An Open-Label Study of the Apollo Device for Fatigue in Systemic Sclerosis
Phase: NA
Conditions: Systemic Sclerosis, Fatigue, Raynaud Phenomenon
Sponsor: Robyn T. Domsic, MD, MPH

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An Open-Label Study of the Apollo Device for Fatigue in Systemic Sclerosis 
 
Test device: 
Apollo  
Study purpose: 
Evaluate the efficacy and use patterns of Apollo  
Clinical study phase: 
II 
Version no: 
1 
Version Date 
February 1, 2021 
Sponsor Investigator: 
 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements. 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the 
guidance of the clinical investigation.  Reproduction or disclosure of this document - whether 
in part or in full - to parties not associated with the clinical investigation, or its use for any 
other purpose, without the prior written consent of the sponsor is not permitted. 
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected. 

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Synopsis 
 
Title 
An Open-Label Study of the Apollo Device for Fatigue in 
Systemic Sclerosis 
Short title 
The Apollo in Systemic Sclerosis 
Clinical study phase 
II 
Study objective(s) 
The primary objective of this study is to provide preliminary data on the 
tolerability and efficacy of the Apollo system for the management of fatigue in 
systemic sclerosis.   
Test device 
Apollo System 
Mechanism of use 
The Apollo system consists of a wearable device whose frequency of use is 
controlled by the participant.  The participant will install the study mobile 
application on a mobile device of their choosing.  The wearable device is 
controlled by the mobile app through which the participant can choose 
when and for how long to use it.    
Location of use 
Wrist or ankle 
Duration of use 
4 weeks 
Background treatment 
Patients will continue any existing prescription medication, including 
prednisone and immunosuppressives, at steady doses for 4 weeks prior to 
baseline (visit 1) and during the four-week intervention period.   
Indication 
Scleroderma-associated fatigue 
Diagnosis and main criteria for 
inclusion 
 
Men or women aged 18 years and older, inclusive 
 
Systemic Sclerosis as defined by 2013 the American College of 
Rheumatology (ACR) / European League Against Rheumatism 
(EULAR) classification. 
 
Steady daily doses of any  immunosuppressive medication, 
vasodilators, antidepressants and anxiolytic use for 4 weeks 
prior to baseline. 
 
PROMIS-fatigue score of at least 45   
 
Currently owns and operates a smart phone regularly  
 
Ability to provide informed consent 
 
Study Design 
Open label, single-arm, single center US study 
Type of control 
None 
Number of participants 
30 
Primary outcome variable 
Change in the PROMIS-Fatigue scale at four weeks 

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30 
Plan for statistical analysis 
The planned sample size of 30 SSc participants is based on practical 
considerations to obtain estimates of the magnitude of treatment differences 
for efficacy and safety rather than a desired power for a pre- specified 
difference.   
 
From similar studies on Rheumatoid Arthritis and Systemic Lupus 
Erythematosus, the improvement of T-score after treatment is about 5.  The 
standard deviation for general population is 10. However, we are restricting 
our population to participants with fatigue T-scores of less than 54 (with low 
score indicating high fatigue).  With the range of T-score reduced about half, 
we expect the standard deviation to be about 5.  The effect size is expected to 
be 1 (5/5).   
 
Using paired t-test,  we have 86% power to detect the effect size of 1 when we 
recruit 30 patients at a significance level of 0.05.  We asked the IRB for the 
option of increasing the number of patients to 40, which will give us about 
81% power to detect a smaller effect size of 0.8 at a significance level of 0.05.  
 
Descriptive statistics will be derived for all clinical variables, mean and 
standard deviation for continuous outcomes and percentages for categorical 
and dichotomous variables.  
 
The primary outcome of interest is fatigue, as measured by the FACIT-
Fatigue. We will compare the mean change from baseline and four weeks in a 
repeated measures model.   
 
 
The p-values resulting from formal statistical tests will be interpreted from a 
hypothesis-generating, rather than a confirmatory framework. 
 

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Table of contents 
1. Introduction ........................................................................................................................ 9 
1.1 Background ......................................................................................................................... 9 
1.1.1 
Scleroderma (systemic sclerosis)................................................................................... 9 
1.1.2 
Fatigue in systemic sclerosis 
1.2 
The Apollo Device ......................................................................................................... 11 
1.3 
Rationale of the Study 
1.4 
Benefit-risk assessment................................................................................................... 11 
2. Study objectives ................................................................................................................ 12 
2.1 Secondary objectives ........................................................................................................ 12 
3. Investigators...................................................................................................................... 13 
4. Study design ...................................................................................................................... 14 
4.1 Design overview ................................................................................................................ 14 
4.1.1 
Screening phase (up to 2 weeks) ................................................................................. 15 
4.1.2 
Double-blind Treatment phase (Week 0 to Week 16) ................................................. 16 
4.1.3 
Open-Label Extension phase (OLE)............................................................................ 17 
4.1.4 
Early Termination Visit and Safety Follow-up Visit ................................................... 18 
5. Study population .............................................................................................................. 18 
5.1 Eligibility ........................................................................................................................... 18 
5.1.1 
Inclusion criteria .......................................................................................................... 18 
5.1.2 
Exclusion Criteria ........................................................................................................ 19 
5.1.3 
Justification of selection criteria .................................................................................. 20 
5.2 Withdrawal of participants from study ......................................................................... 21 
5.2.1 
Withdrawal .................................................................................................................. 21 
6. Treatment ......................................................................................................................... 22 
6.1 Treatments to be administered ....................................................................................... 22 
6.2 
Identity of study treatment .............................................................................................. 23 
6.3 
Treatment assignment ..................................................................................................... 24 
6.4 Dosage and administration .............................................................................................. 24 
6.4.1 
Selection of doses in the study .................................................................................... 24 
6.4.2 
Special populations ..................................................................................................... 24 
6.5 Blinding .............................................................................................................................. 25 
6.6 
Treatment compliance ..................................................................................................... 26 
6.7 
Post-study therapy .......................................................................................................... 26 
6.8 
Prior and concomitant therapy ........................................................................................ 26 
7. Procedures and variables ................................................................................................ 27 

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7.1 Schedule of events ............................................................................................................ 27 
7.1.1 
Schedule of Events ...................................................................................................... 29 
7.1.2 
Timing of assessments ................................................................................................. 31 
7.1.2.1 
Visit 0 − Screening ................................................................................................... 31 
7.1.2.2 
Visit 1 − Baseline (Day 0, Week 0) – Double-Blind Treatment Phase .................... 31 
7.1.2.3 
Visits 2  (end of study) ............................................................................................ 32 
7.1.2.4 
Unscheduled visit ..................................................................................................... 33 
7.2  Population characteristics ............................................................................................... 34 
7.2.1 
Demographic ............................................................................................................... 34 
7.2.2. 
Medical history ............................................................................................................ 35 
7.3 
Efficacy ........................................................................................................................... 35 
7.4 
Pharmacokinetics / pharmacodynamics .......................................................................... 36 
7.5 Safety ................................................................................................................................. 36 
7.5.1 
Adverse events ............................................................................................................ 36 
7.5.1.1 
Definitions ................................................................................................................ 36 
7.5.1.2 
Classifications for adverse event assessment ........................................................... 38 
7.5.1.2.1 
Seriousness ............................................................................................................ 38 
7.5.1.2.2 
Intensity ................................................................................................................ 38 
7.5.1.2.3 
Causal relationship ................................................................................................ 38 
7.5.1.2.4 
Action taken with study treatment ........................................................................ 39 
7.5.1.2.5 
Other specific treatment(s) of adverse events ....................................................... 39 
7.5.1.2.6 
Outcome ................................................................................................................ 40 
7.5.1.3 
Assessments and documentation of adverse events ................................................. 40 
7.5.1.4 
Reporting of serious adverse events ......................................................................... 40 
7.5.1.5 
Expected adverse events........................................................................................... 41 
7.5.1.6 
Adverse events of special safety interest.................................................................. 41 
7.5.1.7 
Overdose of Study Medication ................................................................................. 41 
7.5.2 
Pregnancies .................................................................................................................. 41 
7.6 Other procedures and variables ..................................................................................... 41 
7.6.1 
Pregnancy testing ........................................................................................................ 41 
7.6.2 
Laboratory parameters ................................................................................................. 42 
7.6.3 
Exploratory Biomarkers .............................................................................................. 42 
7.6.4 
Blood pressure and heart rate measurement ................................................................ 42 
7.6.5 
Digital ulcer net burden ............................................................................................... 42 
7.6.6 
Digital Gangrene ......................................................................................................... 43 
7.6.7 
Raynaud’s attacks assessment ..................................................................................... 43 
7.6.8 
Patient-Reported Outcomes (PROs) / Health-Related Quality of Life (HRQoL) 
questionnaires .............................................................................................................. 43 
7.6.9 
Participant and Physician Global Assessment ............................................................. 44 
8. Statistical methods and determination of sample size ................................................... 44 
8.1 General considerations .................................................................................................... 44 
8.2 Analysis sets ...................................................................................................................... 45 

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8.3 
Statistical and analytical plans ........................................................................................ 45 
8.3.1 
Demographic and other baseline characteristics .......................................................... 45 
8.3.2 
Efficacy ....................................................................................................................... 45 
8.3.3 
Safety ........................................................................................................................... 46 
8.4 
Planned interim analyses................................................................................................. 46 
8.5 
Determination of sample size.......................................................................................... 46 
8.6 
Data recording ................................................................................................................ 47 
8.7 
Monitoring ...................................................................................................................... 47 
8.8 
Archiving ........................................................................................................................ 47 
9. Premature termination of the study ............................................................................... 48 
10. Ethical and legal aspects .................................................................................................. 49 
10.1 Ethical and legal conduct of the study ............................................................................ 49 
10.2 Compensation for health damage of participants / insurance.......................................... 49 
11. Appendices ........................................................................................................................ 49 
11.1 Child-Pugh Classification of Liver Disease .................................................................... 49 
11.2 Digital Ulcer Care Protocol ............................................................................................ 50 
12. References ......................................................................................................................... 51 

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1. 
Introduction 
 
1.1 
Background 
 
1.1.1 
Scleroderma (systemic sclerosis) 
 
Systemic sclerosis (SSc) is an uncommon, multisystem autoimmune disease characterized by small 
vessel vasculopathy, immune system activation with autoantibody production and fibroblast 
dysfunction leading to increased deposition of extracellular matrix. 
 
SSc is an orphan disease with an incidence of nearly 20 patients per million per year (1,2) and an 
estimated point prevalence of approximately 250 per million based on US studies (2).   SSc is a 
female-predominant disease, affecting women three to four times more often than men.   SSc may 
affect individuals of all ages, with the peak incidence occurring between 45 and 64 years of age 
(2).   
 
The hallmark of SSc is cutaneous and visceral fibrosis, which is reflected in the commonly used 
term for the disease, scleroderma, which derives from the Greek ‘scleros’ meaning thick and 
‘derma’ referring to skin. While the cutaneous manifestations are the most obvious, it is the 
vascular and internal organ manifestations that contribute most importantly to disease morbidity 
and mortality. 
 
SSc is described as two primary clinical subsets based on the extent of skin thickening: diffuse 
and limited cutaneous disease.  Patients with limited skin disease have no skin thickening or skin 
thickening limited to the distal extremities (below the elbows and knees, but may have thickness 
of the face). Diffuse cutaneous patients experience similar distal changes, but also develop skin 
thickening proximal to the elbows and knees (upper arms, thighs, trunk) during the disease 
course.  This clinical classification is useful as the natural history of the disease is different 
between the clinical subsets.  Diffuse SSc patients develop progressive skin thickening and 
internal organ involvement early in their disease (first 2-3 years).  The natural history of diffuse 
SSc skin thickening is that it may slowly improve over time even if untreated.  Patients with 
limited SSc tend to develop no or minimal progressive skin changes over time, but may develop 
new internal organ involvement (particularly vascular complications) years into their disease.    
 
Of the connective tissue diseases, SSc has the highest case specific mortality (3).   Published 
estimates of mortality consistently report lower survival in the diffuse cutaneous SSc subtype 
compared to the limited SSc subtype (4-7). 
 
SSc has a strong association with morbidity, disability and cost.   Just over twenty years ago 
(1997) Wilson estimated the combined direct and indirect cost of care for SSc patients to be 1.46 
billion dollars annually in the US (8).  In 2015 a study performed in France assessed the average 
annual cost of SSc per patient to be 22,459 Euros (25,193 USD) (9).  Of this, 10,526 Euros 
(11,807 USD) was an indirect cost due to an average SSc patient’s absence from the labor market.   
 
1.1.2 
Fatigue in SSc 
 
Fatigue is defined as an abnormal bodily tiredness that is disproportionate to activity and unrelieved 
by rest. The term can be used to describe difficulty or inability to initiate activity (subjective sense 
of weakness); reduced capacity to maintain activity (easy fatigability); or difficulty with 
concentration, memory, and emotional stability (mental fatigue) (10). Subacute and chronic fatigue 
are common in many rheumatologic conditions, like fibromyalgia, polymyalgia rheumatica, 

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systemic lupus erythematosus, rheumatoid arthritis, and Sjögren's syndrome (11).  
 
SSc patients frequently have fatigue as a characteristic feature of their disease and fatigue negatively 
impacts quality of life (12-15). The prevalence of fatigue among SSc patients is 75%, with 61% 
ranking fatigue among their top three most distressing complaints. Fatigue is also associated with 
poor sleep quality, greater pain and depressive symptoms (16).  
 
SSc patients, have a prevalence of fatigue that is significantly higher than the general population and 
similar to patients with rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, 
and current cancer treatment (17). Fatigue has been identified as one of the main factors negatively 
affecting well-being (18) and it’s been associated with fewer visits to doctors (19). Fatigue is one of 
the main predictors (20, 21) of work disability in SSc patients. Correlations have been shown 
between fatigue and high scores on two different depression scales that have been validated in SSc 
patients, the Patient Health Questionnaire (PHQ-9) and the Center for Epidemiologic Studies 
Depression Scale (CES-D) (22).  
 
Fatigue’s recalcitrance to treatment in SSc patients has been shown in multiple longitudinal studies 
of symptom change over time (23-25). In a two-year longitudinal study of scleroderma patients’ 
change in patient reported outcomes (PROs), fatigue worsened more than the other PROs, which 
included pain, sleep, disability and global health (26).  
 
Treatment options for chronic fatigue are limited and the prognosis is not favorable (27). When the 
underlying medical cause of fatigue cannot be treated, treatment options include Cognitive 
Behavioral Therapy (CBT) and exercise (28, 29). If SSc patients exhibit depressive symptoms, 
treatment can involve an empiric trial of antidepressants (30). A systematic review of chronic 
fatigue’s prognosis found that less than 10% of participants returned to pre-morbid levels of 
functioning, 10-20% worsened, and most remained significantly impaired. Risk factors for fatigue’s 
poor prognosis are often present in SSc patients, and include older age, more chronic illness, having 
a comorbid psychiatric disorder and holding a belief that the illness is due to physical causes (21).  
 
1.2 
The Apollo Device  
 
The Apollo System offers a convenient novel non-invasive, non-habit-forming wearable solution to 
improve performance and recovery under stress in children and adults by delivering gentle wave-
like vibrations to the body that improve autonomic nervous system tone in near real time (Siegle & 
Rabin et al., under review). Apollo is about the size of an Apple Watch and can be worn on the 
ankle, wrist, or arm with two adjustable fabric straps. Apollo vibrations activate touch receptors in 
the skin and are perceived as safety signals by the brain resulting in decreased stress, improved 
recovery, focus, and energy.  
 
In addition to the wearable, Apollo is a software system that curates music for the body, rather than 
for the ears. The scientific principles guiding the use of Apollo and our mechanistic understanding 
of its effects on the body are consistent with our understanding of how music and therapeutic touch 
effect the body to convey feelings of energy, focus, or relaxation by sending safety signals to the 
emotional cortex (limbic system) in the brain. Similar to music and touch used to facilitate a healing 
response in the body, there are no known side effects to this type of therapy.  
 
Prior studies of Apollo have demonstrated significant improvements in fatigue and energy in healthy 
subjects in the real world as well as in subjects with chronic illnesses in clinical trials of Apollo 
within just a few days of use. Early findings strongly suggest that by improving autonomic tone, 
Apollo is attenuating biomarkers of persistent unwanted sympathetic activity, such as low heart rate 
variability (HRV), that over time, correlate with worse prognoses in many chronic illnesses. Low 
HRV is also a predictive factor in fatigue and poor energy recovery. Not only has Apollo been 
demonstrated to improve HRV and decrease heart rate, respirations, blood pressure, and other 

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markers of stress when threat is misappropriated, but it also appears to be inducing Meyer wave 
patterns in the vasculature (study data under analysis), which are known to correspond with nitric 
oxide release. As such, there is significant reason to believe that Apollo will improve symptoms of 
fatigue, inflammation, and vascular dysfunction in subjects with SSc.  
 
 
The gentle vibrations delivered by the Apollo System are extremely low intensity in that they are 
typically just barely noticeable or perceptible by the user. From >2000 use cases in subjects ages 4-
95yo, there have been no reported adverse events. Additionally, the range of frequencies and 
intensities of the Apollo System have been safely used in numerous commercial products without 
adverse events reported. Consistent with learning effects observed in meditation and mindfulness 
practices on the autonomic nervous system, Apollo case study participants report that continued use 
of Apollo results in quicker onset and longer duration of benefit. As such, there is significant 
potential benefit to be gained by the subjects and non-significant risk in the use of this technology in 
this study, as was also deemed to be the case in all of the prior approved IRBs for studies of Apollo. 
The devices tested in this study are commercially available Apollo wearables, built to FDA 
regulatory requirements and HIPAA compliance. 
 
The wearable device used in this and other clinical studies of Apollo has a button on it that can 
always be engaged by the subject at any time to turn the Apollo vibrations off or back on within less 
than a second. The wearable can also be controlled by the Apollo mobile app that will be installed 
on the subjects’ mobile smartphones. As such, the locus of control is always in the hands of the 
subject, providing significantly more autonomy to patients in treatment, which is one healing aspect 
of the Apollo System. 
 
1.3 
Rationale of the study 
Fatigue is the symptom ranked highest by SSc patients as affecting quality of life.   Thus, any 
device, therapy or pharmacologic products that could improve fatigue may have great potential 
benefit with respect to the quality of life associated. 
 
1.4 
Benefit-risk assessment 
 
There are currently no disease-specific pharmacotherapies or devices approved for systemic 
sclerosis in the US.  Management of the disease and its symptoms are clearly an area of unmet 
need.  Thus, the potential for benefit is high.    
 
The risks associated with the Apollo system are primarily associated with discomfort in wearing 
the wrist or ankle band.  The design of this pilot and feasibility study is such that the participant 
determines use, and they have the option to stop at any time.  Therefore, the level of risk is 
minimal. 
 
Risk of breach of confidentiality: All study data collected via the Apollo HIPAA-compliant mobile 
app will be de-identified and registered to a specific study email account that is not linked to any 
identifiable information from the user.  All paper documents (including consent forms)will be kept 
in a locked filing cabinet inside of a locked office. In addition, an ongoing review of study 
procedures will be done to ensure that the privacy of subjects and confidentiality of data is not 
violated. All data will be deidentified with a password protected master list as the only linkage 
between names and subject identification numbers. Consent forms, as well as any forms with 
identifiable information listed will be kept in a locked filing cabinet, separately from each subjects 
deidentified experimental and interview data. All electronic data collected will be accessible 
only with a password that is provided to clinical study staff and those individuals responsible for 
collection, maintaining data integrity and analysis. After the retention period is over, all study 
records will be de-identified and the linkage codes master lists will be destroyed. Study 
records will be kept secure under double lock in an office space devoted to long-term 

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retention of data for the purposes of maintaining scientific integrity. 
 
The Apollo system has been tested and independently validated by individual members of a number 
of different institutions in the military and many Veterans, several academics at Universities, >10 
elite athletics clubs, in pediatric clinics, nursing homes, as well as in two University of Pittsburgh 
clinical trials with 6 more trials currently underway. The Company has over 2000 beta testers and 
has conducted over 500 long-term case studies with consistent results. The technology proposed 
here has also been tested in children (as young as age 4), geriatric users, and other extremely 
vulnerable populations (such as those with treatment-resistant PTSD) without any reported adverse 
reactions. 
 
Participants will be informed about any and all potential risks. There are no known long-term risks 
to the subjects from any of the study procedures, which have been used safely on 
thousands of men, women, and children. All study personnel examine screening materials 
before asking the participant to engage in any of the study activities in order to minimize the risks 
associated with the study procedures. If any additional physiological or mental health conditions are 
revealed during the screening or enrollment, they will be discussed individually with the clinical 
team (Dr. Domsic et al.) prior to officially enrolling the subject in the study. If results are best 
discussed with the participant's physician, the participant will be offered the opportunity to complete 
a release of information form allowing Dr. Domsic to contact the participant's physician directly.  
 
 
2. 
STUDY OBJECTIVES 
 
The primary objective of this study is to provide preliminary data on the efficacy and 
tolerability of the Apollo device in the management of fatigue in SSc. 
 
The primary efficacy outcome is the change from baseline to four weeks of intervention using the 
Apollo system in the PROMIS-Fatigue scale.  This instrument that has been previously validated in 
multiple diseases.    
 
2.1 
Secondary objectives 
 
The secondary objectives of this study are to provide preliminary data on indices of depression, 
health-related quality of life, Raynaud symptoms and tolerability/frequency of use with the Apollo 
device in SSc.   
 
Specific secondary objective measures include:    
 
• Depression, measured by the QUIDS-SR (16 item) score.  
• Health-related quality of life (HRQOL) using PROMIS-29 
• HAQ-DI 
• Visual analog scales from scleroderma-health assessment questionnaire (SHAQ) 
assessing burden of digital ulcers, Raynaud’s disease, gastrointestinal involvement, 
breathing, and overall disease 
• Improvement of Raynaud’s phenomenon (RP) (7, 8) 
o Raynaud’s condition score 
o Raynaud visual analog scale 
o Patient and physician assessment of RP; pain, numbness, and tingling 
o RP frequency and duration of attacks based on one-day use of the Raynaud 
application used at baseline and two weeks.    
•  
 

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3. 
INVESTIGATORS and PERSONNEL 
 
Role: 
Name and 
Contact 
Information: 
Telephone: 
Email: 
Investigator 
Robyn T. Domsic, MD, MPH  
University of Pittsburgh School of Medicine 
S707 Biomedical Science Tower 
200 Lothrop Street 
Pittsburgh, PA 15213 
 
+1 (412) 383-8000 
rtd4@pitt.edu 
Role: 
Name and 
Contact 
Information: 
Telephone: 
Email: 
Research coordinator 
Maureen Laffoon, BA 
University of Pittsburgh School of Medicine 
S707 Biomedical Science Tower 
200 Lothrop Street 
Pittsburgh, PA 15213 
+1 (412) 383-8000 
laffoonm@pitt.edu 
Role:   
Name and 
Contact 
Information:  
Graduate student / research assistant 
Krista Hammaker  
 

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Data Safety and Monitoring Plan 
 
A data and safety monitoring plan will be implemented by the Principal Investigator to ensure that 
there are no changes in the risk/benefit ration during the course of the study and that 
confidentiality of research data is maintained. Each member of the study team will meet with the 
PI and review confidentiality issues and complete a confidentiality agreement, prior to having 
contact with research subjects. Investigators and study personnel will meet every 2 months to 
discuss the study (e.g. study goals and modifications of those goals; subject recruitment and 
retention; progress in data coding and analysis; documentation, identification of adverse events or 
research subject complaints; violations of confidentiality) and address any issues or concerns at 
that time. Minutes will be kept for these meetings and will be maintained in the study regulatory 
bonder. Any instances of adverse events will be reported immediately to the University of 
Pittsburgh IRB. The IRB renewal for this study will include a summary report of the Data and 
Safety Monitoring Plan findings from prior renewal period.  
 
4. 
STUDY DESIGN 
 
4.1 
Design overview 
 
This clinical trial is a single-center, open-label, single-arm study of 30 individuals with SSc and 
fatigue.   
 
The study will allow for subjects to continue standard of care medications for the management 
of SSc as background therapy.  
 
The study design consists of a single, four-week intervention.  The screening and baseline visits 
can be combined when the screening is not able to be performed over the phone in advance.   
 
• Screening phase: up to 4 weeks prior to baseline visit 
 
• Observation period:  During this one week phase participants will track their daily 
Raynaud attack frequency and duration using a diary.  This will occur in the seven days 
preceding the baseline intervention phase.   
 
• Open-label intervention phase:  This consists of a four-week period during which 
participants will use the Apollo wearable system as needed to manage symptoms 
including fatigue. During the intervention phase participants may use the wearable at 
their discretion and control.  Participants will track their daily Raynaud attack frequency 
and duration using a diary during week 4 of Apollo use.  Participants will complete 
questionnaires on day 1 of the open-label and intervention phase, and at their follow-up 
four weeks later.    
 
 
4.1.1 
Screening phase (up to 4 weeks prior to baseline visit) 
 
After providing written informed consent, participants will undergo a screening evaluation to 
determine their eligibility (see Section 7.1 for a detailed schedule of events).  Participants will 
complete the PROMIS-Fatigue scale to determine if they have moderate to severe fatigue.  If a T 
score of 45 is obtained, and all inclusion criteria are met, then the patient may proceed to the 
observation phase.   Participants will be given the 7-day diary to be completed starting one week 
prior to their scheduled baseline visit.  They will be reminded be telephone call or text (based on 

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their preference) to begin their diary collection.  
 
4.1.2 
Intervention Phase 
At the baseline visit, participants who have met all of the inclusion criteria.  At this visit they will 
complete the following questionnaires:  
1) PROMIS-fatigue 
2) PROMIS-29  
3) The QUIDS-SR 
4) HAQ-DQ with SHAQ 
5) Raynaud condition score, Raynaud visual analog scale and digital ulcer visual analog 
scale 
 
 
They will then be provided the wearable Apollo system device.  They will download the mobile 
application, and be taught how to install it and use it to control the wearable Apollo device by 
the research coordinator(s).  Any questions will be answered at this time.  Participants will be 
able to use the device from the time they leave the visit.  Use of the device will be entirely at the 
subject’s control.    
 
In the week prior to their end-of-study visit, participants will complete a daily diary collection of 
Raynaud attack episodes and symptoms using the paper diary form.  This will be provided prior to 
leaving the baseline visit.    
 
Participants will be sent a reminder call or text the day before and day they are to begin their diary 
collection on one week prior to their scheduled end-of-study visit.     
 
4.1.3 
Early Termination  
If participants choose to discontinue using the device, they may remain in the study, and will be 
requested to return for the four-week follow-up visit and complete all questionnaires.   
 
5. 
Study population 
 
5.1 Eligibility 
 
5.1.1 
Inclusion criteria 
 
Participants must meet the following criteria to be eligible for enrollment in the study: 
 
1. 
Signed written informed consent 
2. 
Men or women aged 18 years and older 
3. 
Diagnosis of Systemic sclerosis, as defined by 2013 American College of 
Rheumatology/ European Union League Against Rheumatism classification of 
SSc.   
4. 
Baseline T score of 45 on the PROMIS-Fatigue scale. 
5. 
Steady daily doses and any immunosuppressive medication, vasodilators, 
antidepressants and anxiolytic use for 4 weeks prior to baseline. 
6. 
Currently owns and operates an iOS or Android smart phone regularly  
7. 
Ability to comply with the clinical visits schedule and the study-related procedures. 
8. 
Subjects who have struggled with symptoms of SSc (specifically fatigue and 
Raynauds) who have not received adequate symptom relief from prior treatment 
attempts (treatment-resistant) will be prioritized. 
9. 
 
 
5.1.2 
Exclusion Criteria 

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Participants who meet any of the following criteria will be excluded from enrollment in the 
study: 
 
 
1. Medical and surgical history 
• Major surgery within 8 weeks prior to screening 
• Participants with an active malignancy. 
• End-stage renal disease with an estimated glomerular filtration rate 
(eGFR) < 15 mL/min/1.73m2 (MDRD formula) or on dialysis at the 
screening visit 
• Hepatic insufficiency as defined by the Child-Pugh criteria 
• Hospitalization for any reason within four weeks of the study baseline visit.  
• History of sympathectomy or stellate ganglion block 
• Significant interstitial lung disease with FVC ≤ 50% of predicted, or 
DLCO (uncorrected for hemoglobin) ≤ 40% of predicted 
• Pulmonary hypertension with change in medications in the preceding 
four weeks   
• Actively prescribed standing doses of beta-blockers. 
• Actively prescribed standing doses of sedatives, hypnotics, opioids, or 
benzodiazepines.  
• Active or unstable psychotic disorder requiring current prescriptions of 
standing doses of antipsychotic medications 
• Active suicidal/homicidal ideation or a suicide or homicide attempt in 
the past year. 
2. Pregnant or breastfeeding women 
3. Other 
• Any other condition or therapy that would make the participant unsuitable for this 
study and will not allow participation for the full planned study period 
 
5.1.3 
Justification of selection criteria 
 
The selection criteria were carefully selected to exclude participants from the study who may have 
another significant underlying medical condition contributing to fatigue.   
 
5.2 
Withdrawal of participants from study 
 
5.2.1 
Withdrawal 
 
Participants may be withdrawn from the study at their own request or at the request of their legally 
acceptable representative. At any time during the study and without giving reasons, a participant 
may decline to participate further.  
 
6. 
Intervention 
 
6.1 
Intervention to be administered 
 
The Apollo System offers a convenient novel non-invasive, non-habit-forming wearable solution 
to improve performance and recovery under stress in children and adults by delivering gentle 
wave-like vibrations to the body that improve autonomic nervous system tone in near real time 
(Siegle & Rabin et al., under review). Apollo is about the size of an Apple Watch and can be worn 
on the ankle, wrist, or arm with two adjustable fabric straps. Apollo vibrations activate touch 
receptors in the skin and are perceived as safety signals by the brain resulting in decreased stress, 

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improved recovery, focus, and energy.  
 
In addition to the wearable, Apollo is a software system that curates music for the body, rather than 
for the ears. The scientific principles guiding the use of Apollo and our mechanistic understanding 
of its effects on the body are consistent with our understanding of how music and therapeutic touch 
effect the body to convey feelings of energy, focus, or relaxation by sending safety signals to the 
emotional cortex (limbic system) in the brain. Similar to music and touch used to facilitate a 
healing response in the body, there are no known side effects to this type of therapy.  
 
Prior studies of Apollo have demonstrated significant improvements in fatigue and energy in 
healthy subjects in the real world as well as in subjects with chronic illnesses in clinical trials of 
Apollo within just a few days of use. Early findings strongly suggest that by improving autonomic 
tone, Apollo is attenuating biomarkers of persistent unwanted sympathetic activity, such as low 
heart rate variability (HRV), that over time, correlate with worse prognoses in many chronic 
illnesses. Low HRV is also a predictive factor in fatigue and poor energy recovery. Not only has 
Apollo been demonstrated to improve HRV and decrease heart rate, respirations, blood pressure, 
and other markers of stress when threat is misappropriated, but it also appears to be inducing 
Meyer wave patterns in the vasculature (study data under analysis), which are known to 
correspond with nitric oxide release. As such, there is significant reason to believe that Apollo will 
improve symptoms of fatigue, inflammation, and vascular dysfunction in subjects with SSc.  
 
Storage requirements: 
 
All wearable devices not in use during the trial will be stored at the investigational sites at room 
temperature in a place inaccessible to unauthorized personnel, i.e. in a locked cabinet.  No 
special storage conditions are required. 
 
6.2 
Treatment assignment 
 
This is an open-label, single-arm trial.  No randomization or blinding will occur.    
 
6.4.3 
Special populations 
The Apollo wearable has been used in a wide array of populations.    No adjustments need to be 
made in use or instructions.  
 
 
6.5 
Device use and compliance 
 
The Apollo system including wearable hardware and software will track each subjects’ use of 
Apollo throughout the study. This usage data will be stored in HIPAA-compliant manner and 
linked to a de-identified study subject ID number.  
 
If a participant reduces or stops use of the Apollo wearable, this data will be recorded.  The 
participant will still complete the two week (end of study) visit and assessment as planned.  
 
7. 
Procedures and variables 
 
7.1 
Schedule of events 
 
Please refer to the table in Section 7.1.1 for the schedule of events. 
Study Visit 
Screening 
Visit 0 
Observation 
(seven day prior to  
baseline) 
Baseline 
Visit 1 
Week 4 
Visit 2 
Window (days): 
 
 
+/ 
28 +/- 3 days 

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Type of Contact: 
Office 
Home 
Office 
Office 
Informed consent 
X 
 
 
 
Eligibility assessment 
X 
 
 
 
Demographics, including 
smoking & alcohol history 
X 
 
 
 
Complete medical history 
X 
 
 
 
Prior/Concomitant therapy 
X 
 
X 
X 
Vitals 
 
 
X 
X 
Physical examination 
 
 
X 
 
PROMIS-Fatigue short form 
X 
 
X 
X 
Physician’s Global Assessment 
 
 
X 
X 
Patient’s Global Assessment 
 
 
X 
X 
PROMIS -29 
 
 
X 
X 
HAQ-DI/SHAQ 
 
 
X 
X 
QUIDS-SR 
 
 
X 
X 
Raynaud and digital ulcer VAS 
 
 
X 
X 
Raynaud’s phenomenon diary 
 
 
Xc 
X 
Assess for Adverse Events 
 
 
X 
 
 
Timing of assessments 
 
If not stated otherwise, all assessments and procedures will be performed by or under the 
supervision of an investigator. 
For timing of assessments and procedures, please refer to Section 7. 
 
7.1.2.1 
Visit 0 – Screening 
 
Screening evaluations will be performed only after the participant has provided written informed 
consent.  The following evaluations will be performed and information obtained up to 28 days 
before the baseline visit.    
 
• Participant information and obtaining of written informed consent 
• Eligibility:  Assessment of inclusion and exclusion criteria (see Section 5.1) 
• Demographic data, including sex, race, ethnic group, year of birth, smoking history and 
alcohol consumption 
• Medical and surgical history 
• Prior and concomitant therapy 
• Medication history 
 
7.1.2.2 
Visit 1 – Baseline  
 
The following assessments will be performed at the Baseline visit  
 
• Reconfirmation of eligibility 
• PROMIS-fatigue scale administered 
• Patient reported outcomes (QUIDS-SR, patient global assessment, PROMIS-29, HAQ- 
D1/SHAQ, visual analong scales) and physician global assessment 
• Vital signs (blood pressure and heart rate). The blood pressure is measured in a sitting 

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position after the participant has been at rest for at least 5 minutes. The same arm is always 
used for these measurements 
• Digital ulcer assessment 
• Assessment of Raynaud attacks – participant provided the one-day diary and RCS to 
complete the day following the screening 
• Recording and assessment of AEs (see Section 7.5.1.3) 
• Downloading of the mobile application and teaching of how to use the Apollo wearable 
device.  The participants will be allowed to use it up to 30 minutes to familiarize 
themselves with the working of the device while at this visit.   
 
7.1.2.3 
Visits 2  (28 days + 3 days from the baseline) 
• PROMIS-fatigue scale administered 
• Patient reported outcomes (QUIDS-SR, patient global assessment, PROMIS-fatigue, 
PROMIS-29, HAQ- D1/SHAQ, visual analog scales) and physician global assessment 
• Vital signs (blood pressure and heart rate).  
• Assessment of Raynaud attacks – diary will be collected.  
• Recording and assessment of AEs (see Section 7.5.1.3) 
• Digital ulcer assessment 
 
7.1.2.4 
Unscheduled visit 
 
Should participants report any difficulty or unexpected issues using the Apollo system at 
home, they will be able to contact research study staff to arrange for technical support or  
for an unscheduled (UNSCH) visit to the clinic for additional assistance.  Technical 
support from study staff will be available to subjects within 24 hours of contacting study 
staff. Subjects will be provided with an email address and phone number for study staff 
upon enrollment in the study. 
 
7.2 
Population characteristics 
 
7.2.1 
Demographic 
 
The following demographic data will be recorded: 
 
• Date of birth (age) 
• Sex 
• Race and Ethnicity 
• Alcohol consumption 
• Smoking History 
• Level of Education 
 
7.2.2. 
Medical history 
 
A 12-month medical record review will be requested from each subject prior to entering into 
the study. Medical history findings (i.e., previous diagnoses, diseases or surgeries, 
medications, etc) meeting all criteria listed below will be collected: 
 
• Considered relevant to the study 
• Medical history related to concomitant therapy 
 
7.3 
Efficacy 
 

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Primary efficacy outcome measure: 
 
• Change from baseline to end of study on the PROMIS-Fatigue scale.   
 
Secondary efficacy measures during double-blind period: 
 
• HRQOL using PROMIS-29 
• Physical function as assessed by HAQ-DI, and HDISS-DU 
• Visual analog scales from scleroderma-health assessment questionnaire (SHAQ) 
assessing burden of digital ulcers, Raynaud’s disease, gastrointestinal involvement, 
breathing, and overall disease 
• QUIDS-SR 
• Improvement of Raynaud’s phenomenon 
o Raynaud’s condition score 
o Number of Raynaud’s attacks/day 
o Patient and physician assessment of RP; pain, numbness, and tingling during an 
RP attack; and duration of attacks 
• Patient’s and physician’s global assessment on a Likert scale 
•  
7.5 
Safety 
 
7.5.1 
Adverse events 
The Apollo system has been tested and independently validated by individual members of a 
number of different institutions in the military and many Veterans, several academics at 
Universities, >10 elite athletics clubs, in pediatric clinics, nursing homes, as well as in two 
University of Pittsburgh clinical trials with 6 more trials currently underway. The Company has 
over 2000 beta testers and has conducted over 500 long-term case studies with consistent results. 
The technology proposed here has also been tested in children (as young as 4yo), geriatric users, 
and other extremely vulnerable populations (such as those with treatment-resistant PTSD) without 
any reported adverse reactions. 
 
Participants will be informed about any and all potential risks. There are no known long-term risks 
to the subjects from any of the study procedures, which have been used safely on 
thousands of men, women, and children. All study personnel examine screening materials 
before asking the participant to engage in any of the study activities in order to minimize the risks 
associated with the study procedures. If any additional physiological or mental health conditions 
are revealed during the screening or enrollment, they will be discussed individually with the clinical 
team (Dr. Domsic et al.) prior to officially enrolling the subject in the study. If results are best 
discussed with the participant's physician, the participant will be offered the opportunity to 
complete a release of information form allowing Dr. Domsic to contact the participant's physician 
directly. 
 
Should any adverse events be detected/reported/observed by subjects or study staff, subjects may 
easily discontinue use of the Apollo system immediately either by: 
1) Turning the wearable off with the buttons on the device or 
2) Removing the wearable from their body 
 
 
7.5.1.1 
Definitions 
Definition of adverse event 
(AE) 

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In a clinical study, an AE is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation participant after providing written informed consent for participation in the 
study.  Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
 
A surgical procedure that was planned prior to the start of the study by any physician treating the 
participant should not be recorded as AE (however, the condition for which the surgery is 
required may be an AE). 
 
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal physical examination findings, symptoms, diseases, laboratory results, and 
ECG findings. 
 
• Conditions that started before signing of informed consent and for which no symptoms or 
treatment are present until signing of informed consent are recorded as medical history 
(e.g., seasonal allergy without acute complaints). 
• Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history (e.g., allergic pollinosis). 
• Conditions that started or deteriorated after signing of informed consent will be 
documented as AEs. 
 
Definition of serious adverse event (SAE) 
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f): 
 
a. Results in death 
 
b. Is life-threatening 
 
The term ‘life-threatening’ in the definition refers to an event in which the participant 
was at risk of death at the time of the event, it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
 
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if at 
least one of the following exceptions is met: 
 
- 
The admission results in a hospital stay of less than 12 hours 
- 
The admission is pre-planned 
(i.e., elective or scheduled surgery arranged prior to the start of the study) 
- 
The admission is not associated with an AE 
(e.g., social hospitalization for purposes of respite care). 
 
However, it should be noted that invasive treatment during any hospitalization may fulfill 
the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment.  In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence. 
 
d. Results in persistent or significant disability / incapacity 
 

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Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions. 
 
e. Is a congenital anomaly / birth defect 
 
f. Is another medically important serious event as judged by the investigator 
 
7.5.1.2 
Classifications for adverse event assessment 
 
All AEs will be assessed and documented by the investigator according to the categories detailed 
below. 
 
7.5.1.2.1 Seriousness 
 
For each AE, the seriousness must be determined according to the criteria given in Section  
7.5.1.1 . 
7.5.1.2.2 Severity 
 
The severity of an AE is classified according to the following categories: 
- 
Grade 1 Mild 
- 
Grade 2 Moderate 
- 
Grade 3 Severe 
- 
Grade 4 Very Severe 
- 
Grade 5 Death 
 
7.5.1.2.3 Causal relationship 
 
The assessment of the causal relationship between an AE and the administration of treatment is a 
clinical decision based on all available information at the time of the completion.  The 
assessment is based on the question whether there was a “reasonable causal relationship” to the 
study treatment in question. 
 
Possible answers are “Related” or “Not Related” An assessment of “Not Related” would include: 
 
1. The existence of a clear alternative explanation, or  
2. Non-plausibility, e.g., the participant is struck by an automobile when there is no 
indication that the drug caused disorientation that may have caused the event; cancer 
developing a few days after the first drug administration. 
 
An assessment of “Related” indicates that there is a reasonable suspicion that the AE is 
associated with the use of the study treatment. 
 
Important factors to be considered in assessing the relationship of the AE to study treatment 
include: 
 
- 
The temporal sequence  
- 
Recovery on discontinuation (de-challenge), recurrence on drug re-introduction (re- 
challenge): 
- 
Underlying, concomitant, intercurrent diseases: 
- 
Concomitant medication or treatment: The other drugs the participant is 
taking or the treatment the participant receives should be examined to determine 
whether any of them may be suspected to cause the event in question. 

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Causal relationship to protocol-required procedure(s) 
 
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s). 
 
Possible answers are “yes” or “no” 
 
7.5.1.2.4 Action taken with study treatment 
 
Any action on study treatment to resolve the AE is to be documented using the categories listed 
below. 
 
- 
Device use stopped 
- 
Device use interrupted 
- 
No change 
Not applicable 
 
7.5.1.2.5 Other specific treatment(s) of adverse events 
 
- 
None 
- 
Remedial drug therapy 
- 
Other 
 
7.5.1.2.6 Outcome 
 
The outcome of the AE is to be documented as follows: 
 
- 
Recovered/resolved without sequelae 
- 
Recovered/resolved with sequelae 
- 
Not recovered/not resolved (ongoing) 
- 
Fatal 
- 
Unknown 
 
7.5.1.3 
Assessments and documentation of adverse events 
 
The investigator has the obligation to report AEs. All non-serious events will be assessed and 
recorded during the specified observational phase (from signing the informed consent form up to 
30 [+5] days after last study medication intake), whether believed to be related or unrelated to 
the treatment. AE forms will be included.  The record will include clinical symptoms or final 
diagnosis when available, date of appearance, duration, severity and relationship to treatment. 
A record will also be kept of the action taken and the follow-up until resolution of the AE. 
 
7.5.1.4 
Reporting of serious adverse events  
Notification of the IECs / IRBs 
 
Notification of the IECs / IRBs about all relevant events (e.g., SAEs, suspected, unexpected, 
serious adverse reactions [SUSARs]) will be performed by the investigator according to all 
applicable regulations the serious criteria (as defined in Section 7.5.1.1 ) are applicable. 
 
7.6 
OTHER PROCEDURES AND VARIABLES 

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7.6.1 
Raynaud’s attacks assessment 
Raynaud’s attacks will be assessed using the composite of the following 6 individual outcome 
measures in order to minimize the measurement variability and placebo response(7): Raynaud’s 
condition score, patient assessment of Raynaud’s phenomenon, physician assessment of 
Raynaud’s phenomenon, attack symptoms, duration of attacks, and number of attacks per day. 
 
The Raynaud’s condition score is a daily patient assessment of Raynaud’s phenomenon activity 
using a 0-10 ordinal scale. It incorporates the cumulative frequency, duration, severity and 
impact of Raynaud’s phenomenon attacks, reflecting the overall degree that Raynaud’s has 
affected use of the participant’s hands. The Raynaud’s condition score, along with details of the 
frequency and duration of Raynaud’s attacks, will be incorporated into the daily diary that 
participants will be asked to complete for 1 week (7 days) at the time points shown below. 
The patient and physician assessment assesses the severity of Raynaud’s phenomenon in the past 
week using a 0-100 VAS. 
 
Frequency: The diary is to be completed by participant for one-day during the observation period, 
and one-day at the end of study (to occur the day prior to end of study visit).   
 
7.6.2 
Quick Inventory of Depressive Symptoms  (QUIDS-SR) 
The QUIDS-SR is a 16-item questionnaires that evaluates depression.  The 
QUIDS-SR has been validated and used to screen, diagnose, monitor and measure 
the severity of depression.   
 
7.6.3 
Patient-Reported Outcomes (PROs) / Health-Related Quality of Life (HRQoL) 
questionnaires 
 
Three patient-reported outcomes (PROs)—the HAQ-DI/SHAQ, and PROMIS-29— will be 
completed by all participants in the study.  
 
Scleroderma Health Assessment Questionnaire (HAQ-DI/SHAQ) 
 
The HAQ-DI consists of 8 domains from the Health Assessment Questionnaire disability index, 
a HRQoL instrument that measures self-reported function in 8 domains of activity in 
20 weighted responses and a VAS of pain experienced in the past week.  It additionally measures 
5 domains specific to scleroderma using a continuous VAS: Raynaud’s phenomenon, digital tip 
ulcers, lung symptoms, gastrointestinal symptoms, and a global patient assessment. The VAS 
subscales of the SHAQ were shown to be significantly correlated with objective parameters and 
were responsive to change in a cohort and in a Raynaud’s phenomenon trial in SSc. The SHAQ 
requires approximately 5 minutes to complete. 
 
Patient-Reported Outcomes Measurement Information System (PROMIS)-29 
 
The PROMIS-29 is a validated instrument to measure the health status of SSc patients, 
demonstrating moderate to high correlation with other instruments validated in SSc, including 
the SF-36 physical component score and HAQ-DI. It incorporates 7 core domains from the 
PROMIS questionnaire, which specifically relate to physical, mental, and social health aspects of 
chronic illness: pain, fatigue, depression, anxiety, sleep, and physical function, as well as one 
11-point rating scale for pain intensity. It contains 8 items with 29 weighted responses in total, 

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and requires approximately 5 minutes to complete. 
 
7.6.4 
Participant and Physician Global Assessment 
 
A global assessment for patient and physician will be obtained. 
 
The participant assessment represents the patient’s assessment of the patient’s global 
scleroderma on a 0-10 Likert scale. “On a scale of 0-10, how was your overall health in the last 
week? 0=Excellent; 10=Extremely Poor.  The physician global assessment represents the 
physician’s assessment of the patient’s current disease activity on a 0-10 Likert scale. “On a 
scale of 0-10, how was your patient’s overall health in the last week? 0=Excellent; 10=Extremely 
Poor”. Both assessments are made at baseline and Week 16, OLE Week 0 and OLE Week 16. 
 
8. 
Statistical methods and determination of sample size 
 
8.1 
General considerations 
 
This section presents a summary of the planned statistical analyses. A statistical analysis plan 
(SAP) will be written for the study that contains detailed descriptions of the analyses to be 
performed.  The SAP will be finalized prior to unblinding of the data. 
 
Continuous variables will be summarized using descriptive statistics including n, mean, median, 
standard deviation, range (e.g., minimum and maximum). Qualitative variables will be 
summarized using counts and percentages.  Graphical methods will be used in this pilot study to 
assess the pattern of response over time for key variables and to assess the relationships among 
variables.  
 
Unless otherwise specified, statistical analyses will be performed using SAS Version 9 or higher. 
Where appropriate, statistical tests will be conducted at the 0.05 significance level (with no 
adjustments for multiplicity) using two-tailed tests and p-values will be reported. 
 
Given the rare nature of SSc and the consequent small sample size for this pilot study, the 
statistical power of any comparisons is limited (i.e., there is sufficient power to detect only 
large treatment differences). As such the analysis will be largely descriptive in nature. The p- 
values resulting from formal statistical tests will be interpreted from a hypothesis-generating, 
rather than a confirmatory framework. 
 
Analysis sets 
 
As this is an open-label study, all participant who have used the Apollo system wearable for at 
least one dose (one day) will be analyzed.  The primary endpoint and all secondary outcomes 
will be assessed using this analysis set.   
 
 

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8.2 
Statistical and analytical plans 
 
8.2.1 
Demographic and other baseline characteristics 
 
Demographic variables and baseline characteristics will be summarized by treatment group. 
 
8.2.2 
Efficacy 
 
The primary endpoint is the mean change from baseline to end of the two-week intervention in the 
PROMIS-Fatigue questionnaire.  For the primary analysis, changes in score will be compared in 
the two treatment groups using an repeated measures t-test.  If the assumptions of this 
parametric model are not met, an alternative non-parametric model will be used. This model is 
based on the extension of the Wilcoxon rank-sum test to allow for covariate adjustment (9). 
This rank ANCOVA can provide additional power associated with baseline covariate adjustment, 
even when the outcome variable is not normally distributed 1(10). 
 
Analysis for secondary outcome measures that are continuous will be performed using a similar 
approach as that for the primary endpoint. We will compare the change in each secondary 
outcome measure from baseline to week 2 using an ANCOVA model or its non-parametric 
counterpart if the model assumptions aren’t met. Analyses of secondary outcomes measures that 
are discrete will be performed using Fisher’s exact tests. Analyses of secondary outcome 
measure that are counts will be performed using Poisson regression. 
 
8.3.3 
Safety 
 
Descriptive summary statistics for ] adverse and serious adverse events will be reported. 
Adverse events will be grouped by body system and grade and will be tabulated as numbers and 
percentages; serious adverse events will be enumerated and described as appropriate.  
 
 
8.4 
Planned interim analyses 
 
No formal interim analysis of this short, two-week study will be performed.  
 
8.5 
Determination of sample size 
 
SSc is a rare disease. The planned minimum sample size of 30 SSc participants is based on 
practical considerations to obtain preliminary estimates of the magnitude of treatment 
differences in efficacy and safety rather than a desired power for a pre-specified difference as 
would be necessary for a confirmatory study. However, with this proposed sample of 30 
participants we can calculate the magnitude of treatment differences (riociguat – placebo) for 
the primary efficacy endpoint – the change from baseline to end of double-blind treatment in 
fatigue scales.  There would be 80% power to detect an effect size (mean treatment difference 
divided by standard deviation) of While we expect that 30 subjects will be enough participants to 
see a significant treatment effect in this study population, we have written this protocol to allow 
for the inclusion of up to 100 subjects should 30 subjects be found to be an insufficient number 
for any reason. 
 
8.6 
Data recording 
 

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It is the expectation of the sponsor that all data entered into the eCRF has source documentation 
available at the site. The site must implement processes to ensure this happens.  A source 
document checklist will be used at the site to identify the source data for all data points collected 
and the monitor will work with the site to complete this. 
 
8.7 
Monitoring 
 
Given the enrollment period is dictated by seasonal considerations for DU incidence, we 
anticipate two monitoring visits per site during the course of the study. Once after the first 
subject has been randomized at the site and once after the study has closed to enrollment and all 
subjects have completed study visits. The frequency of monitoring visits may be adjusted 
throughout the life cycle of the study as study conditions and needs evolve. Additional visits can 
be scheduled at the request of the Study Team or DSMB. 
 
The Clinical Research Monitor will ensure that: 
 
• Data collected and entered into the database are verifiable against source documents for 
the randomized participants 
• Appropriate consent is obtained for each participant prior to study procedures 
• Safety and rights of participants are being protected 
• Study is conducted in accordance with the currently approved protocol (including study 
treatment being used in accordance with the protocol) 
• Study medication is properly dispensed and accounted for 
• Any other study agreements, GCP, and all applicable regulatory requirements are met. 
 
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents. 
 
8.8 
Archiving 
 
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.  Study-related files will be archived according to 
the University of Pittsburgh IRB regulations.     
 
9. 
Ethical and legal aspects 
 
Ethical and legal conduct of the study 
 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation 
of this study, are designed to ensure that the sponsor and investigator abide by GCP guidelines 
and under the guiding principles detailed in the Declaration of Helsinki. The study will also be 
carried out in keeping with applicable local law(s) and regulation(s). 
 
Strict adherence to all specifications laid down in this protocol is required for all aspects of study 
conduct; the investigator may not modify or alter the procedures described in this protocol. 
 
Investigators may implement a protocol change after discussing the details and getting IRB 
approval. Any deviations from the protocol must be explained and documented by the 
investigator.  

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10. 
Appendices 
 
10.1 
PROMIS-Fatigue 
10.2 
QUIDS-SR 
10.3 
Promise-29 
10.4 
HAQ-DI/S_HAQ 
10.5 
Raynaud Diary and Raynaud condition score

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