A Phase I Randomized Controlled Trial of a Positive Psychology Intervention for Patients With Multiple Sclerosis
Phase: NA
Conditions: Multiple Sclerosis
Sponsor: Brigham and Women's Hospital

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A Phase I Randomized Controlled Trial of a Positive Psychology Intervention for Patients With 
Multiple Sclerosis 
 
 
 
 
NCT03637699 
 
 
 
 
Version 2.14.2018 
 
 
 

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DETAILED PROTOCOL 
 
I.  BACKGROUND AND SIGNIFICANCE 
 
Living with multiple sclerosis (MS), a chronic autoimmune disease characterized by an 
unpredictable and variable course, presents a significant challenge for many patients. Depression 
and anxiety are common, occurring in up to 50% [1]and 35% [2] of patients, respectively. 
Health-related quality of life (HRQOL) is often impaired and has been shown to deteriorate 
following a relapse [3]. Positive psychological constructs such as positive affect, optimism and 
subjective well-being may play an important role in adaptation to chronic disease [4]. In patients 
with MS, positive constructs have been shown to be negatively associated with depression and 
anxiety [5-7] and positively associated with physical, social and psychological adjustment [7, 8]. 
A psychosocial intervention aimed at increasing positive constructs may facilitate adjustment 
and improve HRQOL in patients with MS. 
 
Positive psychology (PP) uses targeted activities to increase the frequency and intensity of 
positive emotional experiences [9]. Targeted activities span several domains, including gratitude 
(e.g., systematically recalling positive life events), using one’s personal strengths in a deliberate 
manner and altruism (e.g., performing acts of kindness). Two meta-analyses of PP interventions 
(PPI) demonstrated that these interventions significantly enhanced subjective well-being and 
were effective in reducing depressive symptoms in both depressed and non-depressed 
individuals. Studies that included multiple PP exercises were more effective than approaches that 
used a single activity. The benefits of PPI were sustained for periods of up to 6 months [10, 11] 
 
Although there are a few studies of PP for individuals with medical illnesses, no RCT of PP has 
been published in MS. Members of our team have experience adapting PP interventions for 
medically ill patients including patients with acute cardiovascular disease, type 2 diabetes and MS 
and delivering them in research interventions. PP interventions are broadly applicable, require little 
provider training and the exercises are well-accepted and easy to complete. The development of 
an at home, phone-based PP intervention could represent a low cost, innovative and effective tool 
to increase positive affect in patients with MS. This may lead to decreases in depression, anxiety 
and fatigue and improvements in HRQOL and self-reported functional activities such as work. 
 
II.  SPECIFIC AIMS 
 
This phase I randomized controlled trial (RCT) will examine the efficacy of an at home positive 
psychology (PP) training intervention to increase positive affect in patients with multiple 
sclerosis (MS).  The RCT will include a five-week intervention phase and a five-week extension 
phase. 
 
Specific Aim 1: Evaluate the tolerability and acceptability of a five-week at home PP training 
intervention for MS patients. We will assess the tolerability of the intervention by calculating the 
proportion of subjects who complete four of the five weekly exercises.  We will determine the 
acceptability of each exercise by having subjects rate the ease and utility of each exercise after it 
is completed.  

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Specific Aim 2: Examine the efficacy of PP training to improve positive affect, emotional 
function, health-related quality of life (HRQOL), and self-reported functional activities. We will 
compare positive affect in subjects in the intervention and control group at the completion of the 
intervention phase.  We will also assess between-group differences in depression, anxiety, fatigue, 
HRQOL and work productivity following the intervention phase. 
 
Specific Aim 3:  Determine if improvements in positive affect, emotional function, HRQOL and 
self-reported functional activities following PPI training are maintained. For subjects in the 
intervention group who demonstrate a benefit from PPI, we will determine if that benefit is 
maintained by comparing positive affect, depression, anxiety, fatigue, HRQOL and work 
productivity at the completion of the intervention and extension phases. 
 
III.  SUBJECT SELECTION 
 
Thirty subjects with MS will be enrolled at the Partners MS Center.  Subjects will be recruited 
from the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and 
Women’s Hospital Partners MS Center:  The CLIMB Study (1999P010435).  
 
Inclusion criteria: 
1. Diagnosis of clinically isolated syndrome or MS 
2. Age 18-65 
3. Able to read and write in English 
4. Enrollment in the CLIMB study 
 
Exclusion criteria: 
5. Moderate or marked cognitive abnormalities on brief mental status testing identified by 
the treating neurologist during routine visits to the Partners MS Center that would 
preclude meaningful participation in the PP exercises 
 
IV. SUBJECT ENROLLMENT 
 
All CLIMB subjects being seen at the Partners MS Center for a routine clinical visit will be 
identified.  They will be approached by their physician about participation in a PP study and will 
be given a study flyer.  Additional flyers may be posted at the Partners MS Center.  Interested 
individuals will be brought by their physicians to meet with a member of the research staff to 
learn about the study in more detail.  They will be given a copy of the consent form to review.  
They will have the opportunity to discuss the study with their physician as well as other members 
of the research study staff prior to giving consent.  Individuals will have at least 12 hours to 
consider participation.  Consent will be obtained by study co-investigators or by the research 
coordinators listed on the protocol during the enrollment visit at the Partners MS Center. 
 
V.  STUDY PROCEDURES 
 
This RCT will include an intervention phase (Phase I) and an extension phase (Phase II).   

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Enrollment Visit (60 minutes) 
Subjects will be enrolled at the Partners MS Center at the Brigham and Women’s Hospital.  At 
enrollment, all subjects will be consented and assigned a study subject ID.  Subjects will 
complete a battery of patient reported outcome (PRO) measures in REDCap, a secure web 
application for building and managing online surveys.  The PRO measures include: 
 
1. Positive and Negative Affect Scale (PANAS) [12] is comprised of two 10-item mood scales, 
one measuring positive affect and the other negative affect.   
 
2. Life Orientation Test-Revised (LOT-R) [13] is a 6-item measure of optimism and pessimism 
and the most widely used measure of optimism. 
 
3. Center for Epidemiologic Studies Depression Scale (CES-D) [14] is a 20-item self-report 
measure of depression that focuses on the cognitive and affective rather than the somatic 
components of depression.  
 
4. State Trait Anxiety Inventory (STAI) [15] includes two 20-item questionnaires designed to 
measure the current temporary condition of  “state” anxiety and the more general and long-
standing quality of “trait” anxiety.    
 
5. Modified Fatigue Impact Scale (MFIS) [16] is a 21-item questionnaire used to assess the 
impact of fatigue on physical, cognitive and psychosocial functioning. 
 
6. Health Status Questionnaire (SF-36) [17] is a widely-used generic measure of HRQOL.  It 
yields an 8-scale profile of functional health as well as physical and mental health summary 
scores. 
 
7. Work Productivity and Activity Impairment Questionnaire (WPAI) [18] is a 6-item measure 
of health-related work productivity (absenteeism and presenteeism) as well as the effect of 
health problems on the ability to perform regular daily activities. 
 
8. Perceived Stress Scale (PSS) is a 10-item measure of the degree to which situations are 
perceived as stressful [19].  
 
9. Brief Resilience Scale (BRS) is a 6-item scale that measures the ability to bounce back or 
recover from stress [20].  
 
10. State Optimism Measure (SOM) is a 7-item measure of “state” optimism or optimism at the 
present moment. 
 
 
Using a computerized random number generator, subjects will be randomized to the intervention 
or control group.  
 

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Intervention Phase (5 weeks) 
In the intervention phase (Phase I: Weeks 1-5), subjects randomized to the intervention group will 
be given a study participant manual and asked to set up a time for weekly phone calls with the 
study trainer.  They will complete five weeks of PP exercises, one exercise per week. They will be 
asked to rate their mood prior to and after completing each exercise.  They will also be asked to 
rate the ease and utility of each exercise. The weekly calls with the study trainer will be used to 
review the completed exercise and introduce the next exercise. These calls will be recorded so that 
a percentage (10%) of these recordings can be reviewed to ensure that the PP and goal-setting 
portions of the intervention are being delivered as described in the protocol and study trainer 
manual. The control group will have no study activities during intervention phase and will be 
considered a wait-list control. At the completion of the intervention phase, all subjects will be 
emailed a link to complete PRO measures in REDCap.  
 
Extension Phase (5 weeks) 
In the extension phase (Phase II: Weeks 6-10), subjects in the control group will receive their study 
participant manual in the mail. They will be contacted by the study trainer to set up weekly phone 
calls.  They will complete the PPI as described above. The intervention group will complete no 
study activities in the extension phase.  At the completion of the extension phase, all subjects will 
be emailed a link to complete PRO measures.  
Intervention: The PP intervention consists of five weeks of PP training using the following 
exercises: 
 
1. Gratitude for positive events:  Recall three positive events that occurred in the past week 
and write about the events and how the events made you feel. 
 
2. Personal strengths:  Complete a brief survey of personal strengths and select a strength 
such as perseverance or humility and use it deliberately in the next 24 hours. Write about 
how you used the strength and how you felt while using it. 
 
3. Gratitude letter:  Recall another individual’s kind act that resulted in joy, relief, serenity or 
other positive feelings. Write a letter to the person describing feelings of gratitude 
associated with this event. 
 
4. Enjoyable and meaningful activities:  Intentionally complete three acts in a single day – a 
pleasurable act done alone, a pleasurable act done with others and a meaningful or 
important act. 
 
5. Remembering past successes:  Focus on a time when you experienced success and write 
about the event and the positive feelings and thoughts you had during the event 
 
These exercises have all been described by Huffman et al. [21].  Exercises may require anywhere 
from 15 minutes to several hours to complete.   

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The study trainer, Melanie Freedman, serves as the supervising research coordinator for two PP 
intervention trials in medically-ill populations.  She has experience completing phone and in-
person study assessments with patients who have medical illnesses for numerous studies. She 
works under the supervision of Jeff Huffman, MD.  She will receive training utilizing our 
standard protocol (via review of didactic materials, role play, and director work with supervisors) 
and ongoing supervision from our director of behavioral interventions.  She will also receive 
didactic teaching from MS experts on the basics of MS care and will have shadowed in the MS 
clinic to better understand MS patients’ experiences.  During the study, Dr. Huffman or another 
physician study staff member will be available by phone or pager to intervene, if needed, due to 
subject discomfort or to answer specific questions about the study.   
Two study manuals tailored to individuals with MS will be prepared: a study trainer manual and a 
study participant manual. At enrollment, subjects in the intervention group will be given the study 
participant manual and asked to schedule their first weekly phone call with the study trainer. The 
calls will last 45-60 minutes, and will be used by the study trainer to (a) review the weekly exercise 
and discuss the ease and utility ratings recorded by subjects after the exercise was completed; (b) 
discuss the rationale for the next exercise using a guided review of the study participant manual; 
and (c) describe the following week’s exercise and brainstorm ways to complete it. Subjects in the 
control group will be mailed a copy of the study participant manual at the beginning of the 
extension phase of the study. This is to prevent subjects in the control group from completing the 
exercises during the intervention phase. They will be contacted by the study trainer to schedule 
their weekly phone calls.  All subjects will complete PRO measures at enrollment, completion of 
the intervention phase and completion of the extension phase. 
 
VI.  BIOSTATISTICAL ANALYSIS 
 
To assess the tolerability of the intervention (Specific Aim 1), our goal is to demonstrate that the 
proportion who will complete four out of five exercises is greater than 0.5. Given our sample size 
of 30 subjects, we will have 80% power to detect a difference if the true proportion of subjects 
who will complete four out of five exercises is 0.75 using a one sample binomial test of 
proportions (Stata routine: power oneproportion). For the comparison of the treatment groups in 
terms of PRO measures (Specific Aim 2), the intervention effect will be estimated using analysis 
of covariance (ANCOVA) model. In the ANCOVA model, the post-intervention scores will be 
compared between the groups controlling for baseline scores. All outcome measures (PANAS, 
LOT-R, CES-D, STAI, MFIS, SF-36, WPAI, PSS, BRS, and SOM) will be compared using the 
same model. To assess whether PPI benefits are maintained at 10 weeks (Specific Aim 3), we 
will first calculate the change from baseline to week 5 for each of the outcome measures. For the 
subjects who experience a benefit of the intervention, we will then assess if at least 50% of the 
benefit was maintained at the 10-week time point. The proportion of subjects who maintained the 
benefit will be reported. 
 
VII.  RISKS AND DISCOMFORTS 
 

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There are no major risks associated with participating in the study.  Subjects may experience 
discomfort writing down and sharing emotional aspects of their lives.  If they do experience 
discomfort, they may choose not to complete the weekly PP assignments.  If they feel their 
participation is becoming too burdensome or is exacerbating ongoing symptoms, they have the 
option to decline further participation and withdraw from the study. 
 
There is some potential for breach of confidentiality.  No information will be shared with 
treatment providers unless a participant requires immediate assistance.  In such cases, treatment 
providers will be informed and subjects will be referred to a mental health provider at the 
Partners MS Center. 
 
VIII.  POTENTIAL BENEFITS 
 
This is a pilot study designed to determine the tolerability and efficacy of an at home PP training 
intervention for individuals with MS.  If the results suggest that home PP training is tolerable and 
effective, it may advance the use of PP as a low cost, innovative and effective tool for increasing 
positive affect, decreasing depression and anxiety and improving HRQOL in patients with MS. 
 
IX.  MONITORING AND QUALITY ASSURANCE 
 
Bonnie Glanz, the PI, will be responsible for assuring the validity and integrity of the data 
collected, and adherence to the IRB-approved protocol.  The study team will meet weekly to 
review subject recruitment, subject satisfaction and study progress. 
 
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