Modafinil and Exercise for Post Stroke Fatigue (MODEX)

University Health Network, Toronto

Status and phase: Not yet enrolling; Phase 3

Conditions: Stroke; Modafinil; Fatigue; Exercise

Treatments: Drug: Placebo; Behavioral: Exercise Program Two; Behavioral: Exercise Program One; Drug: Modafinil 200mg

Study type: Interventional

Funder types: Other

Identifiers

NCT06354985

FRN:183960 (Other Grant/Funding Number)

23-5996

CTO Project ID: 4701 (Other Identifier)

MODEX2023 (Other Identifier)

Details and patient eligibility

About

A stroke happens when blood flow to the brain is stopped and the brain gets damaged. At least half of people with a stroke have fatigue months and even years later. A lot of people report fatigue as one of the worst symptoms post stroke that can affect daily activities and the length and quality of life. Though all the reasons for fatigue after stroke and how to best treat it are not fully understood, the investigators think that fatigue results from the stroke changing the brain, reducing physical fitness, and decreasing muscle strength. A stroke can also affect sleep and mood, which can impact how people feel too. It is also not known why women experience more fatigue than men after a stroke.

Some studies have tested a drug called Modafinil for post stroke fatigue, while other studies have tested exercise for it. Yet, there is unclear evidence for either treatment, so this study has two main aims:

1. Test if Exercise Program One is better than Exercise Program Two
2. Test if Modafinil is better than a Sugar Pill

As another aim, the investigators will also look at if combining Modafinil with exercise has any benefits.

This study will take place at 6 Canadian research sites to give a good representation of people after a stroke. Each person will be tested on fatigue, mood, fitness, thinking skills, sleep, and usual activity levels.

Participants will be assigned at random (like flipping a coin) to 1 of 4 groups:

1. Sugar Pill plus Exercise Program One
2. Sugar Pill plus Exercise Program Two
3. Modafinil plus Exercise Program One
4. Modafinil plus Exercise Program Two

The treatment will last 8 weeks. The Modafinil or Sugar Pill will be taken once a day. The exercise will be delivered virtually by a trained therapist over computer to people at home 3 times a week. Change in fatigue, quality of life, and other outcomes will be measured over 6 months.

The investigators will assess the results to identify the best treatment for post stroke fatigue and hope to be able to find a treatment that will help reduce fatigue and improve quality of life after a stroke.

Full description

Study Rationale:

Post stroke fatigue (PSF) afflicts as many as 70% of the 400,000 Canadians with stroke. People with stroke endorse PSF as the most serious unmet research priority. Pathological fatigue is not relieved by rest and is characterized by persistent or extreme tiredness, exhaustion, and/or difficulty in initiating or sustaining voluntary activities. PSF is an excellent exemplar to study as the cause of disabling PSF is unclear. Systematic reviews confirm that PSF is multifactorial having both peripheral (e.g. cardiovascular and neuromuscular) and central (e.g. alterations in brain function resulting in both physical and psychological symptoms) components. There are no evidence-based treatments for PSF, however, exercise and the dopaminergic medication Modafinil that targets the dopaminergic movement circuits in the brain, have shown promise in alleviating symptoms in small studies.

Study Design:

This multicentre clinical trial will utilize a factorial design to quantify the effect of exercise or Modafinil 200 mg daily over 8 weeks on severity of fatigue symptoms. It aims to recruit 224 participants into one of four arms. It will also explore the interactions of Modafinil in combination with exercise and the effects of mood, sleep, stroke impairments, activity level as measured by wearable devices, sex, and gender on outcomes.

Study Population:

Study participants must meet the inclusion/exclusion criteria at the time of entry into the study. In general, participants will be >3 months post stroke onset (i.e. intracerebral hemorrhage or ischemic stroke diagnosed by a physician) at the time of consent into the study.

Primary Hypothesis:

There are two primary hypotheses based on outcomes at 8 weeks:

1. Exercise Program One will improve fatigue symptom severity more than Exercise Program Two.
2. Modafinil will improve fatigue symptom severity more than Placebo medication.

Enrollment: 224 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. >18 years of age (on date of consent)
2. >3 months post stroke onset (i.e. intracerebral hemorrhage or ischemic stroke diagnosed by a physician) (on date of consent)
3. evidence of stroke on computed tomography (CT) or magnetic resonance imaging (MRI)
4. disabling post stroke fatigue as measured by Multidimensional Fatigue Inventory score >60
5. Modified Rankin disability score <4
6. mobile enough to participate in exercise (i.e. able to walk with one person assistance or less)

Exclusion criteria

1. contraindications to Modafinil
2. on stimulant medications already
3. subarachnoid hemorrhage
4. impaired comprehension or language impairment that prevents following visual or pictograph adapted instructions or providing informed consent
5. severe motor impairment or inability to participate in the exercise
6. unable to participate in exercise due to musculoskeletal complaints, unstable heart failure, or renal disease
7. untreated hypothyroidism or anemia
8. cancer likely to result in death in <6 months
9. severe depression requiring therapy as indicated by suicidal ideation and/or Depression Anxiety Stress Scales (DASS) depression sub-score >20
10. currently enrolled in a structured exercise program
11. untreated severe sleep apnea with an Apnea/Hypopnea index >30 as measured by validated wearable sleep apnea detector
12. pregnant, breastfeeding, or positive test for pregnancy at baseline

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: Quadruple Blind

---

224 participants in 4 patient groups, including a placebo group

Group A: Placebo Drug + Exercise Program One

Active Comparator group

Description:

Group A: Placebo Drug + Exercise Program One for 8 weeks.

Treatment:

Behavioral: Exercise Program One

Drug: Placebo

Group B: Placebo Drug + Exercise Program Two

Placebo Comparator group

Description:

Group B: Placebo Drug + Exercise Program Two for 8 weeks.

Treatment:

Behavioral: Exercise Program Two

Drug: Placebo

Group C: Modafinil 200 mg/day + Exercise Program One

Active Comparator group

Description:

Group C: Modafinil 200 mg/day + Exercise Program One for 8 weeks.

Treatment:

Drug: Modafinil 200mg

Behavioral: Exercise Program One

Group D: Modafinil 200 mg/day + Exercise Program Two

Active Comparator group

Description:

Group D: Modafinil 200 mg/day + Exercise Program Two for 8 weeks.

Treatment:

Drug: Modafinil 200mg

Behavioral: Exercise Program Two