Feasibility of Cognitive Behavioral Therapy vs. Bright Light Therapy to Treat Insomnia and Fatigue: an RCT
Phase: NA
Conditions: Pulmonary Hypertension, Insomnia, Fatigue
Sponsor: University of Pennsylvania

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CBT-I AND LIGHT THERAPY 
 
 
 
Protocol 
 
Feasibility of Cognitive Behavioral Therapy vs. Bright Light Therapy  
to Treat Insomnia and Fatigue: an RCT 
 
 
Principal Investigator  
Lea Ann Matura, PhD, RN, FAAN 
University of Pennsylvania  
School of Nursing 
Claire M. Fagin Hall 
418 Curie Blvd., Room 322 
Philadelphia, Pennsylvania 19104-4217 
215-746-8819 
 
 
 
Funding Sponsor 
Bayer Corporation 
Original Protocol Date: 
1 November 2021 
 
CONFIDENTIAL 
 

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Table of Contents 
Background and Study Rationale ................................................................................................................. 6 
1. 
Introduction ............................................................................................................................................ 6 
2. 
BACKGROUND ..................................................................................................................................... 6 
2.1.1 
Definition and characterization of PAH ..................................................................................... 6 
2.1.2 
Insomnia .................................................................................................................................... 6 
2.1.3 
Fatigue ...................................................................................................................................... 6 
2.1.4 
Physical Activity ......................................................................................................................... 6 
2.1.5 
Bright Light Therapy .................................................................................................................. 7 
2.1.6 
Cognitive Behavioral Therapy for Insomnia (CBT-I) ................................................................. 7 
3. 
Study Objectives .................................................................................................................................... 8 
3.1 
PRIMARY OBJECTIVE ....................................................................................................................... 8 
3.2 
SECONDARY OBJECTIVES ................................................................................................................ 8 
4. 
Study Population and Duration of Participation ..................................................................................... 8 
4.1 
DURATION OF STUDY PARTICIPATION ............................................................................................... 8 
4.2 
TOTAL NUMBER OF SUBJECTS .......................................................................................................... 8 
4.3 
INCLUSION CRITERIA ........................................................................................................................ 8 
4.4 
EXCLUSION CRITERIA ...................................................................................................................... 9 
4.5 
SUBJECT RECRUITMENT .................................................................................................................. 9 
4.6 
POPULATIONS VULNERABLE TO UNDUE INFLUENCE OR COERCION ..................................................... 9 
5. 
RANDOMIZATION .................................................................................................................................. 9 
6. 
Study Assessments ............................................................................................................................... 9 
6.1 
INFORMED CONSENT ..................................................................................................................... 10 
6.2 
DEMOGRAPHICS AND MEDICAL HISTORY REVIEW ............................................................................ 10 
6.3 
MEDICATION REVIEW ..................................................................................................................... 10 
6.4 
QUESTIONNAIRES .......................................................................................................................... 10 
6.4.1 
Fatigue Severity Scale (FSS) .................................................................................................. 10 
6.4.2 
PROMIS® Sleep Disturbance ................................................................................................. 10 
6.4.3 
Insomnia Severity Index (ISI) .................................................................................................. 10 
6.4.4 
EmPHasis-10 .......................................................................................................................... 11 
6.4.5 
PROMIS® Physical Function Questionnaire ........................................................................... 11 
6.4.6 
Center for Epidemiological Studies- (CES-D) ......................................................................... 11 
6.4.7 
Pittsburgh Sleep Quality Index (PSQI) .................................................................................... 11 
6.4.8 
PROMIS Short Form (SF) v 1.0- Dyspnea-Severity 10a ........................................................ 11 
6.5 
ACTIGRAPHY ................................................................................................................................. 12 
6.6 
SLEEP AND ACTIVITY DIARY ........................................................................................................... 12 
6.7 
BRIGHT LIGHT THERAPY ................................................................................................................ 12 
6.8 
COGNITIVE BEHAVIORAL THERAPY FOR INSOMNIA ........................................................................... 12 
6.9 
STANDARD OF CARE ...................................................................................................................... 12 
7. 
STUDY PROCEDURES ........................................................................................................................ 12 
7.1 
SCREENING VISIT .......................................................................................................................... 12 
7.2 
BASELINE VISIT - DAY 1 ................................................................................................................. 13 
7.3 
TREATMENT PERIOD (CBT-I GROUP) – WEEKS 2 THROUGH 8 ......................................................... 13 
7.4 
TREATMENT PERIOD (ALL GROUPS) – WEEK 9 ............................................................................... 14 
7.5 
END OF TREATMENT (ALL GROUPS) – WEEK 10 .............................................................................. 14 

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7.6 
SUBJECT WITHDRAWAL ................................................................................................................. 14 
7.7 
SUBJECT COMPENSATION .............................................................................................................. 15 
8. 
STUDY ENDPOINTS ............................................................................................................................ 15 
8.1.1 
Primary Study Endpoint .......................................................................................................... 15 
8.1.2 
Secondary Study Endpoints .................................................................................................... 15 
9. 
Statistical Plan ..................................................................................................................................... 15 
9.1 
SAMPLE SIZE AND POWER DETERMINATION .................................................................................... 15 
9.2 
STATISTICAL METHODS .................................................................................................................. 16 
10. 
Safety and Adverse Events ............................................................................................................. 16 
10.1 
DEFINITIONS .................................................................................................................................. 16 
10.1.1 
Unanticipated Problem (UP) ............................................................................................... 16 
10.1.2 
Adverse Event (AE) ............................................................................................................. 16 
10.1.3 
Serious Adverse Event (SAE) ............................................................................................. 16 
10.1.4 
Expectedness ...................................................................................................................... 17 
10.1.5 
Relatedness ........................................................................................................................ 17 
10.1.6 
Adverse Event Reporting Period ......................................................................................... 17 
10.1.7 
Preexisting Condition .......................................................................................................... 17 
10.1.8 
Hospitalization, Prolonged Hospitalization or Surgery ........................................................ 17 
10.2 
RECORDING OF ADVERSE EVENTS ................................................................................................. 18 
10.3 
RELATIONSHIP OF AE TO STUDY .................................................................................................... 18 
10.4 
REPORTING OF ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................................................. 18 
10.4.1 
Reporting Process ............................................................................................................... 19 
10.4.2 
Follow-up Report ................................................................................................................. 20 
11. 
Study Administration, Data Handling and Record Keeping ............................................................ 20 
11.1 
CONFIDENTIALITY .......................................................................................................................... 20 
11.2 
SUBJECT PRIVACY ......................................................................................................................... 20 
11.3 
DATA COLLECTION AND MANAGEMENT ........................................................................................... 20 
11.4 
PERSONNEL TRAINING ................................................................................................................... 21 
12. 
Study Monitoring, Auditing, and Inspecting ..................................................................................... 21 
12.1 
STUDY MONITORING PLAN ............................................................................................................. 21 
12.2 
AUDITING AND INSPECTING ............................................................................................................ 21 
13. 
Ethical Considerations .................................................................................................................... 22 
13.1 
RISKS ........................................................................................................................................... 22 
13.2 
BENEFITS ...................................................................................................................................... 22 
13.3 
RISK BENEFIT ASSESSMENT ........................................................................................................... 22 
14. 
Study Finances................................................................................................................................ 22 
15. 
Appendices...................................................................................................................................... 22 
Sociodemographic History .......................................................................................................................... 23 
 

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Protocol Synopsis 
 
Title 
Feasibility of Cognitive Behavioral Therapy Vs. Bright Light Therapy to Treat Insomnia and 
Fatigue: an RCT 
Short Title 
CBT-I and Light Therapy 
 
 
Methodology 
 
In a single site, 3-arm (Cognitive Behavioral Therapy [CBT-I] group; Bright Light Therapy 
group; Standard of Care group), parallel, randomized controlled trial we will enroll 36 subjects 
(n=12 per group) to assess the feasibility of Bright Light Therapy compared to CBT-I in 
subjects with pulmonary arterial hypertension (PAH) to treat insomnia (difficulty initiating 
sleep or maintaining sleep) and fatigue.  
 
Study Duration 
10 Weeks  
Study Center(s) 
University of Pennsylvania 
Objectives 
 
Primary: 
• 
To assess the recruitment and retention rates of CBT-I and Bright Light Therapy. 
Secondary: 
• 
To compare the effects of CBT-I and Bright Light Therapy to Standard of Care on 
(insomnia and fatigue severity) and secondary (wake after sleep onset and sleep onset 
latency) outcomes.  
• 
To test the effects of CBT-I and Bright Light Therapy to Standard of Care on the 
secondary outcome physical activity. 
• 
To test the effects of CBT-I and Bright Light Therapy to Standard of Care on the 
secondary outcomes: depression, dyspnea and QOL. 
 
Number of Subjects 
Approximately 36 subjects expected to be enrolled from Penn, 12 subjects in each arm. 

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Main Inclusion and 
Exclusion Criteria 
 
Inclusion Criteria 
1. 
Signed informed consent prior to initiation of any study mandated procedure. 
2. 
Male and female subjects ≥ 18 years of age 
3. 
Diagnosis of PAH, including: 
a. 
Idiopathic (IPAH)  
b. 
Heritable (HPAH)  
c. 
Drugs and toxin induced PAH 
d. 
PAH associated with:  
i. Connective tissue disease;  
ii. Human immunodeficiency virus (HIV) infection; 
iii. Congenital heart disease; or 
iv. Portal hypertension 
4. 
Documented hemodynamic diagnosis of PAH by right heart catheterization (RHC), 
prior to enrollment showing:  
a. 
mPAP > 25 mmHg; and  
b. 
PAWP or LVEDP ≤ 15 mmHg. 
5. 
On targeted stable medication doses for 3 months prior to enrollment 
6. 
Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep 
Disturbance 8a > 8 (raw score); > 30 (t score) at enrollment 
7. Fatigue Severity Scale (FSS) > 35 at enrollment  
 
Exclusion Criteria 
1. 
Enrolled in another clinical trial 
2. 
Untreated obstructive sleep apnea,  
3. 
Subjects with left-sided valvular disease (more than moderate mitral valve stenosis or 
insufficiency or aortic stenosis or insufficiency), pulmonary artery or valve stenosis, 
or ejection fraction < 45% on echocardiography before enrollment 
4. 
Hospitalized or acutely ill 
5. 
Any eye disease such as, but not limited to, cataracts, glaucoma, retinal disorders 
(e.g. macular degeneration), or previous eye surgery. 
6. 
Subjects with photosensitivity (e.g. epilepsy) 
7. 
Manic-depressive psychosis or Bipolar Disorder   
 
Data Analysis 
 
We will use intention-to-treat analyses. First, we will calculate the frequencies and percentages 
for all demographic (e.g. sex) and clinical (e.g. medications) categorical variables and use 
Fisher’s exact test to compare baseline differences between groups. We will obtain means, 
medians, standard deviations, and interquartile-ranges for all continuous demographic (e.g. 
age) and clinical variables (e.g. body mass index) and use t-tests to compare baseline 
differences between groups. We will use non-parametric tests to compare the groups if the data 
do not follow normal distribution. To maintain experiment-wise type I error rate at the nominal 
level (α = 0.05), we will conduct an omnibus test for overall differences between the three 
groups using the ANOVA approach. In the presence of a significant overall difference, we will 
conduct post hoc comparison of the two treatment conditions with the Standard of Care group 
using the Dunnett approach. We will verify the assumptions related to the ANOVA using 
residuals. We will use the non-parametric Kruskal-Wallis approach if the data do not satisfy the 
normal distribution assumption. If our preliminary analysis identifies group differences at 
baseline, we will adjust for the difference at baseline and perform analysis of covariance. 
Analyses will be primarily conducted using the R statistical environment. 
 
Data and Safety 
Monitoring Plan  
Connie Ulrich PhD, RN, FAAN will monitor the study. 
 

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Background and Study Rationale 
This study will be conducted in full accordance with all applicable University of Pennsylvania Research 
Policies and Procedures and all applicable Federal and state laws and regulations. 
 
1. 
Introduction 
 
Pulmonary arterial hypertension (PAH) is a chronic, debilitating disease that leads to right heart failure 
and death. Subjects with PAH can have severe symptoms such as fatigue and sleep disturbance.1 Subjects 
with PAH have profound limitations in physical functioning resulting in premature disability and 
impaired quality of life (QOL).7 Symptoms in PAH are burdensome.11 Medication regimens in PAH can 
also be complex. To date, there are no non-pharmacological interventions that have been tested in PAH to 
treat insomnia and symptoms such as fatigue.  
 
2. 
Background 
 
2.1.1 
Definition and characterization of PAH 
Pulmonary arterial hypertension (PAH) is a pulmonary vasculopathy that leads to dyspnea, exercise 
limitation, right heart failure and death if left untreated. PAH is defined by mean pulmonary artery 
pressure (mPAP) > 25 mm Hg with a normal pulmonary capillary wedge pressure in the absence of other 
causes of pulmonary hypertension, such as heart or parenchymal lung disease, sleep apnea, 
thromboembolic disease, or other systemic disease.  
2.1.2 
Insomnia 
Insomnia is the most common sleep disturbance. Insomnia is defined as trouble initiating or maintaining 
sleep which is associated with daytime consequences such as fatigue and daytime sleepiness that is not 
due to environmental circumstances or a lack or opportunity to sleep.12 Sleep disturbance is prevalent in 
PAH (66%).13 In a study of subjects with PAH we found 21% had mild sleep disturbance; 22% moderate 
sleep disturbance and 16% severe sleep disturbance.1 Our preliminary actigraphy data show that  the 
majority of subjects with PAH (92%, N=60) have difficulty maintaining sleep (wake after sleep onset- 
median 69.3 minutes IQR (52.9-93.1).3 Increased daytime sleepiness is associated with worse PAH 
symptoms and QOL.3 In PAH, increasing levels of sleep disturbance are associated with worse symptoms 
(e.g. dyspnea), psychological distress, decreased QOL and physical ability.1 Insomnia (48%) and poor 
sleep quality (73%) in pulmonary hypertension (PH) are common and associated with depression, 
dyspnea and diminished QOL.2 Sleep quality was compared between subjects with idiopathic PAH 
(IPAH) and healthy controls.14 Those with IPAH had significantly worse sleep quality (p<0.01) and worse 
functional capacity (6 minute walk distance (6MWD)). Over half (57%) of subjects with PAH report that 
difficulty sleeping interferes with their lives.11 
2.1.3 
Fatigue 
Fatigue is defined as an overwhelming, debilitating, and sustained sense of exhaustion that decreases 
one’s ability to carry out daily activities and function.15 We found over 90% of subjects with PAH report 
fatigue that interferes with their life.16 In addition, more than 40% of PAH subjects are disabled, with 
fatigue as a strong risk factor for disability.16 Fatigue is associated with dyspnea, physical disability and 
psychological distress in PAH. A recent study of 120 subjects with PH found a high prevalence of 
“severe” to “very severe” fatigue.17 Those taking phosphodiesterase inhibitors plus endothelin receptor 
antagonists combinations reported less fatigue. 
2.1.4 
Physical Activity 
Physical Activity is decreased in PAH.  In a study of subjects with PAH those who had poor sleep quality 
also had shorter 6MWD (IPAH 338 ± 23 vs. 441 ± 29 meters, p < 0.05).18 Using actigraphy, we found 

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subjects with PAH are more sedentary compared to healthy individuals (p<0.001). In a sample of women 
with PAH we found that most of their time was spent sedentary (85%) and only 10% of their time was 
engaged in low levels of activity.19 The 6MWD was positively associated with physical activity bouts 
(r=0.64, p=0.011) and worse energy levels were associated with lower average activity levels (estimate= -
13.965, p=0.013).19 Average physical activity (counts per minute) for the subjects ranged between 172.9 
+ 71.0 and 175.7 + 63.3 over 2 weeks of actigraphy, similar to those seen in another study of actigraphy 
in PAH.20 Normative data from the National Health and Nutritional Examination Survey (NHANES) 
showed average activity counts per minute for females age 60-69 were 251 and 170 for those 70 years and 
older. Our PAH sample was younger (mean age 52 years), but had much lower activity counts, suggesting 
that women with PAH have very limited activity levels even compared to individuals from the general 
population more than 2 decades older. Improving insomnia and fatigue levels may have a positive impact 
on physical activity in PAH.  
2.1.5 
Bright Light Therapy 
Light is an important factor in regulating sleep and wakefulness. Light input is received by photoreceptors 
in the eye, which is communicated via the retinohypothalamic tract to the suprachiasmatic nucleus, where 
it regulates circadian rhythms. Light also inhibits the secretion of melatonin, a hormone that regulates the 
sleep-wake cycle. Therefore, Bright Light Therapy has been used as a treatment for sleep disorders 
including insomnia and circadian rhythm disorders. Bright Light Therapy is a simple, safe and low cost 
treatment, with only mild side effects reported such as headache.21 
 
In a meta-analysis of the effects of light therapy on sleep problems, the effect sizes for fatigue (Hedge’s 
g=0.47) were larger than for sleep variables (sleep onset latency Hedge’s g=0.42; wake after sleep onset 
Hedge’s g=0.35).8 Bright Light Therapy was used to treat cancer-related fatigue. Patients (N=81) were 
randomized to 30 minutes of either Bright Light Therapy or dim light daily for 28 days.9 In another study 
of cancer survivors with cancer-related fatigue (N=44) patients were randomized to either Bright Light 
Therapy or dim light for 30 minutes in the morning for 4 weeks. Sleep efficiency (percentage of time 
spent asleep while in bed) improved in the Bright Light Therapy group (p=0.003) with a large effect size 
(partial η2 = 0.28).22 
2.1.6 
Cognitive Behavioral Therapy for Insomnia (CBT-I) 
CBT-I is a multi-component intervention that includes behavioral and cognitive strategies. The cognitive 
portion of therapy helps subjects recognize and change beliefs that are affecting their ability to sleep. The 
behavioral component helps the subject develop good sleep habits and may include: relaxation therapy, 
stimulus control, sleep restriction, sleep hygiene.1 
 
A literature review was conducted to determine the effects of insomnia in other medical and psychiatric 
conditions (e.g. chronic pain, HIV, depression, posttraumatic stress disorder, generalized anxiety).2 Effect 
sizes (Cohen’s d) ranged from 0.35-2.2. Not only did the review indicate that CBT-I improved insomnia, 
but CBT-I may also indirectly improve other medical and psychological endpoints. For example, in a 
study including cancer subjects with insomnia stimulus control, relaxation techniques, sleep hygiene, and 
cognitive approaches were used to decrease worry and emotional arousal prior to initiating sleep. There 
were significant improvements in sleep quality, sleep latency, time awake after sleep onset, sleep 
efficiency, number of nightly awakenings, and total sleep time (all p<0.05). Additionally, subjects 
reported a reduction in fatigue (p=0.022) and improvement in functioning (p=0.015). 
 
The evidence supports the use of CBT-I for the treatment of insomnia, but CBT-I is not as effective with 
combating waking symptoms of fatigue. While we have some evidence that Bright Light Therapy works 
to improve sleep and fatigue the evidence is inconclusive. The evidence thus far highlights the need for 
research to test the efficacy of CBT-I and Bright Light Therapy in disease specific conditions and 
symptoms such as insomnia and fatigue.  

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3. 
Study Objectives 
 
A single site, 3-arm (CBT-I group; Bright Light Therapy group; Standard of Care group), parallel, 
randomized controlled trial in subjects with insomnia, fatigue and PAH will be conducted.  
 
3.1 
Primary Objective 
• 
To assess the feasibility (recruitment and retention rates) of CBT-I and Bright Light 
Therapy in patients with PAH. 
3.2 
Secondary Objectives 
• 
To compare the effects of CBT-I and Bright Light Therapy to Standard of Care on 
insomnia and fatigue severity and wake after sleep onset and sleep onset latency 
outcomes. 
• 
To test the effects of CBT-I and Bright Light Therapy to Standard of Care on physical 
activity. 
• 
To test the effects of CBT-I and Bright Light Therapy to Standard of Care on: 
depression, dyspnea and QOL. 
4. 
Study Population and Duration of Participation 
4.1 
Duration of Study Participation 
Each subject will be in the study for approximately 10 weeks. 
4.2 
Total Number of Subjects 
Recruitment will end when 36 subjects are enrolled. These subjects will be screened and enrolled from 
Penn only. 
 
4.3 
Inclusion Criteria 
• 
Signed informed consent prior to initiation of any study mandated procedure. 
• 
Male and female subjects ≥ 18 years of age 
• 
Diagnosis of PAH belonging to one of the following subgroups of Group 1 PH according to 
the updated clinical classifications: 
o Idiopathic (IPAH)  
o Heritable (HPAH)  
o Drugs or toxins induced PAH 
o PAH associated with one of the following:  
 
Connective tissue disease;  
 
Human immunodeficiency virus (HIV) infection; 
 
Congenital heart disease; or 
 
Portopulmonary hypertension 
• 
Documented hemodynamic diagnosis of PAH by right heart catheterization (RHC), prior to 
enrollment showing:  
o mPAP > 25 mmHg; and  
o PAWP or LVEDP ≤ 15 mmHg. 
• 
On targeted stable therapy for 3 months prior to enrollment 
• 
Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance 
8a > 8 (raw score) at enrollment 
• 
Fatigue Severity Scale (FSS) > 35 at enrollment  
 

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4.4 
Exclusion Criteria 
• 
Pregnant 
• 
Enrolled in another clinical trial 
• 
Untreated obstructive sleep apnea 
• 
Subjects with left-sided valvular disease (more than moderate mitral valve stenosis or 
insufficiency or aortic stenosis or insufficiency), pulmonary artery or valve stenosis, or 
ejection fraction < 45% on echocardiography before enrollment 
• 
Hospitalized or acutely ill 
• 
Any eye disease such as, but not limited to, cataracts, glaucoma, retinal disorders (e.g. 
macular degeneration), or previous eye surgery 
• 
Subjects with photosensitivity (e.g. epilepsy) 
• 
Manic-depressive psychosis or Bipolar Disorder  
 
4.5 
Subject Recruitment 
In this RCT we will recruit 36 subjects with insomnia, fatigue and PAH from the University of 
Pennsylvania PVD Center who meet the inclusion criteria, to address our study aims. Patients with PAH 
will be screened for insomnia (PROMIS Sleep Distance > 8-raw score), fatigue (Fatigue Severity Scale 
>35). We estimate that a minimum of 50% of our subject pool (approximately 250) will meet eligibility 
criteria (insomnia and fatigue) based on our preliminary data. Therefore, anticipating a conservative 
recruitment rate, we have planned for recruitment of 36 subjects over the course of 9 months. 
 
4.6 
Populations Vulnerable to Undue Influence or Coercion 
Subjects will be informed that participation is voluntary and that they can change their mind at any time.  
They will be informed that participation in this research study is by choice, and if they choose to 
participate or not participate their clinical care will not be affected. Research coordinators will be mainly 
responsible for approaching the potential subjects. The rights and welfare of Penn employees and students 
that could potentially enroll in this study will be protected because the identity of the participants in the 
study will remain anonymous to everyone at Penn except those on the study staff. Study records will be 
kept in locked file cabinets and electronic data will be accessible by password only. The decision of the 
subject to enroll or withdraw from the study will have no effect on their standing at Penn. Finally, eligible 
patients need to have a diagnosis of pulmonary hypertension, making it a very minute population that 
could potentially be eligible. 
 
5. 
Randomization 
 
A Permuted Block Randomization scheme using SAS, consisting of random blocks of 3 and 6 will be 
used for randomization of subjects. Opaque, sealed consecutively numbered envelopes will be assembled 
that either have a “CBT-I”; “Bright Light Therapy” or “Standard of Care” card within the study packet. 
All study packets will look the same and be the same thickness and weight. After informed consent is 
obtained and screening measures are completed, the research coordinator will select the next consecutive 
envelope of study materials to reveal the arm of the study each subject will be assigned. Study personnel 
analyzing the data will be blinded to the treatment arm those analyzing the actigraphs will also be blinded.  
 
 
6. 
Study Assessments 
 

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6.1 
Informed Consent 
A member of the Research Team will review the purpose and procedures of the study, including 
completing either Cognitive Behavioral Therapy sessions or wearing Re-timer device for Bright Light 
Therapy, physical activity monitoring and questionnaires. The Research Coordinator will discuss the risks 
and benefits of participating, compensation for their time, who will be enrolled, the target number of 
subjects to be enrolled, how subject privacy and confidentiality will be protected, as well as the fact that 
subjects can drop out at any time. Subjects will be given an opportunity to ask questions about the study 
and will be encouraged to speak to their family, friends, and PH doctor about study participation. Subjects 
will be given the opportunity to consent, to participate or decline. If the consent process is taking place in 
clinic (in person), the subject will sign the consent form and be handed a copy for their records. If the 
consent process is taking place over the phone or via a web-meeting software, the subject will receive an 
email with a link to the REDcap electronic informed consent form. The subject will electronically sign the 
electronic consent form and have the opportunity to save and print a copy for their own records.  
 
 
6.2 
Demographics and Medical History Review 
Demographic information (sex, age, race, and ethnicity) and a complete medical history will be obtained 
from each subject. A complete subject history of PAH, including diagnosis, associated illness and 
diseases will be collected by chart review and subject interview. 
 
6.3 
Medication Review 
A list of current medications will be documented for each subject. Medications (especially changes in 
medication) will be updated at each scheduled visit and/or telephone call. A detailed history of PAH 
specific medications will also be documented. 
 
6.4 
Questionnaires 
6.4.1 
Fatigue Severity Scale (FSS) 
The FSS is a 9-item self-report questionnaire that measures how fatigue affects motivation, exercise, 
physical functioning, carrying out duties, and interference with work, family or social life. The items are 
measured on a 7-point Likert scale (e.g. 1=strongly disagree; 7=strongly agree). Scoring is completed by 
summing the scores. Score range from 9-63; higher scores indicate increased fatigue. Scores greater than 
35 are considered abnormal and/or increased fatigue. Subjects will complete the questionnaire at 
screening, on Day 1 and on Week 9. 
 
6.4.2 
PROMIS® Sleep Disturbance 
 
The adult 8-item PROMIS Sleep Disturbance 8a questionnaire was used to measure self-reported 
perceptions of sleep quality, depth, and restoration within the past seven days. This includes perceived 
difficulties falling asleep and staying asleep, as well as sleep satisfaction. The measure uses a 5-point Likert 
scale, and the raw score was converted to a standardized T-score using conversion tables published on the 
PROMIS website (nihpromis.org), with higher scores indicating greater sleep/wake disturbances. 
Each item on the measure is rated on a 5-point scale (1=never; 2=rarely; 3=sometimes; 4=often; and 
5=always) with a range in score from 8 to 40 with higher scores indicating greater severity of sleep 
disturbance. A single Physical Function capability score is obtained from a short form. The T-scores are 
interpreted as follows: < 55 none to slight; 55.0-59.9 mild; 60.0-69.9 moderate; >70 severe. Raw scores 
range from 8-40. Subjects will complete at screening, on Day 1 and on Week 9. 
 
6.4.3 
Insomnia Severity Index (ISI) 
The ISI is a 7-item self-report questionnaire assessing the severity and impact of insomnia. The ISI 
evaluates, severity of sleep onset, sleep maintenance, early morning awakening problems, sleep 
dissatisfaction, interference of sleep difficulties with daytime functioning, and distress caused by the sleep 

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difficulties. A 5-point Likert scale is used to rate each item on a 0-4 scale (0 = no problem; 4 = very 
severe problem). Total scores range 0-28 (0-7 = no insomnia; 8-14 = sub-threshold insomnia; 15-21 = 
moderate insomnia; and 22-28 = severe insomnia). Subjects will complete the questionnaire on Day 1 and 
on Week 9. 
 
6.4.4 
EmPHasis-10 
The emPHasis-10 is a pulmonary hypertension-specific questionnaire which is scored from 0-50 (with 
higher scores indicating worse QOL). Subjects will complete the questionnaire on Day 1 and on Week 9. 
 
6.4.5 
PROMIS® Physical Function Questionnaire 
This is an 8-itme questionnaire that measures self-reported capability rather than actual performance of 
physical activities. This includes the functioning of one’s upper extremities (dexterity), lower extremities 
(walking or mobility), and central regions (neck, back), as well as instrumental activities of daily living, 
such as running errands. Each item on the measure is rated on a 5-point scale (1=never; 2=rarely; 
3=sometimes; 4=often; and 5=always) with a range in score from 8 to 40 with higher scores indicating 
greater severity of sleep disturbance. A single Physical Function capability score is obtained from a short 
form. The T-scores are interpreted as follows: < 55 none to slight; 55.0-59.9 mild; 60.0-69.9 moderate; 
>70 severe. Subjects will complete at screening, on Day 1 and on Week 9. 
 
6.4.6 
Center for Epidemiological Studies- (CES-D) 
The Center for Epidemiological Studies-Depression (CES-D) is a 20-item measure that asks how often 
over the past week they experienced symptoms associated with depression, such as restless sleep, poor 
appetite, and feeling lonely. Response options range from 0 to 3 for each item (0 = Rarely or None of the 
Time, 1 = Some or Little of the Time, 2 = Moderately or Much of the time, 3 = Most or Almost All the 
Time). Scores range from 0 to 60, with high scores indicating greater depressive symptoms. A score of 16 
points or more is considered depressed. Subjects will complete the questionnaire on Day 1 and on Week 
9. 
 
6.4.7 
Pittsburgh Sleep Quality Index (PSQI) 
The PSQI measures sleep disturbance and quality. There are seven domains: sleep quality, sleep latency, 
sleep duration, sleep efficiency, sleep disturbance, use of sleep medications and daytime dysfunction on 
most nights over the past month. The PSQI is self-administered and contains 19 sleep-related questions. 
Questions are rated on a 0-3 scale. The global score is calculated from the seven components. Scores 
range form 0-21; higher scores indicated worse sleep quality. Scores greater than 5 indicate worse sleep 
disturbance and poor sleep quality. The sensitivity of the PSQI is 89.6% and 86.5% specificity to 
distinguish good and poor sleepers. Subjects will complete the questionnaire on Day 1 and on Week 9. 
 
6.4.8 
PROMIS Short Form (SF) v 1.0- Dyspnea-Severity 10a  
The PROMIS Dyspnea measures self-reported severity. This is self-administered and measures dyspnea 
severity during activity. The measure contains 10 items on a Likert scale. Each activity is rated in terms of 
degree of dyspnea (no shortness of breath, mildly short of breath, moderately short of breath, severely 
short of breath) while engaging in the activity over the past 7 days, with higher scores reflecting greater 
levels of dyspnea. Respondents who indicate that they did not perform an activity in the past 7 days will 
not produce a score for that item. Subjects will complete the questionnaire on Day 1 and on Week 9. 
 
 
 
Urine pregnancy Test:  

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Female subjects who are not post-menopausal will be sent a urine pregnancy test with 
instructions. They will take a picture of the results and will send to the Research Coordinator to confirm 
the subject is not pregnant.  
 
6.5 
Actigraphy  
Physical activity will be measured by actigraphy. An actigraph is a highly sensitive motion sensor that 
records movement and provides objective data regarding daytime activity and duration of sleep. 
Actigraphs are small, non-invasive devices worn on the wrist and do not interfere with usual daily 
activities or function. Actigraphy is a valid and reliable measure of sleep-wake patterns and physical 
activity by continuously recording activity over a specified time period (e.g., 1 minute intervals). Subjects 
will be mailed an actigraph and begin wearing the wrist actigraph on Day 1 and will wear the wrist 
actigraph for 7 days. Subjects will return the actigraph with a self-addressed pre-paid envelope. At the 
beginning of Week 9, subjects will be mailed an actigraph to be worn for 7 days during the last week of 
the intervention. Subjects will return the actigraph with a self-addressed pre-paid envelope. Actigraphy 
will be analyzed in counts per minute by computer software.  
 
6.6 
Sleep and Activity Diary 
The Sleep Diary form is a self-reported questionnaire to collect data about the patient’s sleep/wake 
patterns. Subjects will complete a sleep and activity diary (e.g. time to bed, time out of bed, exercise), 
each day of the study, starting on Day 1 for the CBT-I group. Those conducting the CBT-I sessions will 
review with subjects at the weekly sessions. The Bright Light Therapy group and Standard of Care group 
will begin on Day 1 for 7 days for Week 1 and for 7 days in Week 9 via REDCap.  
 
6.7 
Bright Light Therapy 
Bright Light treatment will consist of 8 weeks of daily use of the Re-timer device. The Re-timer is worn 
like a pair of glasses and contains light emitting diodes mounted on the lower portion of the frame. The 
Re-timer emits blue-green 500 nm light with an intensity of ~500 lux lm/m2. Subjects will be instructed to 
use the device for 30 minutes within two hours of waking, in the morning. (See appendix for instruction 
manual). 
 
6.8 
Cognitive Behavioral Therapy for Insomnia 
CBT-I treatment will receive 1 session every week, for 8 weeks (8 total sessions). The CBT-I sessions 
will be provided by a pool of clinical PhD psychology students by a trained professional. Each visit will 
be conducted via telehealth. Sessions will include discussions regarding such topics as sleep restriction, 
stimulus control and sleep hygiene. Review of sleep diaries will occur during the sessions. 
 
6.9 
Standard of Care 
Subjects will continue the care they routinely receive. 
 
7. 
Study Procedures 
 
7.1 
Screening Visit 
The following procedures will be performed during the screening process: 
• 
Sign and date the informed consent and HIPAA release 
• 
Review of inclusion/exclusion criteria 
• 
Questionnaires: PROMIS Sleep Disturbance & FSS 
 
After screening procedures have been completed and the subject meets eligibility criteria, the research 
coordinator will randomize the subject based on the randomization scheme described in Section 5.  
 
 

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7.2 
Baseline Visit - Day 1 
Study subjects will be sent the Actigraph (see appendix for education guidelines) with a prepaid return 
envelope. Questionnaires and sleep diary will be sent electronically via REDCap. If the subject is 
randomized to Bright Light Therapy, the Re-Timer Glasses (see appendix for education guidelines) will 
also be sent. 
 
The Research Coordinator will confirm receipt of actigraph/Re-Timer glasses and confirm understanding 
of how to wear each device and review the questionnaires and sleep diary. The Research Coordinator will 
answer any questions the subject has.  
 
The Research Coordinator will: 
• 
Confirm there has been no change in eligibility 
• 
Review demographics and medical history 
• 
Review medications 
 
The devices will be  applied on an agreed upon day with the Research Coordinator and the ActiGraph will 
be worn for 7 days. The Research Coordinator will contact the subject on Day 7 as a reminder to stop 
wearing the Actigraph and to return it to the study center. 
 
Subjects will be instructed to complete the following procedures on the same day they start to wear the 
ActiGraph: 
• 
Questionnaires: 
o FSS 
o PROMS Sleep Disturbance 
o ISI 
o emPHasis-10 
o PROMIS® Physical Function Questionnaire 
o CES-D 
o PSQI 
o PROMIS® Dyspnea Questionnaire 
• 
Sleep Diary (see appendix for education guidelines) 
 
After Baseline study procedures are complete, if the subject has been randomized to the Cognitive 
Behavioral Therapy group, A member of the CBT-I team will reach out to the research subject to set up a 
time for the therapist to meet with them. After the initial 7-days of actigraphy and sleep diary are complete,  
CBT-I treatment will be administered in an individual format by a trained therapist. Training and 
supervision of the study therapists will be conducted by Dr. Jim Findley. Each subject will receive 8 weekly 
60-minute CBT-I sessions remotely. During CBT-I treatment, daily sleep diaries will be completed by 
subjects. After completion of the 8-weeks of CBT-I actigraphy/questionnaires will be repeated. 
 
If the subject has been randomized to the Bright Light Therapy group. The Research Coordinator will 
follow up with the subject when they receive the ReTimer glasses to go over how to use the glasses.  
 
If the subject is randomized to the Standard of Care group, they will continue with their usual PAH care.  
 
7.3 
Treatment Period (CBT-I Group) – Weeks 2 through 8 
Subjects randomized to CBT-I  and Light therapy will be contacted once a week, for 8 weeks (total 8 
visits) for a remote visit.   
 
The following procedures will be performed for the CBT-I group:  
• 
Medication review  

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• 
Adverse event review 
• 
Sleep Diary review 
• 
CBT-I Session 
 
The following will be performed on the Light therapy group: 
• 
Medication review 
• 
Adverse event review 
 
7.4 
Treatment Period (All Groups) – Week 9 
The subject will be contacted via phone for a remote visit. Study subjects will be sent the Actigraph and 
questionnaires along with a prepaid return envelope prior to this visit.    
 
The Research Coordinator will confirm receipt and understanding of how to wear the Actigraph and 
review the questionnaires. The Research Coordinator will answer any questions the subject has. 
 
The Actigraph will be applied on the day after receipt (Week 9) and the ActiGraph will be worn for 7 
days. The Research Coordinator will contact the subject on Day 7 as a reminder to stop wearing the 
Actigraph and to return it to the study center. 
 
The following procedures will be performed: 
• 
Medication review  
• 
Adverse event review 
• 
Sleep Diary review, if applicable 
• 
CBT-I Session, if applicable 
• 
Actigraphy Distribution 
 
7.5 
End of Treatment (All Groups) – Week 10 
The subject will be contacted for a remote visit.    
 
The following procedures will be performed: 
• 
Medication review  
• 
Adverse event review 
• 
Questionnaires: 
o FSS 
o PROMS Sleep Disturbance 
o ISI 
o emPHasis-10 
o PROMIS® Physical Function Questionnaire 
o CES-D 
o PSQI 
o PROMIS® Dyspnea Questionnaire 
• 
Sleep Diary review 
 
 
7.6 
Subject Withdrawal 
Subjects may withdraw from the study at any time without impact to their care. Patients my drop out due 
to fatigue in complying with study procedures or worsened symptoms.  They may also be discontinued 
from the study at the discretion of the Investigator for concurrent illness, AEs, or other reasons deemed to 
be in the subject’s best interest.  It will be documented whether or not each subject completes the study. 

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Subjects who withdraw early will not be asked to return for a final remote visit. For those participants 
who withdraw from the study, their data will be eliminated from data analysis. 
 
7.7 
Subject Compensation 
Subjects will be reimbursed for reasonable travel expenses and the inconvenience of the study procedures 
necessary for participation. We acknowledge that participation in this study is somewhat burdensome due 
to the time needed to complete procedures associated with the study.  The subject will be compensated 
$25 for completion of the first visit after the baseline assessments are complete and the actigraph is 
returned. The subject will receive $50 after the follow up assessments are complete and the actigraph is 
returned. A total of $75 for completion of all study parts.  
 
Reimbursements for participation in the study will be administered using a Greenphire ClinCard, a 
reloadable prepaid card. There are no fees for making online or in-store purchases, cashing out the card 
by presenting it to a teller at any major bank, calling the automated system for balance inquires, calling 
the customer service number and speaking to a live agent, or addition of funds to the card. The following 
activities will incur a fee to the balance on your ClinCard: 1) not using the card or having funds added to 
it for more than 6 months will incur a monthly $3 fee. Every time the card is used or funds are added, this 
6-month period is reset. 2) ATM withdrawals (fees vary based on location) 3) Requesting a paper 
statement (instead you can always check your available balance online or by calling Customer Service) 4) 
Requesting a replacement card through Customer Service will incur a $7.00 fee and take 7-10 days to 
receive by mail. Instead, if your card is lost, stolen or damaged, contact your study coordinator so that 
s/he can replace your card at no charge. 5) Requesting a check through Customer Service to remove funds 
from the card. Please read the ClinCard Cardholder FAQ given to you by the research team. 
 
8. 
Study Endpoints 
 
8.1.1 
Primary Study Endpoint 
• 
The primary endpoint will be the measurement of recruitment and retention rates. 
 
8.1.2 
Secondary Study Endpoints 
• 
To compare the effects of CBT-I and Bright Light Therapy to Standard of Care on 
(insomnia and fatigue severity) and secondary (wake after sleep onset and sleep onset latency) 
outcomes.  
• 
To test the effects of CBT-I and Bright Light Therapy to Standard of Care on the 
secondary outcome physical activity. 
• 
To test the effects of CBT-I and Bright Light Therapy to Standard of Care on the 
secondary outcomes: depression, dyspnea and QOL. 
 
9. 
Statistical Plan 
 
9.1 
Sample Size and Power Determination 
We used parameter estimates from an RCT using Bright Light Therapy to improve cancer related fatigue 
to conduct a sample size calculation for our study.9 The authors reported mean fatigue severity score 
(Fatigue Severity Scale) of 9.48 and 14.45 at the conclusion of their study with standard deviations of 
16.11 and 15.57. Our calculations indicated that we need a total of 312 subjects to achieve 80% power 
while maintaining the type I error rate α = 0.05. We intend to recruit 10% of subjects required to 
determine the sample size for an adequately powered RCT in PAH.44 With an estimated 20% attrition rate 
from our other study45 we will enroll 36 subjects to achieve a sample of 30. 
 

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9.2 
Statistical Methods 
We will use intention-to-treat analyses. First, we will calculate the frequencies and percentages for all 
demographic (e.g. sex) and clinical (e.g. medications) categorical variables and use Fisher’s exact test to 
compare baseline differences between groups. We will obtain means, medians, standard deviations, and 
interquartile-ranges for all continuous demographic (e.g. age) and clinical variables (e.g. body mass 
index) and use t- tests to compare baseline differences. between groups. We will use non-parametric tests 
to compare the groups if the data do not follow normal distribution.  
 
To evaluate Aim 1, we will calculate appropriate descriptive measures for recruitment and retention rates. 
For Aims 2 and 3 our goal is to compare the three groups. As such we will calculate difference scores 
(Week 10 – Baseline scores) for our outcome variables (insomnia and fatigue) . To maintain experiment-
wise type I error rate at the nominal level (α = 0.05), we will conduct an omnibus test for overall 
differences between the three groups using the ANOVA approach. In the presence of a significant overall 
difference, we will conduct post hoc comparison of the two treatment conditions with the Standard of 
Care group using the Dunnett approach. We will verify the assumptions related to the ANOVA using 
residuals. We will use the non-parametric Kruskal-Wallis approach if the data do not satisfy the normal 
distribution assumption. If our preliminary analysis identifies group differences at baseline, we will adjust 
for the difference at baseline and perform analysis of covariance. Analyses will be primarily conducted 
using the R statistical environment. 
 
10. Safety and Adverse Events 
 
10.1 Definitions 
There is a reasonable possibility that the adverse event (AE), experience, or outcome may have been 
caused by the procedures involved in the research.  
 
10.1.1 Unanticipated Problem (UP) 
Any incident, experience, or outcome that meets all of the following criteria: 
• 
unexpected (in terms of nature, severity, or frequency) given 
o a) the research procedures that are described in the protocol-related documents, such as 
the IRB-approved research protocol and informed consent document; and  
o b) the characteristics of the subject population being studied;  
• 
related or possibly related to participation in the research; and  
• 
suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized.  
 
10.1.2 Adverse Event (AE) 
Any symptom, sign, illness or experience that develops or worsens in severity during the course of the 
study. Intercurrent illnesses or injuries should be regarded as AEs. Abnormal results of diagnostic 
procedures are considered to be AEs if the abnormality: 
• 
results in study withdrawal  
• 
is associated with a serious AE  
• 
is associated with clinical signs or symptoms  
• 
leads to additional treatment or to further diagnostic tests  
• 
is considered by the investigator to be of clinical significance  
 
10.1.3 Serious Adverse Event (SAE) 
Adverse events are classified as serious or non-serious. A serious adverse event is any AE that is: 
• 
fatal 
• 
life-threatening 

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• 
requires or prolongs hospital stay 
• 
results in persistent or significant disability or incapacity 
• 
a congenital anomaly or birth defect 
• 
an important medical event 
 
Important medical events are those that may not be immediately life threatening but are clearly of major 
clinical significance. They may jeopardize the subject and may require intervention to prevent one of the 
other serious outcomes noted above. For example, drug overdose or abuse, a seizure that did not result in 
in-subject hospitalization or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious. 
 
All AEs that do not meet any of the criteria for serious should be regarded as non-serious AEs. 
 
10.1.4 Expectedness 
Expected: an AE known to be associated with the intervention or condition under study. 
Unexpected: any AE occurring in one or more subjects participating in a research protocol, the nature, 
severity, or frequency of which is not consistent with either: 
• 
the known or foreseeable risk of AEs associated with the procedures involved in the research that 
are described in: the protocol-related documents, such as the IRB-approved research protocol and 
the current IRB-approved informed consent document, and other relevant sources of information; 
or 
• 
the expected natural progression of any underlying disease, disorder, or condition of the 
subject(s) experiencing the AE and the subject’s predisposing risk factor profile for the AE. 
 
10.1.5 Relatedness 
Definite: the AE is clearly related to the intervention 
Probably: the AE is likely related to the intervention 
Possible: the AE may be related to the intervention 
Unlikely: the AE is doubtfully related to the invention 
Unrelated: the AE is clearly not related to the intervention 
 
10.1.6 Adverse Event Reporting Period 
The study period for which AEs must be reported for this study is defined as the period from the initiation 
of any study procedures to 5 days after the last study visit. 
 
10.1.7 Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition should be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during 
the study period. 
 
10.1.8 Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and 
reported as a serious adverse event unless specifically instructed otherwise in this protocol.  Any 
condition responsible for surgery should be documented as an adverse event if the condition meets the 
criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse 
event in the following circumstances: 

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• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for 
a preexisting condition.  Surgery should not be reported as an outcome of an adverse event if 
the purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
• 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study. 
• 
Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
 
10.2 Recording of Adverse Events 
At each contact with the subject, the research team will seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events will be recorded 
immediately in the source document, and also in the appropriate adverse event case report form (CRF) 
and electronic case report form (eCRF in REDCap).  All clearly related signs, symptoms, and abnormal 
diagnostic procedures results should be recorded in the source document, though should be grouped under 
one diagnosis. 
 
All adverse events occurring during the recording period will be recorded. The clinical course of each 
event will be followed until resolution, stabilization, or until it has been determined that the study 
intervention or participation is not the cause. Serious adverse events that are still ongoing at the end of the 
study period will be followed up to determine the final outcome.  Any serious adverse event that occurs 
after the study period and is considered to be possibly related to the study intervention or study 
participation will be recorded and reported. 
 
10.3 Relationship of AE to Study 
The investigator must assess whether the adverse event represents an unanticipated problem following the 
guidelines described in section 10.1.1 above.  If the investigator determines that the adverse event 
represents an unanticipated problem, the investigator must report it promptly to the IRB. 
 
10.4 Reporting of Adverse Events and Unanticipated Problems 
The University of Pennsylvania IRB (Penn IRB) requires expedited reporting of those events related to 
study participation that are unforeseen and indicate that participants or others are at increased risk of 
harm.   
 
A reportable event is an adverse event or incident that has the potential to be classified by the 
IRB as an unanticipated problem posing risks to participants or others. An incident is determined 
to be reportable to the IRB when it is both:  
1. probably or definitely related to participation in the research 
2. unexpected in terms of nature, severity, or frequency 
Events that meet these criteria, must be submitted to the IRB within 10 business days of 
discovery. However, if the event involved a death, the investigator should report within 3 
calendar days.  
If the event does not meet the reporting criteria above, the following table describes whether the 
event is reportable to the IRB, and if so, when it should be reported.  

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10.4.1 Reporting Process 
Unanticipated problems posing risks to subjects or others as noted above will be reported to the Penn IRB 
using the institution required form or as a written report of the event (including a description of the event 
with information regarding its fulfillment of the above criteria, follow-up/resolution and need for revision 
to consent form and/or other study documentation). 
 
The Principal Investigator is expected to provide as much of the following information as is available: 
• 
Protocol name and number 
 
• 
Subject identifiers 
• 
Demographic data 
• 
Nature of the event 
• 
Severity of the event 
• 
Probable relationship (causality) of AE to study procedure 
• 
Date and time of AE onset 
• 
Date and time of AE resolution, if available 
• 
Concomitant medications that the participant was taking for an underlying medical 
condition or disease and the therapeutic agents used for the treatment of the adverse event 
• 
Clinical assessment of participant conducted at time of SAE/AE 
• 
Results of any laboratory and/or diagnostic procedures, and treatment 
• 
Follow-up plan 
• 
Outcome 
• 
Autopsy findings (if appropriate) 
 
The Principal Investigator and research coordinator will provide details about the AE as they become 
available. If additional information cannot be obtained for whatever reason, this will be documented. 
 
The Principal Investigator should promptly determine an assessment of causality. 

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The Principal Investigator/designee should keep originals or photocopies of all relevant documentation, 
including facsimile confirmations and email exchanges, and file them in the participant's file. 
 
The Principal Investigator/designee should file copies of all correspondence with the IRB in the 
appropriate section of the Regulatory Master File or site study file. 
 
The Principal Investigator will review all SAEs/Ups for the study. 
 
10.4.2 Follow-up Report 
If an AE has not resolved at the time of the initial report and new information arises that changes the 
investigator’s assessment of the event, a follow-up report including all relevant new or reassessed 
information (e.g., concomitant medication, medical history) should be submitted to the IRB. The 
investigator is responsible for ensuring that all SAEs are followed until either resolved or stable. 
 
11. Study Administration, Data Handling and Record Keeping 
 
11.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a 
signed subject authorization informing the subject of the following:  
• 
What protected health information (PHI) will be collected from subjects in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.   
 
11.2 Subject Privacy 
Potentially eligible subjects will be identified by screening Pulmonary Hypertension clinics at Penn 
through EPIC. They will be approached about the study via phone. The subject will provide the best 
number of contact and be given the staff's member card with contact information so that they may call 
with any questions and to schedule the study visit. The study visit will take place remotely via secured 
telehealth software. 
 
11.3 Data Collection and Management 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported. All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. The investigator will maintain adequate case histories of study subjects, including 
accurate case report forms (CRFs), and source documentation. 
 
Clinical data will be obtained from the patients and their clinical charts. Subjects will be assigned a 
unique identifier when the screening data are entered. The unique identifier will be linked to the subject 
name. Only the PI and the research coordinator will have access to the linkage between the subject 
identity and the unique identifier. 
 
Data collection and accurate documentation are the responsibility of the study staff under the supervision 
of the PI. All source documents must be reviewed by the study team and data entry staff, who will ensure 
that they are accurate and complete. Unanticipated problems, adverse events, and severe adverse events 
must be reviewed by the investigator. 

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This study will use a Redcap database. The database will be hosted on secure computing servers and will 
be restricted to only those individuals who are authorized to work on the study. Individual user accounts 
with passwords will be used to restrict access to the database. Specific privilege assignments within the 
database will also be employed to limit the types of functions that authorized users can perform to those 
functions that are appropriate for their role in the study. Additional measures to prevent unauthorized 
external access to the database environment will be employed using network firewall technologies. 
 
Source documents will be identified by the subject ID number and other identifiers will be removed or 
blacked out. All documents (including questionnaires, sleep diaries, subject study binders, etc.) will be 
kept in a locked file cabinet in a locked room. Identifiers will be stored separately, also in a locked 
cabinet and/or a password-protected computer.  
 
Protection against the risk of unintended data disclosure will rely on (1) adequate training of study 
personnel in accordance with NIH human subjects research training policies; (2) study procedures and 
protocols defining appropriate data management principles; and (3) a secure data management 
infrastructure. All study personnel involved in the direct collection and analysis of identifiable research 
data will undergo required training in human subjects’ research participant protections as required by 
NIH. Standards will be formalized among the study team to ensure the maintenance of the study dataset in 
a single, secure location, and prohibiting transfer of study data to removable or portable media for 
personal use. Additional procedures will be defined for de-identification of the final study dataset as 
appropriate for data sharing purposes. No identifiers will be shared, and Data Use Agreements would 
need to be executed before sharing data. 
 
11.4 Personnel Training 
Prior to enrollment of the first subject in the study protocol, the Investigator will ensure that staff has 
completed appropriate training and that all documentation including IRB approval is completed and 
available. The purpose of training is to ensure that study personnel are carrying out the protocol in a 
consistent way and are adhering to good clinical practice guidelines. Staff will have current Human 
Subjects Training Certification on file. Before enrollment begins, study coordinators and research 
assistants who will perform the outcome assessments will be trained in all procedures, including 
completion of case-report forms (CRFs).  
 
The PI and research staff will constitute the first line of monitoring of the safety of the human 
participants. Surveillance for AEs will consist of questioning subjects about potential AEs at every study 
visit, having subjects report any adverse event to the study team. 
 
12. Study Monitoring, Auditing, and Inspecting 
 
12.1 Study Monitoring Plan 
Connie Ulrich PhD, RN, FAAN will monitor this study. Participants will be assessed for eligibility and 
adherence. No interim analysis is planned. Once the 36 participants have completed the study, analyses 
will be conducted. We will make every effort to prevent missing data by carefully explaining how to use, 
Bright Light Therapy, actigraphy equipment, telehealth visit software and reviewing all questionnaires. 
Study representatives will be accessible by phone 24 hours/day for questions. 
 
12.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the sponsor, 
government regulatory bodies, and University compliance and quality assurance groups of all study 
related documents (e.g. source documents, regulatory documents, data collection instruments, study data 
etc.).   

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Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
 
13. Ethical Considerations 
 
This study is to be conducted in accordance with applicable US government regulations and international 
standards of Good Clinical Practice, and applicable institutional research policies and procedures.  
 
13.1 Risks 
There are minimal foreseen risks to participation in this study. The light source of the Re-Timer Glasses 
technology ranges from 115 to 314 hertz. There is a risk of headache, dry mouth, eyestrain, nausea, and 
hyperactivity after use, which are unlikely but not considered serious AEs. Skin irritation from use of the 
actigraphy watch is possible, but not considered a serious AE. Adverse events for CBT-I will be assessed 
by a checklist of 14 somatic and psychological events. This scale asks subjects to check, from a list, 
symptoms experienced.  Checked symptoms are rated in terms of their interference with daytime 
functioning (0–4 scale: ‘not at all’ to ‘very much’). Items include: Low mood, Fatigue/exhaustion, 
Extreme sleepiness, Feeling agitated, Bodily pain, Headache/migraine, Euphoria/intense increase in 
mood, Reduced motivation/energy, Changes in hunger/appetite, Blurred vision, Dizziness, Feeling 
irritable. 
 
The other risk is potential loss of confidentiality during data collection and remote visits. In order to 
minimize this risk, procedures will be in place to maintain confidentiality.  Computer based files will only 
be accessible to study personnel through the use of privileges and passwords. However, the risks of this 
study to subjects are minimal. 
 
13.2 Benefits 
It is not expected that the subject will benefit directly from this research study. The results from the study 
could be applied in the future to subjects (including those in the study) who stand to benefit from the 
information. 
 
13.3 Risk Benefit Assessment 
There is minimal risk to the participants and there is potential benefit to determining a new way to 
measure the impact of fatigue using Bright Light Therapy in PAH, the risk/benefit ratio is favorable. 
 
14. Study Finances 
This study is financed through an investigator-initiated grant from the Bayer, Corporation. 
 
15. Appendices     
 
 

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Table 1: Study Procedures 
 
 
 
 
 
 
 
Sociodemographic History 
Day -30 to 1 
Week 1 Day 1 
 
Weeks 2 → 8 
Week 9 
Week 10 
Screening 
Baseline 
 
Treatment Period 
End of 
Treatment 
Informed Consent 
X 
 
 
 
 
 
Demographics and Medical History 
Review 
X 
 
 
 
 
 
Medications Review 
X 
X 
 
X 
X 
X 
Adverse Events Review 
X 
X 
 
X 
X 
X 
Insomnia Severity Index (ISI) 
X 
 
X 
PROMIS® Sleep Disturbance 
X 
X 
 
 
 
X 
Fatigue Severity Scale (FSS) 
X 
X 
 
X 
emPHasis-10 Questionnaire 
X 
 
X 
PROMIS® Physical Function 
Questionnaire 
 
X 
 
 
 
X 
Center for Epidemiological Studies-
Depression (CES-D) 
 
X 
 
 
 
X 
PROMIS® Dyspnea Questionnaire 
 
X 
 
 
 
X 
Pittsburgh Sleep Quality Index (PSQI) 
 
X 
 
 
 
X 
Sleep Diary 
X 
 
X 
X 
Actigraphy (7 days) 
X 
 
X 
Cognitive Behavioral Therapy Visit 
 
X 
X 
Re-timer Glasses Education 
 
X 
 
 
 
 
Re-timer Glasses Wear 
 
X 
 
X 
X 
 
Randomization 
X 
 
 
 
 
 

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Record ID 
______________________________
____ 
Date of Birth 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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FOR FORMER SMOKERS  
How old were you when you QUIT smoking cigarettes? 
__________________________________ 
On average, about how many cigarettes a day do/did you smoke? 
__________________________________ 
Current NON-SMOKERS ONLY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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__________________________________ 
During the past year about how many 
hours per week were in close contact 
with people when they were smoking? 
(e.g. in your home, in a car, at work or 
other close quarters) 
How old were you when you first started drinking 
alcoholic beverages? 
__________________________________ 
Page 3 
For how many years did you drink alcoholic beverages?  
______________________________
____ 
Skip to Q#12 
(One drink means 1 beer or 1 glass of 
wine or 1 shot of liquor or 1 mixed drink. 
Record 0 if less than one drink per week) 
For how many years have you been drinking alcoholic beverages?  
(Do not count times when you did NOT drink alcohol) 
__________________________________ 
During the past 24 hours, how many drinks have you had? 
__________________________________ 
In the past month, what is the largest number of drinks 
you had in one day? 
__________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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IV drug use:Yes 
No 
Current or past IV drug 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Medical clinical History 
Record ID 

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__________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 

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Adverse Events Symptoms Questionnaire 
Record ID 

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08/11/2021 3:34pm 
projectredcap.org 
Confidential 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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RE-TIMERTM 
 
 
 
 
 
 
 

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**You will be using your Re-Timer device for 30 minutes within two hours of waking in the morning** 
 
Setting up your Re-Timer 
Follow these steps to charge your device:                      
1) Plug the charging cable into the charging port of your 
Re-Timer (A, Diagram 1) 
 
2) Plug the opposite end of the charging cable into either your 
computer’s USB port or a USB wall adapter. 
 
As the battery charges, the orange LED Battery Indication 
Light will light up on the display (B, Diagram 2).  
 
This orange light will remain illuminated until the battery 
is full. If the battery is fully charged the indication panel 
will remain blank. 
 
When the battery is fully charged it contains enough power to 
provide up to 5 hours of battery life. 
 
When your Re-Timer is low on battery power the battery indication  
light will flash red (B, Diagram 2). 
Warning 
You must not use the device while it is charging. 
 
Turning the Re-Timer 
on and selecting the light 
intensity setting 
 
Before you place the Re-Timer on your head,  
turn it on by pressing the control button (E, 
diagram 2) once. This will turn its lights 
on to the half-brightness setting. If you prefer 
the full brightness setting, press the 
control button a second time. You only need to press the 
button for a moment. 
 
You can see which brightness setting you are using by looking at the control 
panel. The low brightness indicator (C, Diagram 2) will light up when the device  
is in low brightness mode. 
 
The high brightness indicator will light up when the device is in high brightness mode 
(D, Diagram 2). 
**You will be using the high brightness mode.** 
 
 
 

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Adjusting Re-Timer 
Once you have turned your Re-Timer on and selected the high brightness setting, place it on your 
head. To wear reading glasses while you use your device, put your reading glasses on first, then 
the Re-Timer. The adjustable nose-piece (Diagram 3) can sit either behind or in front of your 
reading glasses. 
Once the Re-Timer is on your head you can make small adjustments. To move the device closer to 
or further away from your head slide the top section of the nosepiece (F, Diagram 3) in and out of 
the frame (H, Diagram 3). 
 
The height of the Re-Timer can be adjusted by the lower portion of the nose-piece (G, Diagram 
3). This slides up and down and can be used to accommodate your reading glasses. You can 
select a low position (J, Diagram 3) or a high position (I, Diagram 3). Adjust the device until it is 
comfortable. 
Tip  
Adjust the nose-piece until the light is centered on your eyes. You may use a mirror to assist in 
aligning the light with your eyes.   
Turning Re-Timer off 
Once you have finished using your Re-Timer, remove it from your head. Turn it off by pressing the 
control button (E, Diagram 2). Press the button once if you were using the full brightness setting; 
twice if you were using the half brightness setting. 
Notes 
Your eyes must be open when using Re-Timer. Otherwise, you will not receive a therapeutic 
benefit. 
Re-Timer will automatically switch off after 60 minutes of use. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Actigraphy Subject Instructions 
 
Thank you for agreeing to participate in the study. Please read over the following instructions carefully. 
 
What is an Actigraph? 
An Actigraph is a motion sensor that records movement to monitor rest/activity cycles. The actigraph 
measures activity by recording how often and how quickly movements are made. Actigraphs are small, 
non-invasive devices worn on the wrist and do not interfere with usual daily activities or function. 
 
How do I use the Actigraph? 
1. Wear the actigraph all day and night except for showering or bathing so that all of your 
movement in the day and night is measured. 
2. Press the event marker on the actigraph to indicate when you start trying to fall asleep 
(bedtime) and when you rise in the morning. 
3. Wear the Actigraph on your wrist all day. 
4. Do not wear the Actigraph during water activities (bathing, showering, swimming) since it 
is not waterproof.  
When should I wear the Actigraph? 
The Actigraph will have been programmed to start recording data when you receive it in the clinic. We 
would like to collect data for 7 days. We will call you on Day 8 to remind you to mail back the actigraph in 
the stamped, self-addressed envelope we provided you. 
Please wear the Actigraph all day and night after you receive the device and wear it continuously (except 
while swimming or showering).  
 
What happens at the end of the study? 
When you take the Actigraph off after day 7 of testing, please put it back in the envelope we provided and 
mail it back to the study center.  
 
If you have any questions or concerns, please contact:  
 
Lea Ann Matura 
                                                                                                                                            
matura@nursing.upenn.edu                                                                                                                                                      
(215) 746-8819 
 
Thank you for your participation in this study! 
 
 
 
 
1. 
Edinger JD, Means MK. Cognitive–behavioral therapy for primary insomnia. Clinical psychology 
review. 2005;25(5):539-558.  
2. 
Smith MT, Huang MI, Manber R. Cognitive behavior therapy for chronic insomnia occurring within 
the context of medical and psychiatric disorders. Clinical psychology review. 2005;25(5):559-592.