Re-engineering Precision Therapeutics Through N-of-1 Trials: Feasibility Study of Personalized Trials of Light Therapy for Fatigue
Phase: NA
Conditions: Fatigue
Sponsor: Northwell Health

Re-engineering Precision Therapeutics Through N-of-1 Trials: Feasibility Study of 
Personalized Trials of Light Therapy for Fatigue
Research Protocol Document
Principal Investigator: Karina W. Davidson, PhD, MASc
NCT04707846
Document Date: 09/09/2021 

Version Date: 09/9/2021 
Page 1 of 32 
RESEARCH PROTOCOL 
Protocol Title: 
Re-engineering Precision Therapeutics Through N-of-1 Trials: 
Feasibility Study of Personalized Trials of Light Therapy for 
Fatigue 
Principal Investigator: 
Karina W. Davidson, PhD, MASc 
Primary Contact Name: 
Stefani D’Angelo 
Primary Contact Phone: 
646-766-7169
Primary Contact E-mail: 
SDangelo1@northwell.edu 
Date Revised: 
09/9/2021 
IRB Number: 
20-0835
Guidelines for Preparing a Research Protocol 
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1.  PREVIOUS STUDY HISTORY 
 
Has this study ever been reviewed and rejected/disapproved by another IRB prior to 
submission to this IRB? 
 
 No  
 Yes −  if yes, please explain:  
 
 
2. BRIEF SUMMARY OF RESEARCH 
• The summary should be written in language intelligible to a moderately educated, 
non-scientific layperson.  
• It should contain a clear statement of the rationale and hypothesis of your study, a 
concise description of the methodology, with an emphasis on what will happen to the 
subjects, and a discussion of the results.  
• This section should be ½ page 
 
 
The purpose of this pilot study is to determine the feasibility of using N-of-1 
methods in a virtual research study, to assess the feasibility of using online web and 
social media advertising to recruit and enroll participants in a virtual research 
study, and to determine the feasibility of methods used to collect and assess 
participant symptoms in response to a wellness strategy (in this case, light therapy 
for symptoms of fatigue). This pilot will help determine if an N-of-1 study design, 
or what we are terming Personalized Trials, can have widespread use in future 
research and clinical practice to address high public health burdens with a high 
heterogeneity of response.  
 
This study will assess feasibility using a Personalized Trial model to evaluate an 
individual participant’s experience using bright or dim light therapy on symptoms 
of fatigue. Participants (N=60) will be sent a Fitbit device and receive a 
commercially-available light therapy device (bright blue light) and a dim light 
therapy device (dim blue light). Participants will be asked several questions a day 
via text message about their symptoms of fatigue, as well as their pain, 
concentration, confidence, mood, and stress levels to demonstrate relevant 
secondary impacts of fatigue. Participants will also have access to several videos 
explaining the protocol. After 14 weeks, participants will receive a summary of 
their observed data. Creating this type of report will help to assess the feasibility of 
using a N-of-1 trial design through user-acceptability of fatigue and wellness-
related data visualizations and the ability to choose preferred intervention (if any) 
based on the data. Participants will be asked to complete a satisfaction survey 
(electronic or phone if they are non-responders) and participate in a phone 
interview to inform acceptability of protocol requirements, study materials, and 
personalized reports. 
 

 
 
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We believe Personalized Trials are feasible to scale to a large randomized 
controlled trial, and eventually clinical practice specifically to address frequent 
chronic complaints with the custom N-of-1 pathways we are developing. Data 
collected to support our hypothesis includes device adherence, survey adherence, 
adherence to video views, website and social media engagement metrics, and 
participant satisfaction based on qualitative interviews and surveys. Results from 
this pilot study will inform the future development of N-of-1 methodology in the 
research and clinical space. 
 
 
3. INTRODUCTION/BACKGROUND MATERIAL/PRELIMINARY STUDIES AND 
SIGNIFICANCE 
• Describe and provide the results of previous work by yourself or others, including 
animal studies, laboratory studies, pilot studies, pre-clinical and/or clinical studies 
involving the compound or device to be studied.  
• Include information as to why you are conducting the study and how the study differs 
from what has been previously researched, including what the knowledge gaps are. 
• Describe the importance of the knowledge expected to result 
 
This project represents a pilot project under the umbrella of the NIH-funded grant 
“Re-engineering precision therapeutics through N-of-1 trials” (Northwell IRB 19-
0572-MRB) which is funded to test use cases appropriate for N-of-1 methodology 
and evaluate them for acceptability and scalability. 
 
The overarching objective of our parent grant is to develop, test, and implement an 
innovative technology platform for conducting N-of-1 trials that transforms 
precision therapeutics. Right now, clinicians are engaging in clinical encounters in 
which they are trying to determine the best therapy for individual patients. These 
encounters are likely to be unsuccessful. Clinicians rely on the best available 
evidence (e.g., results from parallel group, phase III randomized clinical trials; 
RCTs) for recommending therapies to a patient. Yet, conventional, between-group 
RCTs only provide estimates of the effect of therapies on the hypothetical 
‘average’ patient in those trials. Individual patients, however, often respond 
differently than the hypothetical average patient in the phase III RCTs, and thus, 
heterogeneity of therapy response plagues clinical decisions made for an individual 
patient every day.   
 
The most scientifically rigorous — and potentially transformative — method for 
determining optimal therapy for a patient is a single-patient (N-of-1) trial. N-of-1 
trials are multiple crossover trials, usually randomized, and often masked, 
conducted within a single patient, with data collected objectively, continuously, 
and in the real-world, for a sufficient time period to determine whether the therapy, 
compared to a placebo or other active therapy, is optimal for a particular patient. 
They also yield information on off-target actions, such as side-effects or unintended 
consequences, so that a more complex picture can emerge about the overall 
benefits and harms of the therapy for that one individual patient. Clinicians and 

 
 
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patients do not routinely engage in this type of scientific endeavor because they 
lack the tools.   
 
In many ways, Personalized or N-of-1 Trials are the foundational design for a 
truly patient-centered approach by serving as a clinical decision tool for 
patients. Historically, in introducing evidence-based medicine, Guyatt and others 
have described Personalized Trials as the pinnacle of the evidence-based design 
pyramid.(1)  Clinicians can use these techniques to monitor and make treatment 
decisions in chronically ill patients,(2) of whom 25% experience adverse treatment 
effects.(3) Personalized Trials are specifically designed to help patients and their 
clinicians make healthcare decisions that are informed by high-integrity, evidence-
based information uniquely relevant to the outcomes and values important to 
them.(4) In a series of demonstration trials, Personalized Trials led to valuable 
changes in treatment, cessation of treatment, or confirmation of the original 
treatment.(5-8) For example, of 71 N-of-1 trials for patients with any chronic pain, 
46 patients (65%) decided to change their pain medication due to trial results.(9) 
However, Personalized Trials are conducted infrequently in clinical practice.(10-
12) In post-mortem assessments as to why Personalized Trials had yet to 
become commonly employed, proponents concluded that they were insufficiently 
appealing to patients or clinicians to justify the cost and effort needed to design and 
implement them.(10, 11) Specifically, Personalized Trial design specifications had 
mostly been driven by clinicians or researchers,(13, 14) with little input from 
patients.  
 
Rationale for Selecting Blue Light as an N-of-1 Trial for Fatigue  
Participant report of fatigue meets all of our criteria for selection as a use case as 
outlined in our umbrella grant: it has high public health burden, high heterogeneity 
of observed outcomes, and is high priority for a Personalized Trial approach as 
determined by previously interviewed clinicians and patients. This instance will 
adapt our N-of-1 trial platform to comparing a complementary and alternative 
medicine (CAM) therapy for fatigue symptoms (bright light therapy) to (dim light 
therapy). This alpha-test will enable us to expand our N-of-1 trial platform of non-
pharmacologic therapies, including CAM. Of note, it is possible that N-of-1 trials 
of CAM could be conducted at the direct-to-consumer level.  
 
Rational for Selecting Blue Light  
Blue light has been chosen for this study because it has been shown in multiple 
research studies to be either equal or more efficacious than bright white light in 
light therapy treatments for a variety of therapies, including fatigue (15-19). It has 
also been shown in a number of studies that the blue wavelength of light is a key 
component to the shift of fatigue measures in patient reported outcomes (15-18). 
Additionally, the use of blue light therapy rather than white light therapy allows for 
a lower strength bright light, reducing the eye glare in treatments (17). This allows 
for a more comfortable, low-risk light therapy experience and resulting observed 
outcomes to support the trial methodology.   
 

 
 
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Rationale for Selecting Usual Care over Dim Light as the Control Condition  
Patients don’t frequently ask is treatment A better than Treatment B, but rather 
should I use Treatment A? That is, is Treatment A better than what I’m using for 
fatigue management now? This was indicated to us by the results on our patient 
focus groups and survey; when asked what the most acceptable control condition 
was, over 80% of patients preferred Usual Care as the control for their Personalized 
Trial. We are including a dim blue light therapy device given our prior experience 
conducting pilot studies utilizing light therapy. In those studies, participants often 
chose the “sham” device as the one to which they were most responsive.  In 
addition, we include a usual care condition to control for and observe the influence 
of any expectancy effect on the self-reported data. Usual care data collection will 
enable us to test the effect of bright light therapy compared to usual care, and to 
obtain estimates of the cost-effectiveness of the N-of-1 approach. For this reason, 
we will use usual care as our control condition for light therapy Personalized 
Trials.   
 
Without development of innovative platforms for conducting Personalized Trials, 
with within-participant randomization to eligible wellness management options, 
including when clinically appropriate, usual care, patients and clinicians cannot 
obtain the objective data they need to empirically choose the optimal precise 
therapy. Scientists may be able to use Personalized or N-of-1 trials in the future to 
better understand the uniqueness of light therapy responders versus non-responders. 
Off-target responses (such as increased stress or decreased physical activity) could 
also be detected in this methodology, as the unique responsiveness of one patient to 
several time periods of therapy exposure will be available. Should this pilot 
demonstrate acceptability by participants, scalable implementation and satisfaction 
with this methodology amongst participants, it will be a critical step in broadening 
the application and utilization of this methodology. 
 
 
4. OBJECTIVE(S)/SPECIFIC AIMS AND HYPOTHESES 
• A concise statement of the goal(s) of the current study.  
• The rationale for and specific objectives of the study.  
• The goals and the hypothesis to be tested should be stated. 
 
We believe the delivery of N-of-1 methodology through Personalized Trials is 
feasible to scale to a large randomized controlled trial, and eventually to standard 
clinical practice. In order to demonstrate this feasibility, we must be able to collect 
data illustrating that Personalized Trials can be a low-burden, satisfactory tool that 
can be scaled to individuals and clinicians.  
 
We will additionally examine the novel individual-level heterogeneity of treatment 
effect and observed outcomes made possible by the N-of-1 trial design, and will 
test the feasibility of pooling real-world N-of-1 results across patients to efficiently 
estimate the overall effectiveness of light therapy and thus the N-of-1 trial design.  
To determine whether this “precision therapeutics” paradigm-shifting approach 

 
 
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creates added value for the learning healthcare system, and to confirm engineering 
these innovations into one platform and system to empirically determine the 
precise therapy for each patient is feasible, we will pool N-of-1 results across all 
projects using the N1Thrive platform.   
 
Thus, the goals of this pilot study are to:  
1. Conduct a pilot test (N=60) of a Personalized Trial that is delivered remotely to 
participants in the United States. 
2. Collect data regarding Minimum Viable Product (MVP) specifications for a 
future technology platform to deliver Personalized Trials. 
3. Incorporate web-based research advertising and recruitment in the pilot study. 
4. Elicit participant attitudes and opinions toward using Personalized Trials to help 
inform their personal wellness strategy.  
 
 
5.  RESOURCES AVAILABLE TO CONDUCT THE HUMAN RESEARCH 
• Explain the feasibility of meeting recruitment goals of this project and demonstrate a 
potential for recruiting the required number of suitable subjects within the agreed 
recruitment period 
o How many potential subjects do you have access to? 
• Describe your process to ensure that all persons assisting with the trial are 
adequately informed about the protocol and their trial related duties and functions 
 
Fatigue remains one of the most highly-cited patient complaints to their primary 
care provider(20), yet there are relatively few treatment options available. We have 
conducted focus groups as part of prior grants to determine what chronic symptoms 
or conditions are most acceptable for a Personalized Trial, and fatigue was selected 
by both patients and their health providers(19). With such a broad group 
experiencing symptoms of fatigue, we have planned for a broad base of recruitment 
efforts to potentially recruit a diverse representation of this population.  
 
Northwell employs over 70,000 individuals and Hofstra University has over 11,000 
students enrolled. While these are two organizations that are easily accessible, we 
will be expanding our scope of potential participants through the use of social 
media. Social media and web-based advertisements remain a largely untapped 
resources for research recruitment, and we will be exploring the use of online 
postings to reach several more thousand potential participants through online paid 
advertisement and links to a study website. 
 
Center for Personalized Health staff must meet certain eligibility criteria before 
assisting with this Personalized Trial pilot. All staff members must be listed on the 
IRB and be up-to-date with trainings and attestations as required by the Northwell 
Health Human Research Protection Program. Additionally, staff will be required to 
participate in weekly meetings with the Principal Investigator, and an additional 
weekly meeting with the Project Manager, in order to stay informed about the study 
protocol, staff duties and functions, and to answer any questions that come up 

 
 
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within the group. Staff will have daily access to the Project Manager, Director of 
Clinical Research, and Principal Investigator to answer any protocol questions they 
may have outside these established weekly meetings. 
 
 
6.  RECRUITMENT METHODS 
• Describe the source of potential subjects 
• Describe the methods that will be used to identify potential subjects 
• Describe any materials that will be used to recruit subjects.  A copy of any 
advertisements (flyers, radio scripts, etc.) should be submitted along with the 
protocol.  
• If monetary compensation is to be offered, this should be indicated in the protocol 
 
Since the proposed study will take place virtually, potential participants can reside 
anywhere within the United States.  
 
Potential participants will be recruited via the following avenues: 
- Paid social media advertisements targeted to individuals who meet study 
eligibility demographics and identify as having chronic fatigue. 
-E-mail advertisement through employee and student communication channels, 
both including and outside of Northwell Health and Hofstra University.  
-E-mail advertisements through existing email lists from those who have previously 
expressed an interest in participation in a Personalized Trial with the Center for 
Personalized Health. 
-Flyers, shared at urgent care/walk-in and physician clinics, within and outside of 
the Northwell Health network. 
-Short promotional videos shared online or in clinic waiting rooms. 
-Recruitment posts within online wellness groups, such as those that discuss 
recurring fatigue. 
 
Potential participants will self-identify as having a minimum threshold of fatigue 
over the last 30 days using PROMIS Fatigue measures, and interest in participating 
in a Personalized Trial. Participants will receive a pay card valued at $100 for 
completing all study requirements. 
 
 
7.  ELIGIBILITY CRITERIA 
• Describe the characteristics of the subject population, including their anticipated 
number, age, ranges, sex, ethnic background, and health status. Identify the criteria 
for inclusion or exclusion of any subpopulation.  
• Explain the rationale for the involvement of special classes of subjects, such as 
fetuses, pregnant women, children, prisoners or other institutionalized individuals, or 
others who are likely to be vulnerable.   You cannot include these populations in your 
research, unless you indicate such in the protocol 

 
 
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• Similarly, detail exclusionary criteria: age limits, special populations (minors, 
pregnant women, decisionally impaired), use of concomitant medications, subjects 
with other diseases, severity of illness, etc. 
 
Up to 60 participants will be randomized to receive this pilot study protocol. We 
estimate about 70% will identify as female and 30% will identify as male. We aim 
to recruit a diverse pool of participants with varied ethnic and racial backgrounds. 
 
Inclusion criteria:  
-Age 18 - 59 years old of age 
-Fluent in English 
-Self reported fatigue results score  > 12 on a modified PROMIS Fatigue Short 
Form 8a scale 
-Able to participate in blue light therapy 
-Owns and can regularly access a smartphone capable of receiving text messages 
-Owns and can regularly access an e-mail account 
-Lives in the United States 
 
Exclusion criteria: 
- <18 years old or >60 years old  
- Pregnant women 
-Previous diagnosis of a serious mental health condition or psychiatric disorder, 
such as bipolar disorder 
-Previous diagnosis of eye disease, such as cataracts, glaucoma, macular 
degeneration, Stargardt or family history of Stargardt, retinitis or retinopathy, or 
other retinal disorders 
-Previous diagnosis of diabetes 
- Previous eye surgery 
-Sensitivity to light or use of medication causing sensitivity to light 
-Epilepsy or a history of seizures 
- Participation in shift work (evening/night shifts, early morning shifts, rotating 
shifts, etc.) 
-Lives outside of the United States 
 
 
8.  NUMBER OF SUBJECTS 
• Indicate the total number of subjects to be accrued locally.  If applicable, distinguish 
between the number of subjects who are expected to be pre-screened, enrolled 
(consent obtained), randomized and complete the research procedures. 
• If your study includes different cohorts, include the total number of subjects in each 
cohort. 
• If this is multisite study, include total number of subjects across all sites.   
 
We expect to pre-screen up to 750 potential participants in this study. Up to 150 
potential participants will be invited to enroll. Up to 60 participants will be 
randomized to complete research procedures.  

 
 
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Of those participants who receive randomized treatment schedules, 30 participants 
will be randomized to receive the protocol in the following order of two-week 
treatment periods: Bright Blue Light Therapy, Dim Blue Light Therapy, Usual 
Care, Usual Care, Dim Blue Light Therapy, Bright Blue Light Therapy 
(ABCCBA). The remaining 30 participants will be randomized in the following 
order of two-week treatment periods: Usual Care, Dim Blue Light Therapy, Bright 
Blue Light Therapy, Bright Blue Light Therapy, Dim Blue Light Therapy, Usual 
Care (CBAABC). 
 
 
9. STUDY TIMELINES 
• Describe the duration of an individuals participation in the study 
• Describe the duration anticipated to enroll all study subjects 
• The estimated date of study completion 
 
The study will take place over the course of 14 weeks. The first two weeks will be 
a baseline period, where no light therapy is assigned, but data are collected, 
including self-report of fatigue and accelerometer-derived sleep and activity data. 
After successful completion of the baseline period, participants will be randomized 
to six 2-week treatment blocks of bright blue light therapy, dim blue light therapy, 
and usual care. In usual care treatment periods, participants will be instructed to not 
use any light therapy device and will be asked to continue answering survey 
questions and wearing their Fitbit device. At the end of the 14 weeks, a report 
containing the individual’s analyzed data will be sent to each participant, along 
with a satisfaction survey. This report will be sent within 3 months of study 
completion. After the satisfaction survey is completed, study coordinators will 
reach out to each participant to interview them about their experience in 
Personalized Trials. A $100 pay card (CliniCard) will be mailed to each participant 
as compensation for their time after the successful completion of 14 weeks of data 
collection, satisfaction survey, and phone interview. 
 
Potential participants will have the opportunity to choose from within a provided 
list of start dates during their enrollment process. No more than 20 potential 
participants will begin their baseline period on the same day. Enrollment will be 
ongoing until up to 60 participants have been randomized after baseline to receive a 
personalized trial of light therapy for self-reported fatigue. We estimate that the 
final participant will be randomized by September 30, 2021, and data collection 
will cease by December 31, 2021. 
 
 
10.  ENDPOINTS 
• Describe the primary and secondary study endpoints 
• Describe any primary or secondary safety endpoints  
 

 
 
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This study is a feasibility pilot whose primary objective is to assess the 
acceptability, scalability of implementation and participant satisfaction with a 
personalized trial methodology to resolve a chronic complaint. Thus, the primary 
endpoint is trial completion in the first 3 months. 
 
 
11.  RESEARCH PROCEDURES 
• Include a detailed description of all procedures to be performed on the research 
subject and the schedule for each procedure. 
• Include any screening procedures for eligibility and/or baseline diagnostic tests 
• Include procedures being performed to monitor subjects for safety or minimize risks 
• Include information about drug washout periods 
• If drugs or biologics are being administered provide information on dosing and route 
of administration 
• Clearly indicate which procedures are only being conducted for research purposes. 
• If any specimens will be used for this research, explain whether they are being 
collected specifically for research purposes.   
• Describe any source records that will be used to collect data about subjects 
• Indicate the data to be collected, including long term follow-up 
 
Potential participants who self-identify as experiencing chronic symptoms of 
fatigue will be directed to an information screen with details about the pilot study. 
Those who are interested in participating in this pilot study will be directed to sign 
a HIPAA Authorization form before completing screening survey process that 
includes validated PROMIS measures of fatigue, as well as questions pertaining to 
inclusion and exclusion criteria. Consenting coordinators will review this data and 
determine whether or not a potential participant is eligible to participate. Those 
who are eligible will receive a link to a short video about key details from the 
consent form, as well as an electronic copy of the consent form. Potential 
participants will also be asked to set up a 30-minute phone call with a research 
coordinator, where the research coordinator will describe the study and consent 
process and offer an opportunity for the potential participant to ask any questions. 
After the phone call, the potential participant will be sent a link to view and 
electronically sign the consent form via the N1Thrive by 4Peacocks platform, 
which meets 21 CFR 11 standards for collecting electronic signature. Before being 
able to sign and submit the consent form, potential participants must demonstrate 
understanding of the protocol by correctly answering 4 questions pertaining to the 
information presented in the consent form. 
 
Once potential participants successfully submits their signed consent form, they 
will receive an onboarding questionnaire to collect more information including a 
cell phone number and home address. A consenting coordinator will review this 
information and send the potential participant an email which will include a 
confirmation of the start date of their baseline period, as well as a short video of 
what to expect during onboarding to the study. They will be mailed an initial study 
kit including a Fitbit Charge 3 device and a printed copy of their electronically-

 
 
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signed HIPAA authorization and consent form with a URL to view the informed 
consent video that they watched previously. Potential participants will be asked to 
download the Fitbit app to their smart phone. All baseline periods will begin on a 
Monday. No more than 20 participants will be permitted to begin on the same day.  
 
The baseline period will take place over the course of 2 weeks. Potential 
participants will not use light therapy during the baseline period. At three 
randomized times each day during waking hours, (identified by the potential 
participant during their onboarding survey), baseline participants will receive a text 
message asking them to rate their fatigue, pain, concentration, confidence, mood, 
and stress levels at that exact moment. Each evening, baseline participants will 
receive a survey asking a few questions about their fatigue that day. At the end of 
the week on Sunday evenings, baseline participants will receive a slightly longer 
survey asking them to reflect on their symptoms of fatigue that week. 
 
During the baseline period, potential participants will be asked to wear their Fitbit 
all day and night, even while they are sleeping. Baseline participants will be 
instructed to sync their Fitbit device by opening the Fitbit app on their phone at 
least every two days.  
 
Ten days into the baseline period, a consenting coordinator will review individual 
adherence to Fitbit wear and to survey responses. Adherence to Fitbit wear will be 
defined as recorded activity of greater than 12 hours a day, and recorded sleeping 
activity. Survey adherence will be defined as submission of a given survey. 
Baseline participants that do not achieve at least 80% adherence of Fitbit wear and 
survey submission during the first 10 days of the baseline period will be withdrawn 
from the study. Those that maintain at least 80% adherence will be randomized to 
one of two treatment sequences in the pilot study. Participants who are randomized 
to receive treatment sequences will receive email confirmation including their 
protocol timeline. Participants will also receive a second mailed kit including a 
bright blue light commercial AYO light therapy device, and a dim blue light 
research AYO light therapy device. Enrollment will continue until up to 60 
participants have been randomized into one of two treatment sequences. 
 
Each treatment sequence is made up of 6 2-week periods dedicated to either bright 
blue light therapy, dim blue light therapy, or usual care. During both bright blue 
light and dim blue light therapy weeks, participants will receive a text message 
within an hour of their self-reported wake time instructing them to use their 
designated light therapy device for 30 minutes. During usual care treatment 
periods, participants will not receive any text notifications to complete light 
therapy, and will instead be asked to refrain from using either AYO device.  
 
During all treatment weeks (12 weeks total), participants will be asked to continue 
wearing their Fitbit device each day and night. They will continue to receive 3 
randomized text messages each day with questions about their fatigue, pain, 
concentration, confidence, mood, and stress at that current moment, as well as an 

 
 
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evening text asking them to reflect on their fatigue and any side-effects they may 
be experiencing from their light therapy treatment (if applicable). Participants will 
receive slightly longer surveys on Sunday evenings, asking them to reflect on their 
symptoms of fatigue that week. A study phone number and email address will be 
available as part of each survey to contact the study team if a participant is 
concerned about any side effects they are experiencing. Participants will also be 
instructed to stop their light therapy sessions if they are concerned about their side 
effects.  
 
Participants may receive additional text messages to those outlined above with 
important reminders about their protocol (e.g. transition to a new treatment period), 
or to remind participants to sync their data. We will send a maximum of 6 text 
messages per day during the study, including these reminders and the survey 
questions outlined above.   
 
In the event of an unanticipated circumstance that temporarily prevents a 
participant from completing study activities (illness, injury, death in the family, 
etc.), the participant will have the option of pausing their study to resume once their 
circumstance has been positively resolved. 
 
Participants will complete remote data monitoring after they have gone through one 
baseline period (two weeks), two bright blue light therapy periods (two weeks 
each), two dim blue light therapy periods (two weeks each), and two usual care 
periods (two weeks each), or 14 weeks total. Alternatively, a participant may 
choose to withdraw from the study, or be withdrawn from the study by the research 
team. Upon completion of data monitoring, participants will be given instructions 
on how to un-link their Fitbit from the study account. Daily text messages and 
survey prompts will be cancelled for participants who are withdrawn from the 
study.  
  
We will compile the self-reported data from questionnaires, treatment adherence, 
side effects, pain, fatigue, concentration, confidence, mood, and stress assessments, 
as well as information from the Fitbit regarding activity (steps, flights climbed and 
intensity), sleep (duration, estimated sleep stages) for each individual participant. 
Treatment adherence will be tracked via an AYO research web portal and will be 
included in the compiled data. No identifying information will be provided to AYO 
or included on the treatment adherence report provided by AYO. We will analyze 
this data and create a summary report of the participant’s data and symptoms over 
the study period, relation to the bright blue light therapy, dim blue light therapy, 
and usual care treatment periods.  
 
The participant will be sent this report in an encrypted email and secure web link 
by our study team. Participants will also be sent links to several online videos 
explaining the terms and data visualizations available in their summary report. 
These videos will be general to the template report and will not contain any 

 
 
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individual results or health information. Participants will be sent a satisfaction 
survey along with their individual report.  
 
The satisfaction survey will be sent via email up to two times before a research 
coordinator will attempt to call individual participants to complete the satisfaction 
survey via phone. Participants will be mailed a pay card (Clinicard) valued at $100 
after successful completion of the satisfaction survey. 
 
Within 3 months of an individual ending their remote data monitoring, regardless 
of when that takes place, participants will be asked to schedule a phone call from a 
member of our study team to discuss their study experience. We will ask several 
questions about their experience and opinion toward Personalized Trials, as well as 
for suggestions for improvement for future Personalized Trials. Study participation 
will end after successful completion of this participant phone interview. 
 
 
12.  STATISTICAL ANALYSIS 
• Describe how your data will be used to test the hypotheses.  
• State clearly what variables will be tested and what statistical tests will be used. 
• Include sample size calculations.  
• If this is a pilot study, state which variables will be examined for hypothesis 
generation in later studies.  
 
The sample size of 60 participants was chosen to have a sufficient number of 
patients to obtain a preliminary assessment of the feasibility of personalized trials 
of light therapy for management of symptoms of fatigue. The numbers of 
questionnaires and treatment repetitions per trial were based on expert 
recommendations by a statistician and estimations about maximal duration of the 
trial to maintain patient engagement. Specifically, the primary endpoint is trial 
completion in the first 3 months. We aim to demonstrate a trial completion rate 
greater than 50% in randomized participants.  With n = 60, using a one-sample 
binomial test at 2.5% significance one-sided, this will give us about 90% power if 
the true completion rate is 70%. Data will be reported transparently so that 
individual level heterogeneity can be assessed(21). 
 
Participants will be randomized into one of two different treatment orders, 
ABCCBA or CBAABC, where A=bright light, B=dim light, and C=usual care. 
Two treatment orders were chosen to test out the feasibility of carrying out a 
virtual, N-of-1 study. ABCCBA was chosen as an order to test participant 
acceptability with back-to-back usual care treatment (i.e. no treatment) extending 
through 4 weeks. CBAABC was chosen as a companion treatment order to 
ABCCBA to test participant acceptability with starting a Personalized Trial with a 
usual care treatment after a baseline run-in (i.e. no treatment for the first 4 weeks). 
Treatment order was not included as a factor in the statistical analysis because 
acceptability and feasibility study. 
 

 
 
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The randomization schedule will be set up by a member of the Center for 
Personalized Health data team and provided to the data analyst assigned to 
Personalized Trials of Light Therapy for Fatigue. Randomization will occur with a 
fixed seed value for the purposes of repeatability and auditability, and the list of 60 
participants will be split into two groups of 30 using a random shuffle function that 
takes that seed as in input. The order in which an individual becomes eligible for 
one of these 60 randomizations will determine the placement given (i.e. the first 
person eligible will be randomized to the treatment order given to participant 1, and 
continue sequentially). Eligibility is obtained by a participant maintaining at least 
80% adherence of survey response, Fitbit wear ≥ 12 hours a day, and 80% sleep 
data available through the baseline run-in period. The data analyst will alert the 
research coordinator of the assigned randomization once a participant becomes 
eligible during the baseline run-in period.  
 
The primary outcome measure will be a mean usability score, obtained using the 
System Usability Scale (SUS), a validated 10-item questionnaire originally 
developed by John Brooke in 1986 that asks users to score each item on a Likert 
scale from Strongly Disagree (rating of 1) to Strongly Agree (rating of 5). The SUS 
will be presented to the participant as addressing the ease of use, complexity, 
consistency of the Personalized Trials system as a whole, from recruitment to 
receipt of the report. Individual results are calculated to arrive at a composite 
measure out of 100. Participant SUS scores will be averaged together. Higher 
scored values correlate to a more usable system, and therefore a better outcome.  
 
Other outcome measures assessing feasibility of the Personalized Trials framework 
include:  
• Mean participant satisfaction with Personalized Trials components 
supplemental to the SUS, 
• Qualitative satisfaction data collected during the participant phone 
interview, 
• Mean participant survey adherence rate, defined as completion of each 
assigned survey 
• Mean participant Fitbit adherence rate, defined as recorded heart rate data 
for ≥ 12 hours each day,  
• Mean participant Fitbit sleep rate, defined as recorded sleep and wake 
cycles  
• Mean participant bright AYO adherence rate, defined as completion of each 
assigned 30-minute session 
• Mean participant dim AYO adherence rate, defined as completion of each 
assigned 30-minute session 
• Google Ad metrics 
• Social media activity, including but not limited to: 
o Social media conversion rate, defined as total impressions compared 
to total click-through  
o Cost per social media conversion 
• Website activity, including but not limited to: 

 
 
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o Total number of website visits per traffic source 
o Website bounce rates 
o Mean user total time on website 
 
In order to share a summary report of observed trends back to the participant to 
assess acceptability and satisfaction with the participant report, additional outcomes 
will be analyzed on an N-of-1 level including: 
• Mean Within-Subject Difference in Self-Reported Daily Fatigue During 3 
Treatment Periods from Mean Baseline using the PROMIS Item Bank v1.0 
– Fatigue 7b Daily Short Form 
• Mean Within-Subject Difference in Self-Reported Weekly Fatigue During 3 
Treatment Periods from Mean Baseline, using the PROMIS Item Bank v1.0 
– Fatigue 8a Short Form 
• Mean Within-Subject Difference in Ecological Momentary Assessment 
Three-Times-Daily of Pain During 3 Treatment Periods from Mean 
Baseline, using the Numeric Pain Rating Scale adapted from McCaffery, 
Beebe et al. 1989 
• Mean Within-Subject Difference in Ecological Momentary Assessment 
Three-Times-Daily of Fatigue During 3 Treatment Periods from Mean 
Baseline, using the Numeric Pain Rating Scale adapted from McCaffery, 
Beebe et al. 1989 
• Mean Within-Subject Difference in Ecological Momentary Assessment 
Three-Times-Daily of Concentration During 3 Treatment Periods from 
Mean Baseline, using the Numeric Pain Rating Scale adapted from 
McCaffery, Beebe et al. 1989 
• Mean Within-Subject Difference in Ecological Momentary Assessment 
Three-Times-Daily of Confidence During 3 Treatment Periods from Mean 
Baseline, using the Numeric Pain Rating Scale adapted from McCaffery, 
Beebe et al. 1989 
• Mean Within-Subject Difference in Ecological Momentary Assessment 
Three-Times-Daily of Mood During 3 Treatment Periods from Mean 
Baseline, using the Numeric Pain Rating Scale adapted from McCaffery, 
Beebe et al. 1989 
• Mean Within-Subject Difference in Ecological Momentary Assessment 
Three-Times-Daily of Stress During 3 Treatment Periods from Mean 
Baseline, using the Numeric Pain Rating Scale adapted from McCaffery, 
Beebe et al. 1989 
• Mean Within-Subject Difference in Self-Reported Side Effects from 
Baseline, using the average number of days side effects were reported 
during treatment periods. 
• Mean Within-Subject Difference in Device-Recorded Daily Steps from 
Mean Baseline, using participant Fitbit data 
• Mean Within-Subject Difference in Device-Recorded Nightly Sleep from 
Mean Baseline, using participant Fitbit data 
o The effects of treatment on sleep quality will be assessed using 
generalized estimating equations (GEE) with an unstructured 

 
 
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variance-covariance matrix for measures on the same day. This 
model accounts for possible autocorrelation and linear trends 
between self-reported sleep quality ratings over time.  
 
 
 
13. SPECIMEN BANKING 
• If specimens will be banked for future research, describe where the specimens will be 
stored, how long they will be stored, how they will be accessed and who will have 
access to the specimens 
• List the information that will be stored with each specimen, including how specimens 
are labeled/coded 
• Describe the procedures to release the specimens, including:  the process to request 
release, approvals required for release, who can obtain the specimens, and the 
information to be provided with the specimens. 
 
N/A 
 
 
14.  DATA MANAGEMENT AND CONFIDENTIALITY 
• Describe the data and specimens to be sent out or received.  As applicable, describe: 
o What information will be included in that data or associated with the 
specimens? 
o Where and how data and specimens will be stored? 
o How long the data will be stored? 
o Who will have access to the data? 
o Who is responsible for receipt or transmission of data and specimens? 
• Describe the steps that will be taken to secure the data during storage, use and 
transmission. 
 
Fitbit 
This pilot study uses non-NFC, Fitbit Charge 3 devices to remotely monitor 
participant activity and sleep. All enrolled participants will be provided with a 
study account that has been created by the research team with no identifying 
information to the participant. The email address of the study account contains a 
unique identifier (e.g. northwellf25). Data collected will include daily steps, floors 
climbed, activity intensity, sleep duration, and estimated minutes in sleep stages. A 
file linking the Fitbit identifier to the study participant will be housed in a 
Northwell-approved drive to store PHI, and be accessible only by members of the 
study team listed in the IRB application. Coded data from Fitbit will remain stored 
in a Northwell-approved drive indefinitely with the file linking the Fitbit identifier 
to the study participant stored separately.  Data collected for this study may also be 
maintained in its native state on a Northwell-approved drive to store PHI 
indefinitely.  Data collected under this research may be used for future research in 
coded format without additional consent as per the consent form participants sign 
and with appropriate IRB approval as required. 

 
 
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Fitabase 
This pilot study will use Fitabase to retrieve Fitbit data from participants. Fitabase 
is a secure, online portal. The Fitbit study account provided to the participants will 
be linked to an identification number in the Fitabase system (e.g. FLT01). No 
information that could be used to identify a participant will be stored on Fitabase. 
Only the research team will have access to data that will be able to connect a 
research participant to their Fitabase ID. Data collected will include last sync date, 
battery charge status, daily steps, floors climbed, activity intensity, sleep duration, 
and estimated minutes in sleep stages. Fitabase will stop tracking participant data at 
the trial end date selected by the research coordinator. As an added measure, 
participants will be instructed to remove the Fitbit study account from their device 
if they plan on keeping the Fitbit. 
 
Treatment Delivery 
This pilot study will use commercially-available bright-blue light therapy glasses 
called AYO, as well as a dim blue light therapy device developed by AYO for 
research purposes. The research team will have access to a dashboard that will 
track light therapy device used (bright/full or dim), duration, and date and time 
based on a generic application user ID (e.g. Northwell_001). No information that 
could be used to identify a participant will be stored on the AYO research web 
portal, nor on the AYO device itself. Only the research team will have access to 
data that will be able to connect a research participant to their generic AYO user 
ID.  
 
Eligibility, Consent, and Survey Data 
A goal of this pilot study is to help determine Minimal Viable Product (MVP) 
specifications for the development of a technology platform to support the delivery 
of Personalized Trials. To achieve this goal, we are partnering with a company 
(N1Thrive by 4Peacocks) that was formed specifically for the development of 
technology to support N-of-1 methodology. Data will be collected and stored using 
N1Thrive by 4Peacocks, a Northwell security-review approved system for 
collecting and storing research data, including PHI. The study team will have 
access to all data, including PHI, throughout the study. Coded data using unique 
generic participant IDs will be shared with 4Peacocks in order to assist with 
analyzing the individual reports and to pool N-of-1 results across all projects using 
the N1Thrive platform. Coded reports will be given back to the study team, who 
will identify the document before sending individualized reports to the participant 
via encrypted email.  Pooled N-of-1 results will be used to assess gaps in 
phenotypic understanding to empirically determine if modeling precise therapy is 
feasible.  
 
Interview Data 

 
 
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Qualitative data collected from phone interviews with research participants will be 
collected and stored via REDCap, a Northwell-approved system for collecting and 
storing research data, including PHI. 
 
The study team takes data confidentiality very seriously. The participant will be 
made aware of all data collected and the companies/technology employed to collect 
the data via the consent process. All coded data will be maintained by the study 
team on a Northwell-approved drive to store PHI or stored in its native state in a 
SQL database. All members of the research team with access to identifiable and 
coded data will be trained and included on the IRB submission for approval. 
Regular meetings will take place with the PI and other members of the study team 
to ensure protocol adherence and data accuracy. 
 
This research is funded by the NIH, thus a Certificate of Confidentiality has been 
issued for this research. Certificates of Confidentiality (CoCs) protect the privacy of 
research subjects by prohibiting disclosure of identifiable, sensitive research 
information to anyone not connected to the research except when the subject 
consents or in a few other specific situations.  
  
 
 
15.  DATA AND SAFETY MONITORING PLAN 
 
A specific data and safety monitoring plan is only required for greater than minimal risk 
research.  For guidance on creating this plan, please see the Guidance Document on the 
HRPP website. 
 
Part I – this part should be completed for all studies that require a DSMP.   
Part II – This part should be completed when your study needs a Data and 
Safety Monitoring Board or Committee (DSMB/C) as part of your Data and 
Safety Monitoring Plan.   
 
Part I:  Elements of the Data and Safety Monitoring Plan 
•  Indicate who will perform the data and safety monitoring for this study.   
• Justify your choice of monitor, in terms of assessed risk to the research subject’s 
health and well being.  In studies where the monitor is independent of the study staff, 
indicate the individual’s credentials, relationship to the PI, and rationale for selection 
• List the specific items that will be monitored for safety (e.g. adverse events, protocol 
compliance, etc) 
• Indicate the frequency at which accumulated safety and data information (items listed 
in # above) will be reviewed by the monitor (s) or the DSMB/C.   
• Where applicable, describe rules which will guide interruption or alteration of the 
study design.   
• Where applicable, indicate dose selection procedures that will be used to minimize 
toxicity. 
• Should a temporary or permanent suspension of your study occur, in addition to the 
IRB, indicate to whom will you report the occurrence.   
 

 
 
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Part II:  Data and Safety Monitoring Board or Committee 
 
 
•  When appropriate, attach a description of the DSMB.   
• Provide the number of members and area of professional expertise.   
• Provide confirmation that the members of the board are all independent of the study. 
 
Attached please find the Charter document for the Personalized Trials Pilots 
DSMB. Personnel, roles, and areas of expertise are listed. All voting members of 
the DSMB are independent of the study. 
 
 
16. WITHDRAWAL OF SUBJECTS 
• Describe anticipated circumstances under which subjects will be withdrawn from the 
research without their consent 
• Describe procedures for orderly termination 
• Describe procedures that will be followed when subjects withdraw from the research, 
including partial withdrawal from procedures with continued data collection.   
 
Circumstances under which participants will be withdrawn from the research 
without their consent include failure to maintain protocol adherence, repeated 
failure to complete light therapy treatments, and self-reported adverse side effects 
to bright blue light or dim blue light therapy. A potential participant will not be 
randomized to receive the treatment protocol until he/she has demonstrated at least 
80% adherence to continuous Fitbit monitoring (activity recorded > 12 hours/day, 
and recorded sleep activity) and response to survey questionnaires during the 
baseline period.  
 
Potential participants will be notified of the possibility of being removed from the 
study before treatment randomization due to adherence issues in the informed 
consent. Participants who fail to maintain minimum adherence during baseline will 
be notified by the research team after 10 days of baseline participation.  
Participants who fail to maintain protocol adherence or who deviate from the 
protocol will be contacted by a member of the study team with a reminder of the 
study protocol, and warning that this may impact their continued study eligibility. 
Once a protocol deviation has been repeatedly recorded, the Principal Investigator 
will determine the participant’s continued eligibility in the study, with consultation 
of the DSMB if needed. If it is determined that the participant will be withdrawn 
from the study, the participant will be notified by the research team via email and 
phone call. The participant will stop receiving notifications and survey prompts, 
and will be sent instructions to un-link their Fitbit device. The participant will be 
able to keep their Fitbit and one of the AYO light therapy devices.  
 

 
 
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Should a participant choose to withdraw from research, they will be instructed to 
send a letter or e-mail to the attention of the Principal Investigator at our 130 East 
59th Street office, or to email personalizedtrials@northwell.edu, an e-mail account 
monitored by IRB-approved members of the research team. Participants will be 
contacted by a member of the research team confirming their study withdrawal, and 
to answer any questions they may have. The participant will stop receiving 
notification and survey prompts, and will be sent instructions to un-link their Fitbit 
device. Data collection will stop the business day the letter or email is received. All 
data up until the receipt date of the letter will be included in the research study.   
 
Partial withdrawal, defined as study participation and data collection without the 
use of one of the light therapy devices will be allowed if a participant experiences 
an adverse events to one of the treatment options (bright blue light or dim blue light 
therapy). In instances where participants contact the research team with concerns 
about their self-reported treatment side-effects, participants will be permitted to 
continue their involvement in the study, should they be interested. Participant data 
will continue to be collected and monitored, while removing the self-reported 
adverse treatment option from their randomized protocol (i.e. skip the treatment 
days and continue with usual care). This will allow the participant to still evaluate 
their individual response to the self-reported non-aggravating treatment option. In 
the event that both treatment options create self-reported adverse events for the 
participant, they will be withdrawn from the study.  
 
 
17. RISKS TO SUBJECTS 
• Describe any potential risks and discomforts to the subject (physical, psychological, 
social, legal, or other) and assess their likelihood and seriousness and whether side 
effects are reversible. Where appropriate, describe alternative treatments and 
procedures that might be advantageous to the subjects.  
• Include risks to others , like sexual partners (if appropriate) 
• Discuss why the risks to subjects are reasonable in relation to the anticipated benefits 
and in relation to the importance of the knowledge that may reasonably be expected 
to results 
• Describe the procedures for protecting against or minimizing any potential risks, 
including risks to confidentiality, and assess their likely effectiveness.   
 
This study poses low risk of physical harm to subjects. Bright blue light therapy is 
a mainstream treatment for fatigue symptoms. Several transient side-effects have 
been observed when monitoring patients including jumpiness/jitteriness, headache, 
and nausea, and mania has been infrequently observed in patients with bipolar 
disorder. These side-effects typically resolve soon after cessation of light therapy. 
Monitoring for adverse side-effects will be performed during the N-of-1 trial. 
Subjects will be encouraged to adhere to the light therapy protocol, but will also be 
told that they can discontinue treatment at any time.    
 

 
 
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AYO glasses have 4 Light-emitting diodes (LEDs) with a dominant 
wavelength of approximately 470nm ± 2nm and typical irradiance (100% 
intensity) of approximately 250 µW/cm².  Although there are minimal direct safety 
standards for blue light within the United States, the photochemical blue light 
hazard can be evaluated based on several global standards.  AYO glasses are 
compliant with the following:  Directive 2014/30/EU (EMC) EN 55014-1:2006 + 
A2:2011 EN 55014-2:2015, Directive 2011/65/EU (RoHS), IEC 62321:2008, IEC 
62321-3-1:2013, IEC 62321-4:2013, IEC 62321-5:2013, Radio-Equipment 
Directive 2014/53/EU, EN 62479:2010, EN 300328:2015, EN 301489-1:2011, EN 
301489-17:2012,  RoHS Directive 2011/65/EU of the European Parliament, the 
Council from 08/06/2011 on restriction of the use of certain hazardous substances 
in electrical and electronic appliances,  and with the international standard and 
conformity assessment IEC 62471 “Photobiological safety of lamps and lamp 
systems.”   
 
The international standard and conformity assessment (IEC 62471) provides 
guidance for evaluating the photobiological safety of lamps and lamp systems, 
including luminaires, and specifies the exposure limits, reference measurement 
technique and classification scheme for the evaluation and control of 
photobiological hazards from all electrically powered incoherent broadband 
sources of optical radiation, including LEDs in the wavelength range from 200 nm 
through 3000 nm.  IEC 62471 classifies light sources into Risk Groups 0, 1, 2 and 3 
(from 0 = no risk through to 3 = high risk) and provides for cautions and warnings 
for consumers as needed. These risk groups are determined by spectral irradiance 
and radiance measured at a specified distance, spectral weighting of measurements 
and maximum allowed exposure time based on the hazard type.  Radiance 
measurements are used to assess retinal exposure to radiation.  Irradiance 
measurements are used to assess skin and the outer eye (lens and cornea) exposure 
to radiation.  Retinal Thermal weighting is used to assess risk from localized 
heating of tissue and Blue Light weighting is used to assess photochemical risk to 
tissue.   The four-tier classification structure in IEC 62471, ranging from RG0 
or “Exempt” to “Risk Group (RG) 3.” 
   
RG classification of the source or luminaire is as follows: 1. A luminaire 
employing a light source classified RG0 or RG1 requires no warning or caution. 2. 
If a luminaire uses a light source from a higher risk group (RG2 or RG3), product 
information must indicate the mentioned RG class and include suitable warnings or 
cautions. In this manner, the end use product is suitably labelled if a potential risk 
exists.    AYO blue light glasses are in the “exempt” group (RG0) for photo-
biological risk. The device does not cause photoretinits or retinal burn.  In 
addition, AYO uses narrow band blue light at approximately 470nm, is UV 
and IR free, and the light prism disperses the light making the light source 
very diffused and not concentrated. As such, unlike laser or highly focused or 
intense sources of light, the AYO light is gentle to the eyes and does not reach 
the levels that can cause harm.   In addition, the design of the glasses is such that 
the LED band sits above the eye and is not directed into the eye. The participant 

 
 
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would need to direct their eyes upward in order to experience central retinal 
exposure to prompt a photochemical hazard.   
  
In order to ensure participants adhere to the defined time for use/exposure and thus 
to ensure safety, we will have access to a dashboard that enables us to track the 
participants’ use of the light therapy device (both bright/full or dim), duration, and 
date and time.    
  
AYO light properties are within referent values of one of the most researched, 
direct-to-consumer, blue light products:  the Philips goLiteBLU. Numerous 
trials using the Phillips device with human subjects have demonstrated minimal 
adverse effects and confirm its irradiance is much lower than what is currently 
recommended for light treatment. (21, 22) In comparison, the optical power 
projected on the eye is 300 μWatt/cm2 for the Phillips device vs 250 μWatt/cm2 
for the AYO device.  In addition, the Philips device operates at at 70% of the limits 
stated in the International Commission on Non-Ionizing Radiation Protection 
(ICNIRP) guidelines on limits of exposure to incoherent visible radiation, whereas 
the AYO device operates at 10.5% of the “Blue Light Hazard” limit, far from the 
considered critical or dangerous levels identified as a “Thermal Hazard.”   
  
Lastly, the Philips device emits a wavelength of blue light at 460 nm in comparison 
to AYO’s wavelength of 470nm.  Although the Philips device range falls 
within wavelengths considered “harmless,” Tosini et. al confirmed “exposure to 
blue light in the 470–490 nm range may be less damaging to the eye compared to 
blue light in the 400–460 nm range...[D]evelopment of LEDs with a peak 
emission of around 470–490 nm may represent an important advancement in 
the safety of LEDs for ocular health. Thus, LEDs with an emission peak of 
around 470–480 nm should be preferred to LEDs that have an emission peak 
below 450 nm.” (23)    This wavelength range is important to note given studies 
have shown that peak effectiveness for a photic maculopathy (photochemical injury 
of the retina) occurs at approximately 435 – 440 nm. (24)  See below for functional 
categories of the blue light spectrum comparing harmful vs healthy blue 
light ranges.(25)   
 
There is also the potential risk of loss of privacy of information pertaining to 
research material collected by the study. Yet, we will take precautions, described 
below, to minimize these risks. 
  
Treatment Adverse Events 
As per the manufacturer’s recommendations, individuals below 18 years old, 
individuals who have or had eye disease such as cataracts, glaucoma, macular 
degeneration or other retinal disorders, those who have had previous eye surgery, 
and individuals who have sensitivity to light, epilepsy, or a history of seizures will 
screen out for study participation. We will emphasize to subjects in the intervention 
arm that they can stop light therapy or withdraw from the N-of-1 trial completely at 
any point, particularly if they experience any concerning side-effects. Additionally, 

 
 
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the Principal Investigator will review any serious adverse events and these will be 
reported to the DSMB. All data concerning adverse outcomes will be reviewed by 
the DSMB at least once a year. Any serious adverse effects will also be reported to 
the IRB.  
 
Loss of Confidentiality or Privacy 
One risk of taking part in this study is the possibility of a loss of confidentiality or 
privacy. The study team plans to protect privacy by only sharing necessary 
information about participants to those outlined in the consent form. 
 
All subjects will be informed that their responses are confidential and that they may 
refuse to participate in the project or withdraw at any time without explanation, and 
that such action will not affect their future interactions with their health care 
providers, employment, educational studies, or the research study. The risk of loss 
of confidentiality will be minimized by securely storing data including PHI in a 
Northwell-approved database and minimizing the use of PHI. To ensure 
confidentiality, all data containing personal identifiers, and used to track contact 
with patients, will be kept in a secure, password-protected, encrypted Northwell-
approved database. No paper documents with personal identifiers will be kept. The 
PI will be responsible for ensuring that the confidentiality of the data is maintained 
at all times. All data will be obtained specifically for research purposes. 
 
Personal or identifiable information is not stored on any of the devices used in this 
study. No information about the participants or the participants’ health history will 
be shared with AYO or Fitbit, except for the information the participants directly 
share themselves should they choose to use the device for personal use at the 
conclusion of the study. There is no additional risk with using AYO or Fitbit as part 
of this research study as compared to using the device as a consumer. 
 
 
 
 
18. RESEARCH RELATED HARM/INJURY 
• Describe the availability of medical or psychological resources that subjects might 
need as a result of anticipated problems that may be known to be associated with the 
research. 
• If the research is greater than minimal risk, explain any medical treatments that are 
available if research-related injury occurs, who will provide it, what will be provided, 
and who will pay for it.   
 
Should a participant experience an adverse event, they will be advised to contact 
their primary care provider. The DSMB and IRB will be notified according to 
timelines established in their Charter/Policy and Procedure manual. Should a 
participant report emotional distress in responding to survey questions, the research 
coordinators will refer to our Principal Investigator (a licensed clinical 
psychologist), who will recommend follow-up. 

 
 
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19. POTENTIAL BENEFIT TO SUBJECTS 
 
• Explain what benefits might be derived from participation in the study, noting in 
particular the benefit over standard treatment (e.g. a once-a-day administration 
instead of four times a day, an oral formulation over an IV administration).  
• Also state if there are no known benefits to subjects, but detail the value of knowledge 
to be gained 
 
Although not a primary endpoint, participants randomized to the intervention may 
receive an indirect benefit, i.e. they may gain a better understanding of how bright 
blue light therapy personally affects them or could possibly see a positive effect on 
their fatigue symptoms. This may result in their being more satisfied with their 
fatigue treatment regimen and in achieving reduced fatigue symptoms. Through 
pooling N-of-1 trial data, a greater understanding of the effectiveness of bright blue 
light therapy will arise. Through comparing N-of-1 interventions with usual care, 
participation by all subjects will also contribute to the understanding of the effects 
of engaging fatigued patients in N-of-1 trials, and this knowledge may contribute to 
the incorporation of N-of-1 trials into the clinical practice of fatigue management. 
Additionally, the information collected from participant involvement will inform 
the development of future Personalized Trials to help other research participants 
and eventually patients discover which treatment options are best for them as an 
individual. 
 
 
20. PROVISIONS TO PROTECT PRIVACY INTERESTS OF SUBJECTS 
 
• Describe the methods used to identify potential research subjects, obtain consent and 
gather information about subjects to ensure that their privacy is not invaded.  
• In addition consider privacy protections that may be needed due to communications 
with subjects (such as phone messages or mail).   
 
Names and email addresses from potential study participants will not be collected 
until participants have read through web information explaining the research study 
and protocol and indicated their interest in the study. This information will be 
stored in a Northwell-approved database store PHI, and it will only be accessible to 
research staff listed on the approved IRB protocol. Names or other identifying 
information will not be shared with those outside the research team. Phone 
numbers and email will only be used for study-related communications, and 
employees or students will only be contacted outside the study if they indicate 
interest in participating in a future Personalized Trial.  
 
 
 
21.  COSTS TO SUBJECTS 
 

 
 
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• Describe any foreseeable costs that subjects may incur through participation in the 
research 
• Indicate whether research procedures will be billed to insurance or paid for by the 
research study.   
 
This research study is funded by the National Institutes for Health (NIH). All study 
related devices and platforms will be provided to participants at no cost. Participant 
insurance will not be billed. 
 
This study uses text messaging to deliver notifications, reminders, and study 
questionnaires. Standard message and data rates from the participant’s wireless 
carrier may apply to the study participant. Study participants will not be 
compensated for any costs related to data usage or sending or receiving text 
messages by the study or by members of the study team. 
 
 
 
22. PAYMENT TO SUBJECTS  
 
• Describe the amount of payment to subjects, in what form payment will be received 
and the timing of the payments.   
 
Study participants will receive a Clinicard valued at $100 after successful 
completion of this study. As a thank you, they will also be able to keep their Fitbit 
Charge 3 (a value of $120), and one AYO light therapy glasses device (a value of 
$299).   
 
 
23.  CONSENT PROCESS 
 
If obtaining consent for this study, describe: 
• Who will be obtaining consent 
• Where consent will be obtained 
• Any waiting period available between informing the prospective participant and 
obtaining consent 
• Steps that will be taken to assure the participants’ understanding 
• Any tools that will be utilized during the consent process 
•   Information about how the consent will be documented in writing.  If using a  
standard consent form, indicate such.   
• Procedures for maintaining informed consent.   
 
Consent and written authorization will be obtained electronically via the 21 
CFR 11-approved N1Thrive by 4Peacocks platform, with a copy of the 
electronically signed form mailed to the participants along with their study 
instructions and devices. Before being sent a copy of the consent form, 
potential participants will be sent through a series of web pages that summarize 

 
 
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the study, as well as collect pre-screening information with written 
authorization.  
 
If a potential participant is deemed ineligible, or if the potential participant is 
eligible but needs to be waitlisted due to demand, the consenting coordinator 
will notify the potential participant via email within 2 business days of the 
initial completion date of the pre-screen.  
 
If the potential participant is deemed eligible, potential participants will 
schedule a 30-minute phone call to go over study details with a consenting 
coordinator, and have the opportunity to have any of their questions answered. 
After the phone call takes place, the consenting coordinator will send the 
potential participant text with a link to read and electronically sign the consent 
form. Included in this survey will be a short animated video that explains key 
aspects of the protocol and consent process. Included in these materials will 
contact information to reach a consenting coordinator to answer any additional 
questions before signing the consent form. In order for the consent form to be 
signed and submitted successfully, potential participants will need to correctly 
answer 4 questions about the protocol to demonstrate their understanding. PDF 
versions of signed consent forms will be maintained electronically on a 
HIPAA-compliant, Northwell Health-approved share drive, accessible only to 
members of the research team listed on the IRB protocol. A copy of the consent 
form and signed signature page will be mailed to the potential participant along 
with their baseline study materials.  
 
 
In the state of NY, any participants under the age of 18 are considered children.  If your 
study involves children, additional information should be provided to describe: 
• How parental permission will be obtained 
• From how many parents will parental permission be obtained 
• Whether permission will be obtained from individuals other than parents, and if 
so, who will be allowed to provide permission.  The process used to determine 
these individual’s authority to consent for the child should be provided 
• Whether or not assent will be obtained from the child 
• How will assent be documented 
• Whether child subjects may be expected to attain legal age to consent to the 
procedures for research prior to the completion of their participation in the 
research.  If so, describe the process that will be used to obtain their legal 
consent to continue participation in the study.  Indicate what will occur if consent 
is not obtained from the now-adult subjects.   
 
N/A 
 
 
If the study involves cognitively impaired adults, additional information should be 
provided to describe: 

 
 
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• The process to determine whether an individual is capable of consent 
• Indicate who will make this assessment 
• The plan should indicate that documentation of the determination  and 
assessment will be placed in the medical record, when applicable, in addition to 
the research record. 
• If permission of a legally authorized representative will be obtained, 
o  list the individuals from who permission will be obtained in order of priority 
o Describe the process for assent of subjects; indicate whether assent will be 
required of all, some or none of the subjects.  If some, which subjects will be 
required to assent and which will not. 
o If assent will not be obtained from some or all subjects, provide an 
explanation as to why not 
o Describe whether assent will be documented and the process to document 
assent 
o Indicate if the subject could regain capacity and at what point you would 
obtain their consent for continued participation in the study 
 
N/A 
 
 
If the study will enroll non-English speaking subjects: 
• Indicate what language(s) other than English are understood by prospective 
subjects or representatives 
• Indicate whether or not consent forms will be translated into a language other 
than English 
• Describe the process to ensure that the oral and written information provided 
to those subjects will be in that language 
• If non-English speaking subjects will be excluded, provide a justification for 
doing so 
 
This is a pilot study to assess the N-of-1 trial design and methodology for 
data collection and reporting to participants only, not to test an intervention 
designed to provide therapeutic benefit.   Should we be able to collect data 
that supports the feasibility of such a trial design, we anticipate the 
methodology would be scaled to larger clinical trials designed to assess 
safety and/or efficacy.  Non-English speaking individuals would then be 
included as participants in those separate studies per the principles of justice 
and autonomy.  Exclusion of non-English speaking participants in this pilot 
study will not later negatively impact equitable access, participant 
comprehensibility or research design applicability to the diverse populations 
that may be solicited for participation in future clinical trials run under an 
N-of-1 design.    
 
 
24.  WAIVER OR ALTERATION OF THE CONSENT PROCESS       
 N/A          
 

 
 
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Complete this section if you are seeking an alteration or complete waiver of the consent   
process. 
• Describe the possible risks of harm to the subjects involved in this study and 
explain why the study involves no more than minimal risk to the subject:   
• Explain why the waiver/ alteration will not adversely affect the rights and welfare 
of subjects 
• Explain why it is impracticable to conduct this research if informed consent is 
required   
• Explain why it is not possible to conduct this research without using the 
information or biospecimens in an identifiable form 
• If appropriate, explain how the subjects will be provided with additional pertinent 
information after participation.   If not appropriate to do so, explain why.  
 
 
 
Complete this section if you are obtaining informed consent but you are requesting a 
waiver of the documentation of consent (i.e., verbal consent will be obtained). To 
proceed with a waiver based on these criteria, each subject must be asked whether they 
wish to have documentation linking them to this study.  Only complete subsection 1 OR 
subsection 2.  
 
  SUBSECTION 1 
 
• Explain how the only record linking the subject to the research would be the 
consent document. 
• Explain how the principal risk of this study would be the potential harm resulting 
from a breach in the confidentiality 
• Indicate whether or not subjects will be provided with a written statement 
regarding the research. 
 
 
 
SUBSECTION 2 
•  Describe the possible risks of harm to the subjects involved in this study and 
explain why the study involves no more than minimal risk.   
• Confirm that the research only involves procedure for which consent is not 
normally required outside the research context.  
• Indicate whether or not subjects will be provided with a written statement 
regarding the research. 
 
 
 
. 
 
25. WAIVER OF HIPAA AUTHORIZATION  
 
 
 
 N/A       
 

 
 
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Complete this section if you seek to obtain a full waiver of HIPAA authorization to use 
and/or disclose protected health information.  
• Describe the risks to privacy involved in this study and explain why the study 
involves no more than minimal risk to privacy:   
• Describe your plan to protect identifiers from improper use or disclosure and to 
destroy them at the earliest time. 
•  Indicate why it is not possible to seek subjects’ authorization for use or 
disclosure of PHI. 
• Indicate why it is not possible to conduct this research without use or disclosure 
of the PHI.   
• Indicate if PHI will be disclosed outside NSLIJ Health System, and if so, to whom.   
Note:  PHI disclosed outside NSLIJ Health System, without HIPAA authorization 
needs to be tracked. Please see guidance at www.nslij.com/irb for information 
about tracking disclosures. 
 
 
 
Complete this section if you seek to obtain a partial waiver of the patient’s 
authorization for screening/recruitment purposes (i.e., the researcher does not have 
access to patient records as s/he is not part of the covered entity) 
Note: Information collected through a partial waiver for recruitment cannot be shared 
or disclosed to any other person or entity. 
• Describe how data will be collected and used:  
• Indicate why you need the PHI (e.g.PHI is required to determine eligibility, 
identifiers are necessary to contact the individual to discuss participation, other) 
• Indicate why  the research cannot practicably be conducted without the partial 
waiver (e.g. no access to medical records or contact information of the targeted 
population, no treating clinician to assist in recruitment of the study population, 
other) 
 
 
 
26.  VULNERABLE POPULATIONS: 
 
Indicate whether you will include any of these vulnerable populations. If indicated, 
submit the appropriate appendix to the IRB for review: 
 
  Children or viable neonate 
  Cognitively impaired 
  Pregnant Women, Fetuses or neonates of uncertain viability or nonviable  
  Prisoners 
  NSLIJ Employees, residents, fellows, etc 
  poor/uninsured 
  Students 
  Minorities 

 
 
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  Elderly 
  Healthy Controls 
 
If any of these populations are included in the study, describe additional safeguards that 
will be used to protect their rights and welfare. 
 
Although the study will target social media recruitment for participants, all employees 
of the health system will be eligible to participate in the study. Potential participants 
will go through online documents explaining that participation in this research will not 
impact their employment or standing with Northwell Health. Individuals with a 
supervisory relationship over an employee will not enroll any individual who reports to 
them in this study. Employee participation or non-participation in this study will have 
no bearing on an individual’s position at Northwell Health.  
 
Similarly, all students of Hofstra School of Medicine will be eligible to participate in 
the study. Online documentation in the consent process will explain that their 
participation is voluntary, and that their participation will not impact the educational 
enrollment or standing Hofstra University, nor have any bearing on current or future 
health services received from Northwell Health. Professors or supervisory staff will not 
enroll individuals who report to or work or study under them. Student-participation or 
non-participation will have no bearing on an individual’s position at Hofstra University 
or Northwell Health.  
 
 
 
27.  MULTI-SITE HUMAN RESEARCH (COORDINATING CENTER) 
 
If this is a multi-site study where you are the lead investigator, describe the management 
of information (e.g. results, new information, unanticipated problems involving risks to 
subjects or others, or protocol modifications) among sites to protect subjects. 
N/A 
 
 
 
28.  REFERENCES/BIBIOGRAPHY 
 
Provide a reasonable list of references directly related to the study. Any diagrams for 
new medical devices or brief reprints from journals might also prove useful. 
 
1. Guyatt, G.,Haynes, B., Jaeschke, R.,Cook, D.,Greenhalgh,T., 
Mead,M., Green, L.,Naylor, C.,Wilson,M., McAlister, F., & 
Richardson, W. (2002). Introduction: The philosophy of evidence-
based medicine. In G. Guyatt, & D. Rennie (Eds.), Users’ Guides to 
the Medical Literature : A Manual for Eevidence-based Clinical 
Practice (pp. 3–11). Chicago, IL: American Medical Association. 
2. Ridenour TA, Pineo TZ, Maldonado-Molina MM, Hassmiller-Lich K. 
Toward idiographic research in prevention science: Demonstration of 

 
 
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three techniques for rigorous small sample research. Prevention Science. 
2013;14:267-78.  
3. Gandhi TK. Adverse drug events in ambulatory care. New England 
Journal of Medicine. 2003;348(16):1556-64.   
4. Duan N, Kravitz RL, Schmid CH. Single-patient (n-of-1) trials: a 
pragmatic clinical decision methodology for patient-centered 
comparative effectiveness research. J Clin Epidemiol. 2013;66(8 
Suppl):S21-8. 
5. Guyatt G, Jaeschke R, McGinn T. N-of-1 Randomized Controlled 
Trials: Study Design. In: Guyatt G, Rennie D, Meade MO, Cook DJ, 
eds. Users' Guides to the Medical Literature. 2nd ed. New York; 
London: McGraw Hill Medical 2008:179-92.  
6. Guyatt G, Keller J, Jaeschke R, Rosenbloom D, Adachi J, Newhouse M. 
The n-of-1 randomized controlled trial: clinical usefulness, our three-
year experience. Annals of Internal Medicine. 1990;112:293 - 9.  
7. Larson EB. N-of-1 trials: a new future? J Gen Intern Med. 
2010;25(9):891-2.  
8. Joy TR, Monjed A, Zou GY, Hegele RA, McDonald CG, Mahon JL. N-
of-1 (Single-Patient) Trials for Statin-Related Myalgia. Annals of 
Internal Medicine. 2014;160(5):301-10.  
9. Nikles CJ, Yelland M, Glasziou PP, Del Mar C. Do individualized 
medication effectiveness tests (n-of-1 trials) change clinical decisions 
about which drugs to use for osteoarthritis and chronic pain? Am J Ther. 
2005;12(1):92-7. 
10. Kravitz RL, Duan N, Niedzinski EJ, Hay MC, Subramanian SK, 
Weisner TS. What ever happened to N-of-1 trials? Insiders' perspectives 
and a look to the future. Milbank Q. 2008;86(4):533-55.  
11. Guyatt G. N of 1 randomized trials: a commentary. J Clin Epidemiol. 
2016;76:4-5.  
12. Gabler NB, Duan N, Vohra S, Kravitz RL. N-of-1 trials in the medical 
literature: a systematic review. Medical Care. 2011;49(8):761-8.  
13. Recommended principles and practices for the provision of humanistic 
psychosocial services: Alternative to mandated practice and treatment 
guidelines. Humanistic Psychologist. 2004;32(1):3-75.  
14. Gabler NB, Duan N, Vohra S, Kravitz RL. N-of-1 trials in the medical 
literature: a systematic review. Med Care. 2011;49(8):761-8.  
15. Hanifin J, Lockley S, Cecil K, et al. Randomized trial of polychromatic 
blue-enriched light for circadian phase shifting, melatonin suppression, 
and alerting responses. Physiology & Behavior. 2019;198:57-66. 
doi:10.1016/j.physbeh.2018.10.004. 
16. Sasseville A, Martin JS, Houle J, Hébert M. Investigating the 
contribution of short wavelengths in the alerting effect of bright light. 
Physiology & Behavior. 2015;151:81-87. 
doi:10.1016/j.physbeh.2015.06.028. 
17. Meesters Y, Duijzer WB, Hommes V. The effects of low-intensity 
narrow-band blue-light treatment compared to bright white-light 

 
 
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treatment in seasonal affective disorder. Journal of Affective Disorders. 
2018;232:48-51. doi:10.1016/j.jad.2018.01.024. 
18. Smolders KC, Kort YAD. Bright light and mental fatigue: Effects on 
alertness, vitality, performance and physiological arousal. Journal of 
Environmental Psychology. 2014;39:77-91. 
doi:10.1016/j.jenvp.2013.12.010. 
19. Kronish IM, Alcantara C, Duer-Hefele J, St Onge T, Davidson KW, 
Carter EJ, et al. Patients and primary care providers identify 
opportunities for personalized (N-of-1) trials in the mobile health era. J 
Clin Epidemiol. 2017.  
20. Finley CR, Chan DS, Garrison S, et al. What are the most common 
conditions in primary care? Systematic review. Can Fam Physician. 
2018;64(11):832-840. 
21. Raman G, Balk EM, Lai L, Shi J, Chan J, Lutz JS, et al. Evaluation of 
person-level heterogeneity of treatment effects in published multiperson 
N-of-1 studies: systematic review and reanalysis. BMJ Open. 
2018;8(5):e017641. 
22. Anderson, J. L., Glod, C. A., Dai, J., Cao, Y., Lockley, S. W. (2009).  
Lux vs. wavelength in light treatment of Seasonal Affective Disorder 
(pp. 203-212).  Acta Psychiatrica Scandinaviea, Volume 120, Issue 3.     
23.  Revell, Victoria L., Molina, Thomas A., Eastman, Charmane I. (2012). 
Human phase response curve to intermittent blue light using a 
commercially available device (pp. 4859-4868). The Journal of 
Physiology, Volume 590, Issue 19.    
24. Tosini, Gianluca, Ferguson, Ian,  and Tsubota, Kazuao. (2016).  Effects 
of blue light on the circadian system and eye physiology.  Molecular 
Vision, 22: 61–72.  
25. Miller, Sharon A., et. Al (2020). Light-Emitting Diodes (LEDS): 
Implications for Safety. Health Physics: May 2020 - Volume 118 - Issue 
5 - p 549-561  
26. Heiting, Gary. (2019). Chapter 2: Blue Light and Displays, How to Save 
Your Eyes in the Digital Age - The Handbook for Eye Care and 
Electronics:  https://eyesafe.com/handbook/chapter-2/