1] 300022 0

Summary
Brief summary
This is a Multicentre, prospective, randomised, placebo-controlled, double-blind,
parallel group phase III trial with an adaptive sample size re-estimation in stroke survivors enrolled 3 or more months after their event. The primary objective is to test the hypothesis that in stroke survivors, 200mg of modafinil taken once daily for at least 56 days significantly improves participant quality of life compared to placebo, due to the improvement of severe and persisting fatigue after stroke. The trial will screen potential participants with the Multidimensional Fatigue Inventory (MFI) score of above 60. Upon consent and if patient meets other specified inclusion and exclusion criteria they will be randomised to either modafinil (200mg) or placebo once daily for 56 days. The main study visits include screening, Day 0, Day 28 and Day 56 for trial assessments with the SF-36, TMTs, FSS, MoCA, DASS 42 and the EQ5D and mRS. Caregivers will also be compete CSI and OCBS at each study visit The study sample size has been calculated to be 300 recruited participants (150 in each arm). There are three optional sub-studies.
1. Open-Label modafinil for an additional 10 months and return to the study centre for trial assessments after the 10-month treatment phase.
2. Physical activity monitoring and
3. Cognitive assessments
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 82290 0
Prof Christopher Levi
Address 82290 0
Neurology Department, Level 2, John Hunter Hospital Lookout Road New Lambton Heights, NSW 2305 AUSTRALIA
Country 82290 0
Australia
Phone 82290 0
+612 49213481
Fax 82290 0
Email 82290 0
christopher.levi@unsw.edu.au
Contact person for public queries
Name 82291 0
Dr Andrew Bivard
Address 82291 0
Neurology, Royal Melbourne Hospital
300 Grattan Street
Parkville, VIC, 3050
Country 82291 0
Australia
Phone 82291 0
+61402720510
Fax 82291 0
Email 82291 0
abivard@unimelb.edu.au
Contact person for scientific queries
Name 82292 0
Prof Christopher Levi
Address 82292 0
Neurology Department, Level 2, John Hunter Hospital
Lookout Road
New Lambton Heights, NSW 2305
AUSTRALIA
Country 82292 0
Australia
Phone 82292 0
+612 49213481
Fax 82292 0
Email 82292 0
christopher.levi@unsw.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results