Innovation in the Treatment of Persistent Pain in Adults With Neurofibromatosis Type 1 (NF1): Implementation of the iCanCope Mobile Application- Clinical Trial
Phase: NA
Conditions: Neurofibromatosis 1, Chronic Pain
Sponsor: Yale University

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CLINICAL STUDY PROTOCOL
Innovation in the Treatment of Persistent 
Pain in Adults with NF1: Implementation of 
the iCanCope Mobile Application- Clinical 
Trial
Protocol Number
2000029045
Principal Investigator
Frank Buono
Sponsor
Department of Defense 
Protocol Version
9 November 2020
version 3
Confidentiality Statement:
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NCT04561765   

Protocol Number 2000029045
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Study Personnel
Principal Investigator
Frank Buono
Email: frank.buono@yale.edu

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Synopsis
Study Purpose
OBJECTIVES & HYPOTHESES: To evaluate whether the iCanCope-NF program will 
reduce pain (pain severity and pain interference) in adults with NF1. We hypothesize that 
by customizing the CBT and the MBAA in the mobile application for adults with NF1, 
individuals will engage regularly, thus acquiring a new set of skills to facilitate their own 
pain self-management, while pain will decrease.
SPECIFIC AIM:
To determine the feasibility and preliminary effectiveness of iCanCope-NF in adults 
(n=108) with NF1 suffering from pain in a RCT.
Primary Objective
To evaluate whether the iCanCope-NF program will reduce pain (pain severity and pain 
interference) in adults with NF1.
Secondary Objectives (if applicable)
n/a
General Design Description
A 1x3 pilot randomized control trial (RCT) (iCanCope-NF, iCanCope-NF +Contingency 
Management (CM), Control Group) will be conducted with 108 adults with NF1 who suffer 
from pain.
Study Date Range and Duration
We predict the pilot RCT to take 18 months to complete (February 1, 2021 to August 
2022). The patient networks that we are recruiting from have over 25000 adults across 
both groups. A conservative estimate of 20% of individuals should be within the 
appropriate age criterions (~5000). Given that we are seeking to fulfill 36 in each group for 
a total of 108 for the Pilot RCT and taken in account of a conservative 20% refusal rate. 
We should not encounter an issue with total number of individuals enrolled within the 
study within the time frame.
Number of Study Sites
There will be three study sites for this study: Yale School of Medicine, Connecticut 
Children's Hospital (Hartford, CT), and The Hospital of Sick Children (Toronto, Canada).
Yale School of Medicine: The PI will run the entire clinical trial through Yale School of 
Medicine. All potential participants will be recruited, consented, orientated to a treatment 
group (if applicable). 
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Connecticut Children's Hospital (Hartford, CT): will consult but will not have access to the 
PHI data
The Hospital of Sick Children (Toronto, Canada): will host the server of the iCanCope and 
the dashboard of the server but will not see any personal PHI. 
Primary Outcome Variables
1.Engagement Activity
Total minutes logged on the mobile application will be evaluated between the two groups 
using the mobile application.
2.Pain Severity
A comparison within groups change of pain severity measured by the Brief Pain 
Inventory-Short Form. Respondents rate items on a 0-10 scale to indicate the pain 
severity and interference, and the total score is the mean of each subfactor. The higher 
the score indicates more severity and interference of pain.
3.Pain Interference Index
A comparison within groups change of pain interference measured by the Pain 
Interference Index Scale. Respondents rate items on a 0-6 scale to indicate how much 
pain has interfered with various activities, and the total score is the mean of the six items. 
Where 6 indicates high interference.
Secondary and Exploratory Outcome Variables (if applicable)
Secondary Outcome Measures:
1.
Treatment Services Review what are perceptions of satisfaction across groups 
exposed to the iCanCope mobile application using an The Treatment Services 
Review (TSR)
2.
Anxiety comparison within change of generalized anxiety measured by the 
generalized anxiety disorder scale (GAD-7). After reading each statement, one of 
four choices are provided and respondents can select one response (1=not at all 
sure, 2=several days, 3=over half days, 4=nearly every day). Each column is then 
added, and a total score is obtained, with scores falling into four levels of anxiety, 
including minimal (1-4), mild (5-9), moderate (10-14), and severe (15-21)
3.
Sleep functioning comparison within change of sleep quality measured by the 
PROMIS Sleep inventory. The higher the total score, the more severe the 
symptom. Total scores less than 24 suggest no to slight sleep disturbance, 24-28 
suggest mild disturbance, 29-38 moderate disturbance, and greater than 38 
severe sleep disturbance
4.
Short Form/Quality of Life the Short form survey 20- will measure quality of life 
across 8 subscales on respondent burden (Physical Functioning, Role-Physical, 
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Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and 
Mental Health). Scores were transformed linearly to 0-100 scales, with 0 and 100 
assigned to the lowest and highest possible scores, where high value indicated 
better functioning.
5.
Chronic pain acceptance Chronic Pain Acceptance Questionnaire-Revised 
(CPAQ-Revised) 20-item scale designed to measure acceptance of pain. The 
acceptance of chronic pain is thought to reduce unsuccessful attempts to avoid or 
control pain and thus focus on engaging in valued activities and pursuing 
meaningful goals will be measured across all groups. The items on the CPAQ are 
rated on a 7-point scale from 0 (never true) to 6 (always true). To score the CPAQ, 
add the items for Activity engagement and Pain willingness to obtain a score for 
each factor. To obtain the total score, add the scores for each factor together. 
Higher scores indicate higher levels of acceptance
6.
psychological inflexibility Psychological Inflexibility in Pain Scale (PIPS) 16-item 
scale used to assess psychological inflexibility (i.e. avoidance, acceptance, fusion, 
values orientation, dirty discomfort) in people with chronic pain will be measured 
across all groups. Respondents are asked to rate items on a 7-point scale that 
ranges from 1 (never true) to 7 (always true). Higher scores indicate greater levels 
of psychological inflexibility.
Other Pre-specified Outcome Measures:
1.
Mindfulness based alternative approaches (MBAA)Do individuals with NF1 utilize 
the MBAA more readily because they are on the mobile application, via Five Facet 
Mindfulness Questionnaire. 39-item self-completed questionnaire measuring the 
five facets of mindfulness: Observing (8 items), Describing (8 items), Acting with 
awareness (8 items), Non-judgmental (8 items), and Non-reactive (7 items). 
Participants rated the items on a five-point Likert scale (1 = never or very rarely 
true to 5 = very often or always true), each facet score ranges from 8 to 40, except 
for the non-reactive facet which ranges from 7 to 35.
Study Population
A convenience sample of 108 adults with NF1 aged 18-34 will be recruited through mail 
merge and emails, Internet advocacy web forums (NF Network, NF Northeast: 
Number of Participants
A convenience sample of 108 adults with NF1 aged 18-34 will be recruited through mail 
merge and emails, Internet advocacy web forums (NF Network, NF Northeast: see letters 
of support).
Power Analysis: An a priori power analysis conducted through G*Power (Universität Kiel, 
v. 3.1.9.2) estimated a conservative sample size analysis for the RCT. We are expecting a 
total of 140 participants, given the length of the trial, we estimate 20% attrition rate of the 
final sample, giving us a total sample of (n=36) per group, for a final sample size of 108. 
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The power analysis is based on previously utilized research in which estimated effect 
sizes ranged from 20 to 40 individuals per group (52). We will attempt to enroll equal 
numbers of male and female individuals to evaluate gender differences through urn 
randomization process.
52. Hancock, G. R. and R. O. Mueller, Eds. (2010). The Reviewer's Guide to Quantitative 
Methods. Power Analysis. New York, NY, Routledge.
Visit Schedule Table (0ptional)
n/a
Study Flow Chart (optional)
see flow chart below
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Abbreviations
Abbreviation 
Explanation
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Glossary of Terms
Glossary
Explanation
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Table of Contents
Synopsis.....................................................................................................................................
Study Purpose ........................................................................................................................
Primary Objective ...................................................................................................................
Secondary Objectives (if applicable) ......................................................................................
General Design Description....................................................................................................
Study Date Range and Duration.............................................................................................
Number of Study Sites............................................................................................................
Primary Outcome Variables....................................................................................................
Secondary and Exploratory Outcome Variables (if applicable) ..............................................
Study Population.....................................................................................................................
Number of Participants ...........................................................................................................
Visit Schedule Table (0ptional) ...............................................................................................
Study Flow Chart (optional) ....................................................................................................
Abbreviations .............................................................................................................................
Glossary of Terms......................................................................................................................
1.1 Statement of Compliance .................................................................................................
2.1 Background.......................................................................................................................
3.1 Problem Statement ...........................................................................................................
3.2 Purpose of Study/Potential Impact ...................................................................................
3.3.1 Potential Risks............................................................................................................
3.3.2 Potential Benefits........................................................................................................
4.1 Hypothesis ........................................................................................................................
4.2 Primary Objective .............................................................................................................
4.3 Secondary Objectives (if applicable) ................................................................................
5.1 General Design Description..............................................................................................
5.1.1 Study Date Range and Duration.................................................................................
5.1.2 Number of Study Sites................................................................................................
5.2 Outcome Variables ...........................................................................................................
5.2.1 Primary Outcome Variables........................................................................................
5.2.2 Secondary and Exploratory Outcome Variables (if applicable) ..................................
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5.3 Study Population...............................................................................................................
5.3.1 Number of Participants...............................................................................................
5.3.2 Eligibility Criteria/Vulnerable Populations...................................................................
6.1 Intervention .......................................................................................................................
6.1.1 Description of Intervention..........................................................................................
6.1.2 Method of Assignment/Randomization.......................................................................
6.1.3 Selection of Instruments/Outcome Measures.............................................................
6.1.4 Intervention Administration.........................................................................................
6.1.5 Reaction Management ...............................................................................................
6.2 Assessments ....................................................................................................................
6.2.1 Efficacy.......................................................................................................................
6.2.2 Safety/Pregnancy-related Procedure .........................................................................
6.2.3 Adverse Events Definition and Reporting...................................................................
6.2.4 Pharmacokinetics (if applicable).................................................................................
6.2.5 Biomarkers (if applicable)...........................................................................................
6.3 Study Procedures .............................................................................................................
6.3.1 Study Schedule ..........................................................................................................
6.3.2 Informed Consent.......................................................................................................
6.3.3 Screening ...................................................................................................................
6.3.4 Recruitment, Enrollment and Retention......................................................................
6.3.5 Study Visits.................................................................................................................
6.3.6 End of Study and Follow Up.......................................................................................
6.3.7 Removal of Subjects...................................................................................................
6.4 Statistical Method .............................................................................................................
6.4.1 Statistical Design........................................................................................................
6.4.2 Sample Size Considerations ......................................................................................
6.4.3 Planned Analyses.......................................................................................................
6.4.3.1 Primary Analyses.....................................................................................................
6.4.3.2 Secondary Objectives Analyses, if applicable.........................................................
6.4.3.3 Analysis of Subject Characteristics .........................................................................
6.4.3.4 Interim Analysis (if applicable).................................................................................
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6.4.3.5 Health economic evaluation, if applicable ...............................................................
6.4.3.6 Other........................................................................................................................
6.4.4 Subsets and Covariates .............................................................................................
6.4.5 Handling of Missing Data............................................................................................
7.1 Ethical Considerations: Informed Consent/Assent and HIPAA Authorization...................
7.2 Institutional Review Board (IRB) Review ..........................................................................
7.3 Subject Privacy, Confidentiality & Data Management ......................................................
7.4 Deviations/Unanticipated Problems..................................................................................
7.5 Data Collection .................................................................................................................
7.6 Data Quality Assurance ....................................................................................................
7.7 Study Records ..................................................................................................................
7.8 Access to Source..............................................................................................................
7.9 Data or Specimen Storage/Security .................................................................................
7.10 Retention of Records ......................................................................................................
7.11 Study Monitoring.............................................................................................................
7.12 Data Safety Monitoring Plan ...........................................................................................
7.13 Study Modification ..........................................................................................................
7.14 Study Discontinuation .....................................................................................................
7.15 Study Completion ...........................................................................................................
7.16 Conflict of Interest Management Plan.............................................................................
7.17 Funding Source ..............................................................................................................
7.18 Publication Plan ..............................................................................................................
Appendices ................................................................................................................................
List of Tables..............................................................................................................................
1.1 Statement of Compliance
This document is a protocol for a human research study. The purpose of this protocol is to 
ensure that this study is to be conducted according to the Common Rule at 45CFR46 
(human subjects) and other applicable government regulations and Institutional research 
policies and procedures.
2.1 Background
Background: Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic condition 
affecting 1 in 2500 individuals (1).  NF1 was originally classified as a tumor predisposition 
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syndrome based on the propensity of affected children and adults to develop benign and 
malignant tumors (2,3).  Over 50% of individuals with NF1 report significant pain and 
discomfort (4,5) which can be associated with tumors, but is often not localized to a 
structural lesion, thus presenting treatment challenges for patients and their medical 
caregivers. Moreover, the increased pain in this population can negatively impact an 
individual's perceived quality of life (6,7). Due to the complexity of the disorder (e.g., 
location, severity, number, and type of tumors), there are limited effective therapeutic options 
for treating pain (3). In this regard, tumor-related pain is primarily managed by either surgery 
or medication (8,9). To date, there has been limited research exploring the daily impact of 
living with persistent pain from a qualitative perspective by the individual living with NF1 and 
evaluating NF1 pain and treatments.
Barriers to Pain Treatment: Individuals suffering from persistent pain have multiple potential 
barriers to obtaining comprehensive pain specific treatment including: (a) difficulty accessing 
these services (e.g., no services available in many geographic areas, long wait times); (b) 
limited availability of trained professionals such as psychologists, particularly in non-urban 
centers; (c) patient-related issues (i.e., psychological, communication, and attitude); (d) 
current health care system barriers, (i.e., reimbursement, costs of treatment) and (e) limited 
access to self-management techniques (10-14). Self-management can be defined as the 
individual's ability to manage the symptoms, treatment, physical, and psychological 
consequences and lifestyle changes inherent to living with a chronic illness (15).  Self-
management interventions that provide individuals with disease-specific knowledge, 
strategies to manage symptoms such as pain (e.g., cognitive-behavioral therapies; CBT), 
and social support are needed to promote optimal health outcomes.
Cognitive Behavior Therapy and Pain Treatment: Cognitive Behavior Therapy (CBT) uses 
assessment and evaluation of current behaviors to identify problem behaviors and develop 
skills to manage situations as well as to cope with difficult thoughts and feelings (16,17). 
CBT typically incorporates normalization of the patient's experience through education, 
training in strategies for managing disease-related symptoms and other stressors, enhancing 
self-efficacy, as well as guidance on developing and implementing a long-term self-
management plan (18-19).  Studies have documented the efficacy of CBT across a wide 
range of diseases and disorders. A recent meta-analysis showed that the most successful 
interventions in improving pain and associated functional impairments in adults with chronic 
pain are rooted in CBT (20).  It is well documented that the skills learned through CBT 
continue, sometimes even increase, after treatment has been completed (21,22). To date, 
there has been little peer reviewed research within the NF1 population utilizing CBT to treat 
pain symptoms. CBT like many other psychotherapies has multiple disadvantages: (1) 
mental health clinicians and practitioners require extensive training in both CBT and pain 
treatment, (2) limited access to appropriate care of trained clinicians, and (3) formalized 
face-to-face treatment is relatively expensive. Furthermore, mind-body alternative 
approaches (MBAA) (i.e., yoga, mindfulness), can have impact on pain intensity and have 
been found to alter pain experience (23). Research has shown that when CBT and MBAA 
interventions are combined, they can be effective in decreasing negative emotional 
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responses to pain, decreasing perceptions of disability, and increasing orientation toward 
self-management during treatment (24,25). A recent meta-analysis confirmed a combination 
of CBT and MBAA to be as effective as face-to-face CBT with patients suffering from 
persistent and chronic pain (26).  This same review showed patients preferred mobile-based 
therapy and had more consistent usage than face to face CBT.
Mobile Technologies to Enhance Delivery of Pain Self-Management Care: Mobile 
technologies can be applied to enhance the accessibility of pain self-management therapies 
(27,28). In addition to improving access, these technologies can empower individuals to take 
an active role in managing their condition by providing "in the moment" access to pain 
coping strategies (29).  Additionally, a systematic review showed that incorporating self-
management strategies for persistent pain within standard treatment increases treatment 
efficacy and patient buy-in (30).  Over 78% of U.S. adults own or have access to 
Smartphones; therefore, smartphones offer an ideal platform to prompt practice of CBT-
based coping skills in the moment. This technology can be leveraged to build a tailored self-
management program that emphasizes empowerment, facilitates the creation and tracking 
of personalized goals, and offers a peer-based social support platform to prompt practice of 
CBT-based coping skills as needed. In the current mobile marketplace, there are over 120 
pain applications, but few are empirically valid (31).  The iCanCope mobile and web-based 
program provides personalized goal setting to improve pain and function, CBT-based pain 
self-management training and rehearsal, and peer-based social support, while providing key 
health information and coping skills to individuals. The iCanCope mobile and web-based 
self-management program has been empirically evaluated for multiple painful diseases in 
children and adolescent populations (32,33). Yet, with any mobile application poor 
adherence is a common problem which can limit the effectiveness of intervention, and the 
iCanCope mobile application has not been tested within adults. One approach to combat 
poor adherence and increase patient engagement and retention is contingency management 
(12,34,35)
Contingency management: Contingency management (CM) arranges systematic application 
of behavioral consequences of desired behavior and withholds reinforcement of undesired 
behaviors (36).  CM interventions are based on extensive basic and clinical science 
intervention research supporting that training in a CM setting can develop and improve real 
world skills; therefore, predicting skill use and quality of use in real life (37,38). By using 
points, levels, prizes  or other rewards, and well-established reinforcement schedules, 
individuals are actively engaged (39-41) and CM can encourage individuals to practice 
behavioral change in a novel and entertaining way (42-44) and can be generalized to the 
person's natural environment and enhance motivation for change.
Neurofibromatosis and Pain: Based on my current findings (in press), over 15% of adults 
with NF1 are currently using pharmacological interventions and 60% had at least one 
surgery procedure in the last year for their treatment of persistent pain. Moreover, a majority 
of these individuals are not aware or have not attempted MBAA for their pain symptoms. 
Given these findings, as well as (1) the lack of access to qualified care for pain management 
within NF1, (2) lacking of empirically validated behavioral treatments for persistent pain 
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within NF1 and (3) an inability to empower individuals to take an active role in managing 
their condition, I believe by providing an empirically validated treatment in which individuals 
with NF1 can learn to self-manage their own pain symptoms, while learning new alternative 
treatments can provide tremendous potential and positive change for those living with 
persistent pain.
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The Clinical Journal of Pain, 31(6), 557-563. doi: 10.1097/AJP.0000000000000171.
5.
Stinson, N., Lalloo, C., Harris, L., Isaac, L., Campbell, F., Brown, S., Ruskin, D., 
Gordon, A., Galonski, M., Pink, L. R., Buckley, N., Henry, J. L.,, White M., Karim, A. 
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(2014). iCanCope with Pain: User-centered design of a web- and mobile-based self-
management program for youth with chronic pain based on identified health care 
needs. Pain Research & Management, 19(5), 257-265.
6.
Kohut, A., Stinson, J. N., Ruskin, D., Forgeron, P., Harris, L., van Wyk, M., Luca, S., 
& Campbell, F. (2016). iPeer2Peer program: A pilot feasibility study in adoelscents 
with chronic pain. PAIN, 157(3), 1146-1155.
7.
Bicken, K., Christensen, D. R., Marsch, L. A. (2011). A review of computer-based 
interventions used in the assessment, treatment, and research of drug addiction. 
Substance Use & Misuse, 46(1), 4-9.
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Carroll, M., Ball, S. A., Martino, S., Nich, C., Babuscio, T. A., Nuro, K. F., Gordon,
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A., Portnoy, G. A., & Rounsaville, B. J. (2008). Computer-assisted delivery of 
cognitive behavioural therapy for addiction: A randomized trial of CBT4CBT. 
American Journal of Psychiatry, 165(7), 881-888.
10. Higgins, T., & Petry, N. M. (1999). Contingency management: Incentives for Sobriety. 
Alcohol Research & Health: The Journal of the National Institute on Alcohol Abuse 
and Alcoholism, 23(2), 122-127.
11. Higgins, T., & Silverman, K. (1999). Motivating behavior change among illicit-drug 
abusers: Research on contingency management interventions. Washington, DC: 
American Psychological Association.
38.     Stoops, W. W., Dallery, J., Fields, N. M., Nuzzo, P. A., Schoenberg, N. E., Martin, C. 
A., Casey, B., Wong, c. J. An internet-based abistinence reinforcement smoking cessation 
intervention in rural smokers. 
Drug and Alcohol Dependence, 105, (1-2), 
56-62.
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Greenfield, F., Brooks, A. J., Grodon, S. M., Green, C. A., Kropp, F., Mchugh, K. R., 
Lincoln, M., Hien, D., & Miele, G. M. (2007). Substance abuse treatment entry, 
retention, and outcome in women: A review of the literature. Drug & Alcohol 
Dependence, 86(1), 1-21.
2.
Hodgins, C., El-Guebaly, N., Addington, J. (1997). Treatment of substance abusers: 
Single or mixed gender programs? Addiction, 92(7).
3.
Blum, C., Roman, P. M., & Harwood, E. M. (2002). Employed women with alchohl 
problems who seek help from employee assistance programs. In: Galanter M., 
Begleiter, H., Deitrich, R., Gallant, D., Goodwin, D., Gotthiel, E., Paredes, A., 
Rothschild, M., Thiel, D. V., & Edwards, H. (l ih ed.). Recent Developments in 
Alcoholism (125-156).
4.
Copeland, (1997). A qualitative study of barriers to formal treatment among women 
who self-managed change in addictive behaviours. Journal of Substance Abuse 
Treatment, 14(2), 183-190.
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43.             Substance Abuse and Mental Health Services Administration-Office of Applied 
Studies. The Dasis Report-Facilities Offering Special Programs or Groups for Women: 2005: 
Rockville, MD: Office of Applied Studies, Substance Abuse and Mental Health Services 
Administration (SAMHSA); 2007.
1.
Brady, T., Grice, D. E., Dustan, L., & Randall, C. (1993). Gender differences in 
substance use disorders. The American Journal of Psychiatry, 150(11), 1707-1711.
3.1 Problem Statement
Adults with NF1 are currently using pharmacological interventions and 60% had at least one 
surgery procedure in the last year for their treatment of persistent pain. Moreover, a majority 
of these individuals are not aware or have not attempted MBAA for their pain symptoms. 
Given these findings, as well as (1) the lack of access to qualified care for pain management 
within NF1, (2) lacking of empirically validated behavioral treatments for persistent pain 
within NF1 and (3) an inability to empower individuals to take an active role in managing 
their condition, I believe by providing an empirically validated treatment in which individuals 
with NF1 can learn to self-manage their own pain symptoms, while learning new alternative 
treatments can provide tremendous potential and positive change for those living with 
persistent pain.
3.2 Purpose of Study/Potential Impact
We expect individuals with NF1 utilizing the iCanCope program to have decreased pain 
severity and interference if they regularly engage in the program. In addition, due to the 
added contingency management, we expect to see differences between the intervention 
groups (iCanCope-NF and iCanCope-NF +CM). By adding contingencies to increased 
engagement the CM grouping should have more improvements in pain intensity and pain 
interference in addition to current iCanCope processes. If we demonstrate initial feasibility 
and preliminary impact, in collaboration with Drs. Zempsky and Stinson, a definitive RCT will 
be conducted. In future studies, evaluating the sustainability of impact on the outcomes over 
the course of 12 months is critical to sustaining the impact of the application as well as 
generalization of treatment. Thus, following the patients in a 1, 3 and 6-month follow-up 
post-treatment is necessary.
 
3.3.1 Potential Risks
The main risk associated with the study is the possibility that confidential information 
obtained during the study will be disclosed given the association of a medical disease 
and pain symptoms. Patient names and other identifying information do not appear 
on research records. For patients the iCanCope-NF must enter a unique id and 
passcode for access. All processes of obtaining information via Qualtrics, or 
iCanCope-NF will utilize proper data security methods to minimize any risks of for 
potential loss of confidentially. 3.3.2 Potential Benefits
We expect individuals with NF1 utilizing the iCanCope program to have decreased pain 
severity and interference if they regularly engage in the program. In addition, due to the 
added contingency management, we expect to see differences between the intervention 
groups (iCanCope-NF and iCanCope-NF +CM). By adding contingencies to increased 
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engagement the CM grouping should have more improvements in pain intensity and pain 
interference in addition to current iCanCope processes. If we demonstrate initial feasibility 
and preliminary impact a definitive RCT will be conducted.
4.1 Hypothesis
We hypothesize that by customizing the CBT and the MBAA in the mobile application for 
adults with NF1, individuals will engage regularly, thus acquiring a new set of skills to 
facilitate their own pain self-management, while pain will decrease.
4.2 Primary Objective
To evaluate whether the iCanCope-NF program will reduce pain (pain severity and pain 
interference) in adults with NF1.
4.3 Secondary Objectives (if applicable)
n/a
5.1 General Design Description
A 1x3 pilot randomized control trial (RCT) (iCanCope-NF, iCanCope-NF +Contingency 
Management (CM), Control Group) will be conducted with 108 adults with NF1 who suffer 
from pain.
5.1.1 Study Date Range and Duration
We predict the pilot RCT to take 18 months to complete (February 1, 2021 to August 2022). 
The patient networks that we are recruiting from have over 25000 adults across both groups. 
A conservative estimate of 20% of individuals should be within the appropriate age criterions 
(~5000). Given that we are seeking to fulfill 36 in each group for a total of 108 for the Pilot 
RCT and taken in account of a conservative 20% refusal rate. We should not encounter an 
issue with total number of individuals enrolled within the study within the time frame.
5.1.2 Number of Study Sites
There will be three study sites for this study: Yale School of Medicine, Connecticut Children's 
Hospital (Hartford, CT), and The Hospital of Sick Children (Toronto, Canada).
Yale School of Medicine: The PI will run the entire clinical trial through Yale School of 
Medicine. All potential participants will be recruited, consented, orientated to a treatment 
group (if applicable). 
Connecticut Children's Hospital (Hartford, CT): will consult but will not have access to the 
PHI data. There will be no active recruitment or enrollment at the Connecticut Children’s 
Hospital. 
The Hospital of Sick Children (Toronto, Canada): will host the server of the iCanCope and 
the dashboard of the server but will not see any personal PHI. There will be no active 
recruitment or enrollment at the Hospital of Sick Children.  Dr. Pham (University of 
Toronto/University Health Network) will oversee the development of the ICC NF app and 
ensure that Dr. Buono and the Yale research team receives an intervention that can be 
trialed with their patient population. She will provide ongoing guidance and support of the 
technical requirements for the project, including the maintenance and tier 2 technical support 
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of the ICC NF app through the trial. She will also lead on the development of the 
contingency management dashboard used by Dr. Buono’s research team to monitor 
engagement with the ICC NF app. Dr. Pham’s academic contributions will involve 
participating in regular investigator meetings on clinical trial progress and supporting Dr. 
Buono with data analysis, interpretation, and manuscript preparation. Dr. Pham will not have 
access to any identifiable data.,
5.2 Outcome Variables
5.2.1 Primary Outcome Variables
Primary Outcome Measure:
1. Engagement Activity
Total minutes logged on the mobile application will be evaluated between the two groups 
using the mobile application.
[Time Frame: through the completion of the study, on average 4 months.]
2.Pain Severity
A comparison within groups change of pain severity measured by the Brief Pain Inventory-
Short Form. Respondents rate items on a 0-10 scale to indicate the pain severity and 
interference, and the total score is the mean of each subfactor. The higher the score 
indicates more severity and interference of pain.
[Time Frame: through the completion of the study, on average 4 months.]
3. Pain Interference Index
A comparison within groups change of pain interference measured by the Pain Interference 
Index Scale. Respondents rate items on a 0-6 scale to indicate how much pain has 
interfered with various activities, and the total score is the mean of the six items. Where 6 
indicates high interference.
[Time Frame: through the completion of the study, on average 4 months.]
5.2.2 Secondary and Exploratory Outcome Variables (if applicable)
Secondary Outcome Measures:
1.
Treatment Services Review what are perceptions of satisfaction across groups 
exposed to the iCanCope mobile application using an The Treatment Services 
Review (TSR) [Time Frame: through the completion of the study, on average 4 
months.]
2.
Anxiety comparison within change of generalized anxiety measured by the 
generalized anxiety disorder scale (GAD-7). After reading each statement, one of 
four choices are provided and respondents can select one response (1=not at all 
sure, 2=several days, 3=over half days, 4=nearly every day). Each column is then 
added, and a total score is obtained, with scores falling into four levels of anxiety, 
including minimal (1-4), mild (5-9), moderate (10-14), and severe (15-21)[Time 
Frame: through the completion of the study, on average 4 months.]
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3.
Sleep functioning comparison within change of sleep quality measured by the 
PROMIS Sleep inventory. The higher the total score, the more severe the symptom. 
Total scores less than 24 suggest no to slight sleep disturbance, 24-28 suggest mild 
disturbance, 29-38 moderate disturbance, and greater than 38 severe sleep 
disturbance [Time Frame: through the completion of the study, on average 4 
months.]
4.
Short Form/Quality of Life the Short form survey 20- will measure quality of life 
across 8 subscales on respondent burden (Physical Functioning, Role-Physical, 
Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental 
Health). Scores were transformed linearly to 0-100 scales, with 0 and 100 assigned 
to the lowest and highest possible scores, where high value indicated better 
functioning. [Time Frame: through the completion of the study, on average 4 months.]
5.
Chronic pain acceptance Chronic Pain Acceptance Questionnaire-Revised (CPAQ-
Revised) 20-item scale designed to measure acceptance of pain. The acceptance of 
chronic pain is thought to reduce unsuccessful attempts to avoid or control pain and 
thus focus on engaging in valued activities and pursuing meaningful goals will be 
measured across all groups. The items on the CPAQ are rated on a 7-point scale 
from 0 (never true) to 6 (always true). To score the CPAQ, add the items for Activity 
engagement and Pain willingness to obtain a score for each factor. To obtain the 
total score, add the scores for each factor together. Higher scores indicate higher 
levels of acceptance [Time Frame: through the completion of the study, on average 4 
months.]
6.
psychological inflexibility Psychological Inflexibility in Pain Scale (PIPS) 16-item scale 
used to assess psychological inflexibility (i.e. avoidance, acceptance, fusion, values 
orientation, dirty discomfort) in people with chronic pain will be measured across all 
groups. Respondents are asked to rate items on a 7-point scale that ranges from 1 
(never true) to 7 (always true). Higher scores indicate greater levels of psychological 
inflexibility. [Time Frame: through the completion of the study, on average 4 months.]
Other Pre-specified Outcome Measures:
1.
Mindfulness based alternative approaches (MBAA)Do individuals with NF1 utilize the 
MBAA more readily because they are on the mobile application, via Five Facet 
Mindfulness Questionnaire. 39-item self-completed questionnaire measuring the five 
facets of mindfulness: Observing (8 items), Describing (8 items), Acting with 
awareness (8 items), Non-judgmental (8 items), and Non-reactive (7 items). 
Participants rated the items on a five-point Likert scale (1 = never or very rarely true 
to 5 = very often or always true), each facet score ranges from 8 to 40, except for the 
non-reactive facet which ranges from 7 to 35.[Time Frame: through the completion of 
the study, on average 4 months.]
5.3 Study Population
A convenience sample of 108 adults with NF1 above the age of 18 will be recruited through 
mail merge and emails, Internet advocacy web forums (NF Northwest and NF Network).  
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5.3.1 Number of Participants
A convenience sample of 108 adults with NF1 aged 18-34 will be recruited through mail 
merge and emails, Internet advocacy web forums (NF Network, NF Northeast: see letters of 
support).
Power Analysis: An a priori power analysis conducted through G*Power (Universität Kiel, v. 
3.1.9.2) estimated a conservative sample size analysis for the RCT. We are expecting a total 
of 140 participants, given the length of the trial, we estimate 20% attrition rate of the final 
sample, giving us a total sample of (n=36) per group, for a final sample size of 108. The 
power analysis is based on previously utilized research in which estimated effect sizes 
ranged from 20 to 40 individuals per group (52). We will attempt to enroll equal numbers of 
male and female individuals to evaluate gender differences through urn randomization 
process.
52. Hancock, G. R. and R. O. Mueller, Eds. (2010). The Reviewer's Guide to Quantitative 
Methods. Power Analysis. New York, NY, Routledge.
5.3.2 Eligibility Criteria/Vulnerable Populations
Patients will be included in the study if they meet the following inclusion criteria:
1) adults older than age of 18
2) diagnosis a diagnosis of NF1;
3) permanently reside in the United States and
4) have pain interference aggregate scores of three or more in the last two weeks using the 
Brief Pain Inventory-Short Form (BPI-SF) scale.
Patients will be excluded if they: 1) have an undiagnosed case of NF1; 2) have documented 
major co-occurring psychiatric disease; 3) have moderate to severe cognitive deficits; or 4) 
have depression assessed using the Patient Health Questionnaire (PHQ-9) or anxiety 
assessed using the Generalized Anxiety Disorder scale (GAD-7) greater than or equal to the 
appropriate thresholds (10=mild major depression; 5=mild severe anxiety).
6.1 Intervention
6.1.1 Description of Intervention
Figure 1 presents a CONSORT study flow diagram. Potential participants will be required to 
access an online secure site to learn about the study and to be evaluated for eligibility, 
provide informed consent, and complete baseline assessments. Eligible participants will be 
randomly assigned to one of the 3 conditions: iCanCope-NF, iCanCope-NF +CM, or the 
Control Group (treatment as usual or TAU). Individuals in the iCanCope groups will receive 8 
weeks of 24-hour access to the program.
The proposed architecture of the iCanCope-NF consists of four theory-based 
components, integrated across smartphone: self-monitoring (e.g. Real-time symptom 
tracking via patient self-report. Customizable graphs and reports; smart goal setting (e.g. Set 
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goals related to improving pain, sleep, mood, physical activity and social activity, Adherence to 
SMART' framework); personalized self-management instruction and rehearsal (e.g. ( In-the-
moment access to pain coping strategies, Personalized instruction based on goals); and 
detailed pain education (Provide information on types of pain, strategies for maintaining 
physical activity and strategies managing anxiety, stress and emotions). 
iCanCope Orientation. At study intake, individuals within the iCanCope-NF and iCanCope-
NF +Contingency Management (CM) groups will receive a 10-minute video orientation to the 
iCanCope program. The orientation will emphasize daily usage of the CBT treatment 
platform. Individuals will receive a login and password information, general information and 
instruction, and contact information for technical problems.
iCanCope-NF Group: In this group, individuals will receive the iCanCope-NF program. The 
intervention will be delivered on a restricted password-protected mobile application. 
Participants will be encouraged to log onto the pain diary app (via automated alerts) once 
per day over the 8-week period to complete pain diary entries and develop and track their 
goals related to their pain, physical, social activities, sleep, as well as work through content 
based on their goals.
iCanCope-NF & CM Group: In addition to the iCanCope-NF activities outlined above, 
individuals will be rewarded with incentives such as points that are redeemable for prize-
based gift card vouchers.[i] (#_edn1) Points will be accrued through access to new sections, 
daily check-ins, and engagement of the mobile application. Based on research, the total 
amount of money that can be earned by the patient over the course of the two months is 50 
dollars USD. Individuals who are only randomized in the ICC-CM condition earn from $1 to 
$5 dollar amazon gift card per week for eight weeks (based on their usage). With an 
additional $10 dollar gift card, if they check in every day.  The total of the incentives can 
reach up to 50 dollars.   
Control Group: The control group is designed to assess for potential effects on outcomes of 
time, attention, during the study. In addition to usual care, participants will be required to 
complete baseline and follow-up assessments similar to that of the intervention groups. They 
will be given that patient education, through preapproved flyers and information found from 
national websites regarding pain management, but no self-management strategies or 
opportunities for social support. They will not have access to the mobile application during 
the course of experiment; however, the control group will be offered the full iCanCope-NF 
program following the trial (T2) for a period of 2 months after the study is over.
6.1.2 Method of Assignment/Randomization
Participants will be randomized to one of the three conditions using an urn randomization 
algorithm which modifies ongoing randomization probabilities based on prior group 
composition groups, and controls for other predictive factors. This process greatly reduces 
experimenter bias and other internal validity threats to integrity. Gender be the only variable 
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that will be attempted to controlled for to ensure equal representation across the groups 
within the urn randomization using stratification.
6.1.3 Selection of Instruments/Outcome Measures
In the pilot RCT, we plan to assess a broad range of subject characteristics, feasibility and 
clinical outcome measures over the course of the study. (See Table 1). Baseline 
assessments are designed to ensure that patients meet eligibility criteria and that important 
predictor treatment variables. Data will be self-reported and will be collected online and 
stored as per HIPAA privacy legislation. All measures have evidence of reliability and validity 
in adults in this age range, and include target specific measures of NF1 have recommended 
in previous trials
6.1.4 Intervention Administration
Individuals assigned to the iCanCope-NF, iCanCope-NF +CM will have 8 weeks of 24-hour 
access to the program. Individuals assigned the Control will not have access to the 
iCanCope-NF application.  
6.1.5 Reaction Management
Patients that have technical problems will be connected to the infrastructure team of the 
mobile application. Emergency Contact information will be provided within the mobile 
application (e.g. 911 services, National Suicide Hotline, and referring to their primary care 
office). Additional support will be provided to NF-community advocacy organizations for non-
emergences (NF Northeast, NF Network).
6.2 Assessments
6.2.1 Efficacy
All psychometric measures (see appendix) will be evaluated at intake, discharge, follow-up. 
All of these measures have evidence of reliability and validity in adults in this age range and 
include target specific measures of NF1 have recommended in previous trials. The primary 
research question is what is the feasibility of the iCanCope-NF program? We define 
feasibility as (1) rates of accrual and dropout, daily logins, engagement, and outcome 
measures completed and (2) perceptions regarding intervention acceptability and 
satisfaction; and what are the levels of engagement. logins, with the intervention? The 
secondary questions are: (1) how does the iCanCope-NF program compare with the 
control condition in differences of pain and pain-related activity limitations, sleep functioning, 
emotional functioning (depression, anxiety), opioid usage, pain catastrophizing, self-efficacy, 
respondent burden (i.e. Physical Functioning, R, Vitality, Social Functioning, Role-Emotional, 
and Mental Health), and psychological flexibility immediately post-treatment (T2), (2) does 
the iCanCope-NF + CM increase the engagement of the iCanCope-NF  program as 
compared to iCanCope-NF without CM, and do their corresponding levels of pain and pain-
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related activity decrease with CM?, and (3) do individuals with NF1 utilize the MBAA to help 
reduce pain symptoms? We hypothesize that by customizing and including MBAA to the 
program for adults with NF1, that individuals who engage regularly as seen through 
Analytics Platform for Evaluating Effective Engagement (APEEE) application, will acquire 
new sets of skills to facilitate pain management, while pain as reported with the Brief Pain 
Inventory will decrease.
6.2.2 Safety/Pregnancy-related Procedure
 N/A
6.2.3 Adverse Events Definition and Reporting
In the event your behavioral study involves a drug or device intervention consider the 
following sample language:
Adverse event means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention related.
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view 
of either the investigator or sponsor, it results in any of the following outcomes: death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or a congenital anomaly/birth defect. Important medical events 
that may not result in death, be life-threatening, or require hospitalization may be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
The following guidelines will be used to describe severity of adverse events.

Mild — Events require minimal or no treatment and do not interfere with the 
participant's daily activities.

Moderate — Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
functioning.

Severe — Events interrupt a participant's usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually potentially life-
threatening or incapacitating. Of note, the term "severe" does not necessarily equate 
to "serious".
All adverse events (AEs) must have their relationship to study intervention assessed by the 
investigator who examines and evaluates the participant based on temporal relationship and 
his/her clinical judgment. The degree of certainty about causality will be graded using the 
categories below. 
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
Related — The AE is known to occur with the study intervention, there is a 
reasonable possibility that the study intervention caused the AE, or there is a 
temporal relationship between the study intervention and event. Reasonable 
possibility means that there is evidence to suggest a causal relationship between the 
study intervention and the AE.

Not Related — There is not a reasonable possibility that the administration of the 
study intervention caused the event, there is no temporal relationship between the 
study intervention and event onset, or an alternate etiology has been established.
OR

Definitely Related — There is clear evidence to suggest a causal relationship, and 
other possible contributing factors can be ruled out. The clinical event, including an 
abnormal laboratory test result, occurs in a plausible time relationship to study 
intervention administration and cannot be explained by concurrent disease or other 
drugs or chemicals. The response to withdrawal of the study intervention 
(dechallenge) should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory rechallenge procedure if 
necessary.

Probably Related — There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely. The clinical event, including an abnormal 
laboratory test result, occurs within a reasonable time after administration of the 
study intervention, is unlikely to be attributed to concurrent disease or other drugs or 
chemicals, and follows a clinically reasonable response on withdrawal (dechallenge). 
Rechallenge information is not required to fulfill this definition.

Potentially Related — There is some evidence to suggest a causal relationship (e.g., 
the event occurred within a reasonable time after administration of the trial 
medication). However, other factors may have contributed to the event (e.g., the 
participant's clinical condition, other concomitant events). Although an AE may rate 
only as "possibly related" soon after discovery, it can be flagged as requiring more 
information and later be upgraded to "probably related" or "definitely related", as 
appropriate.

Unlikely to be related — A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study intervention administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the study intervention) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant's clinical 
condition, other concomitant treatments).

Not Related — The AE is completely independent of study intervention 
administration, and/or evidence exists that the event is definitely related to another 
etiology. There must be an alternative, definitive etiology documented by the 
clinician.
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The PI (Frank Buono) will be responsible for determining whether an adverse event (AE) is 
expected or unexpected. An AE will be considered unexpected if the nature, severity, or 
frequency of the event is not consistent with the risk information previously described for the 
study intervention.
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits and interviews of a study participant 
presenting for medical care, or upon review by a study monitor.
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant's 
condition deteriorates at any time during the study, it will be recorded as an AE.
Changes in the severity of an AE will be documented to allow an assessment of the duration 
of the event at each level of severity to be performed. AEs characterized as intermittent 
require documentation of onset and duration of each episode.
The PI (Frank Buono) will record all reportable events with start dates occurring any time 
after informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after 
the last day of study participation. At each study visit, the investigator will inquire about the 
occurrence of AE/SAEs since the last visit. Events will be followed for outcome information 
until resolution or stabilization.
6.2.4 Pharmacokinetics (if applicable)
N/A
6.2.5 Biomarkers (if applicable)
N/A
6.3 Study Procedures
6.3.1 Study Schedule
A total of three visits (all virtual) will be completed.  The three visits will consist of admission, 
discharge and follow-up.  Admission for control group will consist of 30 minutes, while 
admission for individuals within the experimental groups, should take 60 minutes.  Discharge 
evaluations for each should be 45 minutes (30 minutes for assessments, 15 minutes 
debriefing).  Follow-up should be 30 minutes for assessments. Individuals who have access 
to the mobile application are encouraged to provide daily check-in evaluations (estimated 
time of 2 minutes) and utilize the different modules at their discretion. The participants will 
have free reign of the mobile application and are not required to spend any time on the 
mobile application. No other communication with the research team will take place between 
all participants and the time intervals previously mentioned.  For individuals who are placed 
in the control group, they will be encouraged to utilize the materials found on several chronic 
pain websites, with no required time commitments. The mobile application will not remind or 
notify the participant if they have to login or input information. 
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6.3.2 Informed Consent
A waiver of documentation of consent will be requested considering that the entire research 
study is performed remotely. The consent will describe in detail the study intervention, study 
procedures, and risks are given to the participant. The consent will be uploaded through the 
initial meeting between the research team and the participant.   Consent is required prior to 
starting study procedures/administering study intervention. The following consent materials 
are submitted with this protocol Phase 3 consent form.
6.3.3 Screening
Subjects will be interviewed by a trained and supervised research assistant to determine 
interest in participating in the study and eligibility. Participants will be interviewed via Zoom 
using standardized psychological assessments or will complete similar standardized self-
report forms. Eligibility will be evaluated by the research assistant and reviewed with the 
project director or PI prior to initiation
6.3.4 Recruitment, Enrollment and Retention
Describe how potential subjects will be identified:
Adults with NF1 will be recruited from advocacy groups: NF Network and NF Northeast. NF 
Network and NF Northeast are the largest direct support and advocacy cohorts for 
individuals and families with neurofibromatosis in the United States. NF Network has over 
28,000 members on their private network, while NF Northeast has over 2,500 individuals on 
their private network.
Describe how potential subjects are contacted:
Each advocacy group has granted permission for us to contact individuals through their 
websites via email and private Facebook banners.  Examples of the emails are attached 
(see Recruitment Emails).
Who is recruiting potential subjects?
The Principal Investigator (PI; Dr. Frank Buono) or his research assistant will be responsible 
for all recruitment of individuals with NF1.
How will this process take place, including obtaining consent in relation to the start of the 
study procedures?
Individuals with NF1 are consented through the Zoom (www.zoom.com 
(http://www.zoom.com); A Yale-approved vendor). The consent form will be an attached 
document, that can be shared with them while the PI (Dr. Buono)/RA reads the consent 
form.   Zoom allows the PI/RA to interact with the individual with NF1 or the clinician to 
ensure any and all questions are answered prior to the participation of the study.
Use of third parties: N/A
6.3.5 Study Visits
See Appendix 3
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6.3.6 End of Study and Follow Up
At the end of the study, all participants in each group (TAU, iCanCope, iCanCope+CM) will 
be required to complete the identical set of assessments at intake, minus demographic 
information. Individuals who prematurely left early or who withdrawn from the study will not 
be asked to complete the end of the study survey. Additionally, individuals with access to the 
iCanCope mobile application license will end and will not be able utilize the mobile 
application until the follow-up is complete. For individuals who did not have access to the 
iCanCope mobile application they will continue not having access to the mobile application. 
All participants in each group will complete a 6-week post discharge follow-up. The follow-up 
will be identical to the discharge evaluation. Individuals will be emailed a secured email by 
the research assistant to complete the survey one day before the 6-week survey. All 
participants will have a one-week (7days) to complete the assessment, and a reminder email 
will be sent on the last day of the survey to the participants. Individuals will not be required to 
complete but will be encouraged to do so. 
6.3.7 Removal of Subjects
In cases of psychological deterioration, we will recommend to patients to contact their 
physician immediately and consider withdrawing from the study to receive more intensive 
treatments.  When necessary subjects will be withdrawn from this study and research staff 
will assist patients with appropriate sites for treatment such a physician, crisis center, or 
emergency room.  The mobile application will also have emergency information available 
that can be tailored by each patient to provide specific contacts that they may need. In 
instances of suicidal or homicidal risk, appropriate authorities including their primary provider 
will be informed and necessary actions (seeking crisis/suicidality evaluations and possible 
hospitalization) taken.
 
6.4 Statistical Method
6.4.1 Statistical Design
Statistical procedures and models have been selected according to the research questions 
being investigated and the types of data available. We will use α< .05 but will use 
appropriate corrections for multiple tests. Statistical analyses will be conducted by principal 
investigator using SPSS, SAS, or R with consultation from the coinvestigators. Using logistic 
regression for categorical and ANOVA for continuous measures, we will conduct preliminary 
analyses of the adequacy of the randomization procedure, the comparability of baseline 
measures across conditions, and the possible need for covariates in the analyses of 
treatment outcome data.
6.4.2 Sample Size Considerations
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An a priori power analysis conducted through G*Power (Universität Kiel, v. 3.1.9.2) 
estimated a conservative sample size analysis for the RCT. We are expecting a total of 140 
participants, given the length of the trial, we estimate 20% attrition rate of the final sample, 
giving us a total sample of (n=36) per group, for a final sample size of 108. The power 
analysis is based on previously utilized research in which estimated effect sizes ranged from 
20 to 40 individuals per group (52). We will attempt to enroll equal numbers of male and 
female individuals to evaluate gender differences through urn randomization process.
 52. Hancock, G. R. and R. O. Mueller, Eds. (2010). The Reviewer's Guide to Quantitative 
Methods. Power Analysis. New York, NY, Routledge.
6.4.3 Planned Analyses
Statistical procedures and models have been selected according to the research questions 
being investigated and the types of data available. We will use α< .05 but will use 
appropriate corrections for multiple tests. Statistical analyses will be conducted by principal 
investigator using SPSS, SAS, or R with consultation from the coinvestigators. Using logistic 
regression for categorical and ANOVA for continuous measures, we will conduct preliminary 
analyses of the adequacy of the randomization procedure, the comparability of baseline 
measures across conditions, and the possible need for covariates in the analyses of 
treatment outcome data.
For the primary first outcomes: Can we identify the feasibility of the iCanCope-NF program? 
This will be evaluated using general linear model of count data (logins, dropout rates, 
completion of outcome measures, engagement activity, (i.e. user and aggregate levels). 
Additionally, the proportional changes will be evaluated using an ANOVA. Due to potential 
missing data assumptions, a Cox regression will evaluate for differences in relationship 
between pre-and post. For second primary outcome: what are perceptions regarding 
intervention acceptability and satisfaction; and what are the levels of engagement with the 
intervention? Aggregate values will be summed and standardized through a (z-score 
analysis) to ensure equal representation of groups. Lastly, for the levels of engagement and 
number of activities tried/TSN exercises will be examined with linear and non-linear Mixed-
effects Models (LMM) with autoregressive 1 correlation structure (AR1) to test between 
conditions, while allowing for intra-participant serial correlation and unequal variance and 
covariance structure across time.
Secondary analyses will explore three research questions: (1) Does smartphone program 
(iCanCope-NF) compared with control condition lead to differences in pain and pain-related 
activity limitations, sleep functioning, emotional functioning (depression, anxiety), pain 
catastrophizing, self-efficacy, knowledge, psychological flexibility immediately post-treatment 
(T2)? This will be evaluated by incorporating an estimating equation approach to understand 
the differences in scores and using a sequential multilevel logistic regression models to 
estimate the independent and combined effects of proposed time-varying (contextual) 
variables on the probability of pain levels. We will also test interaction effects between 
stable/trait-level participant characteristics and contextual variables. (2) Does the iCanCope-
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NF + CM increase the usage of the iCanCope-NF program as compared to iCanCope-NF 
without CM, and do their corresponding levels of pain and pain-related activity decrease? 
This will be evaluated between the two intervention groups and using the difference in 
nominal data sets, and simple qualitative analyses. (3) Do individuals with NF1 utilize the 
MBAA more readily because they are on the mobile application? To assess the moderation 
effect, we will include an interaction term for each separate moderator variable and key 
predictor of interest (two-way interaction between moderator and group for cross-sectional 
analysis and three-way interaction between moderator, group and time for longitudinal 
analysis) in the regression models and test its significance using Wald t-test.
6.4.3.1 Primary Analyses
For the primary first outcomes: Can we identify the feasibility of the iCanCope-NF program? 
This will be evaluated using general linear model of count data (logins, dropout rates, 
completion of outcome measures, engagement activity, (i.e. user and aggregate levels). 
Additionally, the proportional changes will be evaluated using an ANOVA. Due to potential 
missing data assumptions, a Cox regression will evaluate for differences in relationship 
between pre-and post. For second primary outcome: what are perceptions regarding 
intervention acceptability and satisfaction; and what are the levels of engagement with the 
intervention? Aggregate values will be summed and standardized through a (z-score 
analysis) to ensure equal representation of groups. Lastly, for the levels of engagement and 
number of activities tried/TSN exercises will be examined with linear and non-linear Mixed-
effects Models (LMM) with autoregressive 1 correlation structure (AR1) to test between 
conditions, while allowing for intra-participant serial correlation and unequal variance and 
covariance structure across time.
6.4.3.2 Secondary Objectives Analyses, if applicable
Secondary analyses will explore three research questions: (1) Does smartphone program 
(iCanCope-NF) compared with control condition lead to differences in pain and pain-related 
activity limitations, sleep functioning, emotional functioning (depression, anxiety), pain 
catastrophizing, self-efficacy, knowledge, psychological flexibility immediately post-treatment 
(T2)? This will be evaluated by incorporating an estimating equation approach to understand 
the differences in scores and using a sequential multilevel logistic regression models to 
estimate the independent and combined effects of proposed time-varying (contextual) 
variables on the probability of pain levels. We will also test interaction effects between 
stable/trait-level participant characteristics and contextual variables. (2) Does the iCanCope-
NF + CM increase the usage of the iCanCope-NF program as compared to iCanCope-NF 
without CM, and do their corresponding levels of pain and pain-related activity decrease? 
This will be evaluated between the two intervention groups and using the difference in 
nominal data sets, and simple qualitative analyses. (3) Do individuals with NF1 utilize the 
MBAA more readily because they are on the mobile application? To assess the moderation 
effect, we will include an interaction term for each separate moderator variable and key 
predictor of interest (two-way interaction between moderator and group for cross-sectional 
analysis and three-way interaction between moderator, group and time for longitudinal 
analysis) in the regression models and test its significance using Wald t-test.
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6.4.3.3 Analysis of Subject Characteristics
We will evaluate the relationship between iCanCope module use, patterns, gender and 
change in coping stills and outcomes. Rate and time of specific module use will be 
evaluated, and LMM will be used to evaluate the relationship between minutes using specific 
module categories with corresponding change in coping skills efficacy in those categories
6.4.3.4 Interim Analysis (if applicable)
N/A
6.4.3.5 Health economic evaluation, if applicable
N/A
6.4.3.6 Other
N/A
6.4.4 Subsets and Covariates
N/A
6.4.5 Handling of Missing Data
Another set of automatic email reports, sent on a weekly or less frequent basis, provides a 
set of designated recipients (e.g., the PI) with information about study logistics, such as 
number of subjects enrolled, number of subjects active in the protocol, gender composition 
of the sample, percentage of missing data by each assessment instrument, or any other 
information necessary to monitor the progress of the project and the compliance with the 
protocol. A fully computerized system allows this type of monitoring without furnishing 
investigators with data that could influence the outcome of the study. We will evaluate 
different assumptions about missing data and code it as zero.
7.1 Ethical Considerations: Informed Consent/Assent and HIPAA Authorization
Consent forms will be Institutional Review Board (IRB)-approved and the participant/legally 
authorized representative (LAR) will be asked to read and review the document. The PI or 
research assistant will explain the research study to the participant and answer any 
questions that may arise. This conversation will take place in a private room.
Participants/LAR will have the opportunity to carefully review the electronic consent form and 
ask questions prior to signing. The participants/LAR should have the opportunity to discuss 
the study with their family or surrogates or think about it prior to agreeing to participate. The 
participant will sign the informed consent document prior to any procedures being done 
specifically for the study. Participants/LAR must be informed that participation is voluntary 
and that they may withdraw from the study at any time, without prejudice. The study team 
will document all verbal HIPAA authorizations, from a study potential participant or LAR for 
their use of PHI for the current study.  
7.2 Institutional Review Board (IRB) Review
The protocol will be submitted to the IRB for review and approval. Approval of the protocol 
must be obtained before initiating any research activity. Any change to the protocol will 
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require an approved IRB amendment before implementation.  The IRB will have final 
determination whether informed consent and HIPAA authorization are required. 
A study closure report will be submitted to the IRB after all research activities have been 
completed.   
Other study events (e.g. data breaches, protocol deviations) will be submitted per Yale’s 
IRB's policies.
7.3 Subject Privacy, Confidentiality & Data Management
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s)/funding agency. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating 
to participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study, or the data 
will be released to any unauthorized third party without prior written approval.
All research activities will be conducted in as private a setting as possible.
Representatives of the Institutional Review Board (IRB), regulatory agencies or study 
sponsor/funding agency may inspect all documents and records required to be maintained 
by the investigator for the participants in this study. The study site will permit access to such 
records.
The study participant's contact information will be securely stored at each study site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, 
regulatory, or sponsor requirements.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored in a secure Yale approved server called Box. . 
This will not include the participant's contact or identifying information. Rather, individual 
participants and their research data will be identified by a unique study identification number. 
The study data entry and study management systems used will be secured and password 
protected. At the end of the study, all study databases will be de-identified and archived at 
the [insert location].
7.4 Deviations/Unanticipated Problems
A protocol deviation is any noncompliance with the clinical trial protocol. The noncompliance 
may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented 
promptly.
It is the responsibility of the site investigator to identify and report deviations within 2 working 
days of identification of the protocol deviation. All deviations must be addressed in study 
source documents, reported to the study sponsor, and the reviewing Institutional Review 
Board (IRB) per their policies.
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Unanticipated problems involving risks to participants or others include, in general, any 
incident, experience, or outcome that meets all of the following criteria:

Unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the 
Institutional Review Board (IRB)-approved research protocol and informed consent 
document; and (b) the characteristics of the participant population being studied;

Related or possibly related to participation in the research ("possibly related" means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and

Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized.
This definition could include an unanticipated adverse device effect, any serious adverse 
effect on health or safety or any life-threatening problem or death caused by, or associated 
with, a device, if that effect, problem, or death was not previously identified in nature, 
severity, or degree of incidence in the investigational plan or application (including a 
supplementary plan or application), or any other unanticipated serious problem associated 
with a device that relates to the rights, safety, or welfare of subjects (21 CFR 812.3(s)).
The investigator will report unanticipated problems (UPs) to the reviewing Institutional 
Review Board (IRB) and to the study sponsor. The UP report will include the following 
information:

Protocol identifying information: protocol title and number, PI's name, and the IRB 
project number;

A detailed description of the event, incident, experience, or outcome;

An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP;

A description of any changes to the protocol or other corrective actions that have 
been taken or are proposed in response to the UP.
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline:

UPs that are serious adverse events (SAEs) will be reported to the IRB and study 
sponsor within <insert timeline in accordance with policy> of the investigator 
becoming aware of the event.

Any other UP will be reported to the IRB and to the study sponsor within <insert 
timeline in accordance with policy> of the investigator becoming aware of the 
problem.

All UPs should be reported to appropriate institutional officials (as required by an 
institution's written reporting procedures), the supporting agency head (or designee), 
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and the Office for Human Research Protections (OHRP) within <insert timeline in 
accordance with policy> of the IRB's receipt of the report of the problem from the 
investigator.
7.5 Data Collection
Data monitoring procedures involve an organizational structure of clearly defined tasks 
assigned to all research personnel involved in the conduct of this study. The organizational 
structure used to ensure quality of data in this project include: 1) extensive training and close 
supervision of research assistants in data collection; 2) direct entry of most data at time of 
collection; and 3) utilization of on-line error- checking procedures. The PI supervises data 
procedures. All error corrections are fully documented in the research records of the study. 
All research personnel are required to participate in and document training in protection of 
human subjects and the responsible conduct of scientific research. Data entry and review in 
this study will be conducted using a web-based data collection and monitoring system. 
Another set of automatic email reports, sent on a weekly or less frequent basis, provides a 
set of designated recipients (e.g., the PI) with information about study logistics, such as 
number of subjects enrolled, number of subjects active in the protocol, gender composition 
of the sample, percentage of missing data by each assessment instrument, or any other 
information necessary to monitor the progress of the project and the compliance with the 
protocol. A fully computerized system allows this type of monitoring without furnishing 
investigators with data that could influence the outcome of the study. The system meets the 
highest security and reliability standards. All connections to the systems are secured and 
encrypted using 128-bit strong encryption protocols and only authorized users are able to 
access the system.
7.6 Data Quality Assurance
The PI is responsible for monitoring of quality control and assurance through regular 
communication with the research team via bi-weekly meetings. The PI will train the research 
assistant on ensuring consistent and reliable methods of recruitment, data management, 
and training sessions through initial trainings. Additionally, the PI will provide in situ training 
to the research assistant throughout the research experiment.  A standard operating 
procedure (see appendix) will be implemented and trained on.  
7.7 Study Records
Study records consists of the following: 1) Consent forms, 2) inclusion/exclusion screen 
forms, 3) Process measures (e.g. Patient health questionnaire, generalized anxiety disorder, 
brief pain inventory, background questionnaire), 4) feasibility measures (e.g. iCanCope 
Program usage, patient satisfaction survey), 5) clinical measures (e.g. short form survey, 
chronic pain acceptance questionnaire, psychological inflexibility in pain scale, pain 
catastrophe scale), 6) regulatory message (appendix) indicating the iCanCope mobile 
application is a FDA exempted device. 
7.8 Access to Source
Survey information taken at admission, discharge, and follow-up will be stored on Qualtrics 
(a Yale approved vendor), and only the PI will have access to this.  The source information 
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of the mobile application will be controlled by the APEEE developers and will be transferred 
to the Dr. Buono via access to a secure dashboard that only he has access to.  
7.9 Data or Specimen Storage/Security
Data will be stored two in two servers: 1) Box @ Yale is a cloud-based file sharing and 
storage service workspace which enables people to collaborate, synchronize, and share 
information. This server will collect, record and store all data regarding any data that is 
inputted from the PI. 2) All surveys will be stored through Qualtrics. Qualtrics is an approved 
vendor of Yale University, and will securely store, record and store all participants surveys
7.10 Retention of Records
All records will be maintained on Yale secured server for a minimum of 5 years by the 
principal investigator.  Records will be destroyed after that time by the principal investigator.  
7.11 Study Monitoring
The PI is responsible for monitoring the data and conducting performance and safety 
reviews, at the specified frequency. Either the PI or the IRB have the authority to stop or 
modify the study. The monitoring by the IRB will occur annually at the time of re-approval. 
The PI will conduct data and safety review at least quarterly and at any time a serious 
adverse event occurs. During the review process, the PI will evaluate whether the study 
should continue unchanged, requires modification or amendment to continue, or should 
discontinue enrollment.
7.12 Data Safety Monitoring Plan
a. What is the investigator's assessment of the overall risk level for subjects participating in 
this study? The risks associated with participating in this study can be categorized as 
minimal (i.e., risks are commensurate with everyday risks associated with chronic pain and 
data have adequate protection for maintaining confidentiality).
b. If children are involved, what is the investigator's assessment of the overall risk level for 
the children participating in this study? N/A
c. Include an appropriate Data and Safety Monitoring Plan. Examples of DSMPs are 
available here http://your.yale.edu/policies-procedures/forms/420-fr-01-data-and-
safetymonitoring-plans-templates for Minimal risk
ii. Minimal Risk 
The principal investigator is responsible for monitoring the data, assuring protocol 
compliance, and conducting the safety reviews every month. During the review process the 
principal investigator will evaluate whether the study should continue unchanged, require 
modification/amendment, or close to enrollment.
 
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The principal investigator, the Institutional Review Board (IRB) or the funding agency, DOD 
have the authority to stop or suspend the study or require modifications.
 
This protocol presents minimal risks to the subjects and Unanticipated Problems Involving 
Risks to Subjects or Others (UPIRSOs), including adverse events, are not anticipated. In the 
unlikely event that such events occur, Reportable Events (which are events that are serious 
or life-threatening and unanticipated (or anticipated but occurring with a greater frequency 
than expected) and possibly, probably, or definitely related) or Unanticipated Problems 
Involving Risks to Subjects or Others that may require a temporary or permanent interruption 
of study activities will be reported immediately (if possible), followed by a written report within 
5 calendar days of the Principal Investigator becoming aware of the event to the IRB (using 
the appropriate forms from the website) and any appropriate funding and regulatory 
agencies. The investigator will apprise fellow investigators and study personnel of all 
UPIRSOs and adverse events that occur during the conduct of this research project through 
regular study meetings, The protocol's research monitor(s), e.g.,  study sponsors, funding 
and regulatory agencies, and regulatory and decision-making bodies will be informed of 
adverse events within 5 days of the event becoming known to the principal investigator.
d. For multi-site studies for which the Yale PI serves as the lead investigator:
i. How will adverse events and unanticipated problems involving risks to subjects or 
others be reported, reviewed and managed? Given that no other site (Connecticut Children’s 
Hospital or The Hospital of Sick Children) will be recruiting/enrolling participants, there is no 
possibility for adverse events or unanticipated events from those sites. With regarding any 
reviewing or managed data only the Hospital of Sick Children will have managing data. Any 
unanticipated problem will be reported to the PI (Dr. Frank Buono), within 24 hours and Dr. 
Buono, will report any serious risk to the appropriate organization (e.g. Army HRPO, Yale 
IRB).  
ii. What provisions are in place for management of interim results? NA
7.13 Study Modification
All modifications will have to be approved by the Yale IRB and the funding agency, DOD 
processes.  Any updates or changes will be identified through track changes and highlighted 
for the IRB committees. 
7.14 Study Discontinuation
N/A
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7.15 Study Completion
The proposed research study should be completed by 8-15-22.  The PI will report to the IRB 
through the IRES portal when the study is complete. 
7.16 Conflict of Interest Management Plan
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will 
be required to have such conflicts managed in a way that is appropriate to their participation 
in the trial. The study leadership in conjunction with the appropriate conflict of interest review 
committee has established policies and procedures for all study group members to disclose 
all conflicts of interest and will establish a mechanism for the management of all reported 
dualities of interest.
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by the IRB with a Committee-sanctioned conflict management plan that has 
been reviewed and approved by the study sponsor prior to participation in this study.  All 
investigators will follow the applicable conflict of interest policies.
7.17 Funding Source
Salary support for this study is provided by the U.S. Army Medical Research Materiel 
Command endorsed by the U.S. Army, through the Congressionally Directed Medical 
Research Programs' Neurofibromatosis Research Program under Award No. W81XWH-19-
1-0618.
7.18 Publication Plan
The intent is to publish the findings of the current study.  The funding agency Department of 
Defense will require the following statement:
"This work was supported by the U.S. Army Medical Research Materiel Command endorsed 
by the U.S. Army, through the Congressionally Directed Medical Research Programs' 
Neurofibromatosis Research Program under Award No. W81XWH-19-1-0618."
Frank Buono will have primary responsibility for publishing the study results as he is the PI.  
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Appendices
Appendix #
Title
Section
Topic
1
Flow chart 
Synopsis
Study Flow Chart (optional)
2
6 Methods
6.1.2 Method of 
Assignment/Randomization
3
6 Methods
6.1.3 Selection of 
Instruments/Outcome 
Measures
4
6 Methods
6.2.2 Safety/Pregnancy-
related Procedure
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List of Tables
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