Randomized, Sham-Controlled Trial of Transcranial Photobiomodulation for Major Depressive Disorder With PET and EEG Biomarker Outcomes.
Phase: NA
Conditions: Depression, Depression, Anxiety, Depressive Disorder, Depressive Disorder, Major
Sponsor: NeuroThera DE

Near-infrared Transcranial Laser Therapy in Subjects with Major 
Depressive Disorder: A study of Dosing with Laser 
 
CONFIDENTIAL INFORMATION 
 Near Infrared Transcranial Laser Therapy in Subjects with Major Depressive 
Disorder: A study of Dosing with Laser. 
Study Sponsor: 
Pthera LLC 
18 She Way, Suite 107. 
Newark, Delaware 19713 
Protocol number: 
NITLT01 
Version 5.1 
Page 1 of 49 
December 17, 2023 
CONFIDENTIAL  
The information contained in this protocol is confidential and is 
intended for use by clinical investigators. It should not be copied or 
distributed to persons not involved in the clinical investigation of 
the LiteCure laser device, unless such persons are bound by a 
confidentiality agreement with Pthera LLC. 

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Near Infrared Transcranial Laser Therapy in Subjects with Major 
Depressive Disorder: A study of Dosing with Laser. 
December 17, 2023 
Table of Contents 
1. SUMMARY OF THE STUDY 
 
2. LIST OF ABBREVIATIONS 
11 
3. INTRODUCTION 
12 
3.1 
SUMMARY OF PRIOR CLINICAL EXPERIENCE  ............................................................................. 13 
3.2 
OVERVIEW OF LITECURE LASER SYSTEM ……………………………………………………... 14 
3.3 
OVERVIEW OF POSITRON EMISSION TOMOGRAPHY (PET SCAN) ………………...… 15 
4. RESEARCH PLAN 
16 
4.1 
STUDY AIMS …………………………………………………………………………………………...16 
4.2 
RATIONALE FOR THE USE OF THE EXPI DEVICE: ………………………………………………………….16  
4.3 
DOSING RATIONALE  .......................................................................................................................... 17 
4.4 
STUDY DESIGN ..................................................................................................................................... 19 
4.4.1 
Randomization procedure .............................................................................................. 19 
4.4.2 
Blinding procedure ........................................................................................................ 20 
4.4.3 
Contingency plan for opening of the blind .................................................................... 20 
4.5 
STUDY POPULATION ........................................................................................................................... 21 
4.5.1 
Population Description.................................................................................................. 21 
4.5.2 
Use in Female Subjects of Childbearing Potential ........................................................ 21 
4.5.3 
Criteria for Enrollment - see inclusion and exclusion criteria section ......................... 21 
4.6 
SUBJECT NUMBERING ……………………………………………………………………………… 21 
4.7 
SAMPLE SIZE ......................................................................................................................................... 21 
4.8 
SUBJECT CONFIDENTIALITY  ............................................................................................................ 22 
4.9 
STUDY VISITS........................................................................................................................................ 22 
4.9.1 
Selection Visit – Week 0................................................................................................. 22 
4.9.2 
Treatment Visits 1 to 18 - Visits 1 to 6........................................................................... 23 
4.9.3 
Follow-up visit (Post Treatments) – Week 8 .................................................................. 24 
4.9.4 
Completion .................................................................................................................... 25 
4.10 
SCALES & FORMS …………………………………………………………………………...………. 25 
4.11 
DATA COLLECTION FORMS ............................................................................................................... 27 
4.12 
DATA MANAGEMENT ......................................................................................................................... 27 
4.13 
TRAINING ………………………………………………………………………….  28 
4.14 
COMPENSATION ………………………………………………………………….... 28 
4.15 
ACCOUNTABILITY/INVESTIGATIONAL PRODUCT CONTROL ……………………………….  29 
4.16 
PUBLISHING ………………………………………………………………………………………….  29 
4.17 
CLINICAL ADVERSE EVENTS  ........................................................................................................... 29 
4.17.1 
Overview and Definitions .............................................................................................. 29 
4.17.2 
Safety Monitoring .......................................................................................................... 30 
4.17.3 
Reporting Procedures for all Adverse Events .............................................................. 31 
4.17.4 
Serious Adverse Events .................................................................................................. 33 
4.17.5 
Death ............................................................................................................................. 33 
4.17.6 
Withdrawal for Adverse Events .................................................................................... 33 
4.18 
MEASURES TO ENSURE THE SUBJECT’S SAFETY  ....................................................................... 33 
4.19 
SUBJECT DISPOSITION CRITERIA  .................................................................................................... 33 
4.19.1 
Withdrawal from the Study ............................................................................................ 33 
4.19.2 
Loss of Follow-up .......................................................................................................... 34 

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Near Infrared Transcranial Laser Therapy in Subjects with Major 
Depressive Disorder: A study of Dosing with Laser. 
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4.20 
SUMMARY OF RISKS AND BENEFITS ……………………………………………… 35 
4.20.1 
Potential Adverse Events ............................................................................................... 35 
4.20.2 
Benefits .......................................................................................................................... 36 
4.20.3 
Allowed and prohibited concomitant interventions ....................................................... 36 
5. DATA ANALYSIS METHODS 
37 
5.1 
GENERAL CONSIDERATIONS  ........................................................................................................... 37 
5.2 
AIMS OF THE STUDY ……………………………………………………………………………….   37 
5.3 
SAMPLE SIZE ......................................................................................................................................... 38 
5.4 
BASELINE AND DEMOGRAPHIC CHARACTERISTICS OF SUBJECTS ……………...…… 38 
5.5 
EFFICACY AND SAFETY ANALYSIS FOR THE AIMS .................................................................... 38 
5.6 
SAFETY ANALYSIS .............................................................................................................................. 39 
5.7 
ADDITIONAL SAFETY ANALYSIS .................................................................................................... 39 
6. 
ETHICS REVIEW & REGULATORYCONSIDERATIONS 
40 
6.1 
ETHICAL REVIEW ................................................................................................................................. 40 
6.2 
REGULATORY CONSIDERATIONS  ................................................................................................... 40 
6.3    CLINICALTRIALS.GOV …………………………………………………………….... 40 
6.4 
MONITORING PROCEDURES  ............................................................................................................. 40 
6.4.1 
Security Monitoring ....................................................................................................... 41 
6.4.2 
Measures to ensure the safety of the subject.................................................................. 42 
6.5. 
TRAINING OF THE CENTER'S STUDY PERSONNEL ....................................................................... 42 
6.6 
INFORMED CONSENT .......................................................................................................................... 42 
6.7 
ADHERENCE TO PROTOCOL ………………………………………………………………………. 43 
6.8 
DATA COLLECTION ............................................................................................................................. 43 
6.9 
RECORD RETENTION ........................................................................................................................... 43 
6.10  ACCOUNTABILITY/INVESTIGATIONAL PRODUCT CONTROL ………………………………….43 
7. REFERENCES 
44 
8. TABLE OF ASSESSMENTS 
49 

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Near Infrared Transcranial Laser Therapy in Subjects with Major 
Depressive Disorder: A study of Dosing with Laser. 
December 17, 2023 
SIGNATURE PAGE 
Protocol Number: NITLT01 
SPONSOR'S REPRESENTATIVE: 
MSEE Luis Humberto De Taboada Núñez Borja 
Director of Technology  
Pthera LLC 
Address: 18 Shea Way, Suite 107, Newark, 
Delaware 19713, U.S.A. 
Phone: +1 (760) 889-5440 
Email: luis@detaboada.com 
PROJECT MANAGER: 
Dr. Raúl Yépez Adrianzén 
PERUVIAN CLINICAL RESEARCH S.A.C. 
Address: 206 Circunvalación Los Incas Av. 206, 
Of. 801. Santiago de Surco. Lima, Peru. 
Phone: +51 999962145 Email: r.yepez@pcr.pe 
MEDICAL MONITOR: 
PERUVIAN CLINICAL RESEARCH S.A.C. 
Address: 206 Circunvalación Los Incas Av. 206, 
Of. 801. Santiago de Surco. Lima, Peru. 
Phone: +51 999962145 Email: r.yepez@pcr.pe 
CRO RESPONSIBLE FOR EXECUTION: 
PERUVIAN CLINICAL RESEARCH S.A.C. 
Address: 206 Circunvalación Los Incas Av. 206, 
Of. 801. Santiago de Surco. Lima, Peru. 
Phone: +51 999962145 Email: r.yepez@pcr.pe 

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Near Infrared Transcranial Laser Therapy in Subjects with Major 
Depressive Disorder: A study of Dosing with Laser. 
December 17, 2023 
INVESTIGATOR'S AGREEMENT 
By signing below I agree that: 
I have read this protocol. I approve this document and agree that it contains all the details necessary 
to carry out the study as described. I will conduct this study in accordance with the design and the 
specific provision of this protocol and will make every reasonable effort to complete the study within 
the designated time. I will provide copies of this protocol and access to all information provided by 
Peruvian Clinical Research S.A.C. (Contract Research Organization responsible for the conduct of 
the study) to study personnel under my supervision. I will review this material with them to ensure 
that they are fully informed about the study product and study procedures. 
I will let you know that this information is confidential and proprietary to Pthera LLC, sponsor of 
the study and may not be disclosed to any third party. I understand that the study may be terminated 
or enrollment may be suspended at any time by Pthera LLC, with or without cause, or by me if 
necessary to protect what is in the best interest of the study participants. 
I agree to conduct this study in full compliance with INS Regulations, DIGEMID, Institutional 
Review Board/Ethics Committee Regulations and the International Conference on Harmonization of 
Good Clinical Practice Guidelines. 
Investigator's Name 
Investigator's Signature 
Date: 

Near Infrared Transcranial Laser Therapy in Subjects with Major Depressive Disorder: A study of Dosing 
with Laser. 
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SUMMARY TABLE OF CHANGES TO PROTOCOL AMENDMENT version 5.1 dated December 17, 
2023 
JUSTIFICATION: Amendment 5.1 is proposed due to typographical errors observed in official communication No. 1046-2023-DIIS/INS dated October 
31, 2023. 
N° 
It said 
It should say 
Justification of the 
change 
References 
1 In section 1. Study Summary: (...) All NIR-TLT 
sessions will be 20 minutes, regardless of group 
assignment (...). 
In section 3.2 Lite Cure Laser System Overview: 
(...) the treatment time will be the same in all 
modes: 20 minutes. 
In Section 4.4 Study Design: (...) The entire 
session is estimated to last 30 minutes (...) 
In section 4.8.2 Treatment Visits 1 to 18- Visits 1-
6: (...) Treatment visits are estimated to last 
approximately 20 minutes (...) 
In section 1. Summary of the Study: All NIR-
TLT sessions will be 429 seconds (7.15 
minutes), regardless of group assignment. 
In section 3.2 Lite Cure Laser System 
Overview: (...) the treatment time will be the 
same in all modes: 429 seconds (7.15 minutes). 
In section 4.4 Study Design: (...) The entire 
session is estimated to last (which includes the 
429-second treatment and all procedures 
described in the "Study Visits" section) 30 
minutes (...) 
In section 4.8.2 Treatment Visits 1 to 18 - 
Visits 1-6: (...) It is estimated that treatment 
visits will last approximately 429 seconds 
(7.15 minutes) (...) 
It is being standardized to
429 seconds (7.15 
minutes) in all sections 
to standardize the 
amendment. 
N.A. 

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2 In section 5.1 General Considerations: (...) 120 
patients were included, randomly distributed in 
five groups. (...) 
(...) The purpose of this study is to compare the 
antidepressant effect of five different doses of 
NIR-TLT (...) 
In section 5.2 Objectives of the study: (...) To 
compare the effect(s) of each of the five doses of 
NIR-TLT (...) 
In section 5.1 General Considerations: (...) 112 
patients were included, randomly distributed in 
four groups. (...) 
(...) The purpose of this study is to compare the 
antidepressant effect of four different doses of 
NIR-TLT (...) 
In section 5.2 Study objectives: (...) To 
compare the effect(s) of each of the four doses 
of NIR-TLT (...) 
The arm that was to 
receive the NIR-TLT 
dose 
is 
eliminated: 
Mode 4 (UPW Group). 
The number of patients 
for the study is corrected. 
N.A. 
3 In the paragraphs of the document referring to 
the name of the sponsor, it has been changed. 
Formerly as: Lite Cure LLC 
In the paragraphs of the document referring to 
the name of the sponsor, it has been changed. 
Now it should say: Pthera LLC 
Due to the change in the 
sponsor of the study, the 
change was made to 
standardize 
the 
information 
in 
the 
document. 
N.A. 
N° 
OTHER CHANGES 
1 NOT APPLICABLE 

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1. Summary of the Study 
Objectives 
of the 
Study: 
The objectives of this study are: 
Primary: 
• 
A. To evaluate and compare the effect(s) of each of the four doses 
of NIR-TLT on depressive symptomatology: antidepressant effect, 
in patients with major depressive disorder (MDD). 
Secondary: 
• 
B. Compare safety and tolerability at each dose of NIR-TLT. 
• 
C. Compare the effect(s) of each of the four doses of NIR- TLT 
on brain electrophysiology. 
Exploratory: 
• 
D. To describe the findings visualized in PET, related to the brain 
metabolism of the participants, before and after receiving the 
intervention under study. 
Study 
Design: 
Multi-center, randomized, sham, double-blind. 
This trial will randomize 112 subjects into 4 equal groups: bilateral 
continuous wave (BCW), bilateral pulsed wave (BPW 1-2) and SHAM. 
All subjects, investigators (except the study statistician) and outcome 
assessors will be blinded to group assignments. The device operator will 
be aware of group assignments. 
All subjects will receive 3 NIR-TLT sessions per week for 6 weeks. A 
follow-up evaluation will be performed 2 weeks after the end of the study. 
The treatment will follow these specifications: wavelength 830 nm; 
average irradiance 54.8 mW / cm2; average fluence of 65.8 J / cm2 
(according to the parameters used in the ELATED-2 study at MGH with 
the Omnilux New U device), being the total fluence delivered: 3.6 kJ 
(bilateral) or 1.8 kJ (unilateral), either on the subject's forehead, at or near 
the electroencephalography (EEG) sites F3 and F4. 
All NIR-TLT sessions will be 429 seconds (7.15 minutes), regardless of 
group assignment. 
Study 
population: 
Patients eligible to participate in the study will be diagnosed with MDD by 
DSM criteria (MINI). Subjects will be between 18 and 75 years of age (not 
yet 76 years of age) on the date of the examination. 
Duration of 
participation: 
Research subjects will remain in the study for 8 weeks. 
(6-week treatment period, plus 2-week follow-up). The total duration of 
the study will be 24 months. 

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Criteria for 
valuation: 
- 
Main: Improvement of depressive symptoms from each of the four 
doses of NIR-TLT. Assessed using HAMD-17, at 3 time points 
(visit 1, visit 9 and visit 18). 
- 
Secondary: Safety and tolerability. Assessed by SAFTEE- SI 
(self-assessed), and collection of serious adverse events throughout 
the study. Safety data will be used to assess the tolerability of each 
of the NIR-TLT doses. 
Changes 
in 
brain 
electrophysiology 
(electrical 
activity): 
Commercially available EEG devices will be used to collect data 
on brain electrical activity. At 3 time points (visit 1, visit 9 and visit 
18). 
- 
Changes in measurements of MDD symptom severity assessment 
scales: 
o Doctor Administered Scales: QIDS-C and CGI-S 
o Patient-reported scales: ASQ and SDQ 
Entry 
Criteria: 
Inclusion Criteria 
1. The age of the subjects in the examination will be between 18 and 75 
years (inclusive). 
2. Diagnosis of major depressive disorder (MINI). 
3. QIDS-C≥12 in the selection 
4. CGI-S ≥4 or greater, i.e., "moderately depressed". 
5. Women of childbearing age should use a double-barrier method of 
birth control (e.g., condoms plus spermicides) if they are sexually 
active. 
6. Subject's informed consent obtained in writing in accordance with 
local regulations prior to enrollment in this study. 
7. The subject is willing to participate in this study for at least 12 weeks. 
8. Subjects should receive stable doses of antidepressants (if taking any) 
afor at least six weeks prior to enrollment. 
Exclusion Criteria: 
1. Decrease in SDQ self-reporting from screening to initiation. 
>=30%, calculated as [(SDQselection-88) - (SDQinitial-88) / 
(SDQselection-88)] >=30/100. A score of 88 is "normal" in SDQ. 
2. Subject is pregnant or breastfeeding. 

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3. Subject failed more than 2 adequate FDA-approved antidepressant 
treatments during the current episode according to ATRQ criteria 
(less than 50% decrease in depressive symptomatology). 
4. Structured psychotherapy focused on treating the subject's 
depression (i.e., CBT or IPT) is allowed if initiated at least 8 weeks 
prior to the screening visit. 
5. Substance dependence or abuse in the last 3 months. 
6. History of a psychotic disorder or psychotic episode (current 
psychotic episode by MINI assessment). 
7. Bipolar affective disorder (according to MINI evaluation). 
8. Unstable medical illness, defined as any medical illness that is not 
well controlled with standard of care medications (e.g., insulin for 
diabetes mellitus, HCTZ for hypertension). 
9. Active suicidal or homicidal ideation (both intent and plan are 
present), as determined by C-SSRS screening. 
10. The subject has a significant skin condition (i.e., hemangioma, 
scleroderma, psoriasis, rash, open wound, or tattoo) on the subject's 
scalp that is in close proximity to any of the procedure sites. 
11. Subject has an implant of any type in the head (e.g., stent, clipped 
aneurysm, embolized AVM, implantable shunt - Hakim valve). 
12. Any use of light-activated medications (photodynamic therapy) 
within 14 days prior to study enrollment (in the U.S .Visudin 
(verteporfin) - for age-related macular degeneration; Aminolevulinic 
acid - for actinic keratoses; Photofrin (sodium porfimer) - for 
esophageal cancer, non-small cell lung cancer; Levulan Kerastick 
(aminolevulinic acid HCI) - for actinic keratoses; 5-aminolevulinic 
acid (ALA) - for nonmelanoma skin cancer) 
13. Recent history of stroke (90 days). 
14. Subject had a failed intervention based on an FDA-approved device 
for the treatment of depression, during the current episode (e.g., less 
than 50% decrease in depressive symptomatology with TMS, ECT, 
or VNS). 
15. History of dementia, traumatic brain injury (TBI) or other organic 
neurological disorder. 

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2. List of Abbreviations 
ANCOVA = Analysis of Covariance 
ANOVA = Analysis of Variance 
ASQ = Anxiety Symptom Questionnaire 
ATP = Adenosine Triphosphate 
BOLD fMRI = blood-oxygen level dependent functional magnetic resonance imaging  
C-SSRS = Columbia Suicide Severity Rating Scale 
CFR = Code of Federal Regulations 
CGI-I = Clinical Global Impressions: Improvement 
CGI-S = Clinical Global Impressions: Severity 
CRF= Case Report Form 
CW = Continuous Wave 
DNA = Deoxyribonucleic acid 
DSMB = Data and Safety Monitoring Board 
ECT= Electroconvulsive Therapy 
ETC= Electron Transport Chain  
FDA= Food and Drug Administration 
HAM-D-17 = Hamilton Depression Rating Scale  
HCTZ = Hydrochlorothiazide 
ISO = International Standards Organization 
MDD = Major depressive disorder  
MINI= Mini-International Neuropsychiatric Interview  
NEST 1 = NTS® Effectiveness and Safety Trial - 1  
NEST 2 = NTS® Effectiveness and Safety Trial - 2  
NIMH = National Institute of Mental Health 
NIR-TLT = Near-infrared Transcranial Laser Therapy 
OSHA = Occupational Safety & Health Administration 
PBM = Photobiomodulation 
PET scan / PET: Positron Emission Tomography  
PI = Principal Investigator at the center 
QIDS-CR = Quick Inventory of Depressive Symptomatology: Doctor-rated scale  
RA = Research associate 
SAE = Serious Adverse Events 
SAFTEE-SI = Systematic Assessment for Treatment Emergent Effects  
SCID = Structured Clinical Interview for DSM disorders 
SQL = Structured Query Language 
SSRI = Selective serotonin reuptake inhibitor  
t-PBM = Transcranial photobiomodulation 
TLT = Transcranial Laser Therapy 
TMS = Transcranial Magnetic Stimulation 
VNS= Vagus Nerve Stimulation 

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3. Introduction 
Major depressive disorder (MDD) is a prevalent and disabling condition: 16.2% of the U.S. 
population has MDD at some point in life (Kessler et al., 2003). In the United States, depression 
is the third leading cause of years lost to disability or death, after cardiovascular disease and lung 
and breast cancer (Michaud et al., 2006). Despite the availability of effective treatments such as 
antidepressants and psychotherapy, MDD often remains untreated, with only one-fifth of cases 
receiving adequate treatment (Kessler et al., 2003). In addition, diagnosis and treatment rates for 
depression among Blacks and Hispanics are less than half the rates observed for Whites (Sclar et 
al., 2008). Hispanics and Blacks have far more concerns regarding the effects of medications on 
quality of life than Whites (Huang et al., 2009). Among Hispanics, the stigma associated with 
receiving antidepressants is a major concern (Interian et al., 2007). Delayed treatment for 
depression not only prolongs associated disability, but may result in lower rates of response to 
antidepressants (de Diego-Adelino et al., 2009). 
The current standard treatments for MDD are antidepressants and psychotherapy. 
Antidepressants are effective, but their efficacy is often limited by treatment adherence (Lingam 
and Scott, 2002). Psychosocial interventions are generally preferred in primary care 
(Backenstrass et al., 2006), especially among minorities (Givens et al., 2007), but are generally 
not cost-effective due to the higher upfront costs of providing psychotherapy (Barrett et al.., 
2005). In addition, counseling and psychotherapy are limited in the community because of the 
lack of counselors who are culturally trained and fluent in specific languages (e.g., Spanish). 
Due to the limitations of drug treatment and talk therapy, new treatment approaches for 
depression are needed, especially in primary care and in the community, where several minorities 
are underserved. We propose a new treatment approach for depression based on the use of 
transcranial laser therapy (TLT). The treatment consists of bilaterally exposing the forebrain to 
TLT, which can enhance ATP production in depressed subjects. 
Major depressive disorder has been associated with deficits in brain bioenergetic metabolism. In 
an experimental model of depression, chronic stress inhibited the mitochondrial respiratory chain 
(the cellular site for energy production) (Rezin et al., 2008). Depressed subjects also have 
significantly lower production of ATP (an energy vector) in their muscle tissue and a higher 
incidence of deletions in their mitochondrial DNA (Gardner et al., 2003). Magnetic resonance 
spectroscopy data in subjects with MDD showed that the response to augmentation of a selective 
serotonin reuptake inhibitor (SSRI) with triiodothyronine (a thyroid hormone) is associated with 
restoration of ATP levels in the brain (Iosifescu et al., 2008). 
Near infrared light is a non-ionizing electromagnetic wave, is invisible, penetrates the skin and 
skull into brain tissue, is non-invasive (Zhang et al., 2000), dissipates minimally as thermal 
energy and is absorbed mainly by specific chromophores (Mochizuki-Oda et al., 2002). The 
benefits of NIR-TLT are wavelength specific. A mitochondrial enzyme, cytochrome c oxidase, 
is the primary chromophore for NIR-TLT with a wavelength of about 830 nm (Eells et al., 2003). 
The energy absorbed by cytochrome c oxidase leads to increased production of adenosine 
triphosphate (ATP) through the respiratory chain. Ultimately, the increase in ATP leads to an 
increase in the cell's energy metabolism, and presumably also activates a signaling cascade that 
promotes cell plasticity and cytoprotection. (Eells et al., 2003). 
 
 

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These properties of NIR-TLT have led to new therapeutic applications in neurology. In subjects 
with acute ischemic stroke, acute treatment with NIR-TLT led to a significantly better outcome 
compared to sham treatment (Lampl et al., 2007). These results were confirmed in a different 
cohort of stroke patients with mild to moderate disease severity (Zivin et al., 2009). Both studies 
in stroke subjects showed no significant difference in the rate of adverse events or serious adverse 
events between NIR-TLT and sham-treated subjects (Lampl et al., 2007; Zivin et al., 2009). NIR-
TLT has also been used as a treatment for alopecia (Leavitt et al., 2009) and in animal models 
for methanol-induced retinal toxicity (Eells et al., 2003). Near-infrared light is already widely 
used for noninvasive assessment of brain function (replacing fMRI in studies of infants and 
young adults, under the name of Near Infrared Spectroscopy), underscoring the relatively low 
risk of NIR-TLT. The greatest risk of NIR-TLT when using a laser as a light source is associated 
with accidental exposure of the retina, when beams are projected through the lens, which 
increases the risk of macular injury (Kim et al., 2007). In our study, we will have multiple 
safeguards against this risk [See Section 4.9, Completion]. 
Preliminary uncontrolled studies in 10 and 4 depressed subjects, respectively, have shown NIR-
TLT to be safe, effective and well tolerated (Schiffer et al., 2009; Cassano et al., 2015). Our study 
offers a larger sample size, a cleaner design with placebo control (also called sham treatment) 
and tests the efficacy and tolerability of repeated sessions of NIR-TLT. Because NIR-TLT is 
non-ionizing radiation, multiple sessions, likely necessary for the treatment of depression, are 
expected to be safe. 
The advantage of the NIR-TLT treatment approach over pharmacotherapy is that adherence can 
be easily monitored (since the treatment is administered in the clinic) and the patient is not 
required to ingest any substances. It is possible that exposure to NIR-TLT is more acceptable 
than medication use among some minorities. Compared to talk therapy, NIR-TLT has the 
advantage of not requiring providers with specific cultural expertise or proficiency in a second 
language. Our study will help determine whether NIR-TLT has an antidepressant effect and is 
acceptable in minority populations, thus justifying further study and investment. 
3.1 
Summary of Prior Clinical Experience 
LiteCure conducted two studies on the safety and efficacy of NIR-TLT applied to the forehead 
(prefrontal cortex) twice a week in subjects with MDD. The device used for ELATED-2 is a 
predicate device for EXPi-laser. 
ELATED-1 was a 3-week proof-of-concept study of TLT (EXPi - class IV laser, wavelength 808 
nm; irradiance 700 mW / cm2; fluence 84 J / cm2; total energy 2.4 kJ per session for 6 sessions) 
All subjects (n = 4) were treated with TLT. Mean baseline HAMD-17 scores for depression 
decreased from 19.8 ± 4.4 (SD) to 13 ± 5.35 (SD) after treatment (p = 0.004) (Cassano et al. 
2015). (Cassano et al. 2015). 

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ELATED-2 was an 8-week double-blind, randomized, controlled study of TLT (Omnilux New 
U - LED, 823 nm; 36.2 mW / cm2; up to 65.2 J / cm2; vs. sham for 16 sessions). At completion, 
the mean HAMD-17 for depression decreased 11.7 ± 7.5 points (TLT, n = 9) vs. 5.3 
± 7.0 points (simulation, n = 9) (p = 0.04); the differences were even more pronounced in the 
completer sample as HAMD-17 decreased 15.7 ± 4.4 (TLT, n = 6) points vs. 6.1 ± 7.9 points 
(simulation, n = 7) (p = 0.01).(Cassano et al., 2018). 
3.2 
Overview of LiteCure Laser System  
The EXPi device is a research device based on LiteCure's EXPi Deep Tissue Laser Therapy™ 
system. For this research study, the EXPi system's beam delivery, Empower ™, is modified to 
deliver NIR laser energy non-invasively to the brains of subjects diagnosed with neuropsychiatric 
disorders. Other than the cap, the EXPi device is the same device as LiteCure's EXPi system: 
model LTS-2500, which is marketed under FDA 510 (K) # K173067. The device is manufactured 
and supplied by LiteCure LLC, 101 Lukens Drive, Suite A, New Castle, DE 19702. 
The EXPi device is a Class II medical device according to 21 CFR 890.5500 and 878.4810 and 
is manufactured according to 21 CFR 820. It uses laser diode sources that emit in the near infrared 
(808 +/- 10 nm) with a maximum continuous output of ≤ 30 watts. The device consists of two 
main assemblies: a console and an optical delivery system. Laser power is generated and 
controlled within the console assembly and delivered to the optical delivery system: custom 
helmet (cap), via a flexible double-clad optical fiber. The cap is configured to produce a 4 cm 
diameter (12 cm2) beam of light at each of two sites on the subject's forehead: adjustable at/near 
EEG locations F3 and F4. 
The console is programmed to produce laser energy in one of 4 modes: 
1. Mode 1 (BCW group), NIR-TLT dose: 
i. Treatment site(s): EEG F3 and F4 
ii. Time format: 
continuous wave 
iii. Average radiance: 350 mW / cm2 
iv. Exposure time: 429 sec. 
v. Total fluidity delivered: 3.6 kJ (1.8 kJ per treatment location) 
2. Mode 2 (BPW-1 group), NIR-TLT dose: 
i. Treatment site(s): EEG F3 and F4 
ii. Time format: wave 
pulsed, 10 Hz; 50% duty cycle 
iii. Average radiance: 350 mW / cm2 
iv. Exposure time: 429 sec. 
v. Total fluidity delivered: 3.6 kJ (1.8 kJ per treatment location) 
3. Mode 3 (BPW-2 group), NIR-TLT dose: 
i. Treatment site(s): EEG F3 and F4 
ii. Time format: pulsed wave, 40-50 Hz; 50% duty cycle 
iii. Average radiance: 350 mW / cm2 

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iv. Exposure time: 429 sec. 
v. Total fluidity delivered: 3.6 kJ (1.8 kJ per treatment location) 
4. Mode 4 (SHAM group), NIR-TLT dose: 
i. Treatment site(s): none 
ii. Time format: none 
iii. Average radiance: 0 mW / cm2 
iv. Exposure time: 429 sec. 
v. Total fluidity delivered: 0 kJ 
See section 4.3 - Dosing rationale 
The console display does not provide information on the dose irradiance, showing only the mode 
number, e.g. Mode 1 and, although the laser exposure varies with the treatment mode, to maintain 
blinding, the treatment time will be the same in all modes: 429 seconds (7.15 minutes). In 
addition, the behavior of the device, the performance/output of all visible and audible indicators, 
including the graphical user interface, is identical in all modes, differing only with respect to 
treatment irradiance. Since the laser radiation emitted during the NIR mode is invisible to the 
naked eye, the modes cannot be distinguished from each other, which keeps the operator and 
subject blinded to the group tasks. 
Dose administration for the present trial will follow the specifications: wavelength 830 nm; mean 
irradiance 54.8 mW / cm2; mean fluence 65.8 J / cm2 (according to the parameters used in the 
ELATED-2 study in MGH with the Omnilux New U device), which demonstrated in terms of 
improvement of depressive symptomatology evaluated with HAMD17 in patients with major 
depression. Therefore, by virtue of the ELATED2 findings, doses were considered for this 
intervention in patients with MDD. 
3.3 
Overview of Positron Emission Tomography (PET scan)  
The main metabolite used by the brain to obtain ATP in mitochondrial oxidative processes is 
glucose, although this organ constitutes 2% of the body weight, it is known to use 20-25% of 
the total circulating glucose. We consider that, therefore, it becomes the ideal vehicle to 
determine metabolic rates in the different regions of the brain. 
Positron emission tomography (PET) is a nuclear medicine study that provides maps indicating 
metabolic activity, especially glucose metabolism in different tissues and lesions (Ropper et al. 
2008), using a radiopharmaceutical that is the union of a drug or physiological substance with 
known pharmacokinetics and pharmacodynamics with a positron-emitting radioactive atom. On 
the one hand, the drug has a known biodistribution and, on the other hand, the positron-emitting 
atom indicates the location of this drug after tracking in a PET camera. Because the PET system 
lacks an anatomical reference to determine the exact location of these abnormalities, PET is 
currently fused to a computed tomography (CT) system (Roldán-Valadez et al. 2008). The most 
frequently used radiopharmaceutical is fluorodeoxyglucose, which is 18F-labeled glucose, 
known by the acronym 18FDG. 
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(PET/CT with 18F-FDG) as a means of determining brain metabolism is proposed, not only 
globally but regionally. This tool has already been used in different neuropsychiatric conditions, 
such as: cognitive impairment, dementia and Parkinson's disease, as well as in patients with 
affective disorders, such as major depressive disorders (Lyra et al. 2020; Sacher et al. 2012). 
There is evidence that depression is associated with deficits in brain metabolism. 
There is a growing consensus that there are a number of brain areas that are involved in 
depression. PET shows increased glucose metabolism in the anterior cingulate area, specifically 
in the right pregenual and subgenual regions (Sacher et al. 2012). 
The anterior cingulate cortex has a crucial role in initiation, motivation and goal-directed 
behavior, thus playing a key role in depressive disorders (Alexopoulos et al. 2008), changes in 
these areas, as determined by PET CT is even useful to identify eventual responders after starting 
a treatment (De Crescenzo et al. 2016). 
4. Research Plan 
4.1 
Study Aims  
Primary Aim: 
A. To evaluate and compare the effect(s) of each of the four doses of NIR-TLT on 
depressive symptomatology: antidepressant effect, in patients with major depressive 
disorder (MDD). 
Hypothesis 1: Total HAM-D 17 scale scores will vary in a NIR-TLT dose-dependent 
manner, with BPW dose being more effective. 
We also expect to be able to estimate the effect size of the antidepressant action as a 
function of the irradiance applied to the NIR-TLT skin, with the BPW dose being more 
effective. 
Secondary Aims: 
B. Compare safety and tolerability at each dose of NIR-TLT. 
Hypothesis 2: The doses of NIR-TLT tested in this study will be safe and well tolerated 
by patients with MDD, as assessed by SAFTEE-SI and reports of serious adverse events. 
We do not anticipate dose-dependent differences in reported side effects. 
C. To compare the effect(s) of each of the four doses of NIR-TLT on brain 
electrophysiology. 
Exploratory Aim: 
D. To describe the findings visualized in PET, related to the brain metabolism of the 
participants, before and at the end of the intervention under study. 
4.2 
Rationale for the use of the EXPi device: 
Transcranial photobiomodulation (t-PBM) with near infrared (NIR) laser therapy has emerged 
as a possible antidepressant treatment in both animal models (Mohammed et al.2016; Salehpour 
2016-2017; Xu et al.2017;Wu et al.2012), and in human studies (Cassano 2015- 2017; 
Caldieraro et al.2018) t-PBM. NIR appears to increase brain metabolism (by activating the 
cytochrome C oxidase in the mitochondria), to increase neuroplasticity and to modulate the 

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endogenous opioids, while decreasing inflammation and oxidative stress. (Chung et. al. 2012; 
Yu et. al.1997; Oron et al. 2007, Mochizuki et al. 2002) t-PBM penetrates deep into the cerebral 
cortex, modulates cortical excitability, and improves cerebral perfusion and oxygenation. The 
safety of t-PBM has been studied in a sample of 1410 acute stroke patients, with no significant 
difference in adverse event rates between t-PBM and sham exposure. (Hackee tal.2014; Lamp 
et al.2007, Zivin et al.2009) Uncontrolled studies suggest an antidepressant effect of t-PBM in 
subjects suffering from MDD (Cassano 2015-2017; Caldieraro et al.2018). 
Different devices have been used in the study of the effects of near infrared radiation (NIR) 
treatment in humans. We decided to use a Litecure device specifically adapted for this study to 
allow NIR-TLT testing of different doses in a controlled manner. 
4.3 
Dosing Rationale 
The laser dose to be used in the present clinical trial is derived from previous clinical experience 
with the use of other versions of the medical device in studies conducted in patients with acute 
stroke, major depressive disorder and Alzheimer's disease in whom lasers have been 
administered with this device, which has provided guidance on safe and potentially effective 
doses in the study population. A summary of this information is presented in Table 1. 
Laser devices have a potential risk of retinal injury when used incorrectly; this is mitigated by 
the use of protective eye equipment "goggles" and proper procedures to ensure eye safety 
(Barkana & Belkin, 2000). 
No serious adverse events were found in our literature review (Caldieraro & Cassano, 2019). 
Two open-label studies using 1 and 6 sessions of t-PBM reported no treatment emergent side 
effects (Cassano et al., 2015; Schiffer et al., 2009). 
The safety of a t-PBM session was evaluated in three large RCTs with a combined sample of 
1410 stroke subjects (Hacke et al., 2014; Huisa et al., 2013; Lampl et al., 2007). No significant 
differences in the rate of adverse effects were observed between the group receiving NIR laser 
(808 nm; 5W, 700 mW / cm2) or sham. 
A clinical trial with 16 sessions of t-PBM reported a higher number of mild side effects in the 
active treatment group, the most frequent being insomnia, "seeing bright colors," "an ashtray 
taste," and irritable mood (Cassano et al., 2018, p. 2). Other potential risks are related to 
improper administration and will be mitigated by safety procedures, such as the use of protective 
eyewear. 
The risk of thermal injury from PBM administered with the parameters used in the studies we 
reviewed is considered minimal and limited to the skin. In ten people treated by TBI with 10-15 
W lasers, a much higher power than that used in t-PBM, skin temperature increased to no more 
than 30°C with rapid cooling after removal of the NIR light. Clinically, patients reported slight 
skin heating, but no discomfort (Morries et al., 2015). 

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Table 1 - Summary of doses and efficacy and safety results in previous studies. Source: Lampl et al. (2007), Huisa et al. 
(2013), Zivin et al. (2014), Cassano (2017), Cassano et al. (2018), Cassano (2016), NIMH (2021), NYU (2021). 
 

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4.4 
Study Design 
This study is a multicenter, randomized, sham-controlled, double-blind study on the use of 
transcranial continuous light therapy as a treatment for depressive symptoms in patients with 
major depressive disorder (MDD). Laser light therapy is tested in a strict parallel design. 
This study will include 112 subjects randomly assigned to each of the four NIR-TLT treatment 
groups (28 subjects/group). 
All subjects will receive three NIR-TLT treatments per week for 6 weeks and will complete a 
follow-up evaluation two weeks after treatment completion. All subjects and investigators 
(except the study statistician) will be blinded to treatment sequence assignment. 
Energy will be administered at a wavelength of 808 nm, bilaterally to two frontal areas on the 
left and right side of the forehead, at or near electroencephalography sites F3 and F4. To 
maintain blinding, the treatment duration will be 429 seconds (7.15 minutes) for all groups. The 
treatment exposure (time during which the laser is active for the duration of the treatment) will 
be specific for each group, controlled by the device to normalize the treatment fluence of each 
active session per treatment location. Treatment will follow these specifications: wavelength 
830 nm; average irradiance 350 mW / cm2; average fluence of 65.8 J / cm2 (according to the 
parameters used in the ELATED-2 study at MGH with the Omnilux New U device) being the 
total fluence delivered: 3.6 kJ (bilateral) or 1.8 kJ (unilateral), either on the subject's forehead, 
at or near electroencephalography (EEG) sites F3 and F4. 
The entire session (which includes the 429-second treatment and all procedures described in the 
"Study Visits" section) is estimated to take 30 minutes or less (Schiffer et al., 2009) (Lampl et 
al., 2007, Zivin et al., 2009). Additional time is needed to prepare the subject, fit the necessary 
protections (e.g., goggles), inspect the subject's skin, set up the NIR-TLT devices, and give the 
subject time to rest after irradiation. NIR-TLT treatment will only be administered by trained 
personnel who are on study staff. All personnel administering the treatment must pass laser 
safety training created by the American Institute for Medical Laser Applications and approved 
by the relevant Committees. The duration of irradiation will be decreased if clinically indicated, 
based on tolerability as needed. 
4.4.1 Randomization procedure 
At screening, participants will be assigned an identification number on a first-come, first-served 
basis. When it is confirmed that the participant is eligible for the clinical trial, he/she will be 
randomized. 
The assignment of each participant to a particular treatment arm (experimental and control group 
will be performed in a 1:1:1:1 ratio) will be done by using an electronic system, which is 
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For each participant at each visit, the investigator or center coordinator will communicate with 
the central statistician and, through a user and password assigned for the center, will enter the 
web system where he/she will be able to request and obtain the corresponding treatment number 
assigned to him/her in the study, and then proceed with the laser application. The participants 
and the study investigator will be blinded to the treatment assignment. The screen of the medical 
device does not show information of the dose applied to each participant, only the group to 
which he/she belongs will be referenced, keeping the dosing details confidential. 
At central level, the unblinded statistician (responsible for administering this web system) will 
know which treatment arm corresponds to each participant from each research center. 
4.4.2 Blinding procedure 
This study is a clinical trial where blinding of both the investigator and the study participant will 
be assured. Only the treatment identifiers, the central statistician of the study, will know the 
treatment identifiers. 
The sponsor is responsible for providing the medical device under study, programming and 
maintenance of the device. 
The investigator at each center will be responsible for providing the corresponding dose 
according to the intervention under study (treatment assigned by the statistician through the web 
system) to each study participant. 
Simulation blinding will be effective because the radiation is not visible and because no dose 
from the NIR-TLT will produce any perceptible difference from the simulation patient, e.g., skin 
heating. 
4.4.3 Contingency plan for opening of the blind 
Only in the event of an emergency or serious adverse event or other particular event that alters 
the risk-benefit profile of the intervention will the principal investigator determine whether 
unblinding of a participant's study intervention assignment is warranted. Participant safety 
should always be the first consideration in making such a determination. 
If the investigator decides that unblinding is warranted, every effort should be made to 
communicate this decision by telephone or mail to the sponsor or medical monitor before 
unblinding a participant's treatment assignment, unless this would delay the management of 
unblinding of the participant, as approval from either is necessary to communicate with the 
unblinded statistician responsible for the administration of the randomization web system, who 
has access to the arm assignment lists for each participant, to forward this information to the 
requesting site. 
The date and reason for breaking the blind should be recorded in the source documents and in 
the FRCe by the investigator at the research site. 

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If the treatment assignment blind is opened, this information should only be shared with the 
other investigating doctors at the center on a need-to-know basis (especially when the cause is 
a safety event consistent with a serious adverse reaction). Treatment assignment information 
should not be shared with others, unless decided by of thepat rocinator or mandated by the 
regulatory authority. 
4.5 
Study Population 
4.5.1 
Population Description 
The subject population for this study will consist of 112 randomized subjects between the ages 
of 18 and 75 years, of any ethnicity and diagnosed with MDD. The subject will meet all inclusion 
criteria, will have none of the exclusion criteria, and will provide written informed consent to 
participate in this clinical trial. Any subject who signs an informed consent will be considered 
enrolled in the study, although they will not be able to participate if they are not eligible for the 
study. In the event that a subject's ability to understand and communicate is compromised (as 
assessed by the investigator), local regulations regarding informed consent signatures must be 
followed. 
Subjects will be recruited, through selections, advertisements and publications. Study 
participants will also be recruited through advertisements on the Internet, study center websites, 
etc. According to the strategies proposed by each researcher. 
Participants who contact the respective study site staff in response to any of the announcements 
will complete the telephone screening to determine tentative eligibility for the study. 
4.5.2 Use in Female Subjects of Childbearing Potential 
Women of childbearing age must consent (without any element of coercion) to use a double 
barrier method of birth control (e.g., condoms with spermicide) if they are sexually active. A 
pregnancy test will be performed at the screening visit. The sponsor will provide free access to 
any contraceptive method of the participant's choice. 
4.5.3 Criteria for Enrollment - see inclusion and exclusion criteria section. 
4.6 
Subject Numbering 
Subjects enrolled in the ELATED-4 study will be identified by subject numbers 01 through 150 
(to account for selection failures and drop-out prior to randomization). 
4.7 
Sample Size 
The study is expected to include 112 subjects with analyzable data (at least 3 sessions - 1 week, 
after randomization). 

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4.8 
Subject Confidentiality 
Any information and data provided to Pthera LLC or its designees in reference to any subject's 
participation in this research shall be considered confidential. The investigator shall ensure that 
the anonymity of all subjects is maintained in all documentation submitted to Pthera LLC by 
completely removing each subject's name and/or other identifying information. Identifying 
information will be replaced with the study number and subject's initials. The research site 
should not provide Pthera LLC with information such as subject phone numbers, home address, 
personal identification numbers such as passport numbers, etc. Site research personnel should 
be careful when communicating with Pthera LLC representatives by telephone or electronic 
correspondence not to provide information that could reveal a subject's identity. 
Documents associated with the study that are not intended to be sent to Pthera LLC (e.g., signed 
informed consent forms) must be held in strict confidence by the investigator. Only study site 
personnel, authorized Pthera LLC personnel, and regulatory authority inspectors will have 
access to these confidential files. 
4.9 
Study Visits 
The study includes screening tests, treatment and a series of follow-up visits. 
4.9.1 Selection Visit - Week 0 
Purpose 
The purpose of the screening visit will be to determine the eligibility of patients to participate 
in the study. 
Procedures 
Study personnel will consent subjects to the study, perform a psychiatric evaluation, and 
screen for the presence of MDD using the MINI, QIDS-C, and CGI-S scales. 
Laboratory tests (including urine collection for urine biochemical analysis and urine toxin 
analysis (also called Urine Drug Screen), urine pregnancy test, and a complete physical 
examination including vital signs and weight will be performed. 
Approximately 15 cc ± 5 cc (15 ml) of blood will be drawn for laboratory safety testing. To 
confirm that a patient is healthy enough to participate, a complete blood work-up with 
differentials, thyroid stimulating hormone test, blood biochemistry (glucose, calcium, sodium, 
potassium, carbon dioxide, chlorine, albumin, total protein, alkaline phosphatase, transaminases, 
total and fractionated bilirubins, urea, creatinine) and a high sensitivity C-reactive protein test 
will be performed. A PET scan will be performed on patients within the study subgroup to meet 
the exploratory objective. 

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Once all tests and procedures are available for review, study personnel will determine subject 
eligibility based on all inclusion and exclusion criteria. 
Subjects who report having taken antidepressants at the screening examination may choose to 
continue medication during the study or taper and discontinue therapy prior to the baseline visit 
(under the supervision of a treating doctor). However, subjects who have discontinued more than 
two antidepressants in the current episode of depression will be excluded. 
4.9.2 Treatment Visits 1 to 18 -Visits 1-6 
Regular treatment visits (1 to 18) occur on non-consecutive days, 3 times per week for 6 weeks. 
Purpose: The purpose of the treatment visits is to administer NIR-TLT and collect data to assess 
the effect of each of the NIR-TLT dose effects on MDD symptomatology (antidepressant effect) 
and tolerability. 
Procedures: Trained study personnel will deliver NIR-TLT to study participants. Treatment 
visits are estimated to last approximately 429 seconds (7.15 minutes) and will take place in a 
dedicated NIR-TLT (laser safety) office. Only the subject and the staff administering NIR-TLT 
will be present during the session. The subject will lie comfortably on an examination bed or sit 
in a recliner, a cervical pillow (U-shaped) may be used for comfort and to prevent the helmet 
connector cables from being stepped on, bent or damaged. The NIR-TLT application sites (left 
and right forehead) will be inspected for skin lesions (e.g., lacerations or signs of inflammation) 
that might contraindicate treatment. During treatment sessions, a warning sign will be hung on 
the office door. Ideally the place where treatment is administered should be at a temperature of 
25°C +/- 2°C. 
Prior to treatment with the EXPi device, the subject's forehead is cleaned with 70% isopropyl 
alcohol, the cap is placed on the subject's head and secured, and the treatment beam locations 
are adjusted to match the F3 and F4 EEG sites (or very close if the site is covered by hair), the 
eyebrows may be used as a reference for placement of the lower edge of the helmet. The operator 
and subject are provided with appropriate laser safety glasses (optical density rating> 5.0 at 808 
nm). Disposable caps may be used for hair control if necessary. 
Trained personnel administering NIR-TLT will make every effort to never shine light into or 
near the subject's eyes. Patients and staff will wear safety glasses selected for the biophysical 
properties of NIR-TLT in accordance with Occupational Safety and Health Administration 
(OSHA) guidelines. The patient may sleep during the time of therapy administration. 
The NIR-TLT delivery is expected to last no longer than 7.15 minutes (429 seconds) in total 
(simultaneous application to the left and right forehead). The subject will be allowed to rest for 
5 minutes after NIR-TLT delivery. The skin at the application sites will be inspected again after 
laser application. A log will be kept with the dates of delivery of the NIR-TLT. 

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treatment per study subject. The use of cell phones, tablets, computers or electronic devices 
will not be allowed during laser administration. 
During treatment visits and prior to NIR-TLT, study personnel will collect tolerability (safety) 
and efficacy data: 
1. Safety data: SAFTEE-SI (self-assessed), C-SSRS, adverse events and concomitant 
medication form. 
2. Efficacy data - HAMD-17. 
In addition to the evaluation described above, during visits 1, 9 and 18: 
Prior to the NIR-TLT study, the staff will collect primary efficacy data from metric 
measurements and brain electrophysiology data: 
1. Efficiency data: 
a. Doctor-administered scales (1): HAMD-17, QIDS-C and CGI-S. 
b. Patient-Reported Scales (1): ASQ and SDQ 
2. Brain Electrophysiology Data - Study personnel will conduct a first 10-minute 
EEG recording session, treat the patient according to their NIR-TLT group 
randomization, and then conduct a second 10-minute EEG recording session as soon 
as possible after the end of treatment, but within 15 minutes. 
3. Exploratory PET scan data: A PET scan will be performed on the participants 
selected to be part of the research subgroup, before the first treatment visit and within 
24 hours of the end of the last intervention (visit 18). 
4.9.3 Follow-up visit (Post Treatments) - Week 8 

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The next visit will occur two weeks after the last cerebral blood flow impact visit. 
Purpose: The purpose of the follow-up visit is to evaluate the long-term antidepressant effect 
of NIR-TLT. 
Procedures: During the follow-up study, staff will collect tolerability (safety) and efficacy 
data: 
1. Safety data: SAFTEE-SI (self-assessed), adverse events and concomitant 
medication form. 
2. Efficiency data: 
a. Doctor-administered scales (1): HAMD-17, QIDS-C and CGI. 
b. Patient-reported scales (1): SDQ and ASQ. 
4.9.4 Completion 
If, during the study, a subject's CGI-S increases more than 2 points or rises above a score of 5, 
or if they become actively suicidal according to the C-SSRS scale, the subject will be referred 
to their treating doctor and advised to start or switch to another FDA-approved antidepressant 
medication. Such subjects may or may not be terminated from the study, depending on the 
severity of symptoms, at the clinical judgment of the principal investigator. Subjects who are 
considered actively suicidal and in imminent danger will be terminated from the study and 
referred to the appropriate local MGH or NKI emergency room for evaluation and subsequent 
hospitalization, or, if the subject is appropriate for outpatient monitoring, will be referred to their 
treating doctor for frequent appointments and follow-up. Each subject will have the 
investigator's contact information, as well as instructions on how to call emergency services, if 
necessary. We will encourage subjects to continue enrollment in the study through follow-up 
visits, regardless of discontinuation of NIR-TLT. 
4.10 Scales & Forms 
We will offer clinical interviews and study forms in Spanish. All scales will explore the last 7 
days, except M.I.N.I (lifetime), TSRQ (study duration). 
• 
(M.I.N.I.) - The M.I.N.I. is a brief structured diagnostic interview, developed jointly by 
psychiatrists and clinicians in the United States and Europe, for DSM and ICD psychiatric 
disorders. With an administration time of approximately 15 minutes, it is designed to meet 
the need for a short but accurate structured psychiatric interview for clinical trials. 
According to researchers in the Division of Clinical and Treatment Research at the 
National Institute of Mental Health (NIMH), the 
M.I.N.I. is a fully validated and more time-efficient alternative to the Structured Clinical 
Interview for DSM Disorders (SCID) (Sheehan et al., 1998). Validated in Spanish 
(Ferrando L. et. al, 1998). 
• 
Systematic Assessment for the Treatment of Emergent Events (SAFTEE-SI) - The 
SAFTEE is a commonly used instrument originally developed by NIMH and adapted into 
a self-report instrument. The version of the scale we plan to use is the same 

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used by the NIMH-sponsored CO-MED multicenter trial, and systematically examines all 
potential treatment-emergent side effects and discusses specific adverse symptoms, 
including suicidal thoughts and behaviors, and self-injurious behavior. 
• 
Hamilton Depression Rating Scale - 17 items (HAM-D-17; Hamilton, 1960) 
- The doctor completes this instrument based on his or her assessment of the patient's 
depressive symptoms, using a structured interview and defined anchor items. The goal of 
the HAM-D is to quantify the degree of depression in patients who already have a diagnosis 
of major depression. Questions focus on neurovegetative and other depressive symptoms 
experienced in the past 7 days. There are several different versions of the HAM-D; they 
differ only in the number of questions included. The standard form generally used in 
research studies is the 17-item Hamilton D (HAM-D-17). Responses to the questions are 
scored on a scale of 0-4 or 0-2, with higher scores indicating more severe pathology. Scores 
on the HAM-D-17 generally fall into the following ranges: a) not depressed = 0-7; b) 
mildly depressed = 8-13; c) moderately depressed. 
= 14-18; d) severely depressed = 19-22; e) very severely depressed = 23 or more. Validated 
in Spanish by Ramos-Brieva (1986). 
• 
Quick Inventory of Depressive Symptomatology: Clinician-Rated Scale (QIDS-C) - 
This is a brief (16-item) clinician-rated inventory of core depressive symptoms such as 
sleep, depressed mood, appetite, concentration, suicidal ideation, interest, energy, 
psychomotor retardation, or agitation. Validated in Spanish by Planas et al. (2014). 
• 
Clinical Global Impressions: Severity and Improvement (CGI-S, CGI-I) - The 
clinician scores these two instruments from 1 to 7 based on the assessment of the subject's 
overall clinical status. Measured based on history and scores on other instruments: (a) 
depressive severity (CGI-S) and (b) clinical improvement (CGI-I). Validated in Spanish 
by García-Portilla (2011). 
• 
Anxiety Symptom Questionnaire (ASQ) - This is a 17-item self-report questionnaire, 
used in Spanish, that measures the frequency and intensity of 17 anxiety symptoms, 
including nervousness, worry, irritability, trouble relaxing, insomnia, lack of energy, 
difficulty concentrating, somatic symptoms, and impaired functioning due to anxiety. 
• 
Symptoms of Depression Questionnaire (SDQ) - This is a comprehensive measure of 
depression that includes assessment of symptoms on the anxiety-depression spectrum. It 
assesses irritability, anger outbursts, and anxiety symptoms along with symptoms 
commonly considered to be symptoms of depression. Factor structure analysis of the SDQ 
identified 5 subscales, including one on the anxiety-depression spectrum, with adequate 
internal consistency and concurrent validity in Spanish (Pedrelli et al., 2014). 
• 
Columbia Suicide Severity Rating Scale (C-SSRS) For suicidal ideation and behavior: 
an FDA-endorsed instrument for clinical trials. This instrument systematically tracks 
suicidal ideation and behavior (e.g., suicide attempts, desire to die, suicidal thoughts, plan 
and intent) (Posner et al. 2007) Validated in Spanish by Al-Halabí et al.(2016). 
• 
Adverse Event Form- The adverse event form captures any adverse events (serious or 
otherwise) specifically related to the application of TLT. This form will help determine if 
the side effects of TLT are too great for a participant to continue in the study. 
• 
Concomitant Medication Form - This form will be completed at each TLT study visit, 
including the screening visit, as a safety monitoring tool. 

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4.11 Data Collection Forms 
Study investigators, subjects, and outcome assessors will be blinded to the random assignment 
of treatment 
Several procedures are in place to ensure data integrity and protocol compliance. We will use 
HIPAA-compliant electronic research data capture to support direct data entry by patients and 
study personnel. Web-based surveys will be based on a study-specific data dictionary defined 
by members of the research team with planning assistance from Pthera LLC. A research 
associate (RA) will oversee the automated export of study data from the web-based surveys to 
a relational study database in structured query language (SQL), allowing for systematic data 
query and verification. 
Participants will complete the physical self-report measures, which will then be transcribed into 
the data collection form by the person responsible for data entry on the research team. For 
doctor-administered measures, all doctors will enter responses directly into the database. 
To minimize missing data from the self-report forms, we will program unanswered question 
warnings into the FCRe that will alert participants in real time if they inadvertently skip a 
question. Then, participants can go back and answer the missed questions or, if they intentionally 
skipped questions, they can ignore the warning message and continue answering the remaining 
questions. We will also program real-time range checks in FCRe that generate error messages if 
a value outside the acceptable range is entered for a given field. To ensure confidentiality, data 
will be identified in the database only by subject number, visit number, and visit date. By 
recording study data in this manner, the information can be considered "de-identified" and, 
therefore, complies with the Health Insurance Portability and Accountability Act of 1996 
(HIPAA) Privacy Standards for Individually Identifiable Health Information ("Privacy Rule"). 
Any information transmitted electronically will be fully encrypted and password protected. 
Subjects' names will not be entered into the database; each will be identified only by an 
identification number. Consent forms, any printed PHI, and any study measures completed on 
paper will be stored and filed in locked office cabinets. 
4.12 
Data Management 
The study biostatisticians will oversee the management of the study database. The principal 
investigators, Dr. TBD (PI) is ultimately responsible for the quality of data collection and the 
overall conduct of the study, and directly supervises the study coordinators and data 
management staff. Data management will include doctor- and patient-rated assessments (see 
assessments), screening data, fidelity data, visit compliance data, and rater reliability data and 
safety reports. Weekly database reports will monitor enrollment, completion, attrition, dropout, 
and individual subject progress, as well as completion of critical assessments. Additional reports 
will be done as needed to monitor baseline characteristics, protocol adherence, and other issues of 
interest. 
 
 

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All measurements that are completed on paper will be entered by the RA into the database, and 
a two-step verification system will be used to minimize data entry errors. All records in the 
database have a form completion status that can be Incomplete (appears as a red circle in the 
Record Status Panel), Not Verified (yellow circle), or Verified. The RA initially entering the 
data will save each record entered as Unverified (at which point it will appear as a yellow circle 
in the Record Status Panel). Then, a second or the same RA at each center will go to each 
unverified record, compare each entered value to the paper source document, make corrections, 
and then re-save the record as verified. The unverified and verified identifiers will be 
unambiguous and easy to evaluate. 
4.13 
Training 
Study-trained doctors who are unaware of treatment randomization will administer diagnostic 
assessments and rating scales. All raters will be experienced doctors who will have received 
criteria-specific training in the use of the study measures. Any new evaluators will receive 
training. Periodically, all study doctors will evaluate an audiotape during a staff meeting. These 
duplicate evaluations will be used both for calculating kappa coefficients and for monitoring. 
Differences between raters will be discussed during monitoring to identify reasons for 
disagreement and improve inter-rater reliability. These procedures will help us ensure that study 
doctors refine their diagnostic skills and will also establish common guidelines for continued 
use in diagnostic decision making. Inter-rater agreement will be assessed by evaluating 
recordings of diagnostic interviews. Kappa coefficients will be calculated every 12 months. If 
reliability falls below criteria (ICC ≥ 0.8 for QIDS-C), study doctors will be retrained. 
4.14 Compensation 
Participants will receive 15.00 soles for each study visit (total expected visits = 20 for those who 
completed the study, including screening and follow-up visits, maximum total compensation per 
patient is 300.00 soles). 
The sponsor will guarantee transportation, in coordination with the participant and members of 
the research team, from the research center to the PET scan center and back to the starting point. 
This applies to participants who are included in the exploratory target research subgroup. 
The amount indicated does cover travel and transportation expenses, but should these costs 
exceed this amount, and in order to protect the rights of the participants, the amount will be 
reimbursed taking into account the personal and specific considerations of each of these 
expenses. 

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4.15 Accountability / Investigational Product Control 
U.S. federal law and ICH Guideline E6 § 5.14 require that all investigational medical devices 
be strictly controlled. All investigational devices must be kept in a secure area at clinical sites 
in compliance with all applicable FDA regulations (U.S. sites). 
Principal Investigators or designated study site personnel verifying receipt of devices/device 
accessories must complete the Device/Accessory Acknowledgement Form and fax a copy to 
Pthera LLC. Device accountability and acknowledgement records will be maintained at each 
study site. These records will list all equipment received, date received, serial number of each 
device. Study site personnel will initiate the log each time the device is used. The use of tPBM-
2.0 will also be recorded in the appropriate CRF. 
Malfunctioning devices and device accessories, including all components, will be returned to 
Pthera LLC for investigation at Pthera LLC's expense. 
4.16 Publishing 
Once the preliminary results for the country and globally are available, they will be 
communicated to each of the principal investigators. 
The principal investigators are responsible for informing each of the subjects enrolled in the 
study (both those who completed the study and those who were discontinued) of the results of 
the study. Likewise, the ethics committee and the national health institute (INS) will be 
informed. 
The sponsor agrees to publish the results at the end of the study, whether the results are negative 
or positive. If authorized by the sponsor, this information may also be published by third parties. 
4.17 Clinical Adverse Events 
4.17.1 Overview and Definitions 
All adverse events will be recorded from the time of Informed Consent until completion or 
completion of the study. The adverse event CRF must be completed and submitted to the IRB, 
FDA and Pthera LLC as required. Adverse event management regulations and reporting 
contained in the FDA and ICH Guidelines will be adhered to. 
Consideration of adverse events will hereinafter consist of adverse events, serious adverse 
events, and adverse device effects, including anticipated and unanticipated adverse device 
effects. 
• 
Adverse event is defined as any unfavorable/undesirable clinical event in a clinical 
investigation of a subject using a device and/or product that does not necessarily have 
a causal relationship with this treatment. Therefore, an adverse event can be any 
unfavorable and/or unintended sign, symptom or disease temporally associated with 
the use of a product or device, whether or not considered related to it. Only abnormal  

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laboratory values that the investigator considers clinically significant will be classified 
as adverse events. 
• 
Serious Adverse Event is defined as any adverse/undesirable experience that results 
in any of the following outcomes: 1) death; 2) a life-threatening adverse experience; 3) 
hospitalization or prolongation of existing hospitalization; 4) a permanent/persistent or 
significant disability/incapacity, or congenital anomaly/birth defect; 5) major medical 
events that may not be life-threatening, life-threatening, or require hospitalization may 
be considered a serious adverse experience when, based on appropriate medical 
judgment, they may endanger the subject and may require medical or surgical 
intervention to prevent any of the outcomes listed in this definition. 
• 
Anticipated adverse device effect is defined as any adverse effect related to the device 
or procedure, which is identified in the protocol. 
• 
Unanticipated adverse device effects are defined as any serious adverse health or 
safety effect or any life- or death-threatening problem caused by or associated with a 
device, if that effect, problem, or death was not previously identified in nature, severity, 
or degree of occurrence in the research or implementation plan (including a 
supplemental plan or implementation), or any other serious unanticipated problem 
associated with a device that relates to the rights, safety, or welfare of subjects. 
4.17.2 Safety Monitoring 
Study subjects will undergo frequent clinical assessments including depressive scores, 
concomitant medications, adverse events, and serious adverse events and unexpected device 
events will be recorded from study entry to completion. In addition, clinicians should monitor 
the safety of subjects by frequently asking them about their comfort during treatment delivery. 
If skin erythema occurs, treatment will be discontinued. Patients will be instructed to contact the 
principal investigator of the study site or a member of his or her staff at any time between visits 
regarding adverse events or worsening of symptoms. If at any study visit, the subjects' clinical 
status significantly worsens from baseline (operationalized as the clinical global impression 
severity score, CGI-S, of 6 or greater) or if a subject develops active suicidal intent and/or plan, 
based on the C-SSRS scale and/or the clinical interview, the subject will be referred to the 
treating doctor to start an antidepressant medication or make appropriate changes in the 
treatment regimen. If the subject were considered to be in imminent danger as a result of 
suicidality, he/she would be discontinued from the study and referred to appropriate clinical 
treatment (see 4.9 Termination). 
The two site principal investigators (Dr. TBD, PI) will have bi-weekly conference calls (which 
will include all study staff); during these conference calls, they will discuss all adverse event 
reports to identify any safety concerns, based on such concerns, they may decide to temporarily 
discontinue study enrollment, modifications to the study protocol or terminate the study. 
In addition, a Data and Safety Monitoring Board (DSMB), composed of at least 3 members not 
directly involved in the study, will review the SAEs annually. The research assistants 
responsible for data collection and storage will be aware of and comply with all regulatory 
requirements related to adverse events. In the event that a patient becomes ill or injured as a 
direct result of study participation, medical care will be provided. All adverse events (and device 
events) will be tracked to resolution and reported to the MGH or NKI IRB as serious in the event 
that: 

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1. Not anticipated and possibly study-related (same report as SAE) or 
2. If any of the following criteria are encountered: any fatal event, immediately life-
threatening event, permanently or substantially disabling event, event requiring or 
prolonging hospitalization, or any congenital anomaly. This also includes any event that 
a study investigator judges to impose a significant hazard, contraindication, side effect, 
or precaution. 
An expedited review will be conducted for all events that meet the FDA definition of serious 
adverse events (SAE), i.e., any fatal event, immediately life-threatening, permanently or 
substantially disabling event, event requiring or prolonging hospitalization, or any congenital 
anomaly. This also includes any event that a study investigator or the DSMB judges to impose 
a significant hazard, contraindication, side effect, or precaution. For the purposes of this study, 
all SAEs should be reported to the DSMB, regardless of any judgment about their relationship 
to the study device. All relevant information will be reported to the DSMB for each SAE, 
including event and outcome information, dosing history of all study TLT applications, 
concomitant medications, subject medical history and current conditions, and all relevant 
laboratory data. Per IRB protocol, the principal investigator at each site will report all 
unanticipated serious adverse events to the IRB within 5 working days / 7 calendar days after 
the investigator first becomes aware of the problem. If at any time during the course of the study, 
the DSMB judges that the risk to subjects outweighs the potential benefits, the DSMB will have 
the discretion and responsibility to recommend that the study be terminated. 
4.17.3 Reporting Procedures for all Adverse Events 
After review with the subject by study site personnel, all adverse events occurring during the 
study, whether or not attributed to the tPBM-2.0 device or TLT procedure, observed by the 
investigator or reported by the subject, will be documented in the subject's source document and 
on the appropriate CRF pages. The following attributes should be assigned: 
1. Description of the event 
2. Start Date 
3. Date of resolution (if applicable) 
4. Severity 
5. Relation to the study set-up and / or procedures 
6. Intensity 
7. Action(s) taken 
8. Resolution 
Intensity is defined as a measure of the severity of a reaction, effect or experience. Measures are 
described as mild, moderate or severe. However, the event itself may be of relatively minor 
medical importance. 

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The intensity of adverse events is assessed as mild, moderate or severe according to the 
following index scale: 
Mild 
The adverse event is transient, does not require treatment and does not interfere with 
the subject's daily activity. 
Moderate 
The adverse event introduces a low level of inconvenience or concern for the subject 
and may interfere with daily activities, but is usually ameliorated by simple therapeutic 
measures. 
Severe 
The adverse event disrupts the subject's usual daily activity and requires systematic 
therapy or other treatment. 
If the adverse event is of such intensity in the judgment of the investigator that it warrants 
withdrawal from the study, the subject should be withdrawn from treatment. The subject should 
receive appropriate care under medical supervision until the symptoms disappear. 
The relationship of an adverse event to the study device or procedure will be graded as 
follows: 
None 
The adverse event is not associated with the use of the study device. 
Remote 
The temporal association is such that the study device is not likely to have had an 
association with the observed adverse event. 
Possible 
This causal relationship is assigned when the adverse event: 
a) Follow a reasonable time sequence of device usage, but 
b) It could have been produced by the subject's clinical condition or other methods 
of therapy administered to the subject. 
Likely 
This causal relationship is assigned when the adverse event: 
a) Follow a reasonable time sequence of device use; 
b) It decreases when treatment is suspended; 
c) It cannot be reasonably explained by the known characteristics of the subject's 
clinical condition. 
Definitive 
This causal relationship is assigned when the adverse event: 
a) Follow a reasonable time sequence of device use; 
b) Decreases when treatment is discontinued; and 
c) It is confirmed by the recurrence of the adverse event on repeated exposure. 
*For purposes of immediate reporting of unanticipated adverse events, the investigator's 
judgment will be considered in determining that the adverse event is "more than 50% likely" 
related to the use of the device or treatment procedure. 

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4.17.4 Serious Adverse Events 
All serious adverse events should be reported to the Institutional Review Board (IRB) oversight, 
the FDA and Pthera LLC, as required. 
If Pthera LLC or its designee notifies Investigators of any serious adverse event that is 
considered an unanticipated adverse effect of the device, Investigators should notify their own 
IRB/EC as necessary. 
The investigator should report serious adverse events, serious adverse effects and serious and 
unexpected suspected adverse effects to the ethics committee when the event occurs or becomes 
known within a period of no more than one (1) calendar day. Likewise, it must report to the INS 
OGITT within seven (7) calendar days of the occurrence of the event or as soon as it becomes 
aware of the event, through the Sistema de Reporte Virtual de Eventos Adversos Serios (REAS-
NET). 
4.17.5 Death 
Deaths reportable to Pthera LLC include all deaths during study participation. 
4.17.6 Withdrawal for Adverse Events 
All adverse events resulting in subject withdrawal from the study should be reported 
immediately by telephone to Pthera LLC. 
The investigator may be asked to provide detailed follow-up information. The investigator will 
determine the reportability of the event on a case-by-case basis and report to the appropriate 
regulatory authorities  evaluating the study device as necessary. 
4.18 Measures to Ensure Subject's Safety 
The investigator will be responsible for monitoring the safety of subjects entering this study and 
for alerting Pthera LLC of any study-related events that appear unusual and/or unanticipated to 
their facility. 
The investigator will be responsible for the proper medical care of subjects during the study in 
relation to the protocol procedures for their center. 
The investigator will remain responsible for providing appropriate medical care options after a 
subject terminates or the study is discontinued due to adverse events. 
4.19 Subject Disposition Criteria 
4.19.1 Withdrawal from the Study 
Each subject and the investigator reserve the right at any time to terminate a subject's 
participation in the clinical investigation. 
Possible reasons for withdrawal or removal from the study may include: 

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1. The subject voluntarily withdraws consent. 
2. The subject was ineligible according to the inclusion and exclusion criteria of the study. 
3. The subject develops an adverse event that would not allow continuation in the study. 
4. The subject has an adverse event that, in the opinion of the investigator, warrants 
withdrawal from the study. Pthera LLC must be notified within two business days. 
5. The subject and/or the investigator make the decision that the subject should withdraw 
from the study. 
6. Subject to death of participant. 
7. Positive pregnancy test during eligibility procedures. 
8. The subject misses one of the 3 scheduled sessions per week and it is not possible to 
make it up before the end of the week. When a subject withdraws or is withdrawn from 
the study, the following will be performed, if possible, at the study termination (exit) 
visit: 
• 
HAM-D-17 
• 
QIDS-C 
• 
CGI 
• 
C-SSRS 
• 
ADVERSE EVENT FORM 
• 
Concomitant Medication Form 
• 
ASQ (self-assessment) 
• 
SAFTEE-SI (self-assessment) 
• 
SDQ (self-assessment) 
For all subjects who prematurely withdraw from the study, the date and reason for withdrawal 
will be documented. 
4.19.2 Loss of Follow-up 
If a center is unable to contact a subject or if the subject fails to appear for a visit, three 
documented telephone calls should be made, followed by a certified letter (or its equivalent, 
such as an e-mail). The certified letter should detail the need for the subject to appear for a visit, 
the center's failed attempts to contact the subject, and that failure to contact the center will cause 
the subject to be withdrawn from the study. 
If the certified letter is returned to the center as undeliverable or the letter is delivered but the 
subject does not communicate with the center and no further contact is made with the subject or 
the subject's caregiver, then the subject will be considered lost to follow-up with the subject and 
suspended from the study. All attempts to contact the subject will be documented. 
A delay in the application of the laser, not exceeding 72 hours, will be tolerated for reasons of 
major cause. Provided that this delay allows to comply with the 3 administrations corresponding 
to the week of the intervention under study. If the subject does not comply with the 3 
administrations of the treatment, he/she will be withdrawn from the study. 

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4.20 Summary of Risks and Benefits 
4.20.1 Potential Adverse Events 
Risks to the subject may include, but are not limited to, the following: 
The EXPi device emits light with a wavelength longer than the human eye can see. Personnel 
will be trained in basic safety procedures related to the use of the device. Personnel 
administering the NIR-TLT will be careful not to operate the EXPi device unless it is in direct 
contact with the subject's skin. Both the subject receiving the NIR-TLT and the study doctor 
present in the NIR-TLT room will wear eye protection in the form of goggles or pads. The 
goggles provided with the EXPi device are in direct contact with the area surrounding the 
subject's eye. Since they are reusable, they should not be shared between subjects. The eye pads 
are disposable and should be discarded after use. The eye pads have an adhesive to adhere to the 
subject's eyelids, so there is a possibility of an allergic reaction. 
EXPi device failure resulting in cessation of investigational therapy may cause: 
1. 
No adverse events to our knowledge 
2. 
Unforeseeable adverse events 
Delivery of infrared energy to an inappropriate site, such as directly over the open eye, is not 
recommended and could pose a risk to the subject. 
The application of the EXPi device may cause a slight thermal sensation of heat during use. 
The skin temperature is well below the thermal damage level. 
Based on human clinical trial experience to date, each adverse event listed below has been 
reported with TLT: 
1. 
Erythema at the application site 
2. 
Pain at the application site 
3. 
Discomfort at the application site 
4. 
Heat at the application site 
5. 
Reaction at the application site 
6. 
Headache 
Additional potential side effects of NIR-TLT, documented in previous trials, include: 
- 
See bright colors, abnormal taste 
- 
Feeling "out-of-body" experiences 
- 
Insomnia, restless sleep, erratic sleep, early morning awakening. 
- 
Vivid dreams 
- 
Irritability 
- 
Difficulty finding words 
- 
Abdominal distention 
Other potential risks are described below: 

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Risk of worsening depression, suicidality and manic change: Worsening depression and 
increased suicidality are possible complications of antidepressant treatments prescribed to 
subjects with MDD. We will minimize this risk by selecting only subjects who do not exhibit 
active suicidal ideation at screening. We will also discontinue any subject who develops active 
suicidal ideation during the course of the study (C-SSRS) and is considered to be in imminent 
danger; we will then coordinate appropriate levels of care and standard antidepressant treatment 
(see 4.9 Termination). Manic changes are potential adverse events and will also be closely 
monitored during antidepressant treatment. Our strict schedule of clinical study visits will allow 
early recognition of treatment-emergent suicidal ideation or prodromal hypomanic signs. 
Subjects who develop mania or hypomania will be discontinued and provided with the 
appropriate level of care. 
Answering detailed questionnaires may create a slight degree of inconvenience for subjects. 
Duration of testing for cognitive circuitry: The total testing duration takes a total of 40 minutes 
at baseline and 40 minutes at weeks 5 and 9. There is no expected risk to patients beyond the 40 
minutes of sitting at the computer for testing and possible startle experience. Every effort will 
be made to ensure that patients are comfortable and safe during this period, and the study can be 
stopped at any time. Beyond these problems, there is little or no risk to patients. 
Risk of bruising: venous puncture may cause accidental bruising when blood is drawn from the 
forearms. 
4.20.2 Benefits: 
Study subjects will receive a systematic MINI assessment of their DSM comorbidity. This 
information will be readily available to their treating doctors if subjects so desire and agree to 
disclose. This information can guide long-term treatment. In the short term, the subject will 
receive close and systematic depression follow-up and formalized cognitive assessments beyond 
current standards of care. Easy access to routine physical examinations is also a potential benefit. 
Subjects will have access to a different treatment modality if counseling and/or medications 
were not sufficient or not acceptable to them. The treatment itself with transcranial laser therapy 
(TLT) can potentially alleviate depressive symptoms on a level equal to antidepressant 
medication. 
4.20.3 Allowed and prohibited concomitant interventions: 
No concomitant prohibited interventions have been reported during treatment with this device. 
Contraindications for use: 
• 
Do not apply infrared light to abdominal or lumbosacral points in 
pregnant women. 
• 
Do not apply infrared light to epiphyseal lines in children. 
• 
Do not apply infrared light in the thoracic region or on the pacemaker 
itself in patients with pacemakers. 
• 
Do not apply infrared light to the thyroid gland, ovaries or testicles. 

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• 
Do not apply infrared light to patients who are taking 
• 
drugs that have contraindications that are sensitive to heat or heat sensitive. 
• 
light, such as, among others, certain types of steroids. 
5. Data Analysis Methods 
5.1 
General Considerations 
It is expected that multiple sites, randomized, sham-controlled, double-blinded, double-blinded 
trials will include 112 patients, randomized into four groups. Each group will receive a different 
dose of NIR-TLT. Group tasks and dosing will be blinded to doctors, patients and outcome 
assessors. Device operators will be aware of the group assignments. 
The purpose of this study is to compare the antidepressant effect of four different doses of NIR- 
TLT and to correlate this effect with the effects of the individual dose on brain electrophysiology 
and mitochondrial function. 
5.2 
Aims of the Study 
Primary Aims: 
A. To compare the effect(s) of each of the four doses of NIR-TLT on depression 
symptomatology: antidepressant effect. 
Hypothesis 1: Total HAM-D 17 scores will vary in a NIR-TLT dose-dependent manner, 
with BPW dose being more effective. 
We also expect to be able to estimate the effect size of the antidepressant action as a 
function of the irradiance applied to the NIR-TLT skin, with the BPW dose being more 
effective. 
B. Compare the safety and tolerability of each dose. 
Hypothesis 2: The doses of NIR-TLT tested in this study will be safe and well tolerated 
by patients with MDD, as assessed by SAFTEE-SI and serious adverse events. 
We do not anticipate dose-dependent differences in reported side effects. 
Secondary Aims: 
C. To compare the effect(s) of each of the four doses of NIR-TLT on brain electrophysiology. 
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E. To study the correlations (correlating) antidepressant effects, brain electrophysiology and 
mitochondrial function of each of the NIR-TLT doses. 
5.3 
Sample Size 
The sample size was determined using G Power software version 3.1, considering a calculation 
by double mean difference with common standard deviation, assuming a significance level of 
0.05 and 90% power. The parameters used were obtained from page 7 (section "Antidepressant 
effect according to clinician-rated measurement") of the previous ELATED-2 study (Cassano et 
al., 2018), where the mean difference of the HAM-D17 score for the experimental group was -
10.8± 7.55 and for the control group 4.4±6.65; such data identify a double difference of 6.4 with 
common standard deviation of 7.091. With this information, a total sample of 112 participants 
is obtained, taking into consideration a 20% loss rate. Each group will have 28 participants. 
With n=112, in 4 groups in a longitudinal design, we estimated a power of 90% to 
differentiate (alpha=0.05) the therapeutic effect of the dose, giving an antidepressant 
effect and an effect variance equivalent to that obtained in participants who completed 
the ELATED-2 study for all groups (Cassano et al., 2018b) 
5.4 
Baseline and Demographic Characteristics of the Subjects 
The demographic and baseline characteristics of the subjects will be summarized for each 
treatment. Descriptive summaries will include number of subjects, mean, standard deviation, 
median, minimum and maximum for continuous parameters, frequencies and percentages for 
categorical parameters. 
A t-test or chi-squared test, as appropriate for quantitative or categorical data, will be used to 
determine whether there were differences in the baseline demographic profiles of the groups. 
Differences were considered significant at p values <0.05. 
5.5 
Efficacy and Safety Analysis for the Aims 
It will be carried out as follows: 
A. Antidepressant effect of NIR-TLT doses: 
To compare the antidepressant effects of NIR-TLT doses, mean changes in HAM-D 17 
scores (for evaluation of the Primary Assessment Criteria) and QIDS-C and CGI-S (for 
evaluation of the Secondary Assessment Criteria), will be performed for each dose at 3 
time points (visit 1, visit 9 and visit 18) will be compared using a repeated measures 
ANCOVA. A significant ANCOVA interaction in mean score changes between groups will 
be taken as indicating that the groups have different antidepressant efficacy. If significant 
ANCOVA interactions are found, paired samples t-tests will be used to explore differences 
between scores/groups. 
Both the full analysis and the analysis by intention will be performed to analyze the severity 
of depression at the endpoint. Patient attrition and dropout will be analyzed. The possible 

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differences between treatment groups in dropouts will be examined with Fisher's exact test. 
B. Brain electrophysiological effect of NIR-TLT doses: 
To compare the effects of NIR-TLT doses on brain electrophysiology, changes in EEG 
spectral power in all spectral bands for each dose at 3 time points (visit 1, visit 9, and visit 
18) will be compared using a repeated measures ANCOVA. A significant ANCOVA 
interaction in mean score changes between groups will be taken as indicating that the groups 
have different effects. If significant ANCOVA interactions are found, paired samples t-tests 
will be used to explore differences between groups. 
C. Safety and tolerability of NIR-TLT doses: 
To compare the safety and tolerability of NIR-TLT doses, mean changes in SAFTEE-SI 
scores at 3 time points (visit 1, visit 9, and visit 18) will be compared using a repeated 
measures ANOVA. A significant ANOVA interaction in mean score changes between 
groups will be taken as indicating that the NIR-TLT doses have different tolerability. If 
significant ANOVA interactions are found, paired samples t-tests will be used to explore 
differences between groups. 
In addition, the frequency and severity of side effects and adverse events reported for each 
dose will be compared using a Fisher's exact test. The corrective actions taken by the 
doctors as well as the clinical judgment on the likelihood of association of the side 
effect/adverse event with the NIR-TLT dose will also be reported. 
D. Findings visualized in the PET scan: 
The analysis of the results obtained in the PET will be for exploratory purposes to study the 
brain metabolism of the participants, before and at the end of the study intervention in the 
4 groups. Following the recommendations of Daniel et al. (Daniel, 2012), for the 
exploratory analysis we will work with a minimum number of 5 participants per group, with 
a total of 20 participants. 
The results obtained in the PET will be presented in a descriptive manner. 
5.6 
Safety Analysis 
The number and percentage of adverse events until the end of the study will be presented for each 
treatment group according to adverse event. 
5.7 
Additional Safety Analysis 
Descriptive safety statistics for each treatment group will include the number of subjects, mean, 
standard deviation, minimum and maximum median for continuous variables, and frequencies 
and percentages for categorical variables. 

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6. 
Ethical Review & Regulatory Considerations 
6.1 
Ethical Review 
Prior to the start of the study, the investigator will obtain approval of the protocol and informed 
consent form from the IRB. Additional documentation may be required pending applicable local 
requirements. At least the following documentation should be obtained: 
1. IRB / EC protocol approval. 
2. IRB/EC approval of the informed consent form. 
3. Approval of the annual renewal of the IRB/EC protocol (or at any other frequency when 
applicable, i.e. quarterly, semi-annually in accordance with the local IRB/EC standard 
operating procedure). 
4. IRB/EC approval of any revisions to the Informed Consent Form or amendments to the 
protocol. 
6.2 
Regulatory Considerations 
This study will be conducted in accordance with Good Clinical Practice (GCP) guidelines and 
other applicable regulatory requirements including, but not limited to: 
• 
The Food and Drug Administration's (FDA) Investigational Device Exemption 
Regulations (21 CFR 812), 
• 
FDA's Human Research Regulations (21 CFR 50, 54 and 56), 
• 
Health and Human Services Regulations (DHHS) on human subjects research (45 
CFR 46 Subpart A, B, C and D) and 
• 
The International Conference on Harmonization (ICH) "Good Clinical Practice 
Guideline for Industry-E6: Consolidated Guideline". 
• 
The regulation of clinical trials approved by DS 021-2017-SA. 
6.3 
ClinicalTrials.gov 
The study will be registered and published on ClinicalTrials.gov (www.clinicaltrials.gov). 
6.4 
Monitoring Procedures 
Monitoring will be conducted by the PI, who will periodically review laboratory results and 
clinical information. The PI will coordinate the different phases of protocol implementation, 
such as application and follow-up. The PI will be in frequent contact with the other staff 
members responsible for the delivery of the NIR-TLT and with Pthera LLC, who will loan the 
NIR-TLT device. We have minimized the risks potentially associated with NIR-TLT use by 
providing subjects and the operator with safety goggles or eye pads during NIR-TLT application 
and by requiring two methods of contraception (although NIR-TLT has not been associated with 
a teratogenic effect). We have also included treatment discontinuation rules based on the 
development of skin erythema or discomfort lasting more than 24 hours at TLT delivery sites 
(to avoid the risk of the subject having unknown skin photosensitivity) 
Treatment will end for participants who experience temporary pain or discomfort during a 
treatment session that is present up to 24 hours after the end of the session. 

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6.4.1 Security Monitoring 
Study subjects will undergo frequent clinical assessments including depressive scores, 
concomitant medications, adverse events, and serious adverse events, and unexpected device 
events will be recorded from study entry to completion. In addition, clinicians should monitor a 
subject's safety by frequently asking them about the subject's comfort during treatment delivery. 
If skin erythema occurs, treatment will be discontinued. Patients will be instructed to contact the 
study site principal investigator or a member of his or her staff at any time between visits 
regarding adverse events or worsening symptoms. If at any study visit, the subjects' clinical 
status significantly worsens from baseline (operationalized as Clinical Global Impression 
Severity Score, CGI-S, of 6 or greater) or if a subject becomes actively suicidal with intent 
and/or plan, as per On the C-SSRS scale and/or clinical interview, the subject will be referred to 
the treating doctor to start an antidepressant medication or make appropriate changes in the 
treatment regimen. If the subject were considered to be in imminent danger as a result of 
suicidality, he/she would be discontinued from the study and referred to appropriate clinical 
treatment (see Section - 4.9 Termination). 
The site will have bi-weekly conference calls with a designated Pthera LLC study monitor 
(which will include study RA's); During these conference calls, they will discuss all adverse 
event reports to identify any safety concerns, based on such concerns, they may decide to 
temporarily discontinue study enrollment, modifications to the study protocol or terminate the 
study. 
In addition, a DSMB, consisting of at least 3 members not directly involved in the study and not 
employed by Pthera LLC, will review SAE quarterly. Research assistants responsible for data 
collection and storage will be aware of and comply with all regulatory requirements related to 
adverse events. In the event that a patient becomes ill or injured as a direct result of study 
participation, medical care will be provided. All adverse events (and device events) will be 
tracked to resolution and reported to the DSMB as serious in the event that they were not 
anticipated and possibly related to the study (same report as SAE) or meet any of the following 
criteria, any: 
(1) fatal event, 
(2) immediate life-threatening event, 
(3) event of permanent or substantial disability, 
(4) event requiring or prolonging hospitalization, or any congenital anomaly, 
(5) If a study investigator judges to impose a significant hazard, contraindication, side 
effect, or precaution. 
An expedited review will be conducted for all events that meet the FDA definition of Serious 
Adverse Events (SAE), i.e., any fatal event, immediately life-threatening event, permanent or 
substantial disabling event, event that requires or prolongs hospitalization or any congenital 
anomaly. This also includes any event that a study investigator or the DSMB judges to impose 
a significant hazard, contraindication, side effect, or precaution. For the purposes of this study,  
 
 

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all SAEs should be reported to the DSMB, regardless of any judgment about their relationship 
to the study device. All relevant information will be reported to the DSMB for each SAE, 
including event and outcome information, dosing history of all NIR-TLT applications in the 
study, concomitant medications, medical history and current conditions of the subject, and all 
relevant laboratory data. The principal investigator will report all unanticipated serious adverse 
events to the site IRB within 5 working days / 7 calendar days after the investigator first becomes 
aware of the problem. If at any time during the course of the study, the DSMB judges that the 
risk to subjects outweighs the potential benefits, the DSMB will have the discretion and 
responsibility to recommend that the study be terminated. 
6.4.2 
Measures to ensure the safety of the subject 
The investigator will be responsible for monitoring the safety of subjects entering this study and 
for alerting Pthera LLC of any study-related events that appear unusual and/or unanticipated for 
their site. 
The investigator will be responsible for the proper medical care of the subjects during the study 
in relation to the protocol procedures for their site. 
The investigator will remain responsible for providing appropriate medical care options after a 
subject terminates or the study is discontinued due to adverse events. 
6.5. 
 Training of the center's study personnel 
Training will begin before the protocol is implemented. Training will consist of lecture and 
hands-on practice. Application of the NIR-TLT procedure will be performed only by PI or his/her 
designee trained by the Sponsor (or his/her designee) to perform the procedure. 
6.6 
Informed Consent 
The Principal Investigator will be responsible for developing the Informed Consent Form to be 
prepared in accordance with FDA 21 CFR Part 50 for all U.S. sites. The Informed Consent Form 
will be used to explain in simple terms, before the subject enters the study, the potential risks 
and benefits to the subject. The Informed Consent Form will contain a statement that consent is 
freely given, that the subject is aware of the risks and benefits of entering the study, and that the 
subject is free to withdraw from the study at any time. 
Prior to a subject's participation in the study, the written informed consent form will be signed 
and dated personally by the subject or by an individual authorized to sign on behalf of the subject 
in accordance with local regulations. 
If a subject is unable to read or if a legal representative is unable to read, an impartial witness 
will be present during the entire discussion of the Informed Consent Form. After the Written 
Informed Consent Form and any other written information provided to the subject is read and 
explained to the subject or legal representative, and the subject has given oral consent for 
participation in the study, the witness will sign and date the consent form. 

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A witness in the consent process is considered an unbiased individual independent of the study. 
Note: The investigator should document the acquisition of the written informed consent form 
in the subject's medical records, and the subject or legal representative should receive a copy 
of the informed consent form document prior to enrollment in the study. 
6.7 
Adherence to Protocol. 
The protocol must be read and followed by all personnel participating in the study. 
6.8 
Data Collection 
Data will be captured on Case Report Forms and kept locked at the center. 
6.9 
Record Retention 
The investigator should maintain a file of all documents and records related to the conduct of 
the study. Subject files and other source data should be retained for the maximum period of time 
permitted by the hospital, institution, or private practice, or as specified below. 
Study records are subject to inspection by the FDA and other regulatory agencies. 
6.10 Accountability / Investigational Product Control 
U.S. federal law and ICH Guideline E6 § 5.14 require that all investigational medical devices 
be strictly controlled. All investigational devices must be kept in a secure area at clinical sites 
in compliance with all applicable FDA regulations (U.S. facilities). 
Principal investigators or designated study site personnel verifying receipt of devices/device 
accessories must complete the device/accessory acknowledgement form and fax a copy to Pthera 
LLC. Device accountability and acknowledgement records will be maintained at each study site. 
These records will list all equipment received, date received, serial number of each device. Study 
site personnel will initiate the log each time the device is used. EXPi device usage will also be 
recorded in the appropriate CRF. 
Malfunctioning devices and device accessories, including all components, will be returned to 
Pthera LLC. for investigation at Pthera LLC.'s expense. 

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8. Table of Assessments 
STUDY WEEK 
Week 0 
Week 1 
Week 1 to 3 
Week 3 
Week 4 to 6 
Week 6 
Week 8 
VISIT PROCEDURE 
V0 
Selection 
V1 
V2 to 8 
V9 
V10 to 17 
V18 
V19 
Follow-up 
Consent 
■ 
M.I.N.I. 
■ 
PET scan in study subgroup 
▲ 
▲ 
Concomitant Medication 
■ 
■ 
■ 
■ 
■ 
■ 
■ 
Physical Examination / Lab 
■ / ▲ 
■ 
Progress Note 
■ 
■ 
■ 
■ 
■ 
■ 
Vital Signs 
■ 
■ 
■ 
■ 
■ 
■ 
■ 
Adverse Events Form 
■ 
■ 
■ 
■ 
■ 
■ 
ASQ 
● / ▲ 
● / ▲ 
● / ▲ 
● / ▲ 
● / ▲ 
● / ▲ 
● / ▲ 
CGI 
■ 
■ 
■ 
■ 
■ 
C-SSRS 
■ 
■ 
■ 
■ 
■ 
■ 
■ 
HAMD-17 
■ 
■ 
■ 
■ 
■ 
QIDS-C 
■ 
■ 
■ 
■ 
■ 
SAFTEE-SI 
● / ▲ 
● / ▲ 
● / ▲ 
● / ▲ 
● / ▲ 
● / ▲ 
● / ▲ 
SDQ 
● / ▲ 
● / ▲ 
● / ▲ 
● / ▲ 
● / ▲ 
● / ▲ 
● / ▲ 
EEG 
■ 
■ 
■ 
Treatment- TX 
▲ 
▲ 
▲ 
▲ 
▲ 
     Legend 
 
■ 
DOCTOR 
▲ 
RESEARCH ASSOCIATE 
● 
PATIENT