Conditions: Multiple Sclerosis
Keywords: cognitive behavioral therapy modafinil Provigil fatigue MS
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 343
Healthy volunteers: no

Brief summary:
This clinical trial will compare the effectiveness of 3 treatments for fatigue in Multiple Sclerosis: 1) a commonly used behavioral treatment strategy (telephone-based cognitive behavioral therapy), 2) a commonly used medication (modafinil), and 3) a combination of both therapies. Each participant will receive one of these 3 treatments for a total of 12 weeks. Hypotheses are that, at 12 weeks, treatment with combination therapy will overall lead to greater reductions in fatigue impact, fatigue severity, and fatigability compared to monotherapy, and that comorbid depression, sleep disturbances, and baseline disability level will be important effect modifiers that influence treatment effect and adherence.

Detailed description:

Arms:
arm 1: 8 weekly telephone-based sessions and 2 booster sessions arm 2: 50-400 mg per day (oral) arm 3: Telephone-based cognitive behavioral therapy (8 weekly therapy sessions and 2 booster sessions) + Modafinil 50-400 mg per day (oral)

Interventions: intervention 1: Telephone-based Cognitive Behavioral Therapy intervention 2: Modafinil
Intervention descriptions: intervention 1: Cognitive behavioral therapy (CBT) is a behavioral-based treatment that promotes effective self-management skills, including adaptive thought processes and behaviors (i.e. "coping skills"). CBT also commonly teaches goal-setting and behavioral activation strategies for engaging in physical, social, and other valued activities in the context of fatigue. intervention 2: Modafinil is a safe, well-tolerated and effective wake-promoting agent (oral medication) that is FDA-approved for the treatment of fatigue related to sleep disorders. Modafinil is also one of the most commonly used medications for multiple sclerosis related fatigue in clinical practice, with doses ranging from 50 - 400 mg per day, in divided doses (once to twice daily).

Protocol document:
Prot_SAP_001.pdf: 
COMBO-MS: Cognitive Behavioral Therapy, Modafinil, or Both for MS Fatigue 
Clinical Trials.gov NCT #: 03621761 
IRB Approval Date:  5/7/2020  (with contingencies) 
IRB Approval Notification Date:  5/18/2020 


Protocol 
Title: A randomized controlled trial of telephone-delivered cognitive behavioral-therapy, modafinil, and 
combination therapy of both interventions for fatigue in multiple sclerosis 
Version 6.0, 05/07/20 
HUM00143320 
Phase: 4 
Institution: 
University of Michigan 
Study Sites: 
University of Michigan (1) and University of Washington (2) 
Principal Investigators: 
Tiffany J. Braley, MD, MS and Anna L. Kratz, PhD 
Co-Investigators: 
Dawn Ehde, PhD (UW site PI) 
Kevin Alschuler, PhD 
Deirdre Conroy, PhD 
Gloria Von Geldern, MD 
Ronald D. Chervin MD, MS 
Roderick Little, PhD 
Sponsors: Patient-Centered Outcomes Research Institute (PCORI) 
  National Multiple Sclerosis Society 
Clinical Trials.gov NCT #: 03621761 


Page 2 of 37 
 
TABLE OF CONTENTS 
 
PROTOCOL SUMMARY………………………..………………………………………….. 
4 
1.  INTRODUCTION……………………………………………………………………........ 
6 
1.1 Indication ……………………………………………………………………….……..… 
6 
1.2 Background and Rationale …………………………………………………………….… 
6 
1.3 Safety………………………………………………………………………………….… 
7 
2.  STUDY OBJECTIVES AND ENDPOINTS………………………………………….... 
9 
2.1 Objectives ……………………………………………………………………………… 
9 
2.2 Endpoints……………………………………………………………………………….. 
10 
2.2.1 Primary Outcomes…………………………………………………………………….. 
10 
2.2.2 Secondary Outcomes…………………………………………………………………. 
10 
2.2.3. Exploratory Endpoints……………………………………………………………….. 
10 
3.  STUDY DESIGN……………………………………………………………………..….. 
10 
4.  SUBJECT SELECTION…………………………………………………………….….. 
11 
4.0 Subject Recruitment……………………………………………………………………. 
11 
4.1 Inclusion Criteria………………………………………………………………………… 
11 
4.2 Exclusion Criteria……………………………………………………………….………. 
12 
5.  STUDY TREATMENTS…………………………………………………………..…….. 
12 
5.1 Allocation to Treatment………………………………………………………………… 
12 
5.2 Blinding…………………………………………………………………………..……… 
12 
5.3 Interventions……………………………………………………………………………... 
13 
 6.  STUDY PROCEDURES………………………………………………………….…….. 
15 
6.1 Screening/Baseline visit………………………………………………………………... 
15 
6.2 7-day PRO-Diary application (EMA) – BASELINE AND WEEK 12 ONLY …………. 
  16 
6.3 Randomization………………………………………………………………………….. 
16 
6.4 Interventions……………………………………………………………………………. 
16 
6.5 Week 8, Week 12, and Week 24 Visits …………………………………………..….... 
16 
6.6 Assessment Windows…………………………………………………………………..  
17 
6.7 Treatment Windows…………………………………………………………………….  
18 
6.8 Participant Compensation……………………………………………………………… 
18 
SCHEDULE OF ACTIVITIES TABLE…………………………………………………..…. 
20 
7.  ASSESSMENTS……………………………………………………………………..…... 
23 
7.1.1 Primary Endpoint Assessments………………………………………………………..… 
23 
7.1.2 Exploratory Assessments………………………………………………….................... 
23 
7.2 Data Collection Technologies……………………………………………………………  
26 
7.2.1 The PRO-Diary…………………………………………………………………………... 
26 
7.2.2 REDCap………………………………………………………………………………… 
26 
7.2.3 M+Box…………………………………………………………………………………… 
26 
7.3 General Medical History………………………………………………………………... 
27 
7.4 Concomitant Medication Use………………………………………………………..… 
27 
7.5 Adverse Event Assessments……………………………………………………………….. 
27 
8.  ADVERSE EVENT REPORTING……………………………………………............. 
27 
8.1 AE/SAE relatedness………………………………………………………………………. 
28 


Page 3 of 37 
 
8.2 Serious Adverse Events (SAE) Definition………………………………………………... 
28 
8.3 AE/SAE Expectedness……………………………………………………………………. 
28 
8.4 AE/SAW severity…………………………………………………………………………. 
29 
9.  DATA ANALYSIS/STATISTICAL METHODS……………………………………….. 
29 
9.1 Sample Size Determination…………………………………………………………….... 
29 
9.2 Analysis of Study Aims ………………………………………………………..….. 
30 
9.3 Analysis of Exploratory Endpoints…………………………………………… 
31 
10. MONITORING……………………………………………………………………….. 
31 
10.1 Data Safety Monitoring Plan…………………………………………………………... 
31 
10.2 Independent Medical Monitor…………………………………………………………. 
32 
10.3 Monitoring Plan and Information……………………………………………………… 
32 
11. DATA HANDLING AND RECORD KEEPING……………………………………. 
32 
11.1 CRFs / Electronic Data Record……………………………………………………….... 
32 
11.2 Record Retention……………………………………………………………………..… 
32 
12.  ETHICS………………………………………………………………………………... 
32 
12.1 IRB…………………………………………………………………………………..…. 
32 
12.2 Subject Information and Consent ………………………………………………….….. 
32 
13. STUDY DISCONTINUATION CRITERIA………………………………………… 
33 
14. ENAGEMENT………………………………………………………………………… 
34 
15. REFERENCES…………………………………………………………………………. 
35 
 
 
 
 
 
 
 
 
 
 


Page 4 of 37 
 
PROTOCOL SUMMARY  
 
Background and Rationale 
This pragmatic RCT aims to compare the benefits and harms of a commonly accepted behavioral strategy 
(cognitive behavioral therapy, or CBT), a commonly used pharmacological therapy (modafinil) and 
combination therapy with both treatments for the treatment of fatigue in patients with multiple sclerosis (MS). 
 
Fatigue is one of the most common symptoms of MS, affecting up to 90% of MS patients at some point in their 
disease course.  The majority of persons with MS also describe fatigue as their most disabling symptom, 
surpassing pain and even physical impairment.  Fatigue impacts activities of daily living, social interactions, 
and quality of life, and has profound socioeconomic consequences, including loss of occupation.   
 
Fatigue also remains one of the most difficult MS symptoms to manage, due to an incomplete understanding of 
the daily patient experience of fatigue in MS, poor understanding of factors that influence its severity, and lack 
of evidence regarding how to effectively leverage existing treatments for optimal outcomes. A critical need 
exists to optimize the use of available therapies for fatigue in MS, and to identify tailored, patient-centered 
strategies fueled by pragmatic research that accounts for diversity among MS patients. 
 
Both pharmacological and behavioral strategies exist for the treatment of MS fatigue.  Among behavioral 
treatments, cognitive behavioral therapy (CBT) promotes effective self-management skills, including adaptive 
thought processes and behaviors (i.e. “coping skills”). CBT also commonly teaches goal-setting and behavioral 
activation strategies for engaging in physical, social, and other valued activities in the context of fatigue.  CBT 
has been shown to ameliorate MS fatigue in both placebo-controlled trials, and in trials that have used active 
behavioral comparators.  CBT for MS symptom self-management has also been adapted for telephone-delivery, 
effectively expanding access to this treatment.  Yet, despite promising evidence that CBT is an effective 
monotherapy for many individuals with MS, it remains unknown whether combining CBT with other therapies 
might improve outcomes, particularly for those who do not respond to CBT alone, which patients respond most 
favorably to CBT, or how CBT compares to pharmacological treatments in ameliorating MS-related fatigue.  
 
Pharmacological approaches are also frequently employed to treat fatigue in MS, yet the effects of these 
treatments have never been directly compared to CBT, or studied in combination with CBT, or studied in 
pragmatic trials.  Among such therapies, modafinil is a safe, well-tolerated and effective wake-promoting agent 
that is FDA-approved for the treatment of fatigue related to sleep disorders.  Modafinil is also one of the most 
commonly used medications for MS-related fatigue in clinical practice. Although several studies have 
demonstrated the effectiveness of modafinil for MS-related fatigue (testing doses up to 400 mg per day), 
limitations of previous non-pragmatic trials have precluded formal prescribing recommendations or FDA 
approval of this medication. Consequently, off-label use of this drug is weakly supported in an unofficial 
capacity, commonly followed by the disclaimer that “larger randomized controlled studies are necessary,” 
leading to decisional uncertainly regarding when it should be used and in which patients.  
 
To address these gaps in our knowledge, this pragmatic RCT will capitalize on a representative, heterogeneous 
sample of MS patients, novel patient-centered fatigue measures, and expertise from key stakeholders to 
compare the effectiveness of CBT monotherapy, modafinil monotherapy, and CBT+modafinil combination 
therapy on fatigue impact, fatigue severity, and fatigability in patients with MS (Aim 1), determine 
heterogeneity of treatment effects of common potential modifiers including depression, sleep disturbances, and 
MS disability level (Aim 2), and compare adverse events, treatment adherence, and patient dropout rates among 
the three treatments (Aim 3). 
 
 
Objectives, Aims, Endpoints, and Assessments: 


Page 5 of 37 
 
The Aims of this randomized, rater-blinded clinical trial are to: 1) Compare the effectiveness of 3 therapies: 
CBT monotherapy, modafinil monotherapy, and CBT+modafinil combination therapy on patient-reported 
fatigue impact, fatigue intensity, and fatigability among fatigued individuals with MS; 2) Test whether 
depression, sleep disturbances, or MS disability level modify comparative treatment responsiveness across 
treatment arms in terms of fatigue impact (i.e., heterogeneity of treatment effects); and 3) Compare adverse 
events, side effects, treatment adherence, and patient dropout rates among the three treatment arms and patient 
subgroups of interest. 
 
Self-report measures of fatigue impact (Modified Fatigue Impact Scale - primary endpoint), fatigue intensity 
(Brief Fatigue Inventory) and potential effect modifiers (depression, sleep, and MS subtype/disability level) will 
be assessed at baseline, at 8-weeks, 12-weeks and 24 weeks.  Subjects will also undergo 1 week of continuous 
actigraphy monitoring and EMA data collection with a wrist-worn accelerometer pre-treatment (baseline) and 
12 weeks to collect additional data on physical activity level, fatigue intensity (numerical self-report scale), and 
fatigability (ratio of EMA fatigue intensity/physical activity level).  See Figure 1, study schematic, Section 3.  
Hypotheses to be tested are that, at 12 weeks, treatment with combination therapy will overall lead to greater 
reductions in fatigue impact, fatigue severity, and fatigability compared to monotherapy, and that comorbid 
depression, sleep disturbances, and baseline disability level will be important effect modifiers that influence 
treatment effect and adherence. 
 
 
Statistical Methods  
For Aim 1, the primary outcome measure will be the mean difference in Modified Fatigue Impact Scale (MFIS) 
score between 12 weeks and baseline (delta-MFIS), compared between the 3 treatment groups.  A repeated 
measures mixed effects model will be applied. Similar models using EMA measures of fatigue impact, fatigue 
intensity, and fatigability as outcome variables will be used to assess the treatment effect of each group. 
 
For Aim 2, treatment group effect on fatigue impact scores, fatigue intensity, and fatigability among select 
subgroups, including those with clinically significant depression, progressive MS subtype and higher EDSS 
scores, and confirmed/suspected sleep disorders (not related to poor sleep hygiene), will be evaluated with 
interaction terms in mixed effects models.  Interactions will be treated as random rather than fixed effects. 
 
For Aim 3, descriptive statistics will be used to analyze patterns of treatment side effects (incidence, type, 
severity, and relatedness) and treatment adherence between treatment groups (modafinil vs. CBT vs. 
combination therapy).  Adverse event frequency between treatment groups and among subgroups of interest 
will be evaluated using ANOVA. Multiple linear regression models will be used to determine association 
between treatment group and treatment adherence (percent usage of prescribed therapy).  We also will assess 
whether degree of treatment effects measured in Aim 1 are related to treatment adherence (e.g. “dose 
response”).      


Page 6 of 37 
 
1. INTRODUCTION 
 
1.1 Indication 
A critical need exists to optimize the use of available therapies for fatigue in MS, and to identify tailored, 
patient-centered treatment strategies that accounts for the diversity of MS patients. 
 
1.2 Background and Rationale  
Multiple sclerosis (MS) is a chronic, autoimmune disease that causes inflammation and destruction of the brain 
and spinal cord.  This condition is the leading cause of non-traumatic disability among young adults, and affects 
nearly half a million Americans and 2.5 million people worldwide.  In addition to physical disability, MS 
patients suffer disproportionately from a variety of complications that negatively impact quality of life, 
including fatigue. 
 
Fatigue is one of the most common symptoms of MS, affecting up to 90% of MS patients at some point in their 
disease course.  The majority of persons with MS also describe fatigue as their most disabling symptom, 
surpassing pain and even physical impairment.  Fatigue impacts activities of daily living, social interactions, 
and quality of life, and has profound socioeconomic consequences, including loss of occupation.  Fatigue also 
remains one of the most difficult MS symptoms to manage, due to an incomplete understanding of the daily 
patient experience of fatigue in MS, poor understanding of factors that influence its severity, and lack of 
evidence regarding how to effectively leverage existing treatments for optimal outcomes.  
 
Despite recent prioritization of personalized medicine, there is insufficient information to guide tailored 
treatment decision-making for fatigue management in MS.  For example, although data from other chronic 
health conditions such as major depressive disorder and fibromyalgia suggest that combination therapies of both 
pharmacological and behavioral approaches can have synergistic effects and offer the best chance of long-term 
success for symptom management, only single-treatment modalities have been studied for MS fatigue.  
Furthermore, prior trials of treatments for MS-fatigue have not taken into account specific MS subpopulations 
who may, by virtue of common comorbidities, respond better to one particular treatment or combination of 
treatments.  Finally, existing trials of some of the most commonly used treatments for MS fatigue have relied on 
measures that do not fully reflect the patient experience with this symptom.  Consequently, clinicians have little 
evidence to determine whether a specific monotherapy or combination therapy is indicated for a particular 
patient.  Specifically, three major research gaps have contributed to the current decisional uncertainly regarding 
the approach to fatigue treatment in MS: (1) lack of pragmatic, comparative effectiveness trials, including trials 
of combination therapies, for two of the most commonly used non-pharmacologic and pharmacologic 
treatments in clinical practice; (2) lack of assessment of common treatment effect modifiers associated with MS 
that contribute to fatigue (depression, sleep, and progressive MS/disability severity); and (3) lack of novel, 
reliable patient-centered fatigue outcome measures.   
 
Among behavioral treatments for MS fatigue, cognitive behavioral therapy (CBT) promotes effective self-
management skills, including adaptive thought processes and behaviors (i.e. “coping skills”). CBT also 
commonly teaches goal-setting and behavioral activation strategies for engaging in physical, social, and other 
valued activities in the context of fatigue.  CBT has been shown to ameliorate MS fatigue in both placebo-
controlled trials, and in trials that have used active behavioral comparators such as energy conservation and 
exercise.  CBT for MS symptom self-management has also been adapted for telephone-delivery, effectively 
expanding access to this treatment.  Yet, despite promising evidence that CBT is an effective monotherapy for 
many individuals with MS, it remains unknown whether combining CBT with other therapies might improve 
outcomes, particularly for those who do not respond to CBT alone, which patients respond most favorably to 
CBT, or how CBT compares to pharmacological treatments in ameliorating MS-related fatigue.  
 


Page 7 of 37 
 
Pharmacological approaches are frequently employed to treat fatigue in MS, yet the effects of these treatments 
have never been directly compared to CBT, studied in combination with CBT, or studied in pragmatic trials.  
Among pharmacological therapies, modafinil is a safe, well-tolerated and effective wake-promoting agent that 
is FDA-approved for the treatment of fatigue related to sleep disorders.  Modafinil is also one of the most 
commonly used medications for MS-related fatigue in clinical practice. Although several studies have 
demonstrated the effectiveness of modafinil for MS-related fatigue, the variability and limitations of previous 
non-pragmatic trials (such as low sample size, lack of evaluation of important effect modifiers, and patient 
selection issues) have precluded formal prescribing recommendations or FDA approval of this medication. 
Consequently, off-label use of this drug is weakly supported in an unofficial capacity, commonly followed by 
the disclaimer that “larger randomized controlled studies are necessary,” leading to decisional uncertainly 
regarding when it should be used. 
 
To inform best practice guidelines and address research these current research gaps, this pragmatic comparative 
effectiveness RCT aims to compare the effectiveness of cognitive behavioral therapy, modafinil, and 
combination therapy on MS-related fatigue, in the context of common effect modifiers (depression, sleep 
disturbance, and disability level), using novel methodology that will capture the day-to-day experiences of 
patients with MS. 
 
Clinical Rationale 
Providers and patients need data regarding the real-world effectiveness of CBT and modafinil that accounts for 
the diversity of the MS population, effects of treatment on daily function, and heterogeneous experience of 
fatigue. Experts in the field have called for use of combined therapies that include both medication and self-
management (CBT) interventions, but further evidence is needed to determine 1) which patient characteristics 
determine whether to pursue CBT or modafinil for fatigue; and 2) whether combination therapy with CBT plus 
modafinil leads to a synergistic response in fatigue management, and if so, which patients are most likely to 
benefit.  
 
1.3 Safety  
 
Risks 
Activities involved with this study will involve no more than a minor increase over minimal risk. There are 
no alternatives to these data collection procedures.  Participants may choose to not participate in any part of this 
voluntary study. Medical treatment (e.g. medication management) as received as part of routine clinical care 
will bear no more risk than usual care given the treatment will take place in the same clinical context. 
 
Cognitive Behavioral Therapy phone sessions:  The risks of CBT are minimal. It is possible that some of the 
participants may become fatigued during the treatment sessions or find it uncomfortable to talk about their 
situation with the therapist.  Further, given the frequency with which fatigue is associated with psychological 
distress, as well as the inclusion of people with depression, we anticipate that some of the study participants will 
exhibit signs of psychological distress during treatment.  
The use of telephone sessions will help to reduce the risks related to fatigue. Clinicians will be trained to 
be attentive to signs of fatigue or distress among all participants, who will be told they can stop any study 
procedures at any time if they feel uncomfortable. A participant will be referred to a medical professional if a 
study team member concludes they need attention regarding an acute medical issue as identified in the medical 
evaluation. All participants will be informed they can stop participation at any time without penalty or any 
effect on the medical care or benefits they receive at their MS Center (either UM Medical Center or UW 
Medicine MS Center), or any other medical institution. All participants will be offered the opportunity to 
discuss any situations or experiences associated with the study procedures they deem uncomfortable or adverse 
with one of the Principal Investigators or, for UW participants, the UW Site PI or Co-Investigator. 


Page 8 of 37 
 
 
Modafinil: Use of modafinil involves a minor increase over minimal risk.  Modafinil is generally considered 
to be safe and well tolerated.  The most common adverse reactions (5%) associated with modafinil which 
occurred more frequently than placebo-treated patients in previous clinical trials were headache, nausea, 
nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, and dyspepsia. It is recommended that 
caution be used in patients with a history of psychosis, depression, or mania, to avoid exacerbation of these 
conditions.  Serious rash requiring hospitalization and discontinuation of treatment has rarely been reported.  
Life-threatening skin conditions such as Steven-Johnson Syndrome or Toxic Epidermal Necrosis Syndrome, 
angioedema, anaphylaxis, hypersensitivity reactions involving multiple organs, new or increased psychiatric 
symptoms (including worsening depression, mania, depression, suicidality), or increased blood pressure are 
possible. Dose reduction is recommended in patients with severe hepatic impairment.  Modafinil use may 
decrease the effectiveness of hormonal contraception, use of alternative or concomitant methods of 
contraception while taking modafinil and for one month after discontinuation of modafinil treatment is 
recommended.  Elimination of drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, propranolol, 
omeprazole, and clomipramine) may be prolonged by modafinil via inhibition of metabolic enzymes, with 
resultant higher systemic exposure.   
All potential risks of modafinil will be outlined in the informed consent document and discussed with 
the patient prior to enrollment.  Patients will also be advised that there may be unforeseen risks not outlined in 
the ICF.  Based on the package insert, eligibility criteria will exclude pregnant women, and a urine pregnancy 
test will be required prior to study enrollment.  Women of childbearing age will be advised of the risk of 
decreased effectiveness of hormonal contraception with modafinil use and be advised to use a form of birth 
control that does not involve hormonal contraception (spermicide or condoms) during the study and for one 
month after discontinuation of modafinil treatment.  Participants with a history of hepatic impairment, 
participants over age 65, and participants who use warfarin, phenytoin, MAOIs and cyclosporine will be given 
dose limitations that will not exceed half of the maximal daily dose for healthy patients (50-100 mg once-twice 
daily as tolerated).  Patients will be advised to monitor for common side effects of modafinil including 
headache, nausea, nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, and dyspepsia while 
on modafinil, and if these symptoms occur or worsen, to alert the study team, during which time dose reduction 
or discontinuation will be discussed.  Participants who experience worsening depressive symptoms, psychosis, 
increased suicidality, or suspected allergic reactions (rash, hives, mouth sores, blisters, swelling of the face, 
eyes, lips, tongue, or throat, trouble swallowing or breathing, fever, shortness of breath, swelling of the legs, 
yellowing of the skin or whites of the eyes, or dark urine) will be instructed to stop treatment immediately and 
contact the study team. Participants are also advised not to consume alcohol per the drug label. Participants 
should be instructed to call study team when new drugs are added or removed from their drug regimens so that 
drug interactions can be assessed. Participants may choose to discontinue their treatment at any time if they 
experience any untoward effects that they believe are related to modafinil, but will be encouraged to remain in 
the study until completion for monitoring.  Adverse events and severe adverse events will be assessed/reported 
regularly and on an as-needed basis in accordance with the protocol, GCP, and IRB standards (see sections 7.5 
and 8).  Action involving possible PI discontinuation of study drug will be determined promptly in accordance 
with the protocol, GCP and IRB guidelines, as well as the medical monitor (see section 10 and 13).   
 
Confidentiality (minimal risk):  Loss of confidentiality regarding the subject’s study data (especially data 
regarding MS diagnosis and symptoms) could cause embarrassment or have social/occupational consequences. 
This risk is minimal, because a number of precautions have been taken in order to protect confidentiality. Only 
authorized members of the research team will have access to study records. All collected data will be entered 
into a secure password protected electronic database (REDCap) system, which is a secure, password protected, 
and HIPAA compliant web-based data platform hosted by the Michigan Institute for Clinical and Health 
Research (MICHR) at the UM. This protected database will be accessed and maintained by study personnel 
only. This system features both a local and remote web-based interface, secure data transfer, and an Oracle 
database. Data security, patient privacy, and HIPAA requirements are a premium consideration for clinical trials 


Page 9 of 37 
 
research using REDCap. A complete time-stamped audit of all REDCap activity (including which and when 
study personnel access data) is maintained, adding to the security and fidelity of the data. Study personnel can 
enter data into the database through administrative access to add to the self-report data provided by participants. 
Data coding will be done by subject ID number.  Coded paper records (including ICFs) will be locked in file 
cabinets, and cross-referenced by a name-subject ID key for verification that will be stored in another location. 
Identifying information will not be attached to the collected data. Trained study personnel will enter pertinent 
information into the database. Trained study personnel will enter pertinent information into the database. 
Computers will be locked when not in use.  
 
Study Questionnaires (minimal risk): Risks of study questionnaire completion include discomfort, frustration, or 
boredom.  These risks will be minimized by allowing participants to complete the majority of their 
questionnaires from their home computer using REDCap. The process of administering surveys via REDCap is 
very straightforward; URL links are emailed to study participants, who simply click on the link to complete 
their survey. They can complete the survey in a single sitting or save and return later to complete it. REDCap 
provides study personnel with real-time information on what data a participant has provided; in cases where 
participants do not complete the online surveys in a timely manner reminder calls can be placed. 
 
Ecological momentary assessment (PRO-Diary®, minimal risk): Risks of completing ecological momentary 
assessments (EMAs) on the PRO-Diary (wrist-worn monitor) include discomfort, frustration, and the potential 
hassle of interruption of daily routine.  These risks will be minimized by allowing participants to initiate the 
wake- and bed-time assessments when it is convenient for them and by allowing participants to opt-out of or 
postpone EMAs that are not convenient for them (they will be shown how to silence the monitor/delay 
reporting).  These risks will also be minimized by keeping the assessments as brief as possible. Participants may 
also experience discomfort from wearing the PRO-Diary®, especially if they are not used to wearing a watch on 
a daily basis. This risk is extremely rare in our experience collecting data. We will minimize this risk by 
offering participants choices of wrist band types and by telling them that it may take a few days to get used to 
wearing the PRO-Diary®.  
 
Suicidal Ideation:  
In the event that a participant mentions suicidal ideation or other severe mental distress that could result in harm 
to self or others, an initial assessment, using the Suicidal Ideation Documentation form will be conducted, by 
the study team member who is in communication with the participant. Guidelines in this form indicate what the 
study team member should do in case of a true emergency (i.e. contact emergency services), and how to collect 
information to adequately assess the participants suicidal risk. One of the study investigators who is a licensed 
psychologist (Drs. Kratz, Conroy, Ehde, or Alschuler, depending on location) will then be contacted and 
debriefed on the findings of the assessment. If indicated by the findings of the assessment, one of these 
psychologists may contact the participant by phone and complete a more in-depth self-harm/suicide assessment, 
taking appropriate action (e.g. referral for mental health services, contacting emergency services) as 
needed.  All safety related incidents will be reported to the PI and the IRB according to relevant protocols.  
 
As with any research study, there may be additional risks that are unforeseeable.  
 
 
 
2.  STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 Objectives 
To compare the effectiveness of cognitive behavioral therapy, modafinil, and combination therapy on MS-
related fatigue, in the context of common effect modifiers (depression, sleep disturbance, and disability level), 
using novel methodology that will capture the day-to-day experiences of patients with MS. 


Page 10 of 37 
 
 
2.2 Endpoints 
2.2.1 Primary Outcomes 
Fatigue impact, as assessed by: 
The mean difference in the Modified Fatigue Impact Scale (MFIS) score between 12 weeks and baseline 
(delta-MFIS), compared between the 3 treatment groups 
 
2.2.2 Secondary Outcomes 
Changes between 12 weeks and baseline in fatigue intensity, fatigue impact, and fatigability (measured 
using PRO-Diary ecological momentary assessment and accelerometry, measured 4x/day for 7 days, at 
baseline and 12 weeks), compared between the 3 treatment groups 
 
      2.2.3 Exploratory Endpoints 
a) The mean difference in the Modified Fatigue Impact Scale (MFIS) score between 0 and 8 weeks, and 
0 and 24 weeks (delta-MFIS), compared between the 3 treatment groups 
 
b) clinical treatment patterns post-intervention 
 
3.  STUDY DESIGN  
 
This is a randomized, rater blinded, comparative effectiveness trial.  Consenting participants with MS and 
chronic problematic fatigue who meet all inclusion/exclusion criteria will be enrolled and randomized in a 1:1:1 
ratio to receive telephone-based CBT (Group 1: 12 weeks of one-on-one telephone-delivered sessions of CBT 
that emphasize fatigue self-management skills; 8 weekly programmatic sessions + 2 maintenance/booster 
sessions), modafinil (Group 2: 100-200 mg once-twice daily as tolerated, for 12 weeks); or combination 
treatment with CBT (8 weekly sessions + 2 booster sessions) and 12 weeks of modafinil (Group 3).   
 
Self-report measures of fatigue impact (Modified Fatigue Impact Scale - primary endpoint) and potential effect 
modifiers (depression, sleep, and MS subtype/disability level) will be assessed at baseline and at 8-weeks, 12-
weeks and 24-weeks.  Subjects will also undergo 1 week of continuous actigraphy monitoring and EMA data 
collection with a wrist-worn accelerometer pre-treatment (baseline) and 12 weeks (i.e., concluding at the end of 
therapy) to collect additional data on physical activity level, fatigue intensity (numerical self-report scale), and 
fatigability (ratio of EMA fatigue intensity/physical activity level).  For specific measures and timeline see 
Figure 1, study schematic, below.  


Page 11 of 37 
 
 
 
4.  SUBJECT SELECTION 
 
4.0 Subject Recruitment 
Participants will be recruited from the UM and UW MS Clinics tertiary clinics. Additional participants will be 
recruited through UM and UW medical records; other neurology practices throughout Mid- and Southeastern 
Michigan (by invitation) and the Pacific Northwest, UM and UW electronic clinical trials registries; 
advertisement through community outlets (e.g., posting flyers in community centers, distributing flyers and 
fund raising walks), clinicaltrials.gov; Facebook and other social media campaigns, iConquerMS, and from 
advertisements posted by the NMSS (study stakeholder). 
The table below shows the current enrollment plan for data collection.  
 
Total number of study participants expected to be screened: 
360 
Of those screened, total number of study participants expected to be 
eligible: 
340 
Of those eligible, total number of study participants enrolled: 
330 
Target sample size (i.e., of those eligible, total number of study 
participants expected to be enrolled): 
300 
completers 
 
We anticipate enrolling 50 subjects per site in year 1, 65 subjects per site in year 2, and 50 per site subjects in 
year 3, or an average of 4-5 subjects per month per site throughout the course of the study. 
 
4.1 Inclusion Criteria 
1. Patients with clinically definite MS (all MS subtypes included, regardless of disease duration, disability level, 
or disease modifying therapy status);  


Page 12 of 37 
 
2. Age 18 years or older;  
3. Presence of chronic, problematic fatigue that, in the opinion of the patient, has interfered with their daily 
activities for ≥ 3 months;  
4. Average Fatigue Severity Scale (FSS) score greater or equal to 4 at screening. 
5. Access to the internet with video-capable smart phone or computer if performing study remotely (virtual 
visit). 
 
4.2 Exclusion Criteria 
1. Current shift work sleep disorder, or narcolepsy diagnosed with polysomnography and multiple sleep latency 
test (diagnoses in which modafinil is already widely accepted as symptomatic care) 
2. History of MS relapse within the last 30 days prior to screening (participants will be considered eligible after 
the 30-day window);  
3. Current stimulant or wake-promoting agent use such as amantadine (Symmetrel), modafinil (Provigil), short 
or long acting methylphenidate (Ritalin/Concerta), dextroamphetamine (Dexedrine), dextroamphetamine-
amphetamine (Adderall, Adderall XR), lisodexamfetamine (Vyvanse), armodafinil (Nuvigil), or amphetamine 
(Adzenys XR-ODT, Dyanavel XR, and Evekeo) within 30 days of screening (if present, patients could still be 
eligible after a 30-day washout);  
4. For female participants only: Pregnancy or breastfeeding (modafinil is contraindicated in these conditions);  
5. For female participants only: Reliance on hormonal contraception (such as such as birth control pills, shots, 
implants, patches, vaginal rings) AND concomitant unwillingness to use alternative non-hormonal means of 
birth control (spermicide or condoms) during the course of the study (modafinil can decrease the effectiveness 
of oral contraception); 
6. Current suicidal ideation (SI) with intent or plan (per a response of ≥ 1 on the suicide item from the Patient 
Health Questionnaire-9); these individuals will be assessed by a study psychologist and referred for urgent 
mental health treatment† (people with SI but no intent or plan will be included). 
7. Known hypersensitivity to modafinil or armodafinil or its inactive ingredients. 
8. History of the following cardiovascular conditions: recent myocardial infarction (last 6 months prior to 
screening), unstable angina, left ventricular hypertrophy, mitral valve prolapse, NYHA class III or IV 
congestive heart failure 
9. Diagnosis of hypertension within the past year not managed by a health care provider 
10. Recent history (within 1 year) of prescription or illicit stimulant abuse (such as cocaine, amphetamine, 
methamphetamine) 
11. Any other medical, neurological, or psychiatric condition that, in the opinion of the investigators, could 
affect participant safety or eligibility. 
 
 
†Participant behavior or comments that suggest imminent threat will prompt immediate 911 activation.  
Behavior or comments that suggest SI with plan but no immediate threat will prompt psychiatric ER referral 
 
5.  STUDY TREATMENTS 
 
5.1 Allocation to Treatment (see also 6.4) 
Randomization Process (see also section 6.3): Participants who meet all Inclusion/Exclusion criteria will be 
randomized (1:1:1 randomization) to CBT (Group 1, n~100), modafinil (Group 2, n~100), or combination 
CBT+modafinil after the participant has signed consent and completed the baseline activities. 
 
5.2 Blinding 
The subject, PI, co-investigators, interventionists, and coordinators will not be blinded. 
 


Page 13 of 37 
 
 
5.3 Interventions:  
 
Telephone-based CBT: Cognitive Behavioral Therapy for fatigue (CBT – see table 1), also commonly 
referred to as “fatigue self-management”, was chosen as a comparator given its endorsement in MS fatigue 
treatment guidelines based on previous efficacy studies demonstrating its benefits in MS. For this study, we will 
use telephone-delivered CBT for fatigue self-management, which also has a strong evidence-base for its use in 
MS patients.  Developed and tested by one of our study investigators (Dr. Ehde), this treatment is routinely 
utilized in her clinical practice to manage several chronic symptoms in MS including pain, depression, and 
fatigue in MS.  In her primary trial of this intervention using the telephone-delivered treatment, which targeted 
MS-related pain and depression as well as fatigue, 50% of fatigued participants with MS had a clinically 
meaningful reduction in pain impact that was maintained at 6- and 12-months post treatment.  This treatment 
will be delivered one-on-one via telephone by study interventionists with special training in CBT for symptom 
management and in telehealth delivery. The team of psychologists includes Drs. Kratz, Ehde, Alschuler, and 
Conroy, who are all licensed clinical psychologists, who will supervise the two study interventionists (one per 
study site). Study interventionists will be either licensed clinical psychologists, clinical psychology pre-doctoral 
students or postdoctoral fellows, or Master’s level social workers. Currently, the primary interventionists are 
Kristen Pickup, MSW at UM (Drs. Conroy and Kratz secondary/back-up interventionists) and Jamie Tingey, 
MSW, Tiara Dillworth, PhD, and Elena Mendoza, MS at UW (Drs. Alshculer and Ehde secondary/back-up 
interventionists).  
 
The study interventionists will be trained and supervised in the intervention by the study psychologists, 
including Dr. Ehde (author of the telehealth treatment manual, on which this study is based) and Dr. Alschuler 
at UW, and Drs. Kratz and Conroy at UM. Training will include readings, didactics, and ongoing review and 
supervision of recorded sessions. A fidelity protocol will include therapist manuals, protocol checklists, weekly 
supervision meetings, and an ongoing independent review of randomly selected digital recordings from at least 
10% of all sessions. These procedures will ensure therapist fidelity to the CBT treatment (i.e., make certain that 
patients assigned to CBT get CBT as prescribed in the treatment manual).  If poor treatment fidelity is observed, 
that therapist will receive corrective feedback, additional training, and have all sessions reviewed to ensure 
100% adherence to the protocols.   
 
Table 1.  Major components of the manualized CBT fatigue self-management intervention  
Overall treatment goals: Inform participants about fatigue in MS and engage patients to learn and apply 
fatigue self-management skills tailored to their strengths and priorities. Key self-management skills include: 
energy conservation/self-pacing, self-monitoring, sleep behaviors, identifying strengths and priorities, goal-
setting (based on individual values), behavioral activation, relaxation techniques, and managing thoughts and 
emotions. 
Session Content (8 weekly sessions and 2 booster sessions; each session 45-60 minutes) 
Introduction to MS-related fatigue and fatigue self-management 
- Factors that contribute to MS fatigue, self-management philosophy, self-monitoring, identifying strengths 
Energy management 
- Self-monitoring check-in, energy management strategies/priorities, energy conservation/pacing training, 
staying active 
Sleep 
- Sleep behavior assessment, sleep education about sleep regulation, establish a plan for healthy sleep hygiene, 
problem-solving barriers to sleep disturbance (including morningness/eveningness tendencies); energy 
management check-in 
Goal setting and identifying stressors 
-Exploring priorities, setting goals, stress response, diaphragmatic breathing (intro to relaxation); energy 


Page 14 of 37 
 
management check-in 
Working with thoughts (part 1) 
- Identifying/label thoughts, thought stopping, distraction; relaxation practice; energy management check-in 
Working with thoughts (part 2) 
- Challenging unhelpful thoughts, evidence gathering, alternative thoughts; relaxation practice; energy 
management check-in 
Managing emotions 
- Emotions and fatigue, living in the present, nurturing positive emotions, gratitude, guided imagery; energy 
management check-in 
Building resilience and moving forward 
-    Designing a personal fatigue self-management plan, skills relapse prevention, building resilience 
Two 15-20 minute calls between weeks 8-12, to review and troubleshoot implementation of fatigue self-
management skills, including their personal self-management plan.  
 
 
Modafinil: Modainil will be prescribed by one of the neurologists on the study team.  Modafinil (2-
[(diphenylmethyl) sulfinyl]acetamide) is a centrally-acting oral agent that is FDA-approved to improve 
wakefulness in patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea, or shift 
work disorder.  The mechanism(s) through which modafinil promotes wakefulness is unknown.  Modafinil’s 
benefits for fatigue in MS have been demonstrated in 5 previous studies. Three successful open label studies 
that used various subjective fatigue measures, demonstrated a benefit of modafinil on fatigue intensity.  A 
single-blind placebo-controlled study also demonstrated a significant improvement in fatigue intensity with 
modafinil in a recent study.  One 8-week double-blind placebo-controlled trial which examined the effects of 
modafinil on fatigue intensity showed a significant improvement in fatigue with modafinil.   
Modafinil will be dispensed for Group 2 and 3 patients following 1 week of baseline actigraphy 
monitoring and at 8 weeks.  At baseline, participants will be prescribed the 100 mg pills (enough to take up to 4 
pills per day).  They will be advised to take 100 mg once a day (upon awakening) as a starting point for the first 
week.  Depending on results, participants will be allowed to adjust their dose based on the following scenarios: 
 
- 
If the 100 mg/day dose effectively treats their fatigue throughout the day, participants will remain on 
this dose.   
- 
If the 100 mg/day dose is adequate, but of insufficient duration, participants will be allowed to take 
another half pill or full pill around lunchtime (early afternoon: at least 8 hours before bedtime) for a total 
dose of 150 mg or 200 mg a day. 
- 
If the 100 mg/day dose provides insufficient relief of fatigue, participants may increase the dose to 200 
mg/day (upon awakening). 
- 
If the 200 mg/day dose is adequate, but of insufficient duration, participants will be allowed to take 
another 1 or 2 pills around lunchtime (early afternoon: at least 8 hours before bedtime) for a total dose of 
300 mg or 400 mg a day (max dose = 400 mg per day). 
- 
If the 100 mg dose is perceived by the participant to be helpful with fatigue, but associated with 
excessive side effects (see 1.3), participants will be allowed to decrease their dose to 50 mg, once or 
twice daily, depending on duration of effect. A pill cutter will be provided by the study team if 
necessary. 
 
*Participants who report a history of liver problems, participants age 65 or older, participants who use warfarin, 
phenytoin, MAOIs or cyclosporine†, and participants in whom the investigators think could be at increased risk 
for side effects, will only be permitted to take ½ of the maximum daily dose, prescribed enough pills to take a 
maximum of 1 pill twice a day (200 mg/per day) unless they have previously tolerated and required a higher 
dose prior to enrolling (in which case they will be allowed to return to their previously tolerated dose, up to 400 


Page 15 of 37 
 
mg per day) . At baseline, these participants will be prescribed the 100 mg pills.  They will be advised to take 
50 mg once a day (upon awakening) as a starting point for the first week (A pill cutter will be provided by the 
study team if necessary.).  Depending on results, participants will be allowed to adjust their dose based on the 
following scenarios: 
 
- 
If the 50 mg/day dose effectively treats fatigue throughout the day, participants will remain on this dose.   
- 
If the 50 mg/day dose is adequate, but of insufficient duration, participants will be allowed to take 
another ½ pill around lunchtime (early afternoon: at least 8 hours before bedtime) for a total dose of 50 
mg twice a day. 
- 
If the 50 mg/day dose provides insufficient relief of fatigue, participants may increase the dose to 100 
mg/day (upon awakening). 
- 
If the 100 mg/day dose is adequate, but wears off more quickly than desired, participants will be allowed 
to take another half pill or full pill around lunchtime (early afternoon: at least 8 hours before bedtime) 
for a total dose of 150 mg or 200mg a day (max dose = 200 mg per day). 
 
A medication dispensing log that shows how much drug that was dispensed for each participant at each time 
point (baseline and week 8) will be used for drug medication review.   
 
†if randomized to a modafinil treatment arm, participants on these medications will be told to inform their 
prescribing providers of the addition of modafinil to their regimen, to allow the opportunity for additional blood 
monitoring if the prescriber thinks this is necessary 
 
 
Combination CBT+modafinil: The CBT+modafinil combination therapy will entail simultaneous 
engagement in both therapies as described above. 
 
6.  STUDY PROCEDURES 
 
Pre-screening: We will be completing record review & pre-screening (over the phone) questions prior to 
informed consent procedures in order to evaluate initial study eligibility prior to being scheduled for the 
screening/baseline visit.  
 
6.1 Screening/Baseline Visit 
Depending on state or institutional COVID-19 restrictions at time of screening, baseline visits may be 
conducted virtually (via video meeting) or in-person. Even when in-person visits are permitted, participants will 
still be given the option for virtual visits.   
 
For in-person visits, subjects will be seen at one of several UM or UW sites for baseline visit activities, 
including but not limited to the University of Michigan Taubman Neurology Clinic, Michigan Clinical Research 
Unit (MCRU), and the UW Medicine Multiple Sclerosis Center.  
 
Informed consent will be obtained by qualified study staff.  Inclusion and Exclusion Criteria will be reviewed. 
For virtual visits, the informed consent will be obtained digitally. See section 7.2.4. 
 
The screening portion of this visit will include confirmation of eligibility via:   
1) Participant self-report (e.g. FSS, PHQ-3, etc.)  
2) Demographic information 
3) Focused medical and surgical history as it relates to multiple sclerosis (subtype, prior disease 
modifying therapy use, disease duration), fatigue, mood disorders and hepatic issues (for modafinil) 
4) Medication review  


Page 16 of 37 
 
5) Neurologist assessment of eligibility 
6) Pregnancy test (For individuals of childbearing age who identify their pregnancy status as unsure)  
 
 
Eligible subjects will be randomized into one of the 3 study arms & will complete baseline assessments of self-
reported fatigue, disability, sleep, exercise, self-efficacy, and other quality of life factors via online Redcap 
surveys.  
 
6.2  Home monitoring 7-day PRO-Diary application (EMA) – BASELINE AND WEEK 12 ONLY: After 
completing the above screening/baseline activities, participants will receive instruction on use of the PRO-
Diary® accelerometer watch, which the participant will wear during two separate 7-day “home monitoring” 
periods, at baseline (sent home with watch following baseline visit) and 12 weeks to assess physical activity 
(objectively measured via accelerometry), AND ecological momentary assessment (EMA) of fatigue intensity, 
fatigue impact, fatigability (ration of fatigue intensity/accelerometer activity counts), and sleep. See 
“Assessments” section. 
 
The 7-day monitoring period at 12 weeks will take place at the end of the study treatment interval; so 
that the home monitoring takes place before participants have discontinued their Modafinil, the 
assessment will begin approximately one week before the end of treatment for all treatment arms (i.e., 
home monitoring will conclude around 12 weeks post-treatment initiation).  
 
6.3 Randomization 
Following collection of baseline assessments, participants will be randomized during the baseline screening 
visit and assigned treatment.   
 
Randomization Process/Blinding: Subjects who meet criteria I/E criteria will be randomized using computer-
based randomization via http://cscar-randomization.appspot.com/ (1:1:1 randomization) to determine whether 
they will receive telephone based CBT monotherapy (Group 1, n~100), Modafinil monotherapy (Group 2, 
n~100), or combination therapy with both treatments (Group 3).  Statisticians and study staff who process data 
(subjects will enter data directly into the database, so no study personnel are directly collecting data) will 
remain blinded to group allocation for the duration of the study. The subject, PI, co-investigators, study 
interventionists, and coordinators will not be blinded.   
 
6.4 Interventions: see also section 5.3 
Participants assigned to modafinil or combination therapy will be encouraged to pick up their first supply of 
modafinil within 7 days of the baseline visit. For virtual visits, participants will receive their first supply of 
modafinil by mail. 
For those who receive CBT or combination therapy will also be able to schedule their first CBT session with the 
study team during or shortly after this baseline visit.  
Participants will be instructed to start their assigned treatment following the 7-day home monitoring period.  All 
treatments will be given for a total of 12 weeks, and treatments will begin after participants complete their first 
7-days of PRO-Diary home monitoring. 
6.5 Week 8, Week 12, and Week 24 Visits  
Group 1 (CBT monotherapy): Participants will have the option of completing all post-baseline REDCap 
assessments (week 8, 12, and 24) remotely (computer based assessments via weblink which will be provided, or 
paper forms by mail) or in-person.  An internet-connected device will be provided by the study staff member for 
the participant to complete the REDCap assessments if they choose to complete them during the study visit.  


Page 17 of 37 
 
For Week 12 home monitoring period, the watch and instructions for completing the monitoring and for 
returning the monitor following the 7-day monitoring period (accompanied by a pre-paid return envelope) will 
be mailed to participants, so that the materials are delivered to the participant ahead of the start of the 11th 
week. The study staff member will place a reminder call to the participant on or around the first day of the 
Week 12 home monitoring period and will answer any questions that participant has about completing the Week 
12 home monitoring. 
Group 2 (Modafinil monotherapy)*: Participants will have the option of completing all REDCap assessments 
remotely (computer based assessments via weblink which will be provided, or paper forms by mail), or or in-
person. An internet-connected device will be provided by the study staff member for the participant to complete 
the REDCap assessments if they choose to complete them during the study visit.  Participants will be able to 
receive drug refill at 8-week either in-person at UMHS (for in-person visit) or in the mail (for virtual visit). 
Participants will be encouraged to complete the Week 12 REDCap assessment during the final (12th) week of 
treatment, as close to the end of treatment as possible. For Week 12 home monitoring period, the PROdiary and 
instructions for completing the monitoring and for returning the PROdiary following the 7-day monitoring 
period (accompanied by a pre-paid return envelope) will be mailed to participants, so that the materials are 
delivered to the participant ahead of the start of the 11th week. The study staff member will place a reminder 
call to the participant on or around the first day of the Week 12 home monitoring period and will answer any 
questions that participant has about completing the Week 12 home monitoring. Participants will be asked to 
report number of remaining modafinil pills at the end of the treatment period and can either bring back any 
unused modafinil to the study personnel to properly dispose of it, or receive the drug destroyer via mail at the 
end of the 12-week treatment interval to properly dispose of any unused modafinil. 
Group 3 (Combination therapy)*:  
Participants will have the option of completing all REDCap assessments remotely (computer based assessments 
via weblink which will be provided, or paper forms by mail), or in-person. An internet-connected device will be 
provided by the study staff member for the participant to complete the REDCap assessments if they choose to 
complete them during the study visit.  Participants will be able to receive drug refill at 8-week either in-person 
at UMHS (for in-person visit) or in the mail (for virtual visit).   
Participants will be encouraged to complete the Week 12 REDCap assessment during the final (12th) week of 
treatment, as close to the end of treatment as possible. For Week 12 home monitoring period, the PROdiary and 
instructions for completing the monitoring and for returning the PROdiary following the 7-day monitoring 
period (accompanied by a pre-paid return envelope) will be mailed to participants, so that the materials are 
delivered to the participant ahead of the start of the 11th week. The study staff member will place a reminder 
call to the participant on or around the first day of the Week 12 home monitoring period and will answer any 
questions that participant has about completing the Week 12 home monitoring. Participants will be asked to 
report number of remaining modafinil pills at the end of the treatment period and can either bring back any 
unused modafinil to the study personnel to properly dispose of it, or receive the drug destroyer via mail at the 
end of the 12-week treatment interval to properly dispose of any unused modafinil. 
 
Participants who might be at risk for a sleep disorder (obstructive sleep apnea, restless leg syndrome, excessive 
daytime sleepiness, and clinical insomnia) which might require further evaluation or treatment based on 
assessments administered during the study will be notified by letter after their 12-week visit. The letter will 
recommend that they share the information with their primary care doctor. 
 
6.6 Assessment Windows 
Day 1 (start of Week 1) is designated as the point at which treatment starts; this will be somewhere between 7 
and 14 days after the baseline visit where randomization occurred. The treatment window is the 12 weeks 
between Day 1 and the end of Week 12.  
 


Page 18 of 37 
 
Efforts will be made to ensure that assessments are gathered as close to the target assessment time points (Week 
8, Week 12, and Week 24) as possible; however, unexpected circumstances often arise that make data collection 
at very specific time points difficult.  Therefore, we have established the following assessment windows.  If a 
participant is not able to complete the assessment during the designated assessment window, they will be 
allowed to stay in the study (at the site investigator discretion), completing any later assessments as they are 
able and willing.  
 
Protocol deviations will be completed for participants completing the assessments out of window, with the 
exception of the prescreening to screening assessment window. Protocol deviations will not be reported for self-
report survey data. Self-reported survey data at the baseline, 8 week, 12 week and 24 week surveys is not being 
collected to assess safety-related information (e.g., side effects, AEs). As is standard, participants are not 
required to answer any self-reported survey questions they do not wish do answer, and some participants opt to 
skip questions/surveys they are not comfortable with. If participants skip a question(s) on the surveys 
(administered online via REDCap), they will be prompted by REDCap that they have missed a question(s) and 
they can go back and answer or choose to proceed without answering. We have found that in previous studies, 
skipping questions is rare, and thus we do not expect it to affect data validity.  
 
Additionally, protocol deviations will not be reported for missed EMA assessments administered by the PRO-
Diary data during the home monitoring periods. We expect that there may be instances where participants are 
unable to complete the EMA questions (for example, if it alerts at a time that is inconvenient for them to answer 
or they forget to answer). Previous studies have shown that compliance with these repeated assessments is 
~75%. The EMA assessments do not assess safety so a missed assessment is not a safety concern. We expect 
that participants will miss some of these assessments and have selected the length of the home monitoring 
periods (7 days) to make sure data validity is not compromised if participants miss some of the EMA 
assessments.  
 
Any missed safety assessments will be reported as protocol deviations. Safety assessments are conducted by the 
coordinator in-person or by phone as applicable under the supervision of the study PIs during the baseline, 8 
week, 12 week and 24 week study visits and during any other contact with the participant (e.g., phone calls).  
 
1. 
Prescreening to Screening/Baseline Assessment Window: Study staff will aim to schedule the 
screening/baseline visit within 2 weeks of pre-screening. If the baseline visit is beyond 2 weeks from pre-
screening, a study staff member will ask prior to the visit if there has been any change (in fatigue, meds, 
pregnancy, MS relapses, etc.) since pre-screening.  
2. 
Baseline Home Monitoring Assessment Window: Participants will be given 14 days from their Baseline 
visit to complete their 7-day home monitoring period assessment. Although participants are asked to complete 7 
days of home monitoring, a minimum of 3 full days of home monitoring data will be considered adequate (this 
allows for lost data due to technology malfunction/user error/illness/etc.). 
3. 
Week 8 Assessment Window: A ± 2-week (± 14 days) window around the Week 8 assessment will be 
considered allowable for data collection, as long as participants have not allowed modafinil treatment to 
lapse/run out during this time period. 
4. 
Home Monitoring Prior to Week 12: The Week 12 PRO-Diary home monitoring data collection will 
ideally commence 7 days prior to the final day of modafinil administration.  A minimum of 3 days of 
monitoring during the final week of modafinil administration will be acceptable for completion of this data 
collection, as no monitoring should take place after modafinil has stopped; monitoring will cease following the 
last day of modafinil treatment even if an entire 7 days of data has not been collected.  
5. 
Week 12 Assessment Window: The Week 12 survey (REDCap) assessment can be completed up to 2 
weeks (-14 days) prior to the Week 12 visit, but if possible should be completed within the final week of 
modafinil treatment, and no later than final day of modafinil administration.  


Page 19 of 37 
 
6. 
Week 24 Assessment Window:  A ± 1-month (± 30 days) window around the Week 24 period will be 
allowed for collection of follow-up data.   
 
6.7 Treatment Windows 
CBT: For participants randomized to receive CBT, treatment will commence as soon after the last day of 
baseline PRO-Diary monitoring as therapist/participant schedules will allow. Efforts will be made to complete 1 
session per week for 8 consecutive weeks (main treatment sessions) followed by 2 approximately every-other-
week maintenance sessions (maintenance sessions).  However, flexibility in the scheduling of these sessions 
will allow for, at a minimum, completion of the 8 main treatment sessions within the 12-week treatment period. 
If needed, scheduling of >1 session/week, but no more than 2 sessions in a 7-day period is allowable to ensure 
that the full treatment is delivered in the 12-week treatment period. No treatment sessions will be delivered 
beyond the 12-week treatment period.  
 
Modafinil: For participants randomized to receive modafinil, treatment will commence the day after the last day 
of baseline PRO-Diary monitoring, and continue for a period of 12 consecutive weeks. For patients receiving 
combination therapy, Modafinil will start on or before first day of CBT.  
 
6.8 Participant Compensation 
Participants will be compensated $300 for full completion of the study.  For those who do not complete all 
study assessments, the compensation schedule is noted on the consent form and is as follows: 
 
Baseline Assessment: Participants will receive $100 for fully completing the baseline REDCap surveys and 
home monitoring period assessment. For those who do not complete both components of the baseline 
assessment, participants will receive $25 for completing REDCap survey measures & $75 for completing 
the home monitoring period assessments (minimum 3 days of data). 
 
Week 8 Assessment: Participants will receive $50 for completing the Week 8 REDCap surveys.  
 
Week 12 Assessment: Participants will receive $100 for fully completing the Week 12 REDCap surveys 
and home monitoring period assessment. For those who do not complete both components of the Week 12 
assessment, participants will receive $25 for completing REDCap survey measures & $75 for completing 
the home monitoring period assessments (minimum 3 days of data).  
 
Week 24 Assessment: Participant will receive $50 for completing the Week 24 REDCap surveys.  
 
Participants will be compensated for assessments after each completion; thus, they may be remitted up to 
four separate payments, after completion of each assessment period.  
 
 


Page 20 of 37 
 
6.9 SCHEDULE OF ACTIVITIES 
 
 
Study Activity 
Baseline 
(week -1 
to -2 ) 
Weeks  
1-7** 
Week 8 
Weeks  
9-11 
Week 12 
Weeks 
13-23 
Week 24 
Demographics 
X 
 
 
 
 
 
 
Medical/Surgical 
History 
X 
 
 
X 
 
X 
 
X 
Interview with a 
Neurologist for 
assessment of 
eligibility 
X 
 
 
 
 
 
 
Krupp’s Fatigue 
Severity Scale 
(FSS) 
X 
 
 
 
 
 
 
Patient Health 
Questionnaire-3 
X 
 
 
 
 
 
 
Medication review 
X 
 
X 
 
X 
 
X 
Baseline urine 
Pregnancy test if 
applicable 
X 
 
 
 
 
 
 
AE/SAE review (all 
participants)* 
X 
 
X 
 
X 
 
X 
Randomization 
X 
 
 
 
 
 
 
Modafinil 
dispensing (for 
Groups 2 and 3) 
X 
 
X 
 
 
 
 
Study Intervention 
Administration 
 
X 
 
X 
 
X 
X 
 
 
Treatment 
adherence 
 
 
X 
 
X 
 
 
Treatment 
Utilization Patterns 
(post-intervention) 
 
 
 
 
 
 
X 
Excess modafinil 
destruction (if 
applicable)  
 
 
 
 
X 
 
 
Computer-based self-report measures 
Modified Fatigue 
Impact Scale 
(MFIS) 
X 
 
 
X 
 
X 
 
X 
EDSS self-report 
X 
 
 
 
 
 
 
STOP-BANG 
questionnaire 
X 
 
 
 
 
 
 
RLS Index 
X 
 
 
 
 
 
 


Page 21 of 37 
 
Epworth Sleepiness 
Scale 
X 
 
 
X 
 
X 
 
X 
Insomnia Severity 
Index 
X 
 
 
 
 
 
 
Sleep Hygiene 
Index 
X 
 
 
X 
 
X 
 
X 
Patient Health 
Questionnaire-8 
X 
 
 
X 
 
X 
 
X 
Generalized 
Anxiety Disorder-7 
X 
 
 
X 
 
X 
 
X 
Brief Pain 
Inventory 
X 
 
X 
 
X 
 
X 
Exercise (Godin) 
X 
 
X 
 
X 
 
X 
PROMIS Self-
Efficacy Scale 
X 
 
X 
 
X 
 
X 
PROMIS Cognitive 
Function 
X 
 
X 
 
X 
 
X 
MSQOL54- Quality 
of Life Subscale 
X 
 
X 
 
X 
 
X 
NeuroQoL Ability 
to Participate in 
Social Roles & 
Activities 
X 
 
X 
 
X 
 
X 
Post-Treatment 
Questionnaire 
 
 
 
 
X 
 
X 
Patient Global 
Impression of 
Change 
 
 
 
 
X 
 
X 
7-day home monitoring (PRO-Diary) measures 
Physical Fatigue 
Severity (4x/day) 
X 
 
 
 
X 
 
 
Mental Fatigue 
Severity (4x/day) 
X 
 
 
 
X 
 
 
Physical Fatigue 
Impact (4x/day) 
X 
 
 
 
X 
 
 
Mental Fatigue 
Impact (4x/day) 
X 
 
 
 
X 
 
 
Wake up time 
(1x/day) 
X 
 
 
 
X 
 
 
Bed time (1x/day) 
X 
 
 
 
X 
 
 
Sleep refreshed 
(1x/day) 
X 
 
 
 
X 
 
 
Rest breaks 
(1x/day) 
X 
 
 
 
X 
 
 
Cognitive clarity 
(1x/day) 
X 
 
 
 
X 
 
 
Cognitive speed 
(1x/day) 
X 
 
 
 
X 
 
 


Page 22 of 37 
 
Pain Severity 
(1x/day) 
X 
 
 
 
X 
 
 
Daytime physical 
activity 
(continuous) 
X 
 
 
 
X 
 
 
* For Modafinil-treated participants in Group 2 and 3, AE/SAE review will be additionally assessed at the 
following time intervals:  
- 2-4 days after starting Modafinil 
- 7-10 days after starting Modafinil 
 
**Activities marked Week 1-7 begin after the baseline assessments, which include a 7-day home monitoring 
period. 
 


Page 23 of 37 
 
7.  ASSESSMENTS  
 
7.1.1 Primary Outcome Assessments (see also section 7.1.3) 
The Modified Fatigue Impact Scale (MFIS, primary outcome measure)1,2: is a patient-reported 
21-item validated measure of fatigue impact based on patients’ recent personal experience as it 
relates to physical, cognitive, and psychosocial functioning.  The MFIS has been shown to be 
sensitive to changes secondary to interventions.  Scores range from 0-84.  Higher scores indicate 
more fatigue.   
 
7.1.2 Secondary/exploratory outcome assessments, effect modifier measures, screening 
measures (see also section 7.1.3) 
Self-reported Expanded Disability Status Scale (SR-EDSS)3: is a validated self-report version of 
the clinician-administered EDSS; scores on the SR-EDSS correspond highly with clinician-rated 
EDSS. 
 
STOP-Bang Questionnaire: The STOP-Bang is a validated, 8-item screening instrument that 
assesses characteristics known to confer risk for OSA, and form the acronym “STOP-BANG” 
(Snoring, Tiredness, Observed apneas, high blood Pressure, BMI, Age, Neck circumference, 
Gender).4 Item scores (1/0) are based on yes/no answers. Scores ≥3 indicate elevated risk for 
sleep apnea.  
 
Krupp’s Fatigue Severity Scale (FSS)5 – I/E criterion: The FSS is a validated, 9-item instrument 
that measures the impact of fatigue on multiple outcomes, with a physical focus.  Prior studies 
have shown acceptable internal consistency and stability over time, and sensitivity to change that 
correlates with the subject’s clinical improvement.  Many if not most past studies on MS-related 
fatigue have used the FSS.  
 
Epworth Sleepiness Scale (ESS)6: The ESS is an 8-item questionnaire that asks about the 
likelihood of dozing in variably sedentary situations. This commonly used measure of subjective 
sleepiness, or sleep propensity, is reliable, internally consistent, and validated against objective 
polysomnographic measures.  A score ≥10 suggests excessive sleepiness. 
 
Insomnia Severity Index (ISI)7,8: The Insomnia Severity Index (ISI) is a 7-item questionnaire 
with 5-point Likert scale responses designed to assess the nature, severity, and impact of 
insomnia in adults. Scores of 15 or higher reflect moderate clinical insomnia.   
 
Sleep Hygiene Index (SHI)9: The Sleep Hygiene Index is a 13-item self-report measure designed 
to assess the practice of sleep hygiene behaviors. Each item is rated on a five-point scale ranging 
from 0 (never) to 4 (always). Total scores range from 0 to 52, with a higher score representing 
poorer sleep hygiene . 
Restless Legs Syndrome Diagnostic Index (RLS-DI)10,11: is a 10-item questionnaire designed to 
improve diagnostic decision making in suspected cases of RLS.  This instrument incorporates 
essential diagnostic criteria with additional supportive criteria to rule out false positive cases, 
which can occur in patients with MS.  A score of +11 yields a 93% sensitivity and 96% 
specificity to diagnose RLS.   


Page 24 of 37 
 
 
The Patient Health Questionnaire –8 (PHQ-8)12:  assesses frequency of 8 depressive symptoms 
in the past 2 weeks. It has been validated in MS and provides clinical cut-points ranging from no 
depression to severe depression (range 0-24).  
 
Patient Health Questionnaire-212,13 plus item 9/i from the PHQ-914 (PHQ-3) – I/E criterion: 
assess the frequency of 3 depressive items in the past two weeks. The PHQ-2 has been validated 
as a depression screen and item 9/i from the PHQ-9 is used to assess for suicidal ideation.   
 
The Brief Pain Inventory (BPI)15,16: assesses both pain intensity (4 items) as well as pain 
interference in multiple life domains (7 items) and has demonstrated good psychometric 
characteristics, including validity, in MS. 
 
The Generalized Anxiety Disorder – 7 (GAD-7)12,17: is a commonly used anxiety measure that 
assess 7 symptoms of anxiety in the past 2 weeks, and provides clinical cut-points for anxiety 
severity (scores range 0 – 21).  
 
The Godin Leisure-Time Exercise Questionnaire18: is a brief, 4-item measure of the frequency 
and intensity of exercise during “a typical week” that has been frequently used in MS clinical 
research and has even been used to validate accelerometer measures of physical activity in MS.   
 
Neuro-QoL Ability to Participate in Social Roles & Activities 8-item Short Form19,20: is an 8-
item measure of a person’s ability to participate in various social roles and activities across a 
range of social domains (home/family, recreation).  Raw scores range from 8-40, with higher 
scores indicating better ability to participate. T scores, with a Mean=50 and SD=10 can be 
calculated for comparison to a normative sample of individuals with neurological conditions.  
This measure has been validated in MS. 
 
Patient Reported Outcomes Measurement Information System (PROMIS) Self-Efficacy for 
Managing Symptoms Short Form 8a21,22: is an 8-item measures developed to assess confidence 
or self-efficacy for managing symptoms and is meant to be used across clinical conditions. Raw 
scores range from 8-40 and T-scores have a Mean=50, SD=10; higher scores indicate greater 
self-efficacy.   
 
Patient Reported Outcomes Measurement Information System (PROMIS) Cognitive Abilities 
Short Form 8a: is an 8-item measure that assesses perceived cognitive function. Raw scores 
range from 8-40 and T-score have a Mean = 50, SD=10; higher scores indicate greater cognitive 
functioning.  This measure has demonstrated good reliability and validity in MS23.  
 
Patient Global Impression of Change (PGIC)24: is a commonly-used single-item measure that 
assesses perceived overall change across multiple life domains since beginning treatment. Higher 
scores indicate greater improvement since treatment was initiated.  
 
Quality of Life Subscale from the Multiple Sclerosis Quality of Life-54 Instrument25-27: contains 
two items that assess perceived general quality of life.  The possible range is 0-100 with higher 
values indicating higher quality of life.  
 


Page 25 of 37 
 
Post-Treatment Questionnaire; contains questions about the patient intent to continue the 
treatment they received during the 1st 12 weeks (on a clinical basis), their reasons for doing so, 
and means/barriers to obtaining this treatment. This questionnaire will be administered at 12 and 
24 weeks. 
 
Ecological Momentary Assessment (EMA) measures: Eleven EMA items were created (adapted 
from validated surveys) to assess fatigue, fatigue impact, sleep, pacing, cognitive function, and 
pain. EMA items are as follows: 
 
1) Physical Fatigue (four times daily): 
What is your level of physical (bodily) fatigue right now? on a scale of 0 – 10, where 0 = 
No Fatigue and 10 = Extremely Severe Fatigue. 
2) Mental Fatigue (four times daily): 
What is your level of mental (brain) fatigue right now? on a scale of 0 – 10, where 0 = No 
Fatigue and 10 = Extremely Severe Fatigue. 
3) Physical Fatigue Interference (four times daily): 
How much is your physical fatigue interfering with what you are doing right now?  on a 
scale of 0 – 10, where 0 = no interference and 10 = totally interfering; not able to do what 
I want because of fatigue.  Slight change in wording for bedtime: How much did your 
physical fatigue interfere with what you were doing leading up to your bedtime?  On a 
scale of 0 – 10, where 0 = no interference and 10 = totally interfered, was not able to do 
what I wanted because of fatigue. 
4) Mental Fatigue Interference (four times daily): 
How much is your mental fatigue interfering with what you are doing right now?  on a 
scale of 0 – 10, where 0 = no interference and 10 = totally interfering; not able to do what 
I want because of fatigue.  Slight change in wording for bedtime: How much did your 
mental fatigue interfere with what you were doing leading up to your bedtime?  On a 
scale of 0 – 10, where 0 = no interference and 10 = totally interfered, was not able to do 
what I wanted because of fatigue. 
5) Wake Up Question (administered once daily): 
What time did you wake up this morning?  
6) Go To Bed Question (administered once daily): 
What time did you go to bed [last night]? 
7) Sleep (administered once daily at wake): 
How refreshed did you feel when you woke up this morning? on a scale from 0-10 where 
0=Totally Unrefreshed (not at all rested) and 10=Totally Refreshed (restored, revitalized, 
ready to start the day). 
8) Rest Breaks (administered once daily at bedtime) 
Today, how often have you taken rest breaks to do your activities? On a scale where 0 = 
Not at all, 5 = Sometimes, and 10 = Always.  
9) Cognitive Clarity (administered once daily at bedtime) 
Today, on average, my thinking was: Please rate on a scale of 0-10 where 0 = very clear 
to 10 = very foggy 
10) Cognitive Speed (administered once daily at bedtime) 
Today, on average, my thinking was: Please rate on a scale of 0 – 10, where 0 = very fast 
to 10 = very slow 


Page 26 of 37 
 
11) Pain (administered once daily at bedtime) Today, what was your average level of 
pain?  On a scale where 0 = no pain at all and 10 = worst pain imaginable 
 
Covid Impact Survey: The COVID-19 Impact Survey was designed to assess impacts of 
COVID-19 on participants that could have an effect on study outcomes. It was adapted from the 
COVID-19 Exposure and Family Impact Survey (CEFIS), developed by The Center for Pediatric 
Traumatic Stress. Part 1 consists of 22 items that measure the participants’ “exposure” to 
COVID-19 and related events. The Exposure Score is a count of “yes” responses and may range 
from 0 to 22. Part 2 consists of 13 items that measure the impact of COVID-19. 10 items use a 
five-point Likert scale rating impact on participant’s and family’s life; 1 item uses an 11-point 
distress scale. Higher scores denote more negative impact / higher distress. The Impact Score 
(sum of items 23-35) may range from 12 to 70. Part 3 is an open-ended question so that 
participants can expand upon their experiences and add effects of COVID not covered in the 
other questions. 
 
 
7.2  Data Collection Technologies 
7.2.1 The PRO-Diary  
The PRO-Diary is a wrist-worn accelerometer enhanced with a user interface that allows for 
input of real-time self-reported data. The PRO-Diary will be used in this study to provide 
optimally sensitive assays of fatigue intensity, fatigue impact, physical activity, and fatigability 
(calculated using fatigue severity and activity measures). Ratings at wake and bedtime will be 
initiated by the participant upon waking (not necessarily when they get out of bed) and at 
bedtime (“lights out” or the time they intend to go to sleep, not necessarily the time they get into 
bed). An audible alarm will alert participants to use the touch screen to log symptom ratings at 2 
times between 11am and 7pm. The PRO-Diary collects physical activity data as ‘activity counts’ 
in 15 second epochs during the home monitoring period and stores time-stamped self-report data 
until the watch is returned to the lab, for data download, cleaning and analysis. The PRO-Diary 
also generates accelerometer-derived sleep variables, based on physical activity during sleep.  
These variables include, sleep duration, wake after sleep onset, sleep latency, and sleep 
efficiency.  
 
7.2.2 REDCap 
This study will use REDCap, a secure, password protected, and HIPAA compliant web-based 
data platform hosted by the Michigan Institute for Clinical and Health Research (MICHR) at the 
UM for data capture and storage. This protected database will be accessed and maintained by 
study personnel only. This system features both a local and remote web-based interface, secure 
data transfer, and an Oracle database. Data security, patient privacy, and HIPAA requirements 
are a premium consideration for clinical trials research using REDCap. A complete time-stamped 
audit of all REDCap activity (including which and when study personnel access data) is 
maintained, adding to the security and fidelity of the data. Study personnel can enter data into the 
database through administrative access to add to the self-report data provided by participants. For 
self-report data collection, participants will access individualized study urls to securely enter data 
either during clinic visits or at a time of their choosing on an internet-connected device of their 
choosing (for home-based assessments).  
 


Page 27 of 37 
 
Participant email addresses will be used to send the follow-up survey links. Participant emails 
will be stored in REDCap. The University of Washington study staff will be able to view only 
email addresses of University of Washington participants, but as the data coordinating center, the 
University of Michigan study staff will have access to email address for all study participants, 
including those from University of Washington. 
 
7.2.3 M+Box 
Transfer (from UW to UM) of accelerometer/EMA data from the PRO-Diary will be achieved 
via M+Box, which is Michigan's implementation of the Box.com cloud storage and collaboration 
service. It is capable of handling PHI and other sensitive data (e.g., research data). We have used 
M+Box extensively in previous studies to transfer PRO-Diary data to the lead site for data 
cleaning and analysis. After it is cleaned and scored, the PRO-Diary data will be later merged 
with the REDCap data prior to analysis.  
 
7.2.4 SignNow  
This study will use SignNow to request and obtain digital signatures on informed consent 
document from participants who conduct their baseline visit virtually. SignNow software is an E-
Signature service available for use by U-M staff, faculty, researchers, and students associated 
with all University of Michigan campuses (i.e., Ann Arbor, Dearborn, Flint and Michigan 
Medicine). SignNow is HIPAA and FDA 21 CFR Part 11 compliant for patient signatures. 
 
7.3 General Medical History 
General medical history will be assessed at baseline and in all follow-up visits.  Subjects will be 
queried about any chronic or ongoing health conditions pertinent to MS, fatigue, or potential 
Modafinil side effects that require treatment (which will be recorded in the CRF).  Subjects will 
also be asked to provide their list of medications and allergies. 
 
7.4 Concomitant Medication Use 
Concomitant medications will be assessed at each visit and/or phone contact and recorded in the 
CRF. 
 
7.5 Adverse Event Assessments 
Adverse events that are NOT related to the normal course or chronic symptoms of MS 
(such as relapses, MRI progression, somatic pain, weakness, numbness, visual disturbances, 
bladder/bowel symptoms) or events that are expected to occur in the course of daily life or use of 
disease modifying therapy (injuries, infections, disease modifying therapy infusion reactions, 
disease modifying therapy injection site reactions, disease modifying therapy-induced 
lymphopenia) will be assessed/collected at each visit, scheduled phone call, or unscheduled 
phone call.   
Participants will be queried about any symptoms they have been experiencing while on 
the study, with directed questions toward adverse outcomes previously reported with the study 
treatments (including headache, nausea, nervousness, rhinitis, diarrhea, anxiety, insomnia, 
dizziness, dyspepsia, worsening depressive symptoms, psychosis, increased suicidality) or 
suspected allergic reactions: rash, hives, mouth sores, blisters, swelling of your face, eyes, lips, 
tongue, or throat, trouble swallowing or breathing, fever, shortness of breath, swelling of the 
legs, yellowing of the skin or whites of the eyes, or dark urine. 


Page 28 of 37 
 
 
8.  ADVERSE EVENT REPORTING 
Multiple Sclerosis is a disease with many disease-related symptoms and complications, and there are 
many common mild side effects associated with disease modifying therapy use.  Due to the patient 
population and the nature of the disease, as well as the lack of experimental interventions in this 
study (only standard of care procedures and treatments will be used) we would like to implement the 
following AE/SAE collection/reporting guidelines: 
 
SAE events that meet all 3 of the following criteria will be collected and submitted to the IRB: 
•     Serious;  
•     Related; and 
•     Unexpected 
 
SAEs that are unrelated, regardless of expectedness, will not be reported to the IRB. 
 
In addition, the following AEs will be collected and submitted to the IRB: 
 
•     Any related and unexpected AE that results in a change to research or participant’s 
treatment plan 
 
The medical monitor (see section 10.2) will also receive reports of all AEs collected in section 7.5, 
and SAEs regardless of expectedness or relatedness. 
 
8.1 AE/SAE relatedness: 
 
a. Definitely related: clearly associated with study drug/treatment 
b. Probably related:  likely associated with study drug/treatment 
c. Possibly related:  may be associated with study drug or other treatment 
d. Unlikely to be related, or 
e. Definitely not related to the study drug/treatment 
 
For reporting purposes, an AE should be regarded as definitely or probably related to the regimen if 
the investigator believes that at least one of following criteria are met: 
 
a. There is a clinically plausible time sequence between onset of the AE and the administration of 
the study drug or treatment. 
b. There is a biologically plausible mechanism for the study drug or treatment causing or 
contributing to the AE. 
c. The AE cannot be attributed solely to concurrent/underlying illness, other drugs, or procedures.  
d. A potential alternative cause does not exist. 
 
 
8.2. Serious Adverse Events (SAE) Definition:  An adverse drug experience occurring at any dose 
that results in any of the following outcomes: 
 
a. 
Death 
b. 
A life-threatening adverse drug experience 


Page 29 of 37 
 
c. 
Inpatient hospitalization or prolongation of existing hospitalization 
d. 
A persistent or significant disability &/or incapacity 
e. 
A congenital anomaly or birth defect 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. A serious adverse experience 
includes any experience that is fatal or immediately life threatening, results in a persistent or 
significant disability/incapacity, requires or prolongs in-patient hospitalization, or is a congenital 
anomaly, cancer, or overdose. 
 
Other important medical events that may not result in death, not be life-threatening, or not require 
hospitalization may be considered a serious adverse experience when, based upon appropriate 
medical judgment, the event may jeopardize the subject/patient and may require medical or surgical 
intervention to prevent one of the outcomes listed previously. 
 
8.3 AE/SAE Expectedness:  
Expected adverse events are those adverse events that are listed in the protocol, the Investigator’s 
Brochure (current edition) or in the study informed consent document. 
 
Unexpected adverse events are those that: 
 
a. are not described in the Investigator's Brochure, approved label, or the clinical protocol as far as 
the study drug is concerned. 
b. are not anticipated in the study informed consent.  This includes adverse events for which the 
specificity or severity is not consistent with the description in the informed consent. 
 
Unanticipated problem: Per FDA Procedural Guidance for Clinical Investigators, Sponsors, and 
IRBs (January 2009), a serious problem that has implications for the conduct of the study (requiring 
a significant and usually safety-related, change in the protocol such as revising inclusion/exclusion 
criteria or including a new monitoring requirement, informed consent or investigator’s brochure). 
 
Unanticipated problem Reporting: Per 21 CFR 312.66, 312.53 (c)(1)(vii), and 56.108(b)(1), 
should an Unanticipated problem occur during the investigation, the investigator will promptly 
report all unanticipated problems involving risks to human subjects or others to IRBMED and 
FDA according to the reporting requirements and guidelines. 
 
 
 
8.4 AE/SAE severity: The severity or grade of an adverse event may be measured using the 
following definitions: 
 
Mild:  Noticeable to the subject, but does not interfere with subject’s expected daily activities, 
usually does not require additional therapy or intervention, dose reduction, or discontinuation of the 
study. 
 


Page 30 of 37 
 
Moderate:  Interferes with the subject’s expected daily activities, may require some additional 
therapy or intervention but does not require discontinuation of the study. 
 
Severe: Extremely limits the subject’s daily activities and may require discontinuation of study 
therapy, and/or additional treatment or intervention to resolve. 
 
 
 
9.0 DATA ANALYSIS/STATISTICAL METHODS 
 
9.1 Sample Size Determination 
Estimates are derived from recent data from the study team, and published interventional studies 
of modafinil and CBT monotherapy.  The primary sample size determinant for this study is Aim 
1.   
 
For Aim 1, we have chosen the Modified Fatigue Impact Score (MFIS) as the primary outcome 
variable of interest.  The MFIS has been validated in MS patients, is frequently used in MS 
clinical studies as a reliable measure of fatigue, and is sensitive to changes in intervention.  The 
primary outcome measure will be the mean within-subject difference between baseline and 12-
week MFIS values (delta-MFIS), compared between groups. Based on a power analysis of 2-
sample means (combined monotherapy groups vs. combination therapy, group weights 2:1), with 
a 2-sided alpha of 0.05 and standard deviation of 12, a sample size of n=300 subjects will 
provide 92% power to detect a delta-MFIS of 5 between the monotherapy and combination 
treatment arms (see power curve); this difference is similar to group differences found in 
previous fatigue trials.            
 
For Aim 2 analyses, using fatigue outcomes as the dependent variables (in separate models) a 
multiple linear regression power analysis was performed assuming a full model consisting of up 
to 11 possible predictor variables: treatment group, presence of sleep disturbance (yes/no), 
depression severity (PHQ-9 Score), disability severity (EDSS score), 3 interaction terms 
(treatment*sleep, treatment*depression, and treatment*disability), baseline fatigue level, anxiety, 
pain, and exercise. A similar model will also be constructed using MS subtype and 
treatment*MS subtype interaction term, (in place of EDSS) to determine if subtype conveys 
differences in fatigue outcome separate from pure disability measures.  Based on a sample size of 
n=300, we will have 85% power to detect an R-square difference of 0.04 for the interaction term 
of interest, assuming the R-squared explained by the adjustment variables is at least 0.3.   
 
For Aim 3, using treatment adherence as the dependent variable (continuous outcome), a 
multiple linear regression power analysis was performed assuming a full model consisting of up 
to 8 possible predictor variables: treatment group (independent variable of interest), age, gender, 
EDSS score, baseline fatigue level, baseline activity level, presence of sleep disturbance 
(yes/no), and depression severity (PHQ-9 Score). Based on a sample size of n=300, we will have 
95% power to detect an R-square difference of 0.03 for the test predictor of interest, assuming 
the R-squared explained by the adjustment variables is at least 0.3.   
 
9.2 Analysis of Study Aims: 


Page 31 of 37 
 
Aim 1: Compare the effectiveness of 3 therapies: CBT monotherapy, modafinil monotherapy, and 
CBT+modafinil combination therapy on patient-reported fatigue impact (primary outcome), 
fatigue intensity, and fatigability among fatigued individuals with MS. The primary outcome 
measure will be the mean difference in Modified Fatigue Impact Scale (MFIS) score between 12 
weeks and baseline (delta-MFIS), compared between treatment groups.   A repeated measures 
mixed effects model will be applied. The mean difference will also be adjusted for baseline 
covariates: age, gender, anxiety, pain, and exercise, which were included as covariates based on 
their established association between fatigue and/or activity in MS. Additional secondary 
analyses will also evaluate treatment effect on EMA outcome measures of fatigue impact, fatigue 
intensity, and fatigability. 
 
Aim 2: Test whether depression, sleep disturbances, or MS disability level modify comparative 
treatment responsiveness across treatment arms in terms of fatigue impact (HTE analyses). 
Treatment group effect on fatigue impact scores, fatigue intensity, and fatigability among select 
subgroups, including those with clinically significant depression, progressive MS subtype and 
higher EDSS scores, and confirmed/suspected sleep disorders not related to poor sleep hygiene, 
will be evaluated with interaction terms in mixed effects models as above. 
 
Aim 3: Compare adverse events, side effects, treatment adherence, and patient dropout rates 
among the three treatment arms and patient subgroups of interest.   Descriptive statistics will be 
used to analyze patterns of adverse events including side effects (incidence, type, severity, and 
relatedness) and treatment adherence between treatment groups (modafinil vs. CBT vs. 
combination therapy) throughout the 12-week intervention interval.  Adverse event frequency 
between treatment groups and among subgroups of interest will be evaluated using ANOVA. 
Multiple linear regression models adjusted for age, gender, EDSS score, baseline fatigue level, 
baseline activity level, presence of sleep disorder (yes/no), and depression severity (PHQ-8 
Score) will be used to determine association between treatment group and treatment adherence 
(percent usage of prescribed therapy).  We also will assess whether degree of treatment effects 
measured in Aim 1 are related to treatment adherence (e.g. “dose response”).       
 
9.3 Analysis of Exploratory Aims: 
Additional analyses modeled as in 9.2 above will also evaluate treatment effect on the difference 
between 8 week and baseline MFIS scores, to assess whether treatment effects are detectable 
prior to the 12-week assessment period.  
 
Additional analyses modeled as in 9.2 above will also evaluate treatment effect on the difference 
between 24 week and baseline MFIS scores, to assess whether treatment effects are detectable 
following the 12-week assessment period.  
 
Descriptive statistics will be used to summarize clinical treatment utilization patterns between 
12-24 weeks, following the 12-week intervention interval. 
 
Analyses modeled as in 9.2 will also be used to evaluate treatment effects on other outcomes at 
12 and 24 weeks. We will examine differential treatment effects on changes in the following 


Page 32 of 37 
 
factors (assessed via survey): ability to participate in social roles and activities, pain interference, 
quality of life, and self-efficacy for managing MS symptoms. We will also examine differential 
treatment effects on changes from baseline to 12 and 24 weeks in the following outcomes that 
were assessed via survey and/or EMA: pain intensity, perceived cognitive functioning, and 
pacing behaviors. Treatment group differences in scores on the PGIC measure at 12 and 24 
weeks will be examined in models similar to the approach described in 9.2.  
 
If potential mediators of the treatment effects, such as self-efficacy for managing symptoms, 
sleep, depressed mood, and anxiety, show significant changes from baseline to 8 weeks, 
mediational analyses, either structural equation modeling or mixed effects regression models will 
be used to test whether the effects of the treatment arms are mediated through common (simple 
mediational analyses) or different (moderated mediation) mechanisms.  
 
10. MONITORING 
 
10.1 Data Safety Monitoring Plan 
The Clinical Trial Monitor from the Michigan Institute of Clinical Health Research (MICHR) 
will set up a monitoring plan to include scheduled and as needed in person and remote 
monitoring visits to confirm the accuracy of study data, review study documents (including 
informed consents), and assess compliance with human subjects research.  
 
10.2 Independent Medical Monitor 
This study also has an assigned medical monitor who is not part of the study team (Brandon 
Moss, MD). The primary responsibilities of the Medical Monitor include:  
 
1. 
Provide feedback for protocol changes, if needed 
2. 
Review/provide written feedback/sign off on captured AEs and withdrawals annually (in 
aggregate, to coincide with annual IRB continuing review) 
3. 
Review/provide verbal feedback/sign off SAEs/unanticipated problems as they arise, 
depending on relatedness of the intervention 
4.       Assist with decisions about treatment withdrawal or dose reduction, on a case by case 
basis as they arise, for AEs thought to be probably related or definitely related to one of the 
interventions, regardless of expectedness. 
 
10.3 Monitoring Plan and Information  
To assure adequate protection of the rights of human subjects, per 21 CFR 312.50 and 312.53, 
the study will be monitored to ensure that the study is implemented in accordance with the 
protocol and applicable federal and local regulations, that proper informed consent procedures 
were followed and to insure the integrity and quality of the data. 
 
A qualified trial monitor will be selected, per 21 CFR 312.53(d) to monitor this multi-site trial in 
accordance with the protocol and all applicable regulatory requirements.  A monitoring plan will 
be established to ensure the quality and integrity of the data through pre-investigation, periodic 
site visits (both sites), review of adverse events/subject records, etc.  The Michigan Institute for 
Clinical and Health Research (MICHR) will assist with the selection and support of the monitor 
assigned for this proposed clinical investigation and prepare the monitoring plan.  


Page 33 of 37 
 
 
11.  DATA HANDLING AND RECORD KEEPING 
 
11.1 CRFs / Electronic Data Record 
CRFs, in paper or electronic format, will be utilized and maintained by the study staff.  Entries 
made in the CRF must be verifiable against source documents, unless the CRF is considered to 
be the source document.   
 
11.2 Record Retention 
Per 21 CRF §312.62, study records will be retained for a minimum of 7 years after the 
investigation is discontinued. 
 
12.  ETHICS 
 
12.1 Institutional Review Board 
Prior to study commencement, the study will be reviewed and approved by the Institutional 
Review Board (IRBMED, University of Michigan, Ann Arbor, MI). 
 
12.2 Subject Information and Consent 
A study team member will explain to each subject the nature of the study, its purpose, the 
procedures involved, the expected duration, the potential risks and benefits involved and any 
discomfort it may entail.  Each subject will be informed that participation in the study is 
voluntary and that he/she may withdraw from the study at any time and that withdrawal of 
consent will not affect his/her subsequent medical treatment or relationship with the treating 
physician. 
 
This informed consent will be given by means of a standard written statement, written in non-
technical language. The subject should read and consider the statement before signing and dating 
it, and should be given a copy of the signed document. No patient can enter the study before 
his/her informed consent has been obtained. 
 
The informed consent form is considered to be part of the protocol, and will be submitted for 
IRB approval. 
 
13.  STUDY DISCONTINUATION CRITERIA 
 
Treatment Stopping Rules for Safety Reasons 
 
1. Any SAE, as defined in section 8.2. 
 
2. Psychosis, severe/uncontrolled depression, or increased suicidality.  Participant behavior or 
comments that suggest imminent threat of suicide will prompt immediate 911 activation.  
Behavior or comments that suggest suicide ideation with plan but no immediate threat will 
prompt psychiatric ER referral 
 


Page 34 of 37 
 
3. Participants who demonstrate physical, emotional, or behavioral signs that are thought to be 
probably related or definitely related to one of the interventions, and in whom dose 
adjustments have failed* or are not an option 
 
Modafinil Specific Stopping Rules for Safety reasons 
 
1. Pregnancy.   
 
2. Suspected allergic reactions: rash, hives, mouth sores, blisters, swelling of your face, eyes, 
lips, tongue, or throat, trouble swallowing or breathing, fever, shortness of breath, swelling of 
the legs, yellowing of the skin or whites of the eyes, or dark urine. 
 
3. Participants who decide to start another fatigue treatment medication (stimulant or wake-
promoting agent) such as amantadine (Symmetrel), modafinil (Provigil), short or long acting 
methylphenidate (Ritalin/Concerta), dextroamphetamine (Dexedrine), dextroamphetamine-
amphetamine (Adderall, Adderall XR), lisodexamfetamine (Vyvanse), armodafinil (Nuvigil), 
or amphetamine (Adzenys XR-ODT, Dyanavel XR, and Evekeo)amantadine, 
methylphenidate, or amphetamine during the study. 
 
* Participants who experience intolerable but common side effects associated with modafinil 
(headache, nausea, nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, and 
dyspepsia), that do not fulfill SAE criteria, will be required to stop modafinil at the dose which was 
associated with the symptoms, but upon improvement of symptoms, may be allowed to restart the 
medication at ½ of the dose that previously led to prior symptoms.  Participants who still continue to 
experience symptoms after a re-challenge with ½ dose modafinil will be instructed to discontinue 
modafinil. 
 
Off-Study Criteria 
For participants who must have modafinil withdrawn for safety or ineligibility will still be 
encouraged to stay in the study for observation (and ongoing CBT, for combination treatment 
group) until completion unless they choose not to.  
 
Discontinuation of a Subject 
In the event a patient drops out of the study or is lost to followup, all attempts will be made to 
exit the patient in accordance with the protocol requirements. The reason for discontinuation 
(and the person who decided that discontinuation was necessary) will be recorded. 
 
14. ENGAGEMENT 
 
All patient stakeholders and study team members will participate in regular in-person or webinar 
meetings. At these meetings, aspects of the study will be reviewed, including study protocol and 
progress, interim regulatory issues, patient recruitment/enrollment/retention reports, operational 
issues, adverse events, and treatment adherence. Stakeholders and study team will mutually 
decide if strategic changes are required, and if so, will require stakeholder approval.  
 
Stakeholders will: 


Page 35 of 37 
 
• 
Participate in study monitoring.  If milestones are not met, or are not likely to be met 
based on current methods, stakeholder feedback will be solicited to enhance delivery of 
milestones. 
• 
Assist with distribution of recruitment materials. 
• 
Assist with solicitation of clinic patients. 
• 
Participate in development of a pre-screening procedure so that all potentially-eligible 
patients are identified in a standardized fashion.  
• 
Be involved in authoring and reviewing dissemination materials. 


Page 36 of 37 
 
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