Clinical trial NCT04243837
Conditions: Breast Cancer Related Lymphoedema Lymphoedema
Sponsor: PureTech
Start date: 2020-03-01; Completion date: 2022-09-09
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a trial of up to 6-months duration for safety, tolerability, clinical efficacy assessments, PK and biomarkers analysis in breast carcinoma patients with secondary lymphoedema

Detailed description:
This trial will utilize a randomised, double-blinded, placebo controlled design that will assess the safety, tolerability, and secondarily clinical efficacy of LYT-100 over a period of up to 6-months of dosing in breast carcinoma patients with secondary lymphoedema following sentinel lymph node biopsy and/or axillary node dissection, with or without radiation.

Arms: arm 1: LYT-100 BID for 6 months arm 2: Placebo BID for 6 months
Interventions: intervention 1: LYT-100 BCRL intervention 2: Placebo BCRL
Intervention descriptions: intervention 1: BCRL patients will receive LYT-100 BID for 6 months intervention 2: BCRL patients will receive Placebo BID for 6 months

Protocol documents:
Prot_SAP_001.pdf: 
Protocol Number: LYT-100-2020-01-US-02 
 
PureTech LYT 100, Inc. 
Protocol Version 1.2 
Dated 2 November 2021 
Page 1 
1. 
TITLE PAGE 
 
 
 
A Phase 2a Double-Blind, Placebo-Controlled Study to Determine the 
Safety, Tolerability, Pharmacokinetics, and Efficacy of Deupirfenidone 
(LYT-100) in Patients with Breast Cancer-Related Upper Limb 
Secondary Lymphedema 
 
Protocol Number: LYT-100-2020-01-US-02 
 
 
Authors: Novotech (Australia) Pty Limited 
 
Development Phase: Phase 2a 
Document Version: Protocol Version 1.0 dated 30 April 2021  
Amendment #1: Protocol Version 1.1 dated 08 June 2021 
Amendment #2: Protocol Version 1.2 dated 2 November 2021 
 
Number of Pages: 102 
 
 
 
Property of PureTech LYT 100, Inc. – Confidential 
May not be used, divulged, published, or otherwise disclosed without the consent of PureTech 
LYT 100, Inc. 
 
 


Protocol Number: LYT-100-2020-01-US-02 
 
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Page 2 
 
 
PROTOCOL AUTHORIZATION 
 
Title: A Phase 2a Double-Blind, Placebo-Controlled Study to Determine the Safety, 
Tolerability, Pharmacokinetics, and Efficacy of Deupirfenidone (LYT-100) in Patients 
with Breast Cancer-Related Upper Limb Secondary Lymphoedema 
 
As PureTech LYT 100, Inc. (“Sponsor”) representative, I confirm that the study protocol was 
subjected to critical review. The information it contains is consistent with current knowledge of 
the risks and benefits of the investigational product (IP), as well as with the moral, ethical, and 
scientific principles governing clinical research as set out in the current Declaration of Helsinki 
and the International Council for Harmonisation guidelines on Good Clinical Practice (GCP). 
 
 
 
 
 
 
 
 
 
 
 
 
Michael Chen, PhD, Senior Director 
PureTech LYT 100, Inc.  
 
 
Date 
 


Protocol Number: LYT-100-2020-01-US-02 
 
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INVESTIGATOR’S AGREEMENT 
Title:  A Phase 2a Double-Blind, Placebo-Controlled Study to Determine the Safety, 
Tolerability, Pharmacokinetics, and Efficacy of Deupirfenidone (LYT-100) in Patients 
with Breast Cancer-Related Upper Limb Secondary Lymphoedema 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence. This documentation includes this study 
protocol, Investigator's Brochure(s) (IB), electronic Case Report Forms (eCRFs), and other 
scientific data. 
The study will not be commenced without the prior written approval of a properly constituted 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC). No changes will be 
made to the study protocol without the prior written approval of the Sponsor and the IRB/IEC, 
except where necessary to avert an immediate hazard to the patients. 
I have read the protocol and agree that the study will be conducted in compliance with the 
protocol and in accordance with the principles of the current version of the Declaration of 
Helsinki (Ethical Principles for Medical Research Involving Human Subjects). The conduct of 
the study will be in accordance with the Integrated Addendum to International Council for 
Harmonisation (ICH) guideline E6 (R1), Guideline for GCP ICH E6 (R2) and the United States 
(US) Food and Drug Administration (FDA): Code of Federal Regulations (CFR) Title 21. 
I acknowledge that I am responsible for the overall study conduct. I agree to personally conduct 
or supervise the described clinical study. I agree to ensure that all associates, colleagues, and 
employees assisting in the conduct of the study at my site are informed about their obligations. 
Mechanisms are in place to ensure that site staff receive the appropriate information throughout 
the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigational Site 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed name of Investigator  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 


Protocol Number: LYT-100-2020-01-US-02 
 
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Protocol Version 1.2 
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Page 4 
PROCEDURES IN CASE OF EMERGENCY 
 
Table 1. 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone 
Number 
Clinical Study Leader and 
Responsible Physician 
Aleksandra Filipovic, MD, 
Ph.D 
PureTech Health LLC 
3-8 Bolsover Street, Office 108 | 
Marylebone W1W 6AB London, 
UK  
+ 44(0)2073393084 
24-Hour Emergency Contact 
Aleksandra Filipovic, MD, 
Ph.D  
PureTech Health LLC 
3-8 Bolsover Street, Office 108 | 
Marylebone W1W 6AB London, 
UK  
+ 44(0) 778 660 7099 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
PureTech LYT 100, Inc. 
Name of Investigational Product: 
LYT-100 Capsules 
Name of Active Ingredient: 
LYT-100 (deupirfenidone) 
Protocol Number: 
LYT-100-2020-01-US-02 
Title of Study:  
A Phase 2a Double-Blind, Placebo-Controlled Study to Determine the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of Deupirfenidone (LYT-100) in Patients with Breast Cancer-Related 
Upper Limb Secondary Lymphoedema 
Study Centers: 
Multiple study sites in the USA and Australia 
Studied Period (Years):  
Estimated date first patient enrolled: May 2021 
Estimated date last patient completed: May 2022 
Phase of Study:  
Phase 2a 
Study Objectives:  
This study is a 26-week randomized, double-blind, placebo-controlled assessment of LYT-100 at 
multiple study centers in the US and Australia in patients with secondary lymphedema following 
axillary node dissection and/or sentinel lymph node biopsy treatment for breast carcinoma. Screening 
will be performed up to 28 days prior to administration of the first dose of LYT-100. Only patients 
who provide written informed consent and meet all of the applicable inclusion and none of the 
applicable exclusion criteria will be enrolled.  
This study will be performed in breast carcinoma patients with secondary mild to moderate 
lymphedema following axillary node dissection and/or sentinel lymph node biopsy or 
excision/clearance, with or without radiation, dosed with LYT-100 (750 mg, twice daily [BID]; with 
food for 26 weeks. 
Primary Objectives 
• 
To evaluate the safety and tolerability of LYT-100 on breast cancer carcinoma patients 
with secondary lymphedema following axillary node dissection and/or sentinel lymph 
node biopsy. 
Secondary Objectives 
• 
To explore efficacy signals of double-blinded study medication:  
− 
Lymphatic obstruction and subsequent edema,  
− 
Infection (as characterized by cellulitis and/or lymphangitis), and  
− 
Quality of life (QoL). 
• 
To assess the population pharmacokinetic (PK) profile of double-blinded study medication 


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− 
To describe the association between fibrotic and inflammatory biomarkers, in 
particular transforming growth factor beta 1 (TGF-β1), and disease progression in mild 
to moderate lymphedema. 
Study Design  
Treatment Period 
This is a double-blind, parallel, placebo-controlled evaluation of the safety and efficacy of LYT-100 
compared to placebo. Approximately 50 patients will be randomized to receive LYT-100 or placebo in a 
ratio of 1:1.  
LYT-100 dosing is to be titrated starting at 500 mg BID during the first 3 days of dosing, followed by 
750 mg BID thereafter, or matching placebo. Patients will take double-blind-study medication orally 
with food BID (approximately 10 to 12 hours between the two daily doses) on an outpatient basis for 
26 weeks.  
Table 2. 
Dosing Regimens for Days 1 Through 3 and Thereafter 
Day 1 to Day 3 
Day 4 Through Week 26 
1LYT-100 500 mg BID2 or matching Placebo  
× 3 days 
1LYT-100 750 mg BID2 or matching Placebo 
× 179 days 
Abbreviations: BID = twice a day.  
1Patients will be administered LYT-100 study medication, or placebo, orally with food with approximately 10 to 
12 hours between the two daily doses. 
2Doses may be adjusted according to safety and tolerability to avoid toxicity by adjusting to lower doses in 
response to patient safety and tolerability issues. If dosing titration is not well tolerated, adjustments to dosing 
may be made as follows: reductions to 250 mg BID × 2 days (may be longer if needed), 500 mg BID × 2 days 
(may be longer if needed), 750 mg BID thereafter versus matching placebo.  
Patients with breast cancer-related lymphedema will be assessed for safety, tolerability, clinical 
endpoints, PK, and biomarkers while receiving LYT-100 or placebo over a 26-week (i.e., 6-month) 
dosing period. If a patient is using a standard of care compression sleeve, compression pump therapy, 
and/or manual lymphatic drainage within 4 weeks prior to Screening, they must be agreeable to 
continuing the same routine care throughout the 6-month study treatment period and throughout 
2 weeks post-study drug discontinuation. If a patient is not using a standard compression sleeve, 
compression pump therapy, and/or manual lymphatic drainage ≥ 4 weeks prior to Screening and are 
not planning to be using these prior to the study, they must be agreeable to not using the lymphedema 
therapy(s) throughout treatment and 2 weeks post-study drug discontinuation. Patients will be stratified 
at enrolment into the standard compression sleeve, compression pump therapy, and/or manual 
lymphatic drainage stratum versus non-compression/non-lymphatic drainage stratum. In addition, 
patients will be stratified by higher risk of lymphedema progression (axillary lymph node dissection) 
versus lower risk of lymphedema progression (sentinel node biopsy). 
Table 3. 
Baseline Randomization Stratification Levels  
Compression Sleeve, Compression Pump, and/or Lymphatic Drainage 
Yes 
No 
Risk for Progression 
Risk for Progression 
High 
(history of axillary lymph 
node dissection and/or 
regional lymph node 
radiation posterior field with 
or without supraclavicular) 
Low 
(history of sentinel 
node biopsy or 
excision/clearance) 
High 
(history of axillary lymph 
node dissection and/or 
regional lymph node 
radiation posterior field with 
or without supraclavicular) 
Low 
(history of sentinel 
node biopsy or 
excision/clearance) 


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Following confirmation of study eligibility, patients will be seen in the clinic for their final baseline 
assessments (Day -1). Patients will begin their BID dosing of study medication on the following 
morning (Study Day 1) and will continue for 26 weeks, with clinic visits at Weeks 1, 2, 4, 8, 12, 16, 
20, and 26. The site will contact the patient by phone at Week 23 to check in and assess for compliance 
to study drug, assess for new concomitant medications and adverse events (AEs) and remind the 
patient to complete their Patient Diary 1 week prior to the Week 26 study visit. 
All patients will be monitored for safety, including assessment of hematology, serum chemistry, 
coagulation, and urinalysis parameters, ECGs, vital signs, and AEs. Patients will complete the efficacy 
assessments which will include clinical and QoL measures at time points as delineated in the Schedule 
of Events. Sparse PK samples will be obtained for population PK analysis to determine the variability 
of double-blinded study drug concentration data in individual patients across multiple clinical sites. 
Fibrotic and inflammatory biomarkers will be assessed for changes from baseline. With patients using 
compression sleeves, pumps, and/or lymphatic drainage as a treatment modality(s) at least 4 weeks 
prior to and at Screening, they will remain on compression treatments during the treatment period as 
noted. Compression sleeves will be removed upon arrival at each study visit and until after the 
bioimpedance assessment is collected. Time of sleeve removal will be noted at each study visit. In 
addition to routine practices such as diet, exercise, or skin care, use or non-use of compression sleeves, 
compression pumps and/or lymphatic drainage will be recorded in the Patient Diary 1 week prior to 
each study visit with lymphedema assessments, including frequency of use and the number of hours 
used on each occasion. Medication compliance will also be recorded on the Patient Diary.  
Follow-Up 
Safety and tolerability will be assessed throughout the study by monitoring AEs, physical examination, 
vital signs, 12-lead ECGs, clinical laboratory values (hematology panel, multiphasic chemistry panel, 
and urinalysis), and review of concomitant treatments/medication use. 
Patients will return to the clinic 28 ± 3 days from the last dose of study medication for a safety 
follow-up visit as delineated in the Schedule of Events. 
In the event of premature discontinuation from the study, patients will return to the investigative site 
and complete an early termination visit with assessments as delineated in the Schedule of Events. 
Following the early termination visit, patients will be asked to return to the investigative site for one 
last safety Follow-up visit, approximately 28-days from the last dose of study medication. 
Safety Oversight 
The study will be subject to oversight by a Safety Review Committee (SRC) comprised of the 
Principal Investigator (PI), Medical Monitor (MM), and Sponsor representative, at a minimum. Details 
of the roles and functioning of the SRC will be available in the SRC Charter.  
The SRC will convene after 20% of the patients enrolled have completed Week 8 of the Treatment 
Phase and the double-blind data is available for review. If safety or tolerability issues are identified by 
the MM for patients while receiving LYT-100 versus placebo at any time, the SRC may meet to review 
safety and available population PK data and provide recommendations. Options for changes to dosing 
or protocol assessments may be recommended by the SRC. Ultimate decisions regarding those 
recommendations remain with the Sponsor. 
Number of Patients (Planned):  
Approximately 50 patients with breast cancer-related upper limb unilateral secondary lymphedema.  
Main Criteria for Inclusion and Exclusion 
Inclusion Criteria: 
1. Provides written Ethics Committee approved informed consent prior to any study procedures. 
2. Female or male aged ≥ 18 years old at the time of informed consent. 


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3. At least 6 months and no more than 15 years since the most recent type of surgery performed 
to treat primary breast cancer including sentinel lymph node biopsy or excision/clearance, 
axillary lymph node dissection, or any other type of surgery excluding fine needle aspiration 
biopsy [FNA], at the time of study Screening. No intention to have breast reconstructive 
surgery, nipple reconstruction, and/or tattooing during the course of the study. 
4. At least 3 months since completion of any neoadjuvant therapy, adjuvant chemotherapy, 
intravenous biologic therapy (e.g., trastuzumab and pertuzumab), radiotherapy, and/or any 
investigational adjuvant therapy at the time of study Screening.  
5. At least 3 months since initiation of anti-hormonal oral adjuvant therapy as well as goserelin 
and/or adjuvant zolendronic acid.  
6. Diagnosis of primary breast cancer, and without evidence of local, locoregional and/or distant 
recurrence of breast cancer for at least 6 months since completion of adjuvant therapy 
(excluding anti-hormonal therapy regimens), as determined at Screening and Baseline.  
7. Documented evidence of pitting edema in one arm for at least 3 months and also at Screening, 
and at least one of the following: 
a. Increase in relative limb volume of between 10% to 25% as measured by perometry or 
the truncated cone method of circumferential tape measurement compared to any prior 
documented measurement or relative to current measurement of non-affected arm 
b. A bioimpedance measure of > 10 at baseline visit or a change from pre-surgical 
measure of > +6.5 L-Dex at baseline visit; or 
c. Overt signs of lymphedema in the arm clinically indicating Lymphedema Stage I or II  
and/or confirmed by asymmetry > 2 via LymphaScan tissue dielectric constant (TDC) 
in swell spot.  
8. Receiving standard of care compression or agreeable to using care compression, i.e., sleeves 
and/or pumps and/or manual lymphatic drainage, or no compression care and/or no manual 
lymphatic drainage ≥ 4 weeks prior to Screening and throughout the study. 
9. In good general health at Screening and Baseline apart from a history of breast cancer and 
secondary lymphedema, i.e., free from clinically significant unstable medical, surgical, or 
psychiatric illness (at the discretion of the Investigator); no acute conditions requiring invasive 
care or hospitalization; and no conditions or elective procedures requiring invasive 
intervention within the next 6 months. 
10. Vital signs (measured in supine position after 10 minutes rest) at Screening: 
a. Systolic blood pressure ≥ 90 and ≤ 140 mmHg; 
b. Diastolic blood pressure ≥ 50 and ≤ 90 mmHg; 
c. Heart rate ≥ 45 and ≤ 100 bpm; 
d. Vital signs may be repeated once, within a minimum of 10 minutes of the completion 
of the last set of vital signs (while maintaining supine positions until the repeated set 
of vital signs are collected), if it is suspected that falsely high or low levels have been 
obtained. 
11. Body Mass Index (BMI) ≥ 18 and ≤ 50 kg/m2 at Screening. 
12. Human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B surface 
antigen (HBsAg) negative at Screening. 
13. Adequate venous access in contralateral, unaffected limb. 
14. Willing and able to comply with all study procedures and requirements including adherence to 
maintaining routine in either using or not using compression sleeve, compression pump, 


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lymphatic drainage therapy/self-manual lymph drainage (MLD). Patient should agree to not 
making extreme changes to their routine, also including diet, exercise, or skin care. 
15. Willing and able to abstain from direct whole body sun exposure from 2 days prior to dosing 
and until final study procedures have been conducted. Patients should be instructed to avoid or 
minimize exposure to sunlight (including sunlamps), use an SPF 50 sun block, or higher, wear 
clothing that protects against sun exposure, and avoid concomitant medications known to 
cause photosensitivity. 
16. Women of childbearing potential (WOCBP) must be non-pregnant and non-lactating, and must 
use an acceptable, highly effective double contraception or be abstinent from heterosexual 
intercourse from Screening until study completion, including the follow-up period (please see 
Section 10.4.3 for acceptable methods of contraception). WOCBP must have a negative 
pregnancy test at Screening and Day 1 and be willing to have additional pregnancy tests as 
required throughout the study. Women not of childbearing potential must be postmenopausal 
for ≥12 months or be surgically sterile, including a hysterectomy with retention of ovary 
function is permitted. Postmenopausal status will be confirmed through testing of FSH levels 
≥ 40 IU/mL at Screening for amenorrhoeic female patients. 
17. Male patients must be surgically sterile (> 30 days since vasectomy with no viable sperm), 
abstinent, or if engaged in sexual relations with a WOCBP, the patient and his partner must be 
surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy) or using an acceptable, highly effective contraceptive method from Screening 
until study completion, including the follow-up period and an additional 12 weeks after the last 
dose (please see Section 10.4.3 for acceptable methods of contraception). 
18. Males must not donate sperm for at least 90 days after the last dose of study drug. 
19. Partners of male patients and female patients will report pregnancy occurring within 
90 days from cessation of study medication. 
Exclusion Criteria: 
1. Bilateral lymphedema or history of bilateral axillary lymph node removal (i.e., sentinel lymph 
node biopsy or axillary lymph node dissection), or primary lymphedema or lymphatic or 
vascular malformation, determined at Screening.  
2. Chronic administration (defined as more than 14 consecutive days) of immunosuppressants or 
other immune-modifying drugs within 3 months prior to study drug administration; 
corticosteroids are permitted at the discretion of the PI. 
3. Recent history (in the 8 weeks prior to Screening) of cellulitis, lymphangitis, dermatitis, 
necrotizing fasciitis, or current open wounds or sores in the affected extremity.  
4. Fibrotic stranding on affected arm not related to breast cancer-related lymphedema (BCRL); 
history of breast or arm procedures unrelated to axillary node dissection such as 
non-cancer-related reconstructive or cosmetic breast surgery, Botox for hyperhidrosis, chronic 
intravenous use, port, pic-line, etc., for medical or recreational reasons, tattoos (excluding pink 
ribbon tattoo designated to inform health caretaker not to take blood pressure in affected arm), 
or other extreme body modifications, determined at Screening. 
5. Relative limb volume > 25%, stage III secondary lymphedema, or history of clinically 
diagnosed secondary lymphedema greater than 4 years, determined at Screening.  
6. Initiated use of compression or manual lymphatic drainage or other lymphedema therapies at 
the start of the study within 4 weeks of the Screening visit. Rescreening is allowed following a 
course of stable compression regimen of > 4 weeks. 
7. Metal implant(s) including implantable cardioverter defibrillators, cardiac resynchronization 
therapy-defibrillators, and pacemakers that may be affected by assessments used in the trial, 


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e.g., bioimpedance, and/or that may inconsistently affect collection of secondary lymphedema 
assessments. 
8. Presence of malignancy, with the exception of adequately treated localized skin cancer (basal 
cell or squamous cell carcinoma), carcinoma in-situ of the cervix, or unilateral breast cancer 
history with completed treatment and with no active cancer at the time of Screening or in the 
preceding 6 months.  
9. Evidence of clinically relevant medical history/illness at Screening, as determined by the 
Investigator, including stroke, uncontrolled hypertension, and other cardiac disease, vascular 
disease, pulmonary disease, gastrointestinal disease, hepatic disease, renal failure and other 
kidney disease, rheumatologic disease, coagulopathy or other hematological disease, 
uncontrolled diabetes and other endocrine disorders, any progressive neurologic disorder, 
psychiatric disease, dermatological disorder, or surgical history except for orthopedic and 
reconstructive breast cancer surgery. 
10. Clinically significant infection within 28 days of the start of dosing, as determined by the 
Investigator. 
11. Clinically significant surgical procedure/s, including but not limited to breast cancer 
reconstruction surgery, within 3 months of Screening, or further breast cancer reconstruction 
surgery planned during the Study. 
12. For baseline liver function tests (LFT) 2.5 × upper normal limit (UNL) or severe hepatic 
impairment. 
13. Positive test for HCV, HBsAg, or HIV antibody at Screening. 
14. Currently suffering from clinically significant systemic allergic disease at Screening or 
Baseline or has a history of significant drug allergies including a history of anaphylactic 
reaction (particularly reactions to general anesthetic agents); allergic reaction due to any drug 
which led to significant morbidity; prior allergic reaction to pirfenidone. 
15. Pregnant or lactating at Screening or planning to become pregnant (self or partner) at any time 
during the study, including the follow-up period. 
16. Symptoms of dysphagia or known difficulty in swallowing capsules, determined at Screening. 
17. History or presence of cardiac arrhythmia or congenital long QT syndrome determined at 
Screening. 
18. QTcF > 450 msec demonstrated by two ECGs between 30 and 60 minutes apart at Screening. 
19. Use of tobacco or nicotine-containing products in the previous 30 days prior to dosing or a 
positive urine cotinine test at Screening or Baseline. 
20. Lack of willingness to abstain from the consumption of tobacco or nicotine-containing 
products throughout the duration of the study and until completion of the final follow-up visit. 
21. Regular alcohol consumption defined as > 21 alcohol units per week (where 1 unit = 284 mL 
of beer, 25 mL of 40% spirit, or a 125 mL glass of wine), determined at Screening.  
22. Positive toxicology Screening panel (urine test including qualitative identification of 
barbiturates, amphetamines, opiates, and cocaine) or alcohol breath or urine test, determined at 
Screening.  Repeat urine toxicology screenings may be conducted 
23. History of substance abuse or dependency or history of recreational IV drug use over the last 
2 years, determined at Screening.  
24. Use of any over--the-counter medication, herbal supplements, or diet aids within 48 hours 
prior to dosing without the prior review and approval of the PI and medical monitor  
25. Treated with immunosuppressive or antifibrotic drugs, anti-tumor necrosis factor, 
immunotherapy, or investigational drugs at Screening or within the preceding 30 days. 


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26. Use of any of the following drugs within 28 days or 10 half-lives of that drug, whichever is the 
longer, prior to study drug administration: 
a. Fluvoxamine, enoxacin, ciprofloxacin; 
b. Other inhibitors of CYP1A2 (including but not limited to methoxsalen or mexiletine); 
c. Inducers of CYP1A2 (such as phenytoin), CYP2C9 or 2C19 (including but not limited 
to carbamazepine or rifampin); 
d. Drugs associated with substantial risk for prolongation of the QTc interval (including 
but not limited to moxifloxacin, quinidine, procainamide, amiodarone, sotalol).  
27. Use of any investigational drug or device within 28 days or 10 half-lives of the drug, 
whichever is the longer, prior to start of dosing. 
28. Clinically significant blood loss or any blood or blood product donation > 250 mL within 
28 days of start of dosing. 
29. Any condition (e.g., chronic diarrhea, inflammatory bowel disease or prior surgery of the 
gastrointestinal tract) that would interfere with drug absorption or any disease or condition that 
is likely to affect drug metabolism, or excretion, determined at Screening. 
30. History of anaphylactic reaction (particularly reactions to general anesthetic agents); 
allergic reaction due to any drug which led to significant morbidity; prior allergic reaction 
to pirfenidone. 
31. As a result of medical review and physical examination at Screening, the Investigator 
considers the patient unfit for the study. 
Dosage and Mode of Administration:  
All patients will be randomized to receive LYT-100 or placebo in a 1:1 ratio.  
The dose and dosing regimens are presented below in Table 4. 
Table 4. 
Dose and Dosing Regimen 
Study Design 
Placebo (N) 
LYT-100 (N) 
LYT-100 dose 
Treatment 
Duration 
(Days) 
N = 50 
25 
25 
LYT-100 BID** 
(titrate to 750 mg) or matching placebo**  
182 
** Patients will be administered LYT-100 study medication, or placebo, orally with food with approximately 10 to 
12 hours between the two daily doses (BID). 
Duration of Treatment with Study Medication:  
26 weeks (6 months) 
Criteria for Evaluation: 
Safety: 
Safety and tolerability will be assessed throughout all parts of the study by monitoring AEs, physical 
examination, vital signs, 12-lead ECGs, clinical laboratory values (hematology, serum chemistry, 
coagulation, and urinalysis), and review of concomitant treatments/medication use. 
Efficacy: 
The following parameters will be measured as per the schedule of assessments (Table 5)  
• 
Limb water content, by bioelectrical impedance spectroscopy (BIS). 
• 
Limb volume (truncated cone tape measure and/or perometry). 


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• 
Tissue dielectric constant (MoistureMeterD). 
• 
Tissue firmness (tonometry/SkinFibroMeter). 
• 
Visual analog scales for pain, swelling, discomfort, and function. 
Health-related QoL:  
The following will be assessed as per the Schedule of Assessments (Table 5)   
• 
LYMPH-Q- Upper Extremity Module see Appendix 2. 
• 
Lymphedema Quality of Life Tool, Arm (LYMQOL); see Appendix 3. 
Occurrence of Infection: 
The following will be assessed along with AEs: 
• 
Cellulitis 
• 
Lymphangitis 
Pharmacokinetics: 
Patients will provide blood samples at Baseline (Day -1) for the determination of CYP1A2, CYP2C9, 
CYP2C19, and CYP2D6 genotype to support exploratory PK analyses. Patients are required to provide 
consent for genotyping. 
Blood samples (4 mL each) for population PK will be collected at specified times at any visit from 
Week 1 to Week 26 of the study. Each patient will provide a minimum of 1 sample at each timepoint in 
reference to dosing: Pre-dose, 1 to < 2 hours, 2 to < 4 hours, 4 to < 8 hours, 8 to 12 hours.  
Fibrotic and Inflammatory Biomarkers: 
The following parameters will be measured at select study visits as per the Schedule of Assessments: 
• 
Fibrotic and inflammatory biomarkers (granulocyte colony stimulating factor [G-CSF], 
monokine induced by gamma interferon [MIG], fibroblast growth factor-2 [FGF-2], 
interleukin(IL)-4, IL-10, lymphotoxin-α/ tumor necrosis factor beta [TNF-β], leptin, IL-6, 
IL-1β, tumor necrosis factor alpha [TNF-α], TGF-β1, matrix metalloproteinase 9 
[MMP-9], tissue inhibitor of matrix metalloproteinase 1 [TIMP-1], monocyte 
chemoattractant protein-1 [MCP-1]). 
These data may be reported separately in a supplementary report to the main Clinical Study Report. 
Endpoints for the Study are Defined as Follows: 
Primary Endpoint: 
• 
Safety and tolerability (AEs, physical examination, vital signs, ECGs, clinical laboratory 
parameters [hematology, serum chemistry, coagulation, and urinalysis], and concomitant 
treatments). 
Secondary Endpoint: 
• 
Efficacy: 
− Limb water content, by BIS. 
− Limb volume (perometry). 
− Tissue dielectric constant (MoistureMeterD). 
− Tissue firmness (tonometry/SkinFibroMeter). 
− Visual analog scales for pain, swelling, discomfort, and function. 
• 
Infection: 
− Cellulitis. 


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− Lymphangitis. 
• 
Health-related QoL: 
− LYMPH-Q- Upper Extremity Module (Appendix 2). 
− LYMQOL (Appendix 3). 
• 
Population PK parameters. 
• 
Fibrotic and Inflammatory biomarkers: 
− Fibrotic and inflammatory biomarkers (G-CSF, MIG, FGF-2, IL-4, IL-10, 
lymphotoxinα/TNF-β, leptin, IL-6, IL-1β, TNF-α, TGF-β1, MMP-9, TIMP-1, MCP1). 
Statistical Methods: 
A statistical analysis plan (SAP) will be written that will describe, in greater detail, the analyses to be 
performed for each part. The sections below provide a summary of the general approach to the 
analysis. The analysis is consistent with the study design. Note that this study is not hypothesis testing 
but rather hypothesis-generating, and thus conclusions regarding outcomes will not be based on 
inferential tests but rather descriptive outcomes, magnitude of treatment effects, and a preponderance 
of evidence regarding the risk-benefit profile of LYT-100. 
Sample Size 
Approximately 50 patients with secondary lymphedema will be randomized in a 1:1 ratio to LYT-100 
or placebo, as part of this early development and exploratory study of LYT-100. Formal sample size 
calculations will not be performed; rather, the sample size selected should be adequate for preliminary 
evaluation of safety, tolerability, efficacy signaling, PK, and fibrotic and inflammatory biomarker 
parameters in the targeted patient population. 
General Statistical Plan 
The baseline for all variables will be the last measurement obtained prior to the patient receiving the 
first dose of study treatment.  
Patient disposition (including the number and percent of patients who are enrolled, who receive 
treatment, who prematurely discontinue and reasons for discontinuation, and who complete the study) 
will be tabulated by treatment group. Summary statistics for days of exposure and concentration of 
exposure will be provided by treatment group. 
AEs, concomitant medications, clinical laboratory findings, physical examinations, ECGs, and vital 
signs for each patient will be tabulated or summarized descriptively, where appropriate.  
Demographic information will be presented for each patient and summarized. Treatment-emergent 
adverse events (TEAEs) and laboratory, vital signs, and ECG parameters will be summarized. In 
addition, change from baseline will be summarized for laboratory and vital sign parameters. Shift 
tables will also be provided for clinical laboratory results. ECG results will be classified as normal and 
abnormal and summarized. ECG results for QTcF will also be classified as < 450 msec, 450 to 
500 msec or > 500 msec. Changes in physical exams will be described. 
 
Study Populations 
• 
The Safety Population is defined as all patients who receive LYT-100, or Placebo.  
• 
The Full Analysis Set (FAS) population is defined as all randomized patients who received at 
least one dose of double-blinded study medication and had at least one post-baseline efficacy 
assessment. All efficacy endpoints will be assessed using this population. 
• 
The Pharmacokinetic Population (PP) is defined as all patients who receive the double-blinded 
study medication and for whom an evaluable concentration-time profile is available for the 
determination of at least one PK variable. Patients with emesis after consuming study 


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medication will be assessed on a case-by-case basis for eligibility for inclusion in the PK 
population. In general, patients who vomit after at least 2 half-lives of the given medication 
will be included in the PK population (as Cmax will presumably be reached by that time).  
• 
The Fibrotic and Inflammatory Biomarker Population is defined as all patients who receive the 
double-blinded study medication and who provide biomarker and lymphedema assessment 
data. 
Study-Specific Requirements 
Analysis of clinical assessments and potential progression or disease will be explored. Comparisons 
between LYT-100 and placebo will be based on clinical interpretation of effect, magnitudes of effect, 
and a preponderance of evidence. Estimates of changes over time from these data may be used to 
power future clinical studies. 
The primary endpoints are safety (clinical laboratory parameters, vital signs, ECGs, and spontaneously 
reported AEs) and tolerability of the double-blinded study medication. Secondary endpoints include 
efficacy (lymphedema assessments, infection, and health-related QoL), population PK, and fibrotic and 
inflammatory biomarkers of the double-blinded study medication. 
Change from baseline to each post-baseline visit (through Week 26; on-treatment effect) on the 
following endpoints will be calculated for the following endpoints: fibrotic and inflammatory 
biomarkers (G-CSF, MIG, FGF-2, IL-4, IL-10, lymphotoxin α/TNF-β, leptin, IL-6, IL-1β, TNF-α, 
TGF-β1, MMP-9, TIMP-1, MCP-1), limb water content (BIS), limb volume (truncated cone tape 
measure and/or perometry), tissue dielectric constant (MoistureMeterD), tissue firmness 
(tonometry/SkinFibroMeter), visual analog scales (pain, swelling, discomfort, and function), and QoL 
(LYMPH-Q, LYMQOL). For select efficacy outcomes, use of a mixed model for repeated measures 
(MMRM) will be used to provide model-based estimates of changes over time in each of these 
outcomes. Descriptive statistics will also be provided at each time point. Details for the model 
(including covariates to be included) will be provided in the SAP. 
Data for all endpoints will be tabulated, displayed graphically, or summarized descriptively, as 
appropriate. No formal hypothesis testing will be performed.  


Protocol Number: LYT-100-2020-01 US 
 
 
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3. 
STUDY SCHEDULE OF ASSESSMENTS 
Table 5. 
Schedule of Events  
 
Screening 
Baseline 
LYT-100 Patient Cohort Double-Blind Treatment Phase1 
(N = approximately 50) 1 
Final 
Safety 
Visit 
Study Day 
Day -28 to 
Day -2 
Day -1 
Day 1 
Week 1 
Week 2 
Week 4 
Week 8 Week 12 Week 16 Week 20 
Week 23 
Week 26 or 
Early 
Termination2 
Week 30 
(28 days 
from last 
dose) 
Study Drug 
 
 
Dose 
Dose 
Dose 
Dose 
Dose 
Dose 
Dose 
Dose 
Dose 
D/C Dose 
n/a 
+/- Days Allowable 
 
+/-0 
+/-0 
+/-2 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
Visit 
1 
2 
(no 
visit) 
3 
Phone Call 
4 
5 
6 
7 
8 
Phone 
Call 
9 
10 
Outpatient Clinic Visit 
X 
X 
(no 
visit) 
X 
Phone Call 
X 
X 
X 
X 
X 
Phone 
Call 
X 
X 
Informed Consent3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Assessment 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History4 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
12-lead ECG (QTcF)5 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Physical Exam6 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Vital Signs (Height, 
Weight, BMI, Body 
Temp, HR, BP, RR)7,8 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Bioimpedance8 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
Limb Volume8, 20 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
MoistureMeterD8 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
Tonometry/Skin 
FibroMeter8 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
Visual Analog Scales  
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
LYMPH-Q 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
LYMQOL 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 


Protocol Number: LYT-100-2020-01 US 
 
 
PureTech LYT 100, Inc. 
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Screening 
Baseline 
LYT-100 Patient Cohort Double-Blind Treatment Phase1 
(N = approximately 50) 1 
Final 
Safety 
Visit 
Study Day 
Day -28 to 
Day -2 
Day -1 
Day 1 
Week 1 
Week 2 
Week 4 
Week 8 Week 12 Week 16 Week 20 
Week 23 
Week 26 or 
Early 
Termination2 
Week 30 
(28 days 
from last 
dose) 
Study Drug 
 
 
Dose 
Dose 
Dose 
Dose 
Dose 
Dose 
Dose 
Dose 
Dose 
D/C Dose 
n/a 
+/- Days Allowable 
 
+/-0 
+/-0 
+/-2 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
Visit 
1 
2 
(no 
visit) 
3 
Phone Call 
4 
5 
6 
7 
8 
Phone 
Call 
9 
10 
Sparse  
PK Blood Samples 8, 9 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
Concomitant Medication10 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events11 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test12 
Urine 
Urine 
 
 
 
 
 
Urine 
 
 
 
Urine 
 
FSH13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Genotyping14 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematology 8, 15 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
Chemistry8, 16 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
Coagulation8, 17 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
Urinalysis  
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
Urine Cotinine, drug 
screen & alcohol breath 
test 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
Exploratory Inflammatory 
Biomarkers8, 18 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
Review Patient Diary19 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Week 26 
diary 
reminder 
X 
 
Study Drug Dispensing 
and Drug Accountability 
 
X 
(first 
dose 
taken) 
X 
 
X 
X 
X 
X 
X 
(cont. 
dosing) 
(acct. 
only) 
n/a 
Participant Interview21 
X 
 
 
 
 
 
 
 
 
 
 
 
X 


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Abbreviations: AE = adverse event; ALT = alanine aminotransferase; APTT = activated partial thromboplastin time; AST = aspartate aminotransferase; 
BID = twice a day; BMI = Body Mass Index; BP = blood pressure; D/C = discontinue; ECG = electrocardiogram; FSH = follicle-stimulating hormone; 
HR = heart rate; LYMPH-Q- Upper Extremity Module;; LYMQOL = Lymphedema Quality of Life Tool, Arm; n/a = not applicable; PK = pharmacokinetics; RR 
= respiratory rate. 
 
1. Double-blind treatment is either LYT-100, 750 mg BID or matching placebo by mouth, on an outpatient basis.  
2. Early termination is defined as premature discontinuation t 
3. Informed consent must be documented before any study-specific Screening procedures are performed. 
4. Medical history includes breast cancer, surgical, radiation and therapy history. It should be updated as needed at the final safety visit (# 11). 
5. ECG are to be conducted 2.5 hours (+/- 15 minutes) after the morning study drug dose on Week 1 and Week 12 visits.  
6. A full physical exam will be conducted at the Screening and final safety visits. Symptom directed physical examinations will be performed at all other 
indicated visits. 
7. Height is collected at baseline while vital signs, weight, and BMI are collected only one time at each designated visit. 
8. All breast cancer-related lymphedema (BCRL) assessments should be done toward the end of the study visit.  If the patient is using a compression sleeve, it 
should be removed upon arrival at the study visit and not placed back on until all assessments for the study visit are collected. Where possible, BCRL 
assessments may be conducted at the Screening (in addition to baseline) visit so that patients do not fail eligibility at baseline.  
9. Pharmacokinetic samples are collected at each visit except Screening, baseline, and post-treatment phase. Last dose taken prior to blood collection will be 
recorded. Population PK will be grouped into the following timepoint ranges post-study med dose administration: Hour 0, Hour 1 to < 2, Hour 2 to < 4, 
Hour 4 to < 8, Hour 8 to 12.  
10. Concomitant medications include all medications taken 30 days prior to the Screening visit. 
11. Adverse events include medical conditions such as infections (e.g., cellulitis and lymphangitis) starting or worsening after LYT-100 or placebo 
administration. All other medical conditions reported around Screening and Baseline prior to study treatment administration will be reported as pre-treatment 
AEs. 
12. Not required for amenorrhoeic female patients (see below); if a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
13. Amenorrhoeic female patients only; postmenopausal status will be confirmed through testing of FSH levels (≥ 40 IU/mL). 
14. Patients will provide blood samples at baseline (Day -1) for the determination of CYP1A2, CYP2C9, CYP2C19, and CYP2D6 genotyping – Sample to be 
obtained on Day -1 of the first period only. Patients are required to provide consent for genotyping. 
15. Hematology includes complete blood count and differential. 
16. Serum chemistry includes glucose, total protein, albumin, electrolytes (sodium, potassium, chloride, total CO2), calcium, phosphorus, magnesium, uric acid, 
bilirubin (total, direct), ALT or AST, alkaline phosphatase, creatinine, blood urea nitrogen, creatine phosphokinase (CPK). Liver Function Tests (LFTs) will 
be collected at each visit and includes bilirubin (total, direct), ALT or AST, and alkaline phosphatase. 
17. Coagulation includes international normalized ratio (INR), prothrombin time and APTT. 
18. Inflammatory markers include: G-CSF, MIG, FGF-2, IL-4, IL-10, lymphotoxin-α/TNF-β, leptin, IL-6, IL-1β, TNF-α, TGF-β1, MMP-9, TIMP-1, MCP-1. 
19. Patient completes the Patient Diary starting 1 week prior to each study visit and returns the diary at the end of the week while attending the study visit. 
20. Relative limb volume is measured by perometry. Perometry is a non-invasive technique involving a Perometer (Pero-System), which uses infrared light to 
scan a limb and obtain measurements of the limb's circumference. The truncated cone tape measure method can be used as a backup if the Perometer is 
unavailable, or not working at time of the patient visit. 
21. Patients will be asked to participate in interviews to discuss their Breast Cancer related Lymphedema either during screening (i.e. to include subjects that are deemed 
ineligible and not able to participate in the study) or at the end of the treatment period (Week 30 for those that are deemed eligible and complete study treatment)


 
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4. 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................4 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
STUDY SCHEDULE OF ASSESSMENTS ..............................................................15 
4. 
TABLE OF CONTENTS ...........................................................................................18 
LIST OF TABLES .........................................................................................................................23 
5. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................24 
6. 
FACILITIES AND PERSONNEL .............................................................................28 
7. 
BACKGROUND AND INTRODUCTION ...............................................................29 
7.1. 
Introduction .................................................................................................................29 
7.2. 
Summary of Nonclinical and Clinical Studies ............................................................30 
7.2.1. 
Nonclinical Studies .....................................................................................................30 
7.2.1.1. 
Pharmacology .............................................................................................................30 
7.2.1.2. 
Pharmacokinetics ........................................................................................................30 
7.2.1.3. 
Toxicology ..................................................................................................................30 
7.2.1.4. 
Carcinogenesis ............................................................................................................31 
7.2.2. 
Clinical Studies ...........................................................................................................31 
7.3. 
Summary of Potential Risks and Benefits ..................................................................33 
7.4. 
Dosage and Treatment Periods ...................................................................................33 
7.4.1. 
Rationale for Selection of Dose ..................................................................................34 
7.5. 
Patient Population .......................................................................................................34 
7.6. 
Ethical Principles ........................................................................................................34 
8. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................35 
8.1. 
Objectives ...................................................................................................................35 
8.2. 
Endpoints ....................................................................................................................35 
9. 
INVESTIGATIONAL PLAN .....................................................................................37 
9.1. 
Overall Study Design ..................................................................................................37 
9.1.1. 
Treatment Period ........................................................................................................37 
9.1.2. 
Follow-Up ...................................................................................................................38 


 
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9.2. 
Number of Patients .....................................................................................................38 
9.3. 
Treatment Assignment ................................................................................................38 
9.4. 
Safety Review Committee ..........................................................................................39 
9.5. 
Dose Adjustment Criteria ...........................................................................................39 
9.6. 
Criteria for Study Termination ...................................................................................46 
10. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................47 
10.1. 
Patient Inclusion Criteria ............................................................................................47 
10.2. 
Patient Exclusion Criteria ...........................................................................................49 
10.3. 
Patient Withdrawal Criteria ........................................................................................51 
10.4. 
Diet, Activity, and Other Restrictions ........................................................................52 
10.4.1. 
Medication ..................................................................................................................52 
10.4.2. 
Smoking ......................................................................................................................53 
10.4.3. 
Contraception ..............................................................................................................53 
10.4.4. 
Food ............................................................................................................................54 
10.4.5. 
Other Restrictions .......................................................................................................54 
11. 
TREATMENT OF PATIENTS ..................................................................................55 
11.1. 
Description of Study Drug ..........................................................................................55 
11.2. 
Prior and Concomitant Medications ...........................................................................55 
11.2.1. 
Prior Medications ........................................................................................................55 
11.2.2. 
Concomitant Medications ...........................................................................................55 
11.3. 
Treatment Compliance ................................................................................................55 
11.4. 
Blinding ......................................................................................................................55 
12. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................57 
12.1. 
Study Supplies ............................................................................................................57 
12.2. 
Study Drug Packaging and Labeling ..........................................................................57 
12.3. 
Study Drug Storage .....................................................................................................57 
12.4. 
Study Drug Preparation ..............................................................................................57 
12.5. 
Administration ............................................................................................................57 
12.6. 
Study Drug Accountability .........................................................................................57 
12.7. 
Study Drug Handling and Disposal ............................................................................57 
13. 
STUDY SCHEDULE .................................................................................................58 
13.1. 
Screening (Visit 1), Day -28 to Day -2 .......................................................................58 
13.2. 
Baseline (Visit 2), Day -1 ...........................................................................................59 


 
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13.3. 
Visit 3 (Week 1, +2 days) ...........................................................................................60 
13.4. 
Telephone Visit (Week 2, ± 3 days) ...........................................................................60 
13.5. 
Visit 4 (Week 4, ± 3 days) ..........................................................................................60 
13.6. 
Visit 5 (Week 8, ± 3 days) ..........................................................................................61 
13.7. 
Visit 6 (Week 12, ± 3 days) ........................................................................................62 
13.8. 
Visit 7 (Week 16, ± 3 days) ........................................................................................63 
13.9. 
Visit 8 (Week 20, ± 3 days) ........................................................................................63 
13.10. 
Telephone Visit (Week 23, ± 3 days) .........................................................................64 
13.11. 
Visit 9 (Week 26 ± 3 days) or Early Termination ......................................................64 
13.12. 
Visit 10 (Final Safety Visit), 28 ± 3 Days After Termination of Study 
Treatment ....................................................................................................................65 
14. 
PHARMACOKINETIC AND FIBROTIC AND INFLAMMATORY 
BIOMARKER ASSESSMENTS ................................................................................66 
14.1. 
Blood and Urine Sample Collection ...........................................................................66 
14.1.1. 
Pharmacokinetics ........................................................................................................66 
14.1.2. 
Fibrotic and Inflammatory Biomarkers ......................................................................66 
14.1.3. 
Quality of Life ............................................................................................................67 
14.2. 
Sample Analysis .........................................................................................................67 
15. 
ASSESSMENT OF SAFETY .....................................................................................68 
15.1. 
Safety Parameters .......................................................................................................68 
15.1.1. 
Demographic/Medical History ...................................................................................68 
15.1.2. 
Vital Signs ..................................................................................................................68 
15.1.3. 
Weight and Height ......................................................................................................68 
15.1.4. 
Physical Examination .................................................................................................68 
15.1.5. 
Electrocardiogram .......................................................................................................69 
15.1.6. 
Laboratory Assessments .............................................................................................69 
15.1.6.1. 
Hematology .................................................................................................................69 
15.1.6.2. 
Serum Chemistry ........................................................................................................69 
15.1.6.3. 
Coagulation .................................................................................................................70 
15.1.6.4. 
Urinalysis ....................................................................................................................70 
15.1.6.5. 
Urine Drug Screen ......................................................................................................71 
15.1.6.6. 
Alcohol Breath Test ....................................................................................................71 
15.1.6.7. 
Pregnancy Testing ......................................................................................................71 


 
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15.1.6.8. 
Follicle-Stimulating Hormone Test ............................................................................71 
15.1.6.9. 
Genotyping .................................................................................................................71 
16. 
ADVERSE AND SERIOUS ADVERSE EVENTS ...................................................72 
16.1. 
Definition of Adverse Events .....................................................................................72 
16.1.1. 
Severity of an Adverse Event .....................................................................................73 
16.1.2. 
Causal Relationship of an Adverse Event ..................................................................73 
16.1.3. 
Action Taken with Investigational Products ...............................................................74 
16.1.4. 
Outcome ......................................................................................................................74 
16.2. 
Definition of Serious Adverse Event ..........................................................................74 
16.2.1. 
Notification of a Serious Adverse Event ....................................................................75 
16.3. 
Clinical Laboratory Abnormalities and other Abnormal Assessments as 
Adverse Events and Serious Adverse Events .............................................................75 
16.4. 
Recording Adverse Events .........................................................................................76 
16.5. 
Reporting Adverse Events ..........................................................................................77 
16.6. 
Follow-up of Adverse Events and Serious Adverse Events .......................................77 
16.7. 
Randomization Code Break ........................................................................................77 
17. 
ASSESSMENT OF EFFICACY ................................................................................78 
18. 
STUDY COMPLETION AND DISCONTINUATION .............................................80 
18.1. 
Patient Withdrawal .....................................................................................................80 
18.2. 
Patient Replacement ...................................................................................................80 
19. 
TERMINATION OR SUSPENSION OF THE STUDY............................................81 
20. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................82 
20.1. 
Study Monitoring ........................................................................................................82 
20.2. 
Data Management .......................................................................................................82 
20.3. 
Audits and Inspections ................................................................................................83 
21. 
STATISTICS ..............................................................................................................84 
21.1. 
Sample Size ................................................................................................................84 
21.2. 
General Statistical Plan ...............................................................................................84 
21.3. 
Analysis Populations ..................................................................................................85 
21.4. 
Safety and Tolerability ...............................................................................................85 
21.4.1. 
Prior and Concomitant Medication .............................................................................85 
21.4.2. 
Adverse Events ...........................................................................................................85 
21.4.3. 
Laboratory Evaluations ...............................................................................................86 


 
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21.4.4. 
Vital Signs ..................................................................................................................86 
21.4.5. 
Electrocardiogram Values and Results .......................................................................86 
21.4.6. 
Other Safety Assessments ...........................................................................................86 
21.5. 
Pharmacokinetics ........................................................................................................86 
21.6. 
Fibrotic and Inflammatory Biomarkers ......................................................................86 
21.7. 
Efficacy Endpoints ......................................................................................................87 
22. 
ETHICS ......................................................................................................................88 
22.1. 
Ethics Review .............................................................................................................88 
22.2. 
Ethical Conduct of the Study ......................................................................................88 
22.3. 
Written Informed Consent ..........................................................................................88 
22.4. 
Data Protection ...........................................................................................................89 
23. 
REGULATORY REQUIREMENTS .........................................................................90 
24. 
DATA HANDLING AND RECORDKEEPING .......................................................91 
24.1. 
Inspection of Records .................................................................................................91 
24.2. 
Retention of Records ..................................................................................................91 
24.3. 
Liability/Indemnity/Insurance ....................................................................................91 
25. 
PUBLICATION POLICY ..........................................................................................92 
25.1. 
Publication of Results .................................................................................................92 
25.2. 
Disclosure and Confidentiality ...................................................................................92 
26. 
QUALITY CONTROL AND QULAITY ASSURANCE .........................................93 
26.1. 
Compliance with Good Clinical Practice ...................................................................93 
26.2. 
Archiving and Regulatory Inspection .........................................................................93 
27. 
SPONSOR AND INVESTIGATOR OBLIGATIONS ..............................................94 
27.1. 
Protocol Amendments ................................................................................................94 
27.2. 
Protocol Deviations ....................................................................................................94 
28. 
LIST OF REFERENCES ............................................................................................95 
APPENDIX 1: BLOOD VOLUMES.............................................................................................96 
APPENDIX 2: LYMPH-Q—UPPER EXTREMITY MODULE ..................................................97 
APPENDIX 3: LYMPHEDEMA QUALITY OF LIFE TOOL, ARM (SAMPLE) ....................101 
APPENDIX 4: INFECTION/CELLULITIS FORM (SAMPLE) ................................................102 
 
 


 
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LIST OF TABLES 
Table 1. 
Emergency Contact Information ...................................................................................4 
Table 2. 
Dosing Regimens for Days 1 Through 3 and Thereafter ..............................................6 
Table 3. 
Baseline Randomization Stratification Levels ...............................................................6 
Table 4. 
Dose and Dosing Regimen .........................................................................................11 
Table 5. 
Schedule of Events .....................................................................................................15 
Table 6.  
Facilities and Personnel ..............................................................................................28 
Table 7. 
Dose and Dosing Regimen .........................................................................................34 
Table 8. 
Baseline Randomization Stratification Levels ............................................................39 
Table 9. 
Non-Hematological Adverse Events Dose Adjustment Guidance .............................40 
Table 10. 
Hematological Adverse Events Dose Adjustment Guidance .....................................44 
Table 11: Estimated Blood Volumes ..........................................................................................96 
 
 


 
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5. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse Event 
ALB 
Albumin  
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase  
AMP 
Amphetamines  
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase  
ATC 
Anatomical therapeutic chemical 
BAR 
Barbiturates  
BASO 
Basophils  
BCRL 
Breast cancer-related lymphedema 
BICARB 
Bicarbonate  
BID 
Twice daily 
BILI 
Total Bilirubin 
BILIDIR 
Direct Bilirubin 
BIS 
Bioelectrical impedance spectroscopy 
BMI 
Body Mass Index 
BP 
Blood pressure 
BZO 
Benzodiazepines  
CA 
Calcium  
CFR 
Code of Federal Regulation 
CL 
Chloride  
Cmax 
Observed maximum plasma concentration 
COC 
Cocaine  
CPK 
Creatine phosphokinase 
CREAT 
Creatinine  
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
CRU 
Clinical research unit 
CSR 
Clinical study report 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 


 
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Abbreviation or Specialist Term 
Explanation 
ESN 
Eosinophils  
FDA 
Food and Drug Administration 
FGF-2 
Fibroblast Growth Factor-2 
FNA 
Fine needle aspiration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony stimulating factor 
GGT 
Gamma glutamyl transpeptidase 
GLOBUL 
Globulin  
GLU 
Glucose  
HBsAg 
Hepatitis B surface antigen 
HCT 
Hematocrit  
HCV 
Hepatitis C virus 
HGB 
Hemoglobin 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IL-10 
Interleukin 10 
IL-1β 
Interleukin 1 beta 
IL-4 
Interleukin 4 
IL-6 
Interleukin 6 
INR 
International normalized ratio 
IP 
Investigational product 
IPF 
idiopathic pulmonary fibrosis 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
K 
Potassium  
LFT 
Liver function test 
LYM 
Lymphocytes  


 
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Abbreviation or Specialist Term 
Explanation 
LYMPH-Q 
Lymphedema Questionnaire- Upper Extremity Module 
LYMQOL 
Lymphedema Quality of Life Tool, Arm 
MCP-1 
Monocyte Chemoattractant Protein-1 
MDMA 
Methylenedioxymethamphetamine  
MedDRA® 
Medical Dictionary for Regulatory Activities 
MET 
Methamphetamines  
MIG 
Monokine induced by gamma interferon 
MLD 
Manual lymph drainage 
MM 
Medical Monitor 
MMP-9 
Matrix Metalloproteinase 9 
MMRM 
Mixed model for repeated measures 
MTD 
Methadone  
n 
Number 
n/a 
Not applicable 
NA 
Sodium  
NEUT 
Neutrophils  
OCCBLD 
Occult Blood 
OCP 
Oral contraceptive pill 
OPI 
Opiates  
OTC 
Over-the-counter 
PCP 
Phencyclidine 
PD 
Pharmacodynamics 
PHOS 
Phosphate  
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PLAT 
Platelets 
PP 
Pharmacokinetic population 
PROT 
Protein  
PT 
Preferred term 
QoL 
Quality of life 
QTcF 
QT interval corrected using Fridericia’s formula 
RBC 
Red blood cells 
RETI 
Reticulocytes  
RR 
Respiration rate 


 
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Abbreviation or Specialist Term 
Explanation 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SOC 
System organ class 
SPGRAV 
Specific Gravity 
SRC 
Safety Review Committee 
TDC 
Tissue dielectric constant 
TEAE 
Treatment-emergent adverse event 
TGF-β1 
Transforming growth factor beta 1 
THC 
Tetrahydrocannabinol  
TID 
Three times a day 
TIMP-1 
Tissue inhibitor of matrix metalloproteinase 1 
TNF-α 
Tumor necrosis factor alpha 
TNF-β 
Tumor necrosis factor beta 
TROP1 
Troponin 1 
U 
Urea  
UROBIL 
Urobilinogen  
US 
United States 
WBC 
Leukocytes  
WHO 
World Health Organization 
WOCBP 
Woman of childbearing potential 


 
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6. 
FACILITIES AND PERSONNEL 
 
Table 6.  
Facilities and Personnel  
Sponsor 
PureTech LYT 100, Inc. 
6 Tide Street, Suite 400 
Boston, MA, 02210 
USA 
Local Australian Sponsor 
Novotech (Australia) Pty Limited 
Level 3, 235 Pyrmont Street 
Sydney, NSW, 2009 
Australia 
Pharmacokinetic Laboratory 
Agilex Biolabs 
28 Dalgleish Street 
Thebarton, SA, 5031 
Australia 
Biomarker Laboratory 
Agilex Biolabs 
28 Dalgleish Street 
Thebarton, SA, 5031 
Australia 
Genotyping Lab 
Sonic Clinical Trials 
14 Giffnock Avenue 
Macquarie Park, NSW, 2113 
Australia 
Biostatistical Analysis, Data 
Management, Project Management, 
Monitoring 
Novotech (Australia) Pty Limited 
Level 3, 235 Pyrmont Street 
Sydney, NSW, 2009 
Australia 
 
 
 


 
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7. 
BACKGROUND AND INTRODUCTION 
7.1. 
Introduction 
LYT-100 (deupirfenidone) is a selectively deuterated form of pirfenidone. Pirfenidone is an 
orally active small molecule drug with anti-inflammatory and antifibrotic properties. Pirfenidone 
has been shown to slow the progression of idiopathic pulmonary fibrosis (IPF) in clinical trials 
(King et al., 2014; Noble et al., 2011; Rafii et al., 2013; Taniguchi et al., 2010) and has been 
approved for the treatment of IPF in 30 European countries, Canada, Japan, South Korea, China, 
India, Argentina, and Mexico and was approved for the treatment of IPF in the United States in 
2014. Pirfenidone has been shown to be generally well tolerated; the most common adverse 
events (AEs) were gastrointestinal symptoms (nausea, diarrhea, dyspepsia, vomiting), fatigue, 
rash, and photosensitivity reactions. 
While pirfenidone has established efficacy in treating fibrotic conditions such as IPF, the short 
half-life of the drug requires that it be dosed at least three times per day. In addition, metabolism 
of pirfenidone, primarily by CYP1A2, has the potential to lead to interpatient variability in 
pharmacokinetics (PK), safety, and efficacy. To address the possible limitations of pirfenidone, a 
selectively deuterated form of pirfenidone (referred to as LYT-100) has been developed. 
LYT-100 was designed by substituting three deuterium atoms for hydrogen at the methyl group 
in the pirfenidone molecule, with the objective of attenuating the rate of drug metabolism and 
improving the overall PK profile of the drug. LYT-100 is expected to be metabolized more 
slowly compared with non-deuterated pirfenidone. The possibility of less frequent dosing with 
LYT-100 therapy and slowed rate of drug metabolism may result in improved tolerability and 
efficacy compared with pirfenidone. 
PureTech LYT 100, Inc. intends to study LYT-100 for the treatment of lymphedema, a chronic 
condition that is characterized by swelling due to the build-up of lymph fluid and tissue fibrotic 
remodeling. Lymphedema is a progressive fibrotic and inflammatory disease, and there is no 
approved pharmacologic therapy for lymphedema. LYT-100 has both anti-fibrotic and anti-
inflammatory activity based on in vitro and in vivo models of fibrotic and inflammatory 
conditions. Existing treatments focus on reducing the symptoms and using mechanical 
compression to prevent swelling. However, these treatments do not address the underlying 
mechanisms of lymphedema and are required chronically for management of the condition. 
Millions of people worldwide are affected by secondary lymphedema (Rockson et al., 2019), and 
each year up to 15% of cancer survivors with malignancies ranging from melanoma to sarcoma 
will develop lymphedema (Cormier et al., 2010). As such, there is an unmet medical need for 
developing safe and effective new treatments for lymphedema. 
The purpose of this study is to evaluate the safety, tolerability, PK, and effect on secondary 
clinical endpoints of LYT-100 administered twice daily (BID) for 6 months in breast carcinoma 
patients with secondary lymphedema following axillary node dissection and/or sentinel lymph 
node biopsy, with or without radiation. 


 
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7.2. 
Summary of Nonclinical and Clinical Studies 
7.2.1. 
Nonclinical Studies 
LYT-100 has been evaluated in limited pharmacology, PK, metabolism, and toxicity studies via 
the oral route (along with a pirfenidone comparator arm), since extensive nonclinical and clinical 
data are available for pirfenidone (Center for Drug Evaluation and Research, 2014) including 
pharmacology; safety pharmacology; absorption, distribution, metabolism and excretion; and 
toxicology studies with durations up to 6 months in rats and 9 months in dogs; reproductive 
toxicity, genotoxicity, and carcinogenicity in mice and rats; and photosafety.  
A brief summary of the nonclinical pharmacology, PK, and toxicology of LYT-100 is provided 
herein. More detailed information is provided in the LYT-100 Investigator’s Brochure. 
7.2.1.1. 
Pharmacology  
In vitro and in vivo pharmacology studies conducted with LYT-100 have verified that 
deuteration does not alter the pharmacodynamics (PD) of pirfenidone with respect to its 
anti-fibrotic and anti-inflammatory mechanisms of action.  
Safety pharmacology studies have not been conducted with LYT-100, as data on a full battery of 
safety pharmacology studies are available for pirfenidone including assessments of neurological, 
cardiovascular, respiratory, and gastrointestinal effects.  
7.2.1.2. 
Pharmacokinetics 
Single dose absorption and PK of LYT-100 and pirfenidone and the resulting metabolites have 
been studied in rats, dogs, and chimpanzees, as summarized in the Investigator Brochure.  
In brief, studies of the in vitro hepatic microsomal stability of pirfenidone and LYT-100 in 
human, monkey, dog, rat, and mouse liver microsomes demonstrated that deuteration improved 
the metabolic stability of pirfenidone in all species. An in vitro comparative mass balance study 
of pirfenidone and LYT-100 in human and rat liver microsomes and a comparative study of 
pirfenidone and LYT-100 metabolites in rat, dog, mouse, and monkey liver microsomes revealed 
that metabolism of both compounds was qualitatively similar and showed that deuteration did 
not introduce novel metabolites (although metabolism of LYT-100 occurred more slowly). No 
studies have been carried out examining the potential for LYT-100 to interact with human 
transporter proteins, although pirfenidone does not appear to be a substrate for multiple 
transporters tested. The major human metabolite of pirfenidone, 5-carboxy pirfenidone, did not 
inhibit transporters except for OAT1 and OAT3. Metabolite 5-carboxy pirfenidone is a substrate 
of human breast cancer resistance protein and P-glycoprotein. 
7.2.1.3. 
Toxicology 
A comparative dose range finding study of a single dose (male and female rats) or two daily oral 
doses (female rats) of LYT-100 and pirfenidone (Study AUS-SD-560-NCTP-07) demonstrated 
findings consistent with previous reports on pirfenidone and supported dose selection for a 
subsequent 4-/13-week oral toxicity study in Sprague Dawley rats (Study 1322.03), as described 
briefly below. 


 
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The objective of this repeat-dose study was to evaluate the toxicity of LYT-100 or pirfenidone 
when administered orally once daily for 29 (interim analysis) or 91 consecutive days to Sprague 
Dawley rats and to evaluate the potential reversibility of any findings following a 4-week 
recovery period. In addition, the toxicokinetic characteristics of LYT-100 and pirfenidone were 
determined. The data from the 4-week interim analysis are currently available, as described 
briefly herein and summarized in greater detail in the Investigator Brochure. 
LYT-100 (250, 500, and 750 mg/kg/day) and pirfenidone (750 mg/kg and 875 mg/kg) were 
administered via an oral gavage once daily for 28 consecutive days to fed male and female 
Sprague Dawley rats. The high-dose of pirfenidone was reduced from 1000 mg/kg to 875 mg/kg 
early in the study due to marked clinical signs similar to those described previously for this 
compound. Toxicokinetic analysis revealed that exposure to LYT-100 at a dose of 750 mg/kg 
was similar to the exposure to the same dose of pirfenidone.  
Mortalities were observed in both the LYT-100 and pirfenidone-treated groups, but these were 
not considered test-article-related due to the lack of dose dependency and the sporadic timing of 
the early deaths, which was consistent with gavage error / reflux findings as an unintended 
complication of oral gavage. There were no LYT-100- or pirfenidone-related ophthalmic, group 
mean body weight changes, clinical pathology, or gross pathology findings. Non-adverse 
LYT-100- and pirfenidone-related changes were observed in clinical observations, body weight 
gain, feed consumption, organ weights, and histopathology. Test article-related organ weight 
changes included increased mean liver weights in males and females (LYT-100 250, 500, and 
750 mg/kg; pirfenidone 750 and 875 mg/kg); and increased mean kidney weights in males 
(LYT-100 500 and 750 mg/kg; pirfenidone 750 and 875 mg/kg). Increased liver weight was 
correlated histopathologically with centrilobular hepatocyte hypertrophy (believed to be an 
adaptive change associated with drug metabolizing enzyme induction), and the kidney weight 
changes were possibly caused by hyaline droplet accumulation in the renal tubules (considered 
specific to the male rat). These findings were not considered adverse and were correlated with 
LYT-100 Cmax of up to 187476.1 ng/mL (female) and 135080.3 ng/mL (male) on Day 1. 
 
7.2.1.4. 
Carcinogenesis 
The carcinogenic potential of pirfenidone was evaluated in a 24-month carcinogenicity study in 
B6C3F1 mice and a 24-month carcinogenicity study in Fisher rats. In these studies pirfenidone 
caused increases in hepatocellular adenoma and carcinoma (rats and mice), hepatoblastoma 
(mice), and uterine adenocarcinoma and adenoma (rats). The relevance of these findings in 
rodents to humans is unknown.  
 
7.2.2. 
Clinical Studies 
Administration of LYT-100 in a fed state was tested in a Phase 1, randomized, double-blind, 
single dose crossover study to compare the PK, safety, and tolerability of LYT-100 with 
pirfenidone in 24 healthy volunteers (LYT-100-2020-01-US). The objectives of the study were 
to compare the PK of LYT-100 and pirfenidone and to evaluate and compare the safety and 
tolerability of a single dose of LYT-100 and pirfenidone. Subjects received single 801 mg oral 
doses of LYT-100 and pirfenidone in a random sequence, separated by a washout period of at 


 
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least 7 days. Overall, single doses of LYT-100 and pirfenidone were well tolerated and had a 
comparable safety profile. A total of 44 treatment-emergent adverse events (TEAEs) were 
reported during the study by 14 (58%) of the 24 subjects enrolled. Most of these events were 
mild in severity and there were no events rated as severe. There were no deaths, serious adverse 
events (SAEs), or AEs leading to withdrawal of study drug reported during the study. No 
significant differences were observed between the two treatments in terms of incidence, type, 
severity, relationship, or frequency of TEAEs. The most common AE following either treatment 
was headache, reported by 21% of subjects during each treatment. No significant changes in 
laboratory parameters, vital signs, or ECGs were observed following either treatment. 
Deuteration of pirfenidone resulted in an approximately 25% higher Cmax and 35% higher overall 
exposure relative to the non-deuterated form. The Cmax and overall exposure were not associated 
with an appreciable difference in elimination t½ (2.67 vs. 2.39 hours for LYT-100 and 
pirfenidone, respectively). Increased systemic exposure of deuterated pirfenidone was associated 
with a corresponding decrease in Cmax and overall exposure of the most abundant circulating 
metabolite (5-carboxy metabolite). 
LYT-100 was also tested in a Phase 1 multiple ascending dose study to ascertain the safety, 
tolerability, steady state PK, and food effect of LYT-100. Part 1 assessed multiple ascending 
doses of LYT-100 100, 250, 500, 750, and 1000 mg BID given over 5 days without titration. 
Part 2 assessed the effects of food versus fasting on the pharmacokinetic profile resulting from a 
single 500 mg dose of LYT-100. All doses through 1000 mg were well tolerated with adverse 
events being mild and transient. Exposure was slightly lower in the fed condition. LYT-100 was 
well tolerated and demonstrated a dose-proportional PK profile. The ratio of parent to major 
metabolite concentration is higher than previously reported with pirfenidone, which is consistent 
with an effect of deuteration on metabolism. No maximum tolerated dose was identified through 
1000 mg twice-daily dosing. 
The safety of pirfenidone has been evaluated in over 1500 healthy volunteers and patients with 
IPF, including four Phase 3 multicenter, double-blind, placebo-controlled, randomized studies. 
Three multinational studies (CAPACITY 004 and CAPACITY 006, N = 779 patients; ASCEND, 
N=555 patients) included a total of 1334 patients (King et al., 2014; Noble et al., 2011). A study 
conducted in Japan included 275 patients (Taniguchi et al., 2010).  
Following treatment for up to 72 weeks with either pirfenidone 801 mg TID (three times a day), 
399 mg TID, or placebo, the majority of patients (98%) in both the CAPACITY 004 and 006 
studies (Noble et al., 2011), experienced at least one treatment-emergent AE. The most common 
AEs in the pooled pirfenidone 801 mg TID group, with at least a 1.5-times increased incidence 
relative to placebo, were GI events (nausea, dyspepsia, vomiting, and anorexia), skin-related 
events (rash, photosensitivity), and dizziness; a dose-response in frequency was noted. Most AEs 
were assessed as mild to moderate in severity. SAEs were reported in 33% of the pooled 
pirfenidone group and 31% of the pooled placebo group. The incidence of patients discontinuing 
pirfenidone due to AEs was low (15% of pooled pirfenidone group; 9% of pooled placebo 
group).  
In the ASCEND study (King et al., 2014), gastrointestinal and skin-related events were more 
common in the pirfenidone group than in the placebo group; most AEs were assessed as mild to 
moderate in severity. The incidence of patients discontinuing pirfenidone due to AEs was low 
(14% of the pirfenidone group; 11% of the placebo group). Excluding patients with worsening 


 
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fibrosis, serious AEs were reported in 18.7% of patients in the pirfenidone group and 20.2% of 
patients in the placebo group. 
In the Japanese study (Taniguchi et al., 2010), photosensitivity, anorexia, dizziness, and elevated 
γ-glutamyl-transpeptidase were significantly more common (≥ 5%; p< 0.05) in the high-dose 
(600 mg TID) group than in the placebo group. Skin-related (photosensitivity, asteatotic eczema) 
and gastrointestinal AEs (abdominal discomfort) as well as decrease in white blood cells were 
more common in the low-dose (400 mg TID) group than in the placebo group. Photosensitivity 
was the major AE observed in 51% of the patients in the high-dose group and 53% in the 
low-dose group. Of the patients who developed photosensitivity, most had mild events (70% in 
the high-dose group and 80% in the low-dose group), and the remainder had moderate events. 
Most of the AEs resolved after decreasing the pirfenidone dose or temporarily withholding the 
pirfenidone. The incidence of subjects discontinuing pirfenidone due to AEs was low in both 
dose groups (18% of the high-dose pirfenidone group, 20% of the low-dose pirfenidone group, 
13% of the placebo group). 
Overall, pirfenidone was well tolerated in the Phase 3 studies. The most common AEs were 
gastrointestinal AEs (e.g., nausea, dyspepsia, diarrhea, vomiting), fatigue, anorexia, dizziness, 
rash, and photosensitivity reactions. Serious AEs occurred infrequently and with similar 
incidence for pirfenidone and placebo subjects. AEs leading to discontinuation of study 
treatment were infrequent and included nausea, rash, and photosensitivity reactions. 
Further information on clinical experience with LYT-100 and pirfenidone is provided in the 
Investigator’s Brochure. 
7.3. 
Summary of Potential Risks and Benefits 
In nonclinical studies to date, no meaningful differences have been observed in the in vivo 
pharmacology and toxicology profiles of LYT-100 when compared with pirfenidone. In humans, 
LYT-100 is expected to have an AE profile similar to that of pirfenidone when subjects achieve 
comparable systemic exposure. Therefore, AEs associated with the use of pirfenidone are 
considered expected with use of LYT-100 and prescribing recommendations for pirfenidone are 
expected to be applicable for LYT-100. 
7.4. 
Dosage and Treatment Periods 
Dosage and treatment periods are summarized in Table 7. This study is a placebo-controlled 
assessment of safety and efficacy signals in the target patient population.  
Patients will be randomized in a 1:1 ratio to double-blind treatment with either LYT-100 or 
matching placebo. 


 
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Table 7. 
Dose and Dosing Regimen  
Study Design 
Placebo 
(N) 
LYT-100 
(N) 
LYT-100 dose 
Treatment 
Duration 
(Days) 
N = 50 
25 
25 
LYT-100 BID** 
(titrate to 750 mg) or matching placebo**  
182 
** Patients will be administered LYT-100 study medication, or placebo, orally with food with approximately 10 to 
12 hours between the two daily doses (BID). 
7.4.1. 
Rationale for Selection of Dose  
Pirfenidone has been approved for use at a recommended dose of 801 mg TID (2403 mg per 
day), achieved by weekly titration from a starting dose of 267 mg TID. Preclinical studies have 
shown that LYT-100 and pirfenidone exhibit similar pharmacology at similar concentrations and 
that the toxicity of LYT-100 is not different from that of pirfenidone. Furthermore, the PK on 
LYT-100 and pirfenidone in humans have been shown to be comparable. It is therefore expected 
that 750 mg LYT-100 BID will give exposure lower than that observed with 267 mg pirfenidone 
TID, which has been shown in clinical practice to be a safe dose of pirfenidone with limited 
pharmacological efficacy. 
The dose to be used and instructions to take with food was determined from previous clinical 
trials performed by the Sponsor. The LYT-100 dose level selected was 750 mg BID. If safety or 
tolerability issues arise for patients while receiving their study medication, the dose may be 
reduced. In addition, the dose will be titrated over 3 days unless safety or tolerability issues are 
noted with initiation of treatment in patients.  
7.5. 
Patient Population 
This study will be conducted in breast carcinoma patients with secondary lymphedema following 
axillary node dissection and/or sentinel lymph node biopsy with or without radiation.  
Women of childbearing potential (WOCBP) will be included and are subject to contraceptive 
requirements during the study from Screening until study completion, including the follow-up 
period (see Section 10.4.3). WOCBP must demonstrate negative pregnancy testing at Screening 
and prior to study drug administration on Day 1 and be willing to have additional pregnancy tests 
as required throughout the study. This is in line with regulatory Guidance on Nonclinical Safety 
Studies for the Conduct of Human Clinical Trials and Marketing Authorization for 
Pharmaceuticals (FDA 2006). 
7.6. 
Ethical Principles 
This study will be conducted in accordance with the principles of the current Declaration of 
Helsinki (Ethical Principles for Medical Research Involving Human Subjects). The conduct of 
the study will be in accordance with the ICH Integrated Addendum to E6(R1): Guideline for 
GCP ICH E6(R2). 
This study will be conducted under a protocol reviewed and approved by an appropriate IRB/IEC 
and investigations will be undertaken by scientifically and medically qualified persons, where 
the benefits of the study are in proportion to the risks. 


 
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8. 
TRIAL OBJECTIVES AND PURPOSE 
8.1. 
Objectives 
This study will be performed in breast carcinoma patients with secondary mild to moderate 
lymphedema following axillary node dissection and/or sentinel lymph node biopsy, with or 
without radiation, dosed with LYT-100 750 mg BID with for 26-weeks. 
Primary Objectives 
• To evaluate the safety and tolerability of the double-blinded study medication on 
breast cancer carcinoma patients with secondary lymphedema following axillary node 
dissection and/or sentinel lymph node biopsy. 
Secondary Objectives 
• To explore efficacy signals of LYT-100 on:  
− Lymphatic obstruction and subsequent edema,  
− Infection (as characterized by cellulitis and/or lymphangitis), and  
− QoL.  
• To assess the population PK profile of the double-blinded study medication 
− To describe the association between fibrotic and inflammatory biomarkers, in 
particular: TGF-β1, and disease progression in mild to moderate lymphedema. 
8.2. 
Endpoints 
Primary Endpoints 
• AEs, physical examination, vital signs, ECGs, clinical laboratory parameters 
(hematology, serum chemistry, coagulation, and urinalysis) and concomitant 
treatments. 
Secondary Endpoints 
• Efficacy (see Section 17) 
− Limb water content, by BIS 
− Limb volume (truncated cone tape measure and/or perometry) 
− Tissue dielectric constant (MoistureMeterD) 
− Tissue firmness (tonometry/SkinFibroMeter) 
− Visual analog scales for pain, swelling, discomfort, and function 
• Health-related QoL 
− LYMPH-Q – Upper Extremity Module (Appendix 2) 
− LYMQOL (Appendix 3) 
• Infection 


 
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− Cellulitis 
− Lymphangitis 
• Population PK parameters  
• Fibrotic and Inflammatory Biomarkers: 
− Fibrotic and inflammatory biomarkers (G-CSF, MIG, FGF-2, IL-4, IL-10, 
lymphotoxinα/TNF-β, leptin, IL-6, IL-1β, TNF-α, TGF-β1, MMP-9, TIMP-1, 
MCP1) 


 
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9. 
INVESTIGATIONAL PLAN 
9.1. 
Overall Study Design 
This study will be a 26-week randomized, double-blind, placebo-controlled assessment of 
LYT-100 at multiple study centers in patients with secondary lymphedema following axillary 
node dissection and/or sentinel lymph node biopsy treatment for breast carcinoma.  
Informed consent will be obtained prior to each study part. Screening will be performed up to 
28 days prior to administration of the first dose of LYT-100. Only patients who meet all of the 
applicable inclusion and none of the applicable exclusion criteria will be enrolled. 
9.1.1. 
Treatment Period 
This is a double-blind, parallel, placebo-controlled study being conducted to evaluate the safety 
and efficacy of LYT-100 compared to placebo. This study will be conducted across multiple 
centers in the US and Australia, with approximately 50 patients randomized to receive LYT-100 
or placebo at a ratio of 1:1. LYT-100 dosing is to be titrated starting at 500 mg BID during the 
first 3 days of dosing, followed by 750 mg BID thereafter. 
Patients will take double-blind study medication orally with food BID (approximately 10 to 12 
hours between the two daily doses) on an outpatient basis for 26 weeks.  
Patients with breast cancer-related lymphedema (BCRL) will be assessed for safety, tolerability, 
clinical endpoints, PK, and biomarkers while receiving LYT-100 or placebo over the 6-month 
(26-week) dosing period. If a patient is using a standard of care compression sleeve, compression 
pump therapy, and/or manual lymphatic drainage at least 4 weeks prior to Screening, they must 
be agreeable to continuing the same routine care throughout the 6-month (26-week) study 
treatment period and throughout 2 weeks post-study drug discontinuation. If a patient is not 
using a standard compression sleeve, compression pump therapy, and/or manual lymphatic 
drainage ≥ 4 weeks prior to Screening and are not planning to be using these prior to the study, 
they must be agreeable to not using the lymphedema therapy(s) throughout treatment and 2 
weeks post-study drug discontinuation.  
Following confirmation of study eligibility, patients will be seen in the clinic for their final 
baseline assessments (Day -1). Patients will begin their BID dosing of study medication on the 
following morning (Study Day 1) and will continue for 26 weeks, with clinic visits at Weeks 1, , 
4, 8, 12, 16, 20, and 26.  
All patients will be monitored for safety (including assessment of hematology, serum chemistry, 
coagulation, and urinalysis parameters, ECGs, vital signs, and AEs). Efficacy assessments will 
include clinical and QoL measures at time points as delineated in the Schedule of Events 
(Table 5). Sparse PK samples will be obtained for population PK analysis to determine the 
variability of LYT-100 drug concentration data in individual patients across multiple 
clinical sites. Fibrotic and inflammatory biomarkers will be assessed for changes from baseline. 
With patients using compression sleeves, compression pumps and/or lymphatic drainage as a 
treatment modality at least 4 weeks prior to and at Screening, they will remain on compression 
treatments and/or manual lymphatic drainage during the treatment period as noted. Compression 
sleeves will be removed upon arrival at each study visit and until after the bioimpedance 
assessment is collected, which should be scheduled at the end of the visit. Time of sleeve 


 
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removal will be noted at each study visit. In addition to routine practices such as diet, exercise, or 
skin care, use or non-use of compression sleeves, compression pumps and/or lymphatic drainage 
will be recorded in the Patient Diary 1 week prior to each study visit with lymphedema 
assessments, including frequency of use and the number of hours used on each occasion. Any 
disruptions in taking study medication as instructed will also be recorded in the Patient Diary. 
9.1.2. 
Follow-Up 
Safety and tolerability will be assessed throughout the study by monitoring AEs, physical 
examination, vital signs, 12-lead ECGs, clinical laboratory values (hematology, serum chemistry, 
coagulation, and urinalysis), and review of concomitant treatments/medication use. 
Patients will return to the clinic 28 ± 3 days from the last dose of study medication for a safety 
follow-up visit as delineated in the Schedule of Events (Table 5). 
In the event of premature discontinuation from the study, patients will return to the investigative 
site and complete an early termination visit with assessments as delineated in the Schedule of 
Events (Table 5). Following the early termination visit, patients will be asked to return to the 
investigative site for one last safety follow-up visit, approximately 28 days from the last dose of 
study medication. 
9.2. 
Number of Patients 
Approximately 50 patients, randomized to LYT-100 or placebo in a 1:1 ratio, with breast 
cancer-related upper limb unilateral secondary lymphedema. 
9.3. 
Treatment Assignment 
Novotech will prepare a randomization list and will manage the randomization of eligible 
patients accordingly. A randomization list will be prepared using a statistical software package 
by a Novotech Biostatistician.  
Each patient will be provided with a unique screening number post documentation of informed 
consent. Once deemed eligible for enrolment in the study, the patient will be assigned a 
sequential randomization number prior to first dosing. Patients who withdraw from the study 
during Screening, for any reason, without completing all necessary screening assessments will be 
considered screen failures. Screen failures will not receive a randomization number; however, 
source documents may be transcribed onto the electronic Case Report Forms (eCRFs). 
Randomization will be stratified by higher risk of lymphedema progression (axillary lymph node 
dissection) versus lower risk of lymphedema progression (sentinel node biopsy) (Table 8). 
Patients will be stratified upon enrolment into the standard compression sleeve, compression 
pump therapy, and/or manual lymphatic drainage stratum compression versus non-
compression/non-lymphatic drainage groups stratum. 
 
 


 
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Table 8. 
Baseline Randomization Stratification Levels  
Compression Sleeve, Compression Pump, and/or Lymphatic Drainage 
Yes 
No 
Risk for Progression 
Risk for Progression 
High 
(history of axillary lymph 
node dissection and/or 
regional lymph node 
radiation posterior field 
with or without 
supraclavicular) 
Low 
(history of sentinel node 
biopsy or 
excision/clearance) 
High 
(history of axillary lymph 
node dissection and/or 
regional lymph node 
radiation posterior field 
with or without 
supraclavicular) 
Low 
(history of sentinel node 
biopsy or 
excision/clearance) 
9.4. 
Safety Review Committee 
The study will be subject to oversight by an SRC comprised of the PI, MM, and Sponsor 
representative as core members and guided by an SRC charter.  The SRC will convene to review 
any safety signals deemed relevant relative to the study conduct i.e., incidence and nature of any 
AEs, SAEs, vital sign changes, changes in physical findings, ECGs, and laboratory 
abnormalities.  
The SRC will convene after 20% of the patients enrolled on study have completed Week 8 of the 
Treatment Phase and the double-blind data is available for review. If safety or tolerability issues 
are identified by the MM for patients while receiving LYT-100 versus placebo at any time, the 
SRC may meet to review safety and available population PK data and provide recommendations. 
Options for changes to dosing or protocol assessments may be recommended by the SRC. 
Ultimate decisions regarding those recommendations remain with the Sponsor 
AEs of special interest including elevated liver enzymes (e.g., alanine aminotransferase [ALT], 
aspartate aminotransferase [AST], total bilirubin elevations), photosensitivity and rash, and 
gastrointestinal disorder (e.g., nausea, vomiting diarrhea, dyspepsia, gastroesophageal reflux, and 
abdominal pain) will be reviewed by the MM periodically for changes in IP tolerability 
throughout the trial and, if warranted, may trigger additional ad hoc SRC meeting(s). 
Following each review, the SRC will make the following recommendations: 
1. To continue the study as planned. 
2. To continue the study with modifications. 
3. To temporarily suspend or terminate the study. 
If at any time the study is terminated, a written statement fully documenting the reasons for 
termination will be provided to the relevant IRB/IEC 
 
 
9.5. 
Dose Adjustment Criteria  
  


 
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Dose adjustment guidance for non-hematological adverse events are listed below.   
 
Table 9. 
Non-Hematological Adverse Events Dose Adjustment Guidance  
 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Abdominal Pain* 
 
Maintain 
LYT-100 
dose 
Dose reduce to 
500 mg BID 
until resolved 
to ≤ grade 1 
then resume 
750 mg BID 
dosing 
 
If with dose 
reduction it 
does not 
resolve to ≤ 
grade 1, stop 
treatment until 
resolved to ≤ 
grade 1 then 
re-titrate by 
administering 
500 mg BID 
over a period 
of 3 days then 
escalate to 750 
mg BID 
 
 
 
Cease treatment 
until resolved to 
≤ grade 1, then 
re-titrate by 
administering 
500 mg BID over 
a period of 3 days 
then escalate to 
750 mg BID 
 
If the same AE at 
grade 3 recurs 
upon re-
escalation to 750 
mg BID, cease 
treatment until 
resolved to ≤ 
grade 1, then 
continue with 
500mg BID  
 
If the same AE 
recurs at grade 3, 
permanently 
discontinue LYT-
100 
 
Involve a 
gastroenterologist 
if needed as per 
PI’s and medical 
monitor’s 
judgement 
Permanently 
discontinue 
LYT-100  
Diarrhea 
Maintain 
LYT-100 
dose 
Dose reduce to 
500 mg BID 
until resolved 
to ≤ grade 1 
then resume 
750 mg BID 
dosing 
Cease treatment 
until resolved to 
≤ grade 1, then 
re-titrate by 
administering 
500 mg BID over 
a period of 3 days 
Permanently 
discontinue 
LYT-100 


 
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If with dose 
reduction it 
does not 
resolve to ≤ 
grade 1, stop 
treatment until 
resolved to ≤ 
grade 1 then 
re-titrate by 
administering 
500 mg BID 
over a period 
of 3 days then 
escalate to 750 
mg BID  
then escalate to 
750 mg BID 
 
If the same AE at 
grade 3 recurs 
upon re-
escalation to 750 
mg BID, cease 
treatment until 
resolved to ≤ 
grade 1, then 
continue with 
500 mg BID  
 
If the same AE 
recurs at grade 3, 
permanently 
discontinue LYT-
100 
 
Involve a 
gastroenterologist 
if needed as per 
PI’s and medical 
monitor’s 
judgement 
Vomiting 
Maintain 
LYT-100 
dose 
Dose reduce to 
500 mg BID 
until resolved 
to ≤ grade 1 
then resume 
750 mg BID 
dosing 
 
If with dose 
reduction it 
does not 
resolve to ≤ 
grade 1, stop 
treatment until 
resolved to ≤ 
grade 1 then 
re-titrate by 
administering 
500 mg BID 
over a period 
Cease treatment 
until resolved to 
≤ grade 1, then 
re-titrate by 
administering 
500 mg BID over 
a period of 3 days 
then escalate to 
750 mg BID 
 
If the same AE at 
grade 3 recurs 
upon re-
escalation to 750 
mg BID, cease 
treatment until 
resolved to ≤ 
grade 1, then 
continue with 
500 mg BID  
Permanently 
discontinue 
LYT-100 


 
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of 3 days then 
escalate to 750 
mg BID  
 
If the same AE 
recurs at grade 3, 
permanently 
discontinue LYT-
100 
 
Involve a 
gastroenterologist 
if needed as per 
PI’s and medical 
monitor’s 
judgement 
 
Photosensitivity/Rash** 
 
Maintain 
LYT-100 
dose 
Stop treatment 
until resolved 
to ≤ grade 1 
then resume 
by titrating 
with 500 mg 
BID for 3 days 
then escalating 
to 750 mg BID 
750 mg BID 
dosing 
If the AE 
recurs at grade 
2, stop until 
resolved to ≤ 
grade 1, then 
resume 500 
mg BID 
dosing 
Permanently 
discontinue LYT-
100 
 
Permanently 
discontinue 
LYT-100  
Weight Loss 
 
Maintain 
LYT-100 
dose 
Dose reduce to 
500 mg BID 
until resolved 
to ≤ grade 1 
then resume 
750 mg BID 
dosing 
 
If with dose 
reduction it 
does not 
resolve to ≤ 
grade 1, stop 
Cease treatment 
until resolved to 
≤ grade 1 then 
resume 750 mg 
BID dosing 
 
If with dose 
reduction it does 
not resolve to ≤ 
grade 1 
permanently 
discontinue LYT-
100 
Permanently 
discontinue 
LYT-100 


 
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treatment until 
resolved to ≤ 
grade 1 then 
re-titrate by 
administering 
500 mg BID 
over a period 
of 3 days then 
escalate to 750 
mg BID 
Dyspepsia/ Gastro-
esophageal Reflux 
 
Maintain 
LYT-100 
dose 
Dose reduce to 
500 mg BID 
until resolved 
to ≤ grade 1 
then resume 
750mg BID 
dosing 
 
If with dose 
reduction it 
does not 
resolve to ≤ 
grade 1, stop 
treatment until 
resolved to ≤ 
grade 1 then 
re-titrate by 
administering 
500 mg BID 
over a period 
of 3 days then 
escalate to 750 
mg BID  
Cease treatment 
until resolved to 
≤ grade 1, then 
re-titrate by 
administering 
500 mg BID over 
a period of 3 days 
then escalate to 
750 mg BID 
 
If the same AE at 
grade 3 recurs 
upon re-
escalation to 750 
mg BID, cease 
treatment until 
resolved to ≤ 
grade 1, then 
continue with 
500 mg BID  
 
If the same AE 
recurs at grade 3, 
permanently 
discontinue LYT-
100 
Permanently 
discontinue 
LYT-100 
Other non-
hematological AEs 
Maintain 
LYT-100 
dose 
 
Dose reduce to 
500 mg BID 
until resolved 
to ≤ grade 1 
then resume 
750mg BID 
dosing 
 
If with dose 
reduction it 
Cease treatment 
until resolved to 
≤ grade 1, then 
re-titrate by 
administering 
500 mg BID over 
a period of 3 days 
then escalate to 
750 mg BID 
 
Permanently 
discontinue 
LYT-100 


 
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does not 
resolve to ≤ 
grade 1, stop 
treatment until 
resolved to ≤ 
grade 1 then 
re-titrate by 
administering 
500 mg BID 
over a period 
of 3 days then 
escalate to 750 
mg BID 
 
If the same AE at 
grade 3 recurs 
upon re-
escalation to 750 
mg BID, cease 
treatment until 
resolved to ≤ 
grade 1, then 
continue with 
500 mg BID  
 
If the same AE 
recurs at grade 3, 
permanently 
discontinue LYT-
100 
*Includes lower abdominal pain, upper abdominal pain, abdominal distension, and stomach 
discomfort. **Rash includes acneiform and maculo-papular 
 
Dose adjustment guidance for hematological adverse events are listed below. 
 
Table 10. 
Hematological Adverse Events Dose Adjustment Guidance   
 
 
Dose modification 
ANC ≥ 1.0 mm3 
No dose modification 
0.5 < ANC < 1.0 mm3 
Stop LYT-100, repeat blood test in 48-72 hrs, or at a clinically 
indicated time interval, and when resolved to ANC>1.0 then resume 
at 500mg BID for 3 days followed by 750mg BID 
 
If the same AE repeats, stop LYT-100, repeat blood test in 48-72 hrs, 
or at a clinically indicated time interval, and when resolved to 
ANC>1.0 then resume at 500mg BID 
 
If the same AE repeats, discontinue LYT-100 permanently 
ANC < 0.5 mm3 
Discontinue LYT-100 permanently 
 
 
Hgb ≤ 8.5 g/dL 
Stop LYT-100, clinically manage as appropriate and when Hgb > 
10.0 resume LYT-100 at 500mg BID for 3 days followed by 750MG 
BID 
 
If the same AE repeats, permanently discontinue LYT-100 
Platelets > 100,000 mcL 
No dose modification 


 
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Platelets 50,000-100,000 
mcL 
Stop LYT-100 until resolved to >100,000 then resume at 500mg BID 
for 3 days followed by 750mg BID 
 
If the same AE repeats, stop LYT-100, repeat blood at a clinically 
indicated time interval, and when resolved to >100,000 then resume 
at 500mg BID 
 
If the same AE repeats, discontinue LYT-100 permanently 
Platelets < 50,000 mcL 
Stop LYT-100 until resolved to >100,000 then resume at 500mg BID 
for 3 days followed by 750mg BID 
 
If the same AE repeats, permanently discontinue LYT-100 
 
Hepatic Impairment 
No dose modifications are needed for AST and/or ALT elevation ≤ 3 x the upper limit of normal 
(ULN) without symptoms or hyperbilirubinemia. 
If a patient exhibits >3 but ≤5 × the upper limit of normal (ULN) ALT and/or AST without 
symptoms or hyperbilirubinemia after starting LYT-100 therapy:  
• Discontinue any potential confounding co-medications, exclude other causes, and monitor 
the patient closely.  
• Repeat liver chemistry tests as clinically indicated.  
• Dose reduce to 500 mg BD until resolved to ≤ 3 x upper limit of normal (ULN) ALT and/or 
AST with subsequent re-titration to the full dosage as tolerated.  
If a patient exhibits >3 but ≤5 × ULN ALT and/or AST accompanied by symptoms or 
hyperbilirubinemia:  
• Permanently discontinue LYT-100. Do not rechallenge patient with LYT-100. 
If a patient exhibits >5 × ULN ALT and/or AST:  
• Permanently discontinue LYT-100. Do not rechallenge patient with LYT-100. 
Renal Impairment 
No dose modifications are needed for in patients with mild renal impairment (CLcr 50–80 
mL/min). 
In patients with moderate renal impairment (CLcr 30–50 mL/min): 
Discontinue any potential confounding co-medications, exclude other causes, and monitor the 
patient closely.  
• Repeat renal function tests as clinically indicated.  
• Dose reduce to 500 mg BD until resolved to  CLcr 50–80 mL/min, with subsequent re-
titration to the full dosage as tolerated 


 
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Avoid use if eGFR less than 30 mL/minute. Patients with end-stage renal diseases requiring 
dialysis are not eligible. 
 
 
 
9.6. 
Criteria for Study Termination 
The study will be completed as planned unless: 
• New information or other evaluation regarding the safety of the study medication 
indicates a change in the known risk/benefit profile for the compound, such that the 
risk/benefit is no longer acceptable for patients in the study. This may be determined 
by the Sponsor, the Investigator, the SRC, the IRB/IEC, or regulatory authorities. 
• The study is terminated by the Sponsor for administrative reasons. 
If the Sponsor, the IRB/IEC, or regulatory authority elects to terminate or suspend the study or 
the participation of the investigational site, a study-specific procedure for early termination or 
suspension will be provided by the Sponsor. The procedure will be followed by the 
investigational site during the course of termination or study suspension. 


 
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10. 
SELECTION AND WITHDRAWAL OF PATIENTS 
10.1. 
Patient Inclusion Criteria 
To be eligible for this study, patients have to meet all of the following inclusion criteria: 
1. Provides written Ethics Committee approved informed consent prior to any study 
procedures. 
2. Female or male aged ≥ 18 years old at the time of informed consent. 
3. At least 6 months and no more than 15 years since the most recent type of surgery related 
to breast cancer including sentinel lymph node biopsy or excision/clearance, axillary lymph 
node dissection, or any other type of surgery excluding FNA biopsy at the time of study 
screening. No intention to have breast reconstructive surgery, nipple reconstruction, 
and/or tattooing during the course of the study. 
4. At least 3 months since completion of any neoadjuvant therapy, adjuvant chemotherapy, 
intravenous biologic therapy (e.g., trastuzumab and pertuzumab), radiotherapy, and/or 
any investigational adjuvant therapy at the time of study Screening. 
5. At least 3 months since initiation of anti-hormonal oral adjuvant therapy as well as 
goserelin and/or adjuvant zolendronic acid. 
6. Diagnosis of primary breast cancer, and without evidence of local, locoregional and/or 
distant recurrence of breast cancer for at least 6 months since completion of adjuvant 
therapy (excluding anti-hormonal therapy regimens), as determined at Screening and 
Baseline.  
7. Documented evidence of pitting edema in one arm for at least 3 months and also at 
Screening, and at least one of the following: 
a. Increase in relative limb volume of between 10% to 25% as measured by 
perometry or the truncated cone method of circumferential tape measurement 
compared to any prior documented measurement or relative to measurement of 
non-affected arm.  
b. A bioimpedance measure of > 10 at baseline visit or a change from pre-surgical 
measure of > +6.5 L-Dex at Baseline visit; or 
c. Overt signs of lymphedema in the arm clinically indicating Lymphedema Stage I 
or II and/or confirmed by asymmetry > 2 via LymphaScan (TDC) in swell spot.  
8. Receiving standard of care compression or agreeable to using care compression, i.e., 
sleeves and/or pumps and/or manual lymphatic drainage, or no compression care and/or 
no manual lymphatic drainage ≥ 4 weeks prior to Screening and throughout the study. 
9. In good general health at Screening and Baseline apart from a history of breast cancer and 
secondary lymphedema, i.e., free from clinically significant unstable medical, surgical, or 
psychiatric illness (at the discretion of the Investigator); no acute conditions requiring 
invasive care or hospitalization; and no conditions or elective procedures requiring 
invasive intervention within the next 6 months. 
10. Vital signs (measured in supine position after 10 minutes rest) at Screening: 


 
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a. Systolic blood pressure ≥ 90 and ≤ 140 mmHg; 
b. Diastolic blood pressure ≥ 50 and ≤ 90 mmHg; 
c. Heart rate ≥ 45 and ≤ 100 bpm; 
d. Vital signs may be repeated once, within a minimum of 10 minutes of the 
completion of the last set of vital signs (while maintaining supine positions until 
the repeated set of vital signs are collected), if it is suspected that falsely high or 
low levels have been obtained. 
11. Body Mass Index (BMI) ≥ 18 and ≤ 50 kg/m2 at Screening. 
12. HIV, HCV, and HBsAg negative at Screening. 
13. Adequate venous access in contralateral, unaffected limb. 
14. Willing and able to comply with all study procedures and requirements including 
adherence to maintaining routine in either using or not using compression sleeve, 
compression pump, lymphatic drainage therapy/self-manual lymph drainage (MLD). 
Patient should agree to not making extreme changes to their routine, also including diet, 
exercise, or skin care. 
15. Willing and able to abstain from direct whole body sun exposure from 2 days prior to 
dosing and until final study procedures have been conducted. Patients should be 
instructed to avoid or minimize exposure to sunlight (including sunlamps), use an SPF 50 
sun block, or higher, wear clothing that protects against sun exposure, and avoid 
concomitant medications known to cause photosensitivity. 
16. WOCBP must be non-pregnant and non-lactating, and must use an acceptable, highly 
effective double contraception or be abstinent from heterosexual intercourse from 
Screening until study completion, including the follow-up period (please see 
Section 10.4.3 for acceptable methods of contraception). WOCBP must have a negative 
pregnancy test at Screening and Day 1 and be willing to have additional pregnancy tests 
as required throughout the study. Women not of childbearing potential must be 
postmenopausal for ≥ 12 months or be surgically sterile, including a hysterectomy with 
retention of ovary function is permitted. Postmenopausal status will be confirmed through 
testing of FSH levels ≥ 40 IU/mL at Screening for amenorrhoeic female patients.  
17. Male patients must be surgically sterile (> 30 days since vasectomy with no viable 
sperm), abstinent, or if engaged in sexual relations with a WOCBP, the patient and his 
partner must be surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy) or using an acceptable, highly effective 
contraceptive method from Screening until study completion, including the follow-up 
period and an additional 12 weeks after the last dose (please see Section 10.4.3 for 
acceptable methods of contraception). 
18. Males must not donate sperm for at least 90 days after the last dose of study drug. 
19. Partners of male patients and female patients will report pregnancy occurring within 
90 days from cessation of study medication. 


 
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10.2. 
Patient Exclusion Criteria 
To be eligible for this study, patients must not meet any of the following exclusion criteria: 
1. Bilateral lymphedema or history of bilateral axillary lymph node removal (i.e., sentinel 
lymph node biopsy or axillary lymph node dissection), or primary lymphedema or 
lymphatic or vascular malformation, determined at Screening. 
2. Chronic administration (defined as more than 14 consecutive days) of 
immunosuppressants or other immune-modifying drugs within 3 months prior to study 
drug administration; corticosteroids are permitted at the discretion of the PI.  
3. Recent history (in the 8 weeks prior to Screening) of cellulitis, lymphangitis, dermatitis, 
necrotizing fasciitis, or current open wounds or sores in the affected extremity.  
4. Fibrotic stranding on affected arm not related to BCRL; history of breast or arm 
procedures unrelated to axillary node dissection such as non-cancer-related reconstructive 
or cosmetic breast surgery, Botox for hyperhidrosis, chronic intravenous use, port, pic-
line, etc. for medical or recreational reasons, tattoos (excluding pink ribbon tattoo 
designated to inform health caretaker not to take blood pressure in affected arm), or other 
extreme body modifications, determined at Screening. 
5. Relative limb volume > 25%, stage III secondary lymphedema, or history of clinically 
diagnosed secondary lymphoedema greater than 4 years, determined at Screening.  
6. Initiated use of compression or manual lymphatic drainage or other lymphedema 
therapies at the start of the study within 4 weeks of the Screening visit. Rescreening is 
allowed following a course of stable compression regimen of > 4 weeks. 
7. Metal implant(s) including implantable cardioverter defibrillators, cardiac 
resynchronization therapy-defibrillators, and pacemakers that may be affected by 
assessments used in the trial, e.g., bioimpedance, and/or that may inconsistently affect 
collection of secondary lymphedema assessments. 
8. Presence of malignancy, with the exception of adequately treated localized skin cancer 
(basal cell or squamous cell carcinoma), carcinoma in-situ of the cervix, or unilateral 
breast cancer history with completed treatment and with no active cancer at the time of 
Screening or in the preceding 6 months.  
9. Evidence of clinically relevant medical history/illness at Screening, as determined by the 
Investigator, including stroke, uncontrolled hypertension, and other cardiac disease, 
vascular disease, pulmonary disease, gastrointestinal disease, hepatic disease, renal 
failure and other kidney disease, rheumatologic disease, coagulopathy or other 
hematological disease, uncontrolled diabetes and other endocrine disorders, any 
progressive neurologic disorder, psychiatric disease, dermatological disorder, or surgical 
history except for orthopedic and reconstructive breast cancer surgery. 
10. Clinically significant infection within 28 days of the start of dosing, as determined by the 
Investigator. 


 
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11. Clinically significant surgical procedure/s, including but not limited to breast cancer 
reconstruction surgery, within 3 months of Screening, or further breast cancer 
reconstruction surgery planned during the Study. 
12. For baseline LFTs, 2.5 × upper normal limit (UNL) or severe hepatic impairment. 
13. Positive test for HCV, HBsAg, or HIV antibody at Screening. 
14. Currently suffering from clinically significant systemic allergic disease at Screening or 
Baseline or has a history of significant drug allergies including a history of anaphylactic 
reaction (particularly reactions to general anesthetic agents); allergic reaction due to any 
drug which led to significant morbidity; prior allergic reaction to pirfenidone. 
15. Pregnant or lactating at Screening or planning to become pregnant (self or partner) at any 
time during the study, including the follow-up period. 
16. Symptoms of dysphagia or known difficulty in swallowing capsules, determined at 
Screening. 
17. History or presence of cardiac arrhythmia or congenital long QT syndrome determined at 
Screening. 
18. QTcF > 450 msec demonstrated by two ECGs between 30 and 60 minutes apart at 
Screening. 
19. Use of tobacco or nicotine-containing products in the previous 30 days prior to dosing or 
a positive urine cotinine test at Screening or Baseline. 
20. Lack of willingness to abstain from the consumption of tobacco or nicotine-containing 
products throughout the duration of the study and until completion of the final follow-up 
visit. 
21. Regular alcohol consumption defined as > 21 alcohol units per week (where 1 unit = 
284 mL of beer, 25 mL of 40% spirit, or a 125 mL glass of wine), determined at 
Screening.  
22. Positive toxicology Screening panel (urine test including qualitative identification of 
barbiturates, , amphetamines, , opiates, and cocaine) or alcohol breath or urine test, 
determined at Screening. Repeat urine toxicology screenings may be conducted.  
23. History of substance abuse or dependency or history of recreational IV drug use over the 
last 2 years, determined at Screening.  
24. Use of any over-the-counter medication, herbal supplements, or diet aids within 48 hours 
prior to dosing, without the prior review and approval of the PI and medical monitor 
25. Treated with immunosuppressive or antifibrotic drugs, anti-tumor necrosis factor, 
immunotherapy, or investigational drugs at Screening or within the preceding 30 days. 
26. Use of any of the following drugs within 28 days or 10 half-lives of that drug, whichever 
is the longer, prior to study drug administration: 
a. Fluvoxamine, enoxacin, ciprofloxacin 
b. Other inhibitors of CYP1A2 (including but not limited to methoxsalen or 
mexiletine) 


 
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c. Inducers of CYP1A2 (such as phenytoin), CYP2C9 or 2C19 (including but not 
limited to carbamazepine or rifampin) 
d. Drugs associated with substantial risk for prolongation of the QTc interval 
(including but not limited to moxifloxacin, quinidine, procainamide, amiodarone, 
sotalol) 
27. Use of any investigational drug or device within 28 days or 10 half-lives of the drug, 
whichever is the longer, prior to start of dosing. 
28. Clinically significant blood loss or any blood or blood product donation > 250 mL within 
28 days of start of dosing. 
29. Any condition (e.g., chronic diarrhea, inflammatory bowel disease, or prior surgery of the 
gastrointestinal tract) that would interfere with drug absorption or any disease or 
condition that is likely to affect drug metabolism, or excretion, determined at Screening. 
30. History of anaphylactic reaction (particularly reactions to general anesthetic agents); 
allergic reaction due to any drug which led to significant morbidity; prior allergic 
reaction to pirfenidone. 
31. As a result of medical review and physical examination at Screening, the Investigator 
considers the patient unfit for the study. 
10.3. 
Patient Withdrawal Criteria 
Patients may withdraw their consent to participate in the study at any time. If a patient withdraws 
consent, the date and reason for consent withdrawal should be documented. Patients will be 
encouraged to remain in the CRU to complete all necessary assessments and until the 
Investigator deems that it is safe to be discharged. Patient data will be included in the analysis up 
to the date of the withdrawal of consent.  
Apart from withdrawal of consent, reasons for early termination of individual patients can 
include: 
• Protocol deviations or patient non-compliance (must be specified on the appropriate 
eCRF) 
• Serious or severe AEs 
• Administrative decision by the Investigator or the Sponsor 
• Death 
• Other (must be specified). 
Wherever possible, the tests and evaluations, including those listed for the final visit, should be 
performed for all patients who discontinue prior to the completion of the study. 


 
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10.4. 
Diet, Activity, and Other Restrictions 
10.4.1. 
Medication 
Patients are required to have completed their treatment for breast cancer (including but not 
limited to neoadjuvant, radiotherapy, chemotherapy, and immunotherapy) at least 3 months 
before Screening, with the exception of adjuvant treatment with hormonal or anti-HER2 therapy 
(which must be stable for at least 3 months prior to Screening, with no planned changes during 
the study). If a patient is using a standard of care compression sleeve, compression pump, and/or 
manual lymphatic drainage for at least 4 weeks prior to Screening, they must be agreeable to 
continuing the same care throughout treatment and through 2 weeks post-study drug 
discontinuation. If a patient is not using a standard compression sleeve, compression pump, 
and/or was using manual lymphatic drainage for at least 4 weeks prior to Screening, they must be 
agreeable to not using these routine lymphatic therapy(s) throughout treatment and through 
2 weeks post-study drug discontinuation. 
Immunosuppressants or other immune-modifying drugs are not permitted, except for 
corticosteroids at the discretion of the Investigator. Chronic administration (defined as more than 
14 consecutive days) of immunosuppressants or other immune-modifying drugs must be 
discontinued at least 30 days prior to study drug administration. 
 
Use of any over-the-counter medication (OTC), herbal supplements, or diet aids should be 
discontinued at least 48 hours prior to dosing, unless approved by the PI and MM. These may be 
resumed on study, however the following OTC/supplements are not allowed on study: 
• Preparations containing a mixture of more than one of the following: kola nut, grape seed 
extract, or green tea extract 
• Goldenseal  
• St. John’s wort 
• Curcumin 
Treatment with immunosuppressive or antifibrotic drugs, anti-tumor necrosis factor, 
immunotherapy, or investigational drugs is not permitted during the study, and must be 
discontinued at least 30 days prior to Screening. 
The following drugs are not permitted during the study, and they must be discontinued at least 
28 days or 10 half-lives (whichever is the longer) prior to study drug dosing: 
• Fluvoxamine, enoxacin, ciprofloxacin 
• Other inhibitors of CYP1A2 (including but not limited to methoxsalen or mexiletine) 
• Inducers of CYP1A2 (such as phenytoin), CYP2C9 or 2C19 (including but not limited to 
carbamazepine or rifampin) 
• Any drug associated with substantial risk for prolongation of the QTc interval 
(including but not limited to moxifloxacin, quinidine, procainamide, amiodarone, sotalol) 


 
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Use of investigational drugs or devices is not permitted and must be discontinued at least 28 days 
or 10 half-lives (whichever is the longer) prior to start of dosing. 
10.4.2. 
Smoking 
All patients are required to abstain from tobacco or nicotine-containing products in the 30 days 
prior to dosing and for the duration of the study until completion of the final follow-up visit. 
10.4.3. 
Contraception 
No estrogen preparations (e.g., oestradiol, ethinyloestradiol) are to be used throughout the trial 
for contraception, hormone replacement therapy, or menopausal replacement therapy.  
Acceptable, highly effective double contraception is defined as a condom AND one other form 
of the following: 
• Established hormonal contraception (oral contraceptive pills [OCPs], long-acting 
implantable hormones, injectable hormones) except for preparations containing 
oestradiol, ethinyloestradiol 
• A vaginal ring or an intrauterine device (IUD) 
• Documented evidence of surgical sterilization at least 6 months prior to Screening 
(e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy for women or vasectomy for men [with appropriate post-vasectomy 
documentation of the absence of sperm in semen] provided the male partner is a sole 
partner). 
Women not of childbearing potential must be postmenopausal for ≥ 12 months. Postmenopausal 
status will be confirmed through testing of FSH levels ≥ 40 IU/mL at Screening for 
amenorrhoeic female patients. Females who are abstinent from heterosexual intercourse will also 
be eligible. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not considered highly effective methods of birth control. Patient complete 
abstinence for the duration of the study and for 1 month after the last study treatment is 
acceptable. 
Female patients who are in same sex relationships are not required to use contraception. 
Males must be surgically sterile (> 30 days since vasectomy with no viable sperm), abstinent, or 
if engaged in sexual relations with a WOCBP, the patient and his partner must be surgically 
sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or 
using an acceptable, highly effective contraceptive method from Screening until study 
completion, including the follow-up period. Acceptable methods of contraception include the use 
of condoms and the use of an effective contraceptive for the female partner that includes: OCPs, 
long-acting implantable hormones, injectable -hormones, a vaginal ring, or an IUD. Patients with 
same sex partners (abstinence from penile-vaginal intercourse) are eligible when this is their 
preferred and usual lifestyle.  


 
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10.4.4. 
Food 
Patients are required to take study medication with food. 
10.4.5. 
Other Restrictions 
All patients must be willing to abstain from direct whole body sun exposure from 2 days prior to 
dosing and until final study procedures have been conducted. Patients should be instructed to 
avoid or minimize exposure to sunlight (including sunlamps), use an SPF 50 sun block, or 
higher, wear clothing that protects against sun exposure, and avoid concomitant medications 
known to cause photosensitivity. 
All patients must refrain from blood or blood product donation > 250 mL within 28 days of 
Screening, and blood or blood products donation is not permitted from Screening until the final 
visit. 


 
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11. 
TREATMENT OF PATIENTS 
11.1. 
Description of Study Drug 
The LYT-100 drug product and matching placebo are presented as follows: 
• LYT-100, 250 mg and matching placebo – Size 0 or 1, Swedish orange opaque, 
hard-gelatin capsules.  
The capsules are packaged in high-density polyethylene (HDPE) bottles and a white, 
polypropylene screw cap with an induction sealed aluminum inner seal. The IPs should be stored 
at a controlled room temperature of 15C to 25C.  
11.2. 
Prior and Concomitant Medications 
11.2.1. 
Prior Medications 
All medications, including over-the-counter (OTC) medications, vitamins, and herbal 
supplements, taken during the 30 days prior to the first study drug administration will be 
recorded and reviewed by the Investigator to determine whether the patient is suitable for 
inclusion in the study. 
11.2.2. 
Concomitant Medications 
All medications, including OTC medications, vitamins, and herbal supplements, taken by 
patients during the course of the study will be recorded in the eCRF and coded using the most 
current World Health Organization (WHO) drug dictionary available at Novotech. Prior and 
concomitant medications will be listed by patient and summarized by anatomical therapeutic 
chemical (ATC) and Preferred Term (PT). 
11.3. 
Treatment Compliance 
Patients will be provided with enough LYT-100 study medication bottles to cover the prescribed 
daily dose until their next study visit. The number of capsules dispensed at each study visit will 
be recorded in the patient’s source documents. Patients will be instructed to retain and return all 
emptied and non-emptied bottles to each study visit. Study drug capsule counts returned at each 
visit will be totaled and recorded in the patient’s source document record. The difference in the 
number of capsules dispensed and number of capsules returned will be reconciled against the 
anticipated number of capsules administered to account for all dosing intervals since the last 
study visit to determine study drug medication compliance. 
A phone application to provide medication reminders will be used to assist the patient with 
medication adherence during the study treatment phase of the trial. 
11.4. 
Blinding 
The study will be double blinded to patients, research staff, the Sponsor and CRO, with the 
exception of one unblinded statistician who will provide the randomization. There will be 
specific unblinded members at the site (pharmacist), CRO, and Sponsor to ensure study drug 
accountability/management is performed accurately and for medical oversite of patient safety. 


 
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The Sponsor, Investigator, MM, study personnel, and patients are not to make any effort to 
determine which study drug therapy is being received. Unblinded pharmacy (or other qualified 
site) personnel will be used in this study to prepare the study drug. 
Only in the case of an emergency, when knowledge of the study drug is essential for the clinical 
management or welfare of a specific patient, the Investigator may unblind a patient’s treatment 
assignment. Please see Section 16.7 for details of the procedure to be followed for randomization 
code breaking. 
As soon as possible, and without revealing the patient’s study treatment assignment (unless 
important to the safety of patients remaining in the study), the Investigator must notify the 
Sponsor if the blind is broken for any reason and the Investigator was unable to contact the 
Sponsor prior to unblinding.  
In the event that the Investigator considers an AE to be of such severity as to require immediate 
specific knowledge of the identity and dose of the relevant product, the Investigator may break 
the study code for that patient.  
All unblinding events must be reported to the Sponsor, MM, and Novotech promptly. 


 
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12. 
STUDY DRUG MATERIALS AND MANAGEMENT 
12.1. 
Study Supplies 
The Sponsor will supply the study drug to the investigational site. The study drug provided for 
this study was manufactured under current Good Manufacturing Practices and will be suitable 
for human use. 
12.2. 
Study Drug Packaging and Labeling 
The Sponsor is responsible for the preparation and labeling of the study drug and for providing 
details of batch numbers, safety, and stability data. 
The study drug is labeled in accordance with local regulatory requirements and will be shipped at 
a temperature of 15°C to 25°C. 
12.3. 
Study Drug Storage 
Upon receipt, the study drug must be stored at 15°C to 25°C. 
The Investigator will be fully responsible for the security, accessibility, and storage of the study 
drug while it is at the investigational facility. 
12.4. 
Study Drug Preparation 
Procedures relating to study drug preparation and dispensing are outlined in the Pharmacy 
Manual. 
12.5. 
Administration 
The Investigator is responsible for the education of study staff and patients as to the correct 
administration of the study drug. 
12.6. 
Study Drug Accountability 
A record will be maintained by the investigational site that will account for all dispensing and 
return of any used and unused study drug. At the end of the study, the study drug will be 
reconciled, and a copy of the record given to the study monitor. 
12.7. 
Study Drug Handling and Disposal 
On completion of the study, any surplus study drug supplies will be destroyed upon receipt of 
written approval from the Sponsor and evidence of destruction supplied to the study monitor. If 
no supplies remain, this will be documented in the dispensing record. 


 
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13. 
STUDY SCHEDULE 
Please see Table 5 for Schedules of Event. 
Where possible, assessments should be conducted in order of least invasive to most invasive. 
13.1. 
Screening (Visit 1), Day -28 to Day -2 
Prior to enrolling in the study, and before performance of any procedures, potential patients will 
attend a Screening session at which time they will be provided with full information concerning 
details of the study assessments and procedures. They will also be provided with an Informed 
Consent Form (ICF). Prior to being asked to sign the ICF, patients will be given time to review 
study information and ask any questions. 
After the consent form is signed, Screening assessments will be carried out as follows: 
• Eligibility assessment 
• Review of medications, medical/surgical history (including breast cancer, surgical, 
radiation, and chemotherapy history, and inclusion/exclusion criteria) 
• Recording of demographic information 
• 12-lead ECG (after patient has been resting in a supine position for at least 5 minutes 
and prior to blood draws and assessment of vital signs) 
• Complete physical examination 
• Vital signs (body temperature, heart rate [HR], blood pressure [BP], respiratory rate 
[RR])  
• Height, weight, and BMI 
• Pre-treatment AEs and concomitant medication, including name, indication, dose, 
route, start and end dates. Pre-treatment concomitant medication will include all 
medications 30 days prior to Screening visit 
• Urine pregnancy test: Not required for amenorrhoeic female patients (see below); if a 
urine pregnancy test is positive, it must be confirmed by a serum pregnancy test 
• FSH test: Amenorrhoeic female patients only; postmenopausal status will be 
confirmed through testing of FSH levels (≥ 40 IU/mL) 
• Blood hematology (complete blood counts and leukocyte differential counts) 
• Serum chemistry: including glucose, total protein, albumin, electrolytes [sodium, 
potassium, chloride, total CO2], calcium, phosphorus, magnesium, uric acid, bilirubin 
(total, direct), ALT or AST, alkaline phosphatase (ALP), creatinine, blood urea 
nitrogen, and creatine phosphokinase (CPK). LFTs will be collected at each visit and 
includes bilirubin (total, direct), ALT or AST, and ALP 
• Coagulation: INR, prothrombin time, activated partial thromboplastin time (APTT) 
• Urinalysis (dipstick – microscopy if abnormal)  
• Urine drug screen (including cotinine test) and alcohol breath test 


 
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• Patients will be asked to participate in interviews to discuss their Breast Cancer 
related Lymphedema to help further research. Subjects will either be asked to 
participate in interviews as part of screening or as part of the post-blinded treatment 
follow up Visit (week 30) 
 
13.2. 
Baseline (Visit 2), Day -1 
The following assessments will be performed: 
• Visual analog scales 
• LYMPH-Q—Upper Extremity Module  
• LYMQOL 
• Eligibility assessment 
• Vital signs (Body Temperature, HR, BP, RR) 
• Weight and BMI 
• Concomitant medication 
• Adverse events 
• Review patient diary 
• Bioimpedance 
• Limb volume  
• MoistureMeterD  
• Tonometry/Skin FibroMeter 
• Study drug dispensing  
• Urine pregnancy test: Not required for amenorrhoeic female patients; if a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test 
• Genotyping, for CYP1A2, CYP2C9, CYP2C19, and CYP2D6. Patients are required 
to provide consent for genotyping. 
• Urinalysis (dipstick – microscopy if abnormal) 
• Urine drug screen (including cotinine test) and alcohol breath test 
• Inflammatory biomarkers: G-CSF, MIG, FGF-2, IL-4, IL-10, lymphotoxin-α/TNF-β, 
leptin, IL-6, IL-1β, TNF-α, TGF-β1, MMP-9, TIMP-1, MCP-1 
•  
Following completion of all baseline assessments, and assuming patients still meet all eligibility 
criteria, patients will be randomized to study treatment. Patients will be provided with a quantity 
of study medication sufficient for self-administration BID until Visit 3. Study drug 
self-administration begins on Day 1. 


 
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13.3. 
Visit 3 (Week 1, +2 days) 
Patients will attend an onsite visit at the CRU. The following assessments will be performed: 
• Visual analog scales  
• LYMPH-Q  
• LYMQOL  
• Concomitant medication  
• AE monitoring  
• Review patient diary 
• 12-lead ECG (QTcF), to collected 2.5 (+/- 15 minutes) after the morning study drug 
dose 
• Symptom directed physical exam  
• Bioimpedance  
• Limb volume  
• MoistureMeterD  
• Tonometry/Skin FibroMeter  
• Vital signs (weight, BMI, body temperature, HR, BP, RR)  
• Study drug dispensing and drug accountability 
• Sparse PK blood sample collection  
• Blood hematology  
• Serum chemistry  
• Coagulation  
• Urinalysis  
• Inflammatory biomarkers  
Patients will then be provided with a quantity of study medication sufficient for 
self-administration BID until Visit 4. 
13.4. 
Telephone Visit (Week 2, ± 3 days) 
Phone call made with patients to assess ongoing study medication compliance, AEs, concomitant 
medications, and reminder to complete the Patient Diary 1 week prior to Visit 4 (Week 4). 
 
13.5. 
Visit 4 (Week 4, ± 3 days) 
Patients will attend an onsite visit at the CRU. The following assessments will be performed: 


 
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• Visual analog scales 
•  LYMPH-Q  
• LYMQOL 
• Concomitant medication  
• Adverse events  
• Review patient diary 
• Bioimpedance  
• Limb volume  
• MoistureMeterD  
• Tonometry/Skin FibroMeter  
• Vital signs (weight, BMI, body temperature, HR, BP, RR)  
• Study drug dispensing and drug accountability 
• Sparse PK blood samples  
• Blood hematology 
• Serum chemistry (including LFT panel) 
• Coagulation 
• Urinalysis 
Patients will be provided with a quantity of study medication sufficient for self-administration 
BID until Visit 5. 
13.6. 
Visit 5 (Week 8, ± 3 days) 
Patients will attend an onsite visit at the CRU. The following assessments will be performed: 
• Visual analog scales  
• LYMPH-Q 
• LYMQOL 
• Concomitant medication  
• Adverse events  
• Review patient diary 
• Bioimpedance  
• Limb volume  
• MoistureMeterD  
• Tonometry/Skin FibroMeter  


 
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• Vital signs (weight, BMI, body temperature, HR, BP, RR)  
• Study drug dispensing and drug accountability 
• Sparse PK blood samples  
• Serum chemistry (including LFT panel) 
• Inflammatory biomarkers  
Patients will be provided with a quantity of study medication sufficient for self-administration 
BID until Visit 6. 
13.7. 
Visit 6 (Week 12, ± 3 days) 
Patients will attend an onsite visit at the CRU. The following assessments will be performed: 
• Visual analog scales  
• LYMPH-Q 
• LYMQOL  
• 12-lead ECG (QTcF), to be collected 2.5 (+/- 15 minutes) after the morning study 
drug dose 
• Symptom directed physical exam  
• Concomitant medication  
• Adverse events  
• Review patient diary 
• Bioimpedance  
• Limb volume  
• MoistureMeterD  
• Tonometry/Skin FibroMeter  
• Vital signs (weight, BMI, body temperature, HR, BP, RR)  
• Study drug dispensing and drug accountability 
• Sparse PK blood samples  
• Urine pregnancy test: Not required for amenorrhoeic female patients; if a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test.  
• Blood hematology  
• Serum chemistry (including LFT panel) 
• Coagulation  
• Urinalysis 


 
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Patients will be provided with a quantity of study medication sufficient for self-administration 
BID until Visit 7. 
13.8. 
Visit 7 (Week 16, ± 3 days) 
Patients will attend an onsite visit at the CRU. The following assessments will be performed: 
• Visual analog scales 
• LYMPH-Q 
• LYMQOL 
• Concomitant medication 
• Adverse events 
• Review patient diary 
• Bioimpedance  
• Limb volume 
• MoistureMeterD 
• Tonometry/Skin FibroMeter 
• Vital signs (weight, BMI, body temperature, HR, BP, RR)  
• Study drug dispensing and drug accountability 
• Sparse PK blood samples 
• Serum chemistry (including LFT panel) 
• Inflammatory biomarkers 
Patients will be provided with a quantity of study medication sufficient for self-administration 
BID until Visit 8. 
13.9. 
Visit 8 (Week 20, ± 3 days) 
Patients will attend an onsite visit at the CRU. The following assessments will be performed: 
• Visual analog scales 
• LYMPH-Q 
• LYMQOL 
• Concomitant medication 
• Adverse events 
• Review patient diary 
• Bioimpedance 
• Limb volume 


 
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• MoistureMeterD 
• Tonometry/Skin FibroMeter 
• Vital signs (weight, BMI, body temperature, HR, BP, RR) 
• Study drug dispensing and drug accountability 
• Sparse pharmacokinetic blood samples 
• Serum chemistry (including LFT panel) 
Patients will be provided with a quantity of study medication sufficient for self-administration 
BID until Visit 9. 
13.10. 
Telephone Visit (Week 23, ± 3 days) 
Phone call made with patients to assess ongoing compliance, AEs, concomitant medications, and 
reminder to take study medication through the morning of their Week 26 visit and to complete 
the Patient Diary 1 week prior to Visit 9 (the Week 26 clinic visit). 
13.11. 
Visit 9 (Week 26 ± 3 days) or Early Termination 
Patients will attend an onsite visit at the CRU. This visit marks the conclusion of the study 
treatment. The following assessments will be performed: 
• Visual Analog Scales 
• LYMPH-Q 
• LYMQOL 
• 12-lead ECG (QTcF) 
• Symptom directed physical exam  
• Concomitant medication 
• Adverse events 
• Review patient diary 
• Bioimpedance 
• Limb volume 
• MoistureMeterD 
• Tonometry/Skin FibroMeter 
• Vital signs (BMI, weight, body temperature, HR, BP, RR) 
• Study drug accountability only - no further dispensing 
• Sparse PK blood samples 
• Urine pregnancy test: Not required for amenorrhoeic female patients; if a urine 
pregnancy test is positive, it must be confirmed by a serum pregnancy test 


 
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• Blood hematology 
• Serum chemistry 
• Coagulation 
• Urinalysis  
• Urine drug screen (including cotinine test) and alcohol breath test 
• Inflammatory biomarkers 
13.12. 
Visit 10 (Final Safety Visit), 28 ± 3 Days After Termination of Study 
Treatment 
Patients will attend an onsite visit at the CRU. Every effort should be made to conduct this final 
safety visit for both completers and patients who terminated early from study treatment. The 
following assessments will be performed: 
• 12-lead ECG (QTcF) 
• Symptom directed physical exam  
• Concomitant medication 
• Adverse events 
• Vital signs (BMI, weight, body temperature, HR, BP, RR) 
• Blood hematology 
• Serum chemistry 
• Coagulation 
• Urinalysis  
• Patients will be asked to participate in qualitative interviews about their Breast 
Cancer-related Lymphedema. Subjects will either be asked to participate in 
interviews as part of screening or as part of the post-blinded treatment follow-up Visit 
(week 30) 
 


 
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14. 
PHARMACOKINETIC AND FIBROTIC AND INFLAMMATORY 
BIOMARKER ASSESSMENTS  
14.1. 
Blood and Urine Sample Collection 
Blood samples (for PK and fibrotic and inflammatory biomarker analysis) and urine samples (for 
Screening and safety evaluations) will be obtained at the time points delineated in the Schedule 
of Events (Table 5). The actual collection time of each sample must be recorded in the source 
data documentation, on the collection tube, and in the eCRF.  
All blood and urine samples will be collected in accordance with the site’s standard operating 
procedures and will be processed according to instructions provided in the Laboratory Manual at 
the time points delineated in the Schedule of Assessments. 
The total volumes of blood to be taken from each patient is detailed in Appendix 1. Blood 
samples will be drawn from the opposite arm from the site of axillary dissection and sentinel 
node biopsy. 
The Sponsor will supply complete written instructions for handling, processing, storage, and 
shipping of samples prior to study initiation. 
14.1.1. 
Pharmacokinetics 
Blood samples (4 mL each) for population PK will be collected at specified times at any 
on-treatment visit from Week 1 to Week 26 of the study. Throughout the course of the study, 
each patient will provide up to a minimum of 1 sample at each timepoint in reference to dosing: 
Pre-dose, 1 to < 2 hours, 2 to < 4 hours, 4 to < 8 hours, 8 to 12 hours. The following is an 
example of blood collection options: 
• Week 1(4 to < 8 hours sample collected)  
• Week 2 (pre-dose sample collected; note, the patient should bring medication with them 
to the visit to take it following the PK blood collection) 
• Week 4 (1 to < 2 hours, 2 to < 4 hours samples collected; note, the site can collect two 
timepoints at the same visit if the patient plans to be at the site for an extended period of 
time) 
• Week 20 (8 to 12 hours sample collected; note, again, the patient should bring 
medication with them to the visit if next dose is due shortly after the blood collection). 
For trough or later timepoint intervals such as 8 to 12 hours, the patient should be instructed to 
hold their next study medication dose and bring it with them to their study visit(s) to 
accommodate the longer time intervals required from their last dose taken. 
14.1.2. 
Fibrotic and Inflammatory Biomarkers  
Blood samples will be collected for assessment at the time points delineated in the Schedule of 
Events (Table 5): 
• Fibrotic and inflammatory biomarkers (G-CSF, MIG, FGF-2, IL-4, IL-10, 
lymphotoxin-α/TNF-β, leptin, IL-6, IL-1β, TNF-α, TGF-β1, MMP-9, TIMP-1, MCP-1). 
Of these, the TGF-β1 biomarker is of primary interest. 


 
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These data may be reported separately in a supplementary report to the main Clinical Study 
Report. 
14.1.3. 
Quality of Life 
The following will be assessed at Day -1, Weeks 1, 12, and 26 (or early termination), and during 
follow-up post end of treatment (Weeks 28): 
• LYMPH-Q (Appendix 2) 
• LYMQOL (Appendix 3) 
14.2. 
Sample Analysis 
Plasma PK and fibrotic and inflammatory biomarker sample analysis will be performed using 
validated procedures and methods as outlined in the Laboratory Manual. The methods used for 
PK analysis and TGF-β1 will be appropriately validated. Methods for other biomarkers will not 
be validated, as these biomarkers are exploratory only. 


 
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15. 
ASSESSMENT OF SAFETY 
Safety and tolerability will be assessed throughout all parts of the study by monitoring AEs, 
physical examination, vital signs, 12-lead ECGs, clinical laboratory values (hematology, serum 
chemistry, coagulation, and urinalysis), and review of concomitant treatments/medication use. 
15.1. 
Safety Parameters 
Study procedures should be completed as delineated in the Schedule of Assessments (Table 5). 
However, if a patient is unable to attend a visit within the specified window, the Investigator or 
designee should discuss appropriate scheduling with the Sponsor’s MM or appropriate designee. 
Any unscheduled procedures required for urgent evaluation of safety concerns must take 
precedence over all routine scheduled procedures. 
15.1.1. 
Demographic/Medical History 
Medical history (including alcohol and smoking status), date of birth, age (calculated), sex, 
ethnicity, and race will be recorded at Screening. 
15.1.2. 
Vital Signs 
Vital signs (body temperature, BP, HR, RR) will be measured at the time points specified in the 
Schedule of Assessments with patients resting for at least 5 minutes in a supine position. When 
the time of vital signs measurement coincides with a blood draw, the vital signs will be taken 
before the scheduled blood draw where possible while ensuring the blood draw is within the 
window specified in the protocol. 
Additional vital signs may be performed at other times if deemed necessary. 
15.1.3. 
Weight and Height 
Body height (centimeters) and body weight (kilograms) will be measured at the time points 
delineated in the Schedule of Assessments and will be used to calculate BMI. BMI is calculated 
by dividing the patient’s body weight in kilograms by the patient’s height in meters squared 
(kg/m2). Body weight and height will be obtained with the patient’s shoes and jacket or coat 
removed. 
15.1.4. 
Physical Examination 
Complete and directed physical examinations will be performed by a licensed physician at the 
time points specified in the Schedule of Assessments. 
Complete physical examinations include general appearance, head, ears, eyes, nose, throat, 
dentition, thyroid, chest (heart, lungs), abdomen, skin, neurological, extremities, back, neck, 
musculoskeletal, and lymph nodes. 
Directed physical examinations may include head, ears, eyes, nose, throat, chest (heart, lungs), 
abdomen, skin, musculoskeletal, lymph nodes, and any pertinent system based on any prior 
findings, at the discretion of the Investigator.  
Physical examinations may be performed at various unscheduled time points if deemed 
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15.1.5. 
Electrocardiogram 
A 12-lead ECG will be taken at the time points delineated in the Schedule of Assessments. 
Additional ECG monitoring may be performed at other times if deemed necessary. 
ECGs will be performed prior to vital signs with patients in a supine position. Patients must be in 
this position for at least 5 minutes before the reading is taken. 
All ECG tracings will be reviewed by the PI or designee.  
When the time of ECG monitoring coincides with a blood draw, the ECG will be taken before 
the scheduled blood draw while ensuring the blood draw is within the window specified in the 
protocol. 
15.1.6. 
Laboratory Assessments 
Safety laboratory tests (hematology, serum chemistry, coagulation, and urinalysis) will be 
performed at the time points specified in the Schedule of Assessments. Additional clinical 
laboratory tests may be performed at other times if deemed necessary based on the patient’s 
clinical condition. 
Medically indicated laboratory tests (emergency or unscheduled tests) should be conducted at the 
local laboratory. 
A blood sample will be taken from each patient for hematology, coagulation, and serum 
chemistry analyses at the time points delineated in the study schedules. 
15.1.6.1. Hematology 
Hematology parameters to be tested are: 
• Hemoglobin (HGB) 
• Hematocrit (HCT) 
• Erythrocytes (RBC) 
• Platelets (PLAT) 
• Leukocytes with differential — including Eosinophils (ESN), Neutrophils (NEUT), 
Basophils (BASO), Lymphocytes (LYM), and Reticulocytes (RETI) 
15.1.6.2. Serum Chemistry 
Serum chemistry parameters to be tested are: 
• C-reactive protein (CRP) 
• Urea (U) 
• Creatinine (CREAT) 
• Total Bilirubin (BILI) and Direct Bilirubin (BILIDIR) 
• Urate (URATE) 
• Albumin (ALB) 


 
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• Globulin (GLOBUL) 
• Alkaline Phosphatase (ALP) 
• Creatine phosphokinase (CPK) 
• Troponin 1 (TROP1) 
• Aspartate Aminotransferase (AST) 
• Alanine Aminotransferase (ALT) 
• Gamma- glutamyl transpeptidase (GGT) 
• Glucose (GLU) (fasting labs only) 
• Sodium (NA) 
• Potassium (K) 
• Calcium (CA) 
• Chloride (CL) 
• Phosphate (PHOS) 
• Bicarbonate (BICARB) 
15.1.6.3. Coagulation 
Coagulation parameters to be tested are: 
• INR 
• Prothrombin time 
• APTT 
15.1.6.4. Urinalysis 
A urinalysis test (dipstick) will be performed for each patient. Urinary analysis will be performed 
at Screening and other times according to the study schedule. If abnormality is noted for protein, 
blood, nitrite, or leukocyte esterase (and at the discretion of the Investigator) a microscopic 
examination of RBC, white blood cells, bacteria, and casts will be performed. 
Macroscopic urinalysis parameters to be tested are: 
• pH (PH) 
• Specific Gravity (SPGRAV) 
• Creatinine (CREATININE) 
• Protein (PROT) 
• Glucose (GLUC) 
• Ketones (KETONES) 
• Total Bilirubin (BILI) 


 
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• Occult Blood (OCCBLD) 
• Nitrite (NITRITE) 
• Urobilinogen (UROBIL) 
• Leukocytes (WBC) 
15.1.6.5. Urine Drug Screen 
A urine drug screen will be performed at the time points outlined in the Schedule of Assessments 
and will include Screening for: 
• Amphetamines (AMP)  
• Methamphetamines (MET)  
• Methadone (MTD)  
• Barbiturates (BAR)  
• Cocaine (COC)  
• Opiates (OPI)  
• Methylenedioxymethamphetamine (MDMA)  
• Phencyclidine (PCP) 
• Cotinine (as indicated) 
15.1.6.6. Alcohol Breath Test 
An alcohol breath test will be performed at the time point indicated in the Schedule of 
Assessments. 
15.1.6.7. Pregnancy Testing 
A urine pregnancy test will be performed at the time points indicated in the Schedule of 
Assessments for WOCBP only. If a urine test is positive, a serum test will be performed 
immediately for confirmation. 
15.1.6.8. Follicle-Stimulating Hormone Test 
Postmenopausal status will be confirmed and documented through confirmation of FSH levels 
(≥ 40 IU/mL) at Screening for amenorrhoeic female patients, as applicable. 
15.1.6.9. Genotyping  
CYP1A2, CYP2C9, CYP2C19, and CYP2D6 genotyping is conducted prior to study entry as 
indicated in the Schedule of Assessments; patients are required to provide consent for 
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16. 
ADVERSE AND SERIOUS ADVERSE EVENTS 
In this study, AEs will be reported for all patients from the time of consent until the completion 
of the follow-up/EOS visit. AEs reported prior to the first dose will be denoted as pre-treatment. 
SAEs will be reported for all patients (enrolled and not enrolled) from the time of consent. AEs 
reported from the time of consent to confinement on Day -1 will be recorded as pre-treatment 
AEs. Treatment-emergent AEs will be evaluated from the first administration of study drug until 
the EOS visit. AEs that are ongoing at the final onsite visit will be marked as Not Recovered/Not 
Resolved on the AE eCRF page (see Section 16.1.4). 
All spontaneously volunteered and enquired for, as well as observed AEs, will be recorded in the 
patient’s medical records and the eCRF. 
Infection due to cellulitis and lymphangitis will be reported as an AE. When noted, the 
Australian Lymphology Association’s Infection/ Cellulitis Form will also be completed (see 
Appendix 4). 
16.1. 
Definition of Adverse Events 
An AE is any event, side-effect, or other untoward medical occurrence that occurs in conjunction 
with the use of a medicinal product in humans, whether or not considered to have a causal 
relationship to this treatment. An AE can, therefore, be any unfavorable and unintended sign 
(that could include a clinically significant abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. 
Events meeting the definition of an AE include: 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition; 
• New conditions detected or diagnosed after study drug administration that occur 
during the reporting periods, even though it may have been present prior to the start 
of the study; 
• Signs, symptoms, or the clinical sequelae of a suspected interaction; 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug 
or concomitant medications (overdose per se will not be reported as an AE/SAE). 
Events that do not meet the definition of an AE include: 
• Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure should be reported as an AE if it meets the criteria of an AE; 
• Situations where an untoward medical occurrence did not occur (e.g., social and/or 
convenience admission to a hospital); 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
If there is evidence of an AE through report or observation, the Investigator or designee will 
evaluate further and record the following information: 


 
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• Time of onset and resolution 
• Severity 
• Causality/relation to study treatment 
• Action taken regarding study drug 
• Outcome 
16.1.1. 
Severity of an Adverse Event 
Severity of AEs will be graded by the Investigator using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE version 5.0) or as follows: 
• Mild (Grade 1): A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with 
usual activities of daily living. 
• Moderate (Grade 2): A type of AE that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the research 
patient. 
• Severe (Grade 3): A type of AE that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic intervention. 
• Life-threatening (Grade 4): A type of AE that places the patient at immediate risk 
of death. 
• Death (Grade 5): Events that result in death. 
16.1.2. 
Causal Relationship of an Adverse Event 
The Investigator will assess the relationship between study drug and the occurrence of each AE. 
The Investigator’s assessment of the relationship of each AE to study drug will be recorded in 
the source documents and the eCRF. Alternative causes, such as medical history, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study drug should be 
considered and investigated, if appropriate. The following definitions are general guidelines to 
help assign grade of attribution:  
• Not related: The event is clearly related to other factors such as the patient’s 
environment or clinical state, therapeutic interventions or concomitant drugs 
administered to the patient. This is especially so when an event occurs prior to the 
commencement of treatment with the study drug. 
• Possible: The event follows a reasonable temporal sequence from the time of study 
drug administration or follows a known response to the study drug but could have 
been produced by other factors such as the patient's clinical state, other therapeutic 
interventions, or concomitant drugs administered to the patient. 
• Probable:  The event follows a reasonable temporal sequence from the time of study 
drug administration and follows a known response to the study drug and cannot be 


 
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reasonably explained by other factors such as the patient's clinical state, other 
therapeutic interventions, or concomitant drugs administered to the patient. 
16.1.3. 
Action Taken with Investigational Products 
Should the Investigator need to alter the administration of the study drug from the procedure 
described in the protocol due to the well-being and safety of the patient then the action taken will 
be recorded on the AE eCRF page, as one of the following options: 
• Dose Reduced 
• Drug Interrupted 
• Drug Withdrawn 
• Not Applicable 
• Other 
16.1.4. 
Outcome 
Outcome of an AE will be recorded on the AE eCRF as follows: 
• Recovered/Resolved or attributable to other (defined) cause 
• Recovering/Resolving 
• Recovered/Resolved with Sequelae 
• Not Recovered/Not Resolving, up to a 30-day follow-up period for treatment-related 
AEs 
• Fatal 
• Unknown (or patient lost to follow-up after 4 attempts at contact over a period of 
30 days) 
16.2. 
Definition of Serious Adverse Event 
An SAE is an AE occurring during any study phase (i.e., baseline, treatment, washout, or 
follow-up), and at any dose of the study drug (active or placebo), that fulfills one or more of the 
following: 
• Results in death. 
• It is immediately life-threatening. 
• It requires in-patient hospitalization or prolongation of existing hospitalization. 
• It results in persistent or significant disability or incapacity. 
• Results in a congenital abnormality or birth defect. 
• It is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed above. 


 
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Important medical events that may not be one of the above may be considered an SAE by the 
Investigator when, based upon appropriate medical judgment, they are considered clinically 
significant and may jeopardize the patient, or may require medical or surgical intervention to 
prevent one of the outcomes listed above. 
An AE is considered “life-threatening” if, in the opinion of either the Investigator or the Sponsor, 
its occurrence places the patient at immediate risk of death. It does not include an AE that, had it 
occurred in a more severe form, might have caused death.  
16.2.1. 
Notification of a Serious Adverse Event 
All SAEs regardless of relationship to the IP during the period starting from the time of informed 
consent through the follow-up visit, will be recorded in the eCRF. Once the Investigator becomes 
aware of an SAE, they must report the SAE to the Clinical Research Organization (CRO) Safety 
Department within 24 hours of knowledge of the event.  
A written SAE report must include a full description of the event including the below parameters 
(include any protocol specific requirements): 
• Diagnosis or description of event  
• Onset date  
• Severity assessment 
• Causal relationship to the IP  
• Assessment of seriousness of the event  
• Corrective treatment administered for the SAE 
• Action taken related to IP including the following: dose interruption, dose delay, dose 
reduction, or IP discontinuation  
• Outcome of event and end date 
Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported to the CRO Safety Department as soon as information is available. 
As further information regarding the SAE becomes available, such follow-up information should 
be documented on a new SAE report form, marked as a follow-up report, scanned, and emailed 
to the address at the bottom of the report form. 
Withdrawal from the study in the event of an SAE and therapeutic measures taken shall be at the 
discretion of the Investigator. A full explanation for the discontinuation from the study should be 
made in the patient’s medical records and in the eCRF. 
16.3. 
Clinical Laboratory Abnormalities and other Abnormal Assessments 
as Adverse Events and Serious Adverse Events 
Abnormal laboratory findings (e.g., hematology, serum chemistry, coagulation, and urinalysis) or 
other abnormal assessments (e.g., ECG and vital signs) per se are not reported as AEs. However, 
those abnormal findings that are deemed clinically significant or are associated with signs 
and/or symptoms must be recorded as AEs if they meet the definition of an AE (and recorded as 


 
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an SAE if they meet the criteria of being serious) as previously described. Clinically significant 
abnormal laboratory or other abnormal findings that are detected after consent or that are present 
at baseline and worsen after consent are included as AEs (and SAEs if serious).  
The Investigator should exercise their medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant. Usually, the 
abnormality should be associated with a clinically evident sign or symptom or be likely to result 
in an evident sign or symptom in the near term, to be considered clinically significant. A 
clinically significant laboratory abnormality in the absence of clinical symptoms may jeopardize 
the patient and may require intervention to prevent immediate consequences. For example, a 
markedly low serum glucose concentration may not be accompanied by coma or convulsions yet 
be of a magnitude to require glucose administration to prevent such sequelae. 
16.4. 
Recording Adverse Events 
AEs spontaneously reported by the patient and/or in response to an open question from the study 
personnel or revealed by observation will be recorded in accordance with the Investigator’s 
normal clinical practice and on the AE page of the eCRF during the study at the investigational 
site. 
However, abnormal values that constitute an SAE or lead to discontinuation of administration of 
study drug must be reported and recorded as an AE. Information about AEs and SAEs will be 
collected from the time of consent until the end of the study. The AE term should be reported in 
standard medical terminology when possible. For each AE, the Investigator will evaluate and 
report the onset (date and time), resolution (date and time), intensity, causality, action taken, 
serious outcome (if applicable), and whether or not it caused the patient to discontinue the study. 
AEs that occur during the study must be documented in the patient’s medical record, on the AE 
eCRF, and on the SAE report form. If an SAE report is completed, pertinent laboratory data 
should be recorded on the SAE form, preferably with baseline values and copies of laboratory 
reports. 
In addition, if the abnormal assessment meets the criteria for being serious, the SAE form must 
also be completed. A diagnosis, if known, or clinical signs or symptoms if the diagnosis is 
unknown, rather than the clinically significant laboratory finding or abnormal assessment, should 
be used to complete the AE/SAE page. If no diagnosis is known and clinical signs or symptoms 
are not present, then the abnormal finding should be recorded. 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 16.2. An AE of severe intensity may 
not be considered serious. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that a study drug may have 
interfered with the effectiveness of a contraceptive medication. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) must be followed up and documented even if the patient was 
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All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should 
also be reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. 
16.5. 
Reporting Adverse Events 
Any SAEs considered possibly or probably related to the study drug and discovered by the 
Investigator at any time after the study should be reported. All SAEs must be reported to the 
Sponsor and/or the CRO Safety Department within 1 business day of the first awareness of the 
event. The Investigator must complete, sign and date the SAE pages, verify the accuracy of the 
information recorded on the SAE pages with the corresponding source documents, and send a 
copy to the Sponsor and/or CRO Safety Department.  
Additional follow-up information, if required or available, should all be emailed to the Sponsor 
and/or CRO Safety Department within 1 business day of receipt and this should be completed on 
a follow-up SAE form, placed with the original SAE information, and kept with the appropriate 
section of the eCRF and/or study file. 
The Sponsor is responsible for notifying the relevant regulatory authorities of certain events. It is 
the Investigator’s responsibility to notify the IRB/IEC of all SAEs that occur at their site in 
accordance with the IRB/IEC SAE reporting policy. The Investigator will also be notified of all 
unexpected, serious, drug-related events that occur during the clinical trial. The investigational 
site is responsible for notifying its IRB/IEC of these additional SAEs. 
16.6. 
Follow-up of Adverse Events and Serious Adverse Events 
All AEs and SAEs that are deemed related, possibly related, or probably related to the study drug 
must be followed until resolution, until the condition stabilizes, until the event is otherwise 
explained, or until the patient dies or is lost to follow-up. The Investigator is responsible to 
ensure that follow-up includes any supplemental investigations as may be indicated to elucidate 
as completely as practical the nature and/or causality of the AE/SAE. This may include 
additional laboratory tests or investigations or consultation with other health care professionals. 
The Sponsor may request that the Investigator perform or arrange for the conduct of 
supplemental measurements and/or evaluations. If a patient dies during participation in the study 
or during a recognized follow-up period, the Sponsor should be provided with a copy of any 
post-mortem findings, including histopathology. 
16.7. 
Randomization Code Break  
An electronic Interactive Web Response System (IWRS) will be utilized to perform patient 
randomization (and stratification) using a master randomization list. Therefore, in the event of an 
emergency and the identification of an individual patient’s treatment must be unblinded, the 
treatment blind for that specific patient can be broken within the IWRS system and made 
available to appropriate site personnel immediately. A complete audit trail of unblinding will be 
available within the IWRS. 


 
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17. 
ASSESSMENT OF EFFICACY 
Efficacy will be assessed in an exploratory fashion. In general, efficacy will be based on 
changes from baseline to each post-baseline visit (through the end of treatment at Week 26). 
The following parameters will be measured at all study visits (except the Screening visit): 
• Limb water content, by Bioelectrical impedance spectroscopy (BIS): Multiple 
frequency BIS (L-dex) provides accurate relative measures of protein-rich fluid in the 
upper limb of patients. BIS is a non-invasive technique that involves passing an 
extremely small electrical current through the body and measuring the impedance (or 
resistance) to the flow of this current. The electrical current is primarily conducted by 
the water containing fluids in the body. BIS quantifies the amount of protein-rich 
fluid in lymphedema by comparison of the affected to the non-affected limb.  
• Limb volume (perometry): Relative limb volume is measured by perometry. 
Perometry is a non-invasive technique involving a Perometer (Pero-System), which 
uses infrared light to scan a limb and obtain measurements of the limb's 
circumference. The truncated cone tape measure method can be used as a backup if 
the Perometer is unavailable, or not working at time of the patient visit. 
• Tissue dielectric constant (MoistureMeterD): The TDC measures the local tissue 
water content under the skin at various depths ranging from skin to subcutis. The 
results are converted into a 0% to 100% scale to reflect subcutaneous fluid deposition 
that can occur in early stage lymphedema. 
• Tissue firmness (tonometry/SkinFibroMeter): A tonometer device is pressed into the 
skin to measure the amount of force required to make an indent in the tissue. The 
resulting measurement gauges the degree of firmness or fibrosis (tissue scarring) 
under the skin to assess the severity of lymphedema. (r) at dorsal surface of arm 
10 cm below the elbow. 
• Visual analog scales for pain, swelling, discomfort, and function: This graphic scale 
has a straight line with endpoints of 0 and 10 that is marked by the patient to calibrate 
to their extreme limits of pain, swelling, discomfort and function, ranging from “not 
at all” to “as bad as it could be”. The higher marks on the line indicates the worse 
condition. 
Additionally, health-related QoL assessments will be collected to assess the following: 
• LYMPH-Q (Appendix 2): This is a patient completed questionnaire that measures the 
degree of symptoms, function, and psychological impact with patients who have 
upper extremity lymphedema. Symptoms are rated on a 15-item scale (severe, 
moderate, mild to none) to measure how the arm feels, the function portion is 
measured on a 12-item scale (extremely difficult, moderately difficult, a little difficult 
and not at all difficult) to determine arm function capability, and the psychological 
portion is measured on a 12-item scale (always, often, sometimes, never) to evaluate 
how a patient feels having lymphedema.  
• LYMQOL (Appendix 3): This is a patient completed questionnaire that assesses 
upper limb lymphedema and symptoms, and ability to perform common functional 


 
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activities in patients with BCRL. It addresses the following four domains – 
Symptoms, Body Image/Appearance, Function, and Mood. Each item is scored as 
1 = Not at all; 2 = A little; 3 = Quite a bit; and 4 = A lot. Total scores for each domain 
are summed and divided by the total number of completed question responses. The 
overall QoL item ranges from 1 to 10. Lower scores indicate a higher QoL. 
• Patient Interviews: Patients will be asked to participate in the qualitative interviews. 
The interviews will occur during screening and/or after completion of blinded 
treatment. The sample size was elected to be in line with best practice 
recommendations for cognitive debriefing of existing measures to provide evidence 
of content validity.  Participants recruited for qualitative interviews will match the 
main inclusion and exclusion criteria found in the trial protocol (BCRL patients that 
have at least 6 months and no more than 15 years since the most recent type of breast 
cancer related surgery, have unilateral upper arm lymphedema no greater than 4 
years). 
 
The interviews will begin with concept elicitation using a set of open-ended questions 
that ask the patients to spontaneously identify the BCRL symptoms and daily activity 
impacts they experience.  These data will be compared with the content of the 
existing instruments to determine whether they are complete and relevant in this 
target population.  
 
After the open-ended portion of each interview is completed, interviewers will 
cognitively debrief the BCRL-specific questionnaires included in the current trial 
protocol. These questionnaires are LYMPH-Q and LYMPHQOL. Participants will be 
asked to comment on the content of each questionnaire including the clarity of the 
instructions and the understandability and relevance of each item and its response 
options. 
•  
Infection due to cellulitis and lymphangitis will be reported as an AE.  
• When noted, the Australian Lymphology Association’s Infection/ Cellulitis Form will 
also be completed (see Appendix 4). 


 
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18. 
STUDY COMPLETION AND DISCONTINUATION 
18.1. 
Patient Withdrawal 
In accordance with applicable regulations, a patient has the right to withdraw from the study, at 
any time and for any reason, without prejudice to his future medical care. 
If a patient is withdrawn because of an AE, the Investigator must arrange for the patient to have 
appropriate follow-up care until the AE is resolved or has stabilized. Unresolved AEs will be 
followed until the last scheduled follow-up visit or until the PI and MM determine that further 
follow-up is no longer indicated. In addition to AEs, other reasons for removal of patients from 
the study might include, but are not limited to, withdrawal of consent, administrative decision by 
the Investigator or the Sponsor, protocol deviation, or patient noncompliance. 
If a patient asks or decides to withdraw from the study, all efforts will be made to complete and 
report the observations, especially the listed primary and secondary objectives, as thoroughly as 
possible up to the date of withdrawal. The primary reason for withdrawal will be identified and 
recorded on the appropriate eCRF, along with the date of withdrawal. 
18.2. 
Patient Replacement 
Patients enrolled who withdraw consent or discontinue for other reasons will not be replaced. 


 
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19. 
TERMINATION OR SUSPENSION OF THE STUDY 
The Sponsor, Investigator, and the IRB/IEC reserve the right to terminate or suspend the study at 
any time; however, this should be discussed between the relevant parties beforehand and the 
reason for such decision recorded. Should this occur, all data available will also be recorded in 
the eCRFs. The Investigator should notify the relevant IRC/IEC in writing of the study’s 
completion or early discontinuation. 


 
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20. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
20.1. 
Study Monitoring 
Before an investigational site can enter a patient into the study, a representative of the Sponsor 
will visit the investigational study site to: 
• Determine the adequacy of the facilities. 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of the Sponsor or its representatives. 
This will be documented in a Clinical Study Agreement between the Sponsor and the 
Investigator. 
The Sponsor has appointed Novotech to manage and monitor the study so as to assure them of 
the adequate conduct of the study and to act as the contact with the investigational site. A study 
monitor will be identified and will be responsible for liaison with, and support of, the 
investigational site. 
The study monitors and the regulatory authority inspectors are responsible for contacting and 
visiting the investigative site for the purpose of inspecting the facilities and, upon request, 
inspecting the various records of the study (e.g., eCRFs, essential documentation, and other 
pertinent data) provided that patient confidentiality is respected. 
During the study, the monitor will have regular contacts with the investigational site for the 
following: 
• Provide information and support to the Investigator(s). 
• Confirm that facilities remain acceptable. 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the eCRFs, and that study drug accountability checks are being 
performed. 
• Perform source data verification. This includes a comparison of the data in the eCRFs 
with the patient’s medical records at the hospital or practice, and other records 
relevant to the study. This will require direct access to all original records for each 
patient (e.g., clinic charts). 
• Record and report any protocol deviations not previously sent to the Sponsor. 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to the Sponsor and those SAEs that met criteria for 
reporting have been forwarded to the IRB/IEC. 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
20.2. 
Data Management 
All data will be recorded in individual source documents. An eCRF will be created by the data 
management group for recording of the required data in the study database. All eCRF 


 
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information is to be filled in by site staff as per the eCRF Completion Guidelines. If an item is 
not available or is not applicable, this fact should be indicated. Blank spaces should not be 
present unless otherwise directed. 
The study monitor will perform source data verification of data entered into the eCRF and raise 
queries for correction by the site. The data entered into the eCRF will be subject to data 
validation checks for consistency and completeness by the data management group. Data queries 
will then be generated and sent to the investigational site for response before the database is 
locked and released for statistical analysis. 
All eCRFs should be maintained on the system with details of any changes logged accordingly. 
20.3. 
Audits and Inspections 
Authorized representatives of the Sponsor, a regulatory authority, or an IRB/IEC may visit the 
site to perform audits or inspections, including source data verification. The purpose of a 
Sponsor audit or inspection is to systematically and independently examine all study-related 
activities and documents to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, GCP guidelines of the 
ICH, and any applicable regulatory requirements. The Investigator should contact the Sponsor 
immediately if contacted by a regulatory agency about an inspection. 


 
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21. 
STATISTICS 
A statistical analysis plan (SAP) will be written that will describe, in greater detail, the analyses 
to be performed. The sections below provide a summary of the general approach to the analysis. 
The analysis is consistent with the study design and objectives. Note that this study is not 
hypothesis testing but rather hypothesis-generating, and thus conclusions regarding outcomes 
will not be based on inferential tests but rather descriptive outcomes, magnitude of treatment 
effects, and a preponderance of evidence regarding the risk-benefit profile of LYT-100.  
As this study is hypothesis-generating, we will calculate effect sizes (Cohen's D, a standardized 
difference between the treatment arms) for efficacy and other endpoints as the data warrant. 
These values may be used to estimate sample sizes and/or power estimates for future clinical 
studies of LYT-100 in this population. 
21.1. 
Sample Size 
This study will randomize approximately 50 patients with secondary lymphedema, in a 1:1 ratio 
to LYT-100 or placebo, as part of this early development and exploratory study of LYT-100. 
Formal sample size calculations were not performed; rather, the sample size selected should be 
adequate for preliminary evaluation of safety, tolerability, efficacy signaling, PK, and fibrotic 
and inflammatory biomarker parameters in the target patient population. 
21.2. 
General Statistical Plan 
Statistical methods will be further outlined in an SAP and approved by the Sponsor prior to any 
analysis. Procedures outlined in the SAP will supersede protocol specified statistical methods in 
the event of divergence. 
The baseline value for all variables will be the last measurement obtained prior to the patient 
receiving the first dose of study treatment. 
Patient disposition (including the number and percent of patients who are enrolled, who receive 
treatment, who prematurely discontinue and reasons for discontinuation, and who complete the 
study) will be tabulated by treatment group. Summary statistics for days of exposure and 
concentration of exposure will be provided by treatment group. 
AEs, concomitant medications, clinical laboratory findings, physical examinations, ECGs, and 
vital signs for each patient will be listed and also summarized in tabular form, as appropriate.  
Demographic information will be listed for each patient and summarized. TEAEs and laboratory, 
vital signs, and ECG parameters will be summarized. In addition, change from baseline will be 
summarized for laboratory and vital sign parameters. Shift tables will also be provided for 
clinical laboratory results. ECG results will be classified as normal and abnormal and 
summarized. ECG results for QTcF will also be classified as < 450 msec, 450 to 500 msec or 
> 500 msec. Changes in physical exams will be described in the final study report. 
In general, descriptive statistics (arithmetic mean, standard deviation [SD], median, minimum, 
and maximum) will be calculated for continuous valued safety data by specified assessment time 
point. Frequency summaries (i.e., number and percentage of each observed category) will be 
provided for categorical and ordinal safety data by treatment and by specified assessment time 
point. 


 
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No formal hypothesis testing will be performed for this study. 
21.3. 
Analysis Populations 
Patient inclusion into each population will be determined prior to the final analysis. In general: 
Safety Population:  
The Safety Population will consist of all patients who received any amount of study drug. The 
Safety Population will be used for the summaries of all safety assessments as well as 
efficacy/biomarker outcomes. 
Full Analysis Set Population: 
The Full Analysis Set (FAS) Population is defined as all randomized patients who received at 
least one dose of double-blinded study medication and had at least one post-baseline efficacy 
assessment. All efficacy endpoints will be assessed using this population. 
Pharmacokinetic Population:  
The Pharmacokinetic Population (PP) is defined as all patients who receive  the double-blinded 
study medication and for whom an evaluable concentration-time profile is available for the 
determination of at least one PK parameter. Patients with emesis after consuming study 
medication will be assessed on a case-by-case basis for eligibility for inclusion in the PK 
population. In general, patients who vomit after at least 2 half-lives of the given medication will 
be included in the PK population (as Cmax will presumably be reached by that time).  
Fibrotic and Inflammatory Biomarker Population: 
The Fibrotic and Inflammatory Biomarker Population is defined as all patients who receive the 
double-blinded study medication and provide biomarker and lymphedema assessment data. 
21.4. 
Safety and Tolerability 
All safety assessments, including prior and concomitant medications, AEs, laboratory 
evaluations, vital signs, ECGs, and other safety assessments will be analyzed using the Safety 
Population. Data for all endpoints will be tabulated, displayed graphically, or summarized 
descriptively, as appropriate. Statistical analyses will be descriptive only, no inferential testing 
will be performed.  
21.4.1. 
Prior and Concomitant Medication 
Prior and concomitant medications will be coded using the most current version of the WHO drug 
dictionary. Prior and concomitant medications will be listed by patient and summarized by 
treatment using ATC and PT. 
21.4.2. 
Adverse Events 
AEs will be coded using the MedDRA® version 23.0. A by patient AE data listing, including 
verbatim term, PT, system organ class (SOC), treatment, severity, and relationship to study drug 
will be provided. The number of patients experiencing TEAEs and the number of individual 
TEAEs will be provided by treatment as well as by SOC and PT. The severity and the relationship 
to study drug of TEAEs will be summarized by treatment.  


 
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21.4.3. 
Laboratory Evaluations 
Laboratory evaluations (including hematology, serum chemistry, coagulation, and urinalysis) will 
be listed and summarized by treatment and by protocol specified collection time point. This will 
be done both for actual observed laboratory values and for changes from baseline. 
The abnormal urinalysis results (dipstick and microscopy), if applicable, will be listed only. 
21.4.4. 
Vital Signs 
Vital signs will be listed and summarized by treatment and by protocol specified collection time 
point. This will be done both for actual observed vital sign values and for changes from baseline. 
21.4.5. 
Electrocardiogram Values and Results  
ECG values will be listed and summarized by treatment and by protocol specified collection time 
point. This will be done both for actual observed ECG values and for changes from baseline.  
21.4.6. 
Other Safety Assessments 
Findings of the following assessments will be listed by patient: 
• Medical history 
• Pregnancy test/FSH test 
• Urine drug screen (including Cotinine Test)/ alcohol breath test 
• Physical examination 
• Serology (HIV, Hepatitis B and C screen) 
21.5. 
Pharmacokinetics 
Sparse PK sampling will be employed for population PK analysis (as a secondary endpoint) to 
determine the variability of LYT-100 drug concentration data from individual patients across 
multiple clinical sites. 
PK parameter values will be listed and summarized by treatment and assessment time point. 
21.6. 
Fibrotic and Inflammatory Biomarkers  
The association between fibrotic and inflammatory biomarkers (in particular TGF-β1), and 
disease progression in mild to moderate lymphedema will be examined.  
Exploratory analysis of fibrotic and inflammatory biomarkers include: G-CSF, MIG, FGF-2, 
IL-4, IL-10, lymphotoxin α/TNF-β, leptin, IL-6, IL-1β, TNF-α, TGF-β1, MMP-9, TIMP-1, and 
MCP-1.  
For each biomarker of interest, scatterplots of the recorded biomarker value against each of the 
disease progression metrics (limb water content, limb volume, TDC, tissue firmness, and visual 
analog scales; see Section 17 and Section 21.7) will be provided on a single set of axes, (with 
color used to identify the different disease progression metrics). All patients and all time points 
at which both biomarker assessment and disease progression assessment are performed will be 
included on the one plot. This will be repeated considering the change from baseline in the 


 
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biomarker values as opposed to actual observed values. Further details of this exploratory 
biomarker analysis will be provided in the SAP. 
21.7. 
Efficacy Endpoints 
Analysis of clinical assessments and potential progression or disease will be explored. 
Comparisons between LYT-100 and placebo will be based on clinical interpretation of effect, 
magnitudes of effect, and a preponderance of evidence. Estimates of changes over time from 
these data may be used to power future clinical studies. 
Lymphatic obstructions and subsequent edema will be measured using each of the following 
metrics:  
• Limb water content (BIS) 
• Limb volume (truncated cone tape measure and/or perometry) 
• Tissue dielectric constant (MoistureMeterD)  
• Tissue firmness (tonometry/SkinFibroMeter) 
For each of these metrics, use of a mixed model for repeated measures (MMRM) will be used to 
provide model-based estimates of changes over time in each of these outcomes. Descriptive 
statistics will also be provided at each time point. Details for the model (including covariates to 
be included) will be provided in the SAP. 
The number of occurrences of cellulitis and lymphangitis within the treatment period will be 
tabulated. 
Visual analog scales for pain, swelling, discomfort, and function, and QoL assessments using the 
LYMPH-Q (Appendix 2) and LYMQOL (Appendix 3) questionnaires will be provided at 
baseline and treatment period timepoints. Both an MMRM and descriptive statistics will be used 
to describe the outcomes over time, considering each of their respective domains as listed in 
Section 17. 


 
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22. 
ETHICS 
22.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB/IEC as appropriate. The Investigator must submit written 
approval to the Sponsor before they can enroll any patient into the study. 
The Investigator is responsible for informing the IRB/IEC of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB/IEC must approve all advertising used 
to recruit patients for the study. The protocol must be re-approved by the IRB/IEC upon receipt 
of amendments and annually, as local regulations require. 
The Investigator is also responsible for providing the IRB/IEC with reports of any reportable 
serious adverse drug reactions from any other study conducted with the study drug (active). The 
Sponsor will provide this information to the Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the 
IRB/IEC according to local regulations and guidelines. 
22.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH GCP applicable regulatory requirements and 
the Sponsor’s policy on Bioethics. 
22.3. 
Written Informed Consent 
The Investigator will ensure that the patient is given full and adequate oral and written 
information about the nature, purpose, possible risk, and benefit of the study. Patients must also 
be notified that they are free to discontinue from the study at any time without prejudice. The 
patient should be given the opportunity to ask questions and allowed time to consider the 
information provided before voluntarily signing the written ICF. 
The patient’s signed and dated informed consent must be obtained before conducting any study 
procedures. The patients will be informed of their rights to privacy but will be made aware that 
the study data will be submitted to the Sponsor and possibly to drug regulatory authorities for 
review and evaluation. They will be informed also that the study monitor may inspect their 
medical records to verify the accuracy and completeness of the study records and results. 
The acquisition of informed consent should be documented in the patient’s medical records, as 
required by the Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice ICH 
E6(R2), and the ICF will be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion. 
The Investigator must maintain the original, signed ICF. A copy of the signed ICF must be given 
to the patient or legal representative. The date that informed consent was signed will be recorded 
on the eCRF. 


 
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22.4. 
Data Protection 
Patients will be informed that data will be held on file by the Sponsor and that these data may be 
viewed by staff including the study monitor and by external auditors on behalf of the Sponsor 
and appropriate regulatory authorities. Patients will also be informed that a study report will be 
prepared and may be submitted to regulatory authorities and for publication. However, patients 
will be identified in such reports only by study identification number, gender, and age. All 
patient data will be held in strict confidence. 


 
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23. 
REGULATORY REQUIREMENTS 
The Sponsor will fulfill the obligations that their role entails. Aside from approval by the 
IRB/IEC, no other regulatory approval will be required. 
The Sponsor will file the protocol to an Investigation New Drug following all US FDA 
requirements. 


 
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24. 
DATA HANDLING AND RECORDKEEPING 
24.1. 
Inspection of Records 
The Sponsor will be allowed to conduct site visits to the investigation facilities for the purpose of 
monitoring any aspect of the study. The Investigator agrees to allow the monitor to inspect the 
drug storage area, study drug stocks, drug accountability records, patient charts and study source 
documents, and other records relative to study conduct. 
24.2. 
Retention of Records 
All source data, clinical records and laboratory data relating to the study will be archived for 
15 years after the completion of the study. All data will be available for retrospective review or 
audit. 
Source documents are original documents, data, and records from which the patient’s eCRF data 
are obtained. These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, radiographs, angiograms, study drug 
accountability logs, and correspondence.  
The Investigator and study staff are responsible for maintaining a comprehensive filing system of 
all study-related (essential) documentation. These include but are not limited to: IRB/IEC 
correspondence, study drug accountability logs, and curricula vitae of all personnel participating 
in the study. These files must be suitable for inspection at any time by the Sponsor, monitor, 
and/or applicable regulatory authorities. All essential documentation should be retained by the 
institution for 15 years. 
No study document should be destroyed without prior written agreement between the Sponsor 
and the Investigator. If the Investigator wishes to assign the study records to another party or 
move them to another location, they must notify the Sponsor in writing of the new responsible 
person and/or the new location. 
24.3. 
Liability/Indemnity/Insurance 
The Sponsor will ensure sufficient insurance is available to enable it to indemnify and hold the 
Investigator(s) and relevant staff as well as any hospital, institution, ethics committee or the like, 
harmless from any claims for damages for unexpected injuries, including death, that may be 
caused by the study drug, but only to the extent that the claim is not caused by the fault or 
negligence of the patients or Investigator(s). 


 
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25. 
PUBLICATION POLICY 
25.1. 
Publication of Results 
The publication, presentation, or other public disclosure of study results (each, a “Publication”) 
will be accurate and honest, undertaken with integrity and transparency and in accordance with 
the Sponsor’s approval.  
Publication of results will be subjected to fair peer-review. Authorship will be discussed between 
researchers prior to study commencement (or as soon as possible thereafter) and reviewed 
whenever there are changes in participation.  
Acknowledgment will be given to collaborating institutions and hospitals and other individuals 
and organizations providing finance or facilities. Patient confidentiality will be maintained by 
referring to individual patients by their identifying code used in the trial. Data will not be 
released publicly until the manuscript is accepted for publication. In the case of no publication, 
information will only be released to the public and media in accordance with the Sponsor’s 
approval. 
Study data that have not been published, presented, or otherwise disclosed in accordance with the 
clinical trial agreement shall remain confidential information of the Sponsor, the Investigator 
may not disclose or permit the disclosure of such unpublished data to any third party, nor may 
they disclose or permit the disclosure of any study data to any third party in greater detail than 
the same have been disclosed in any permitted publication, presentation, or other disclosure. 
The clinical trial will be posted to the Clinicaltrials.gov registry as required by legal agreement, 
local law, or regulation. 
25.2. 
Disclosure and Confidentiality 
By signing this protocol, the Investigator agrees to keep all information provided by the Sponsor 
in strict confidence and to request similar confidentiality from their staff and the IRB/IEC. Study 
documents provided by the Sponsor (Protocols, IBs, eCRFs, etc.) will be stored appropriately to 
ensure their confidentiality. The information provided by the Sponsor to the Investigator may not 
be disclosed to others without direct written authorization from the Sponsor, except to the extent 
necessary to obtain informed consent from patients who wish to participate in the study. 
The Investigator must ensure that the patient’s anonymity is also maintained. Patients should 
only be identified by their initials and a patient study number on the eCRFs and other source 
documents. Other study-related documents (e.g., signed ICFs) should be kept in strict confidence 
by the Investigator. 


 
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26. 
QUALITY CONTROL AND QULAITY ASSURANCE 
26.1. 
Compliance with Good Clinical Practice 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor may 
conduct a quality assurance audit. Please see Section 20.3 for more details regarding the audit 
process. 
The study will be carried out in accordance with the current version of the Declaration of 
Helsinki (Ethical Principles for Medical Research Involving Human Subjects), Integrated 
Addendum to ICH E6(R1): Guideline for GCP ICH E6(R2), and the applicable local regulations. 
26.2. 
Archiving and Regulatory Inspection 
All study-related documents and records are to be retained for a minimum of 15 years after trial 
completion. Written agreement from the Sponsor must precede destruction of the same. 
In accordance with ICH GCP, this study may be selected for audit. Inspection of site facilities 
(e.g., pharmacy, medication storage areas, laboratories) and review of study-related records may 
occur by the Sponsor, the Sponsor’s representative(s), or regulatory authority to evaluate the 
study conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 


 
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27. 
SPONSOR AND INVESTIGATOR OBLIGATIONS 
27.1. 
Protocol Amendments 
Neither the Investigator nor the Sponsor will modify or alter this protocol without the agreement 
of the other. All agreed protocol amendments will be clearly recorded on a protocol amendment 
form and will be signed and dated by the original protocol approving signatories. All protocol 
amendments will be submitted to the relevant IRB/IEC for approval before implementation, as 
required by local regulations. The only exception will be when the amendment is necessary to 
eliminate an immediate hazard to the trial patients. In this case, the necessary action will be taken 
first, with the relevant protocol amendment following shortly thereafter. 
27.2. 
Protocol Deviations 
Should any protocol deviation occur, it must be reported to the study monitor as soon as is 
reasonably practical. The deviation and the reason for its occurrence must be documented, 
reported to the relevant IRB/IEC (if required) and included in the clinical study report. 


 
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28. 
LIST OF REFERENCES 
Center for Drug Evaluation and Research (2014). Esbriet (Pirfenidone). NDA 22-535. 
Pharmacology/Toxicology NDA Review and Evaluation Addendum. 
Cormier, J.N., Askew, R.L., Mungovan, K.S., Xing, Y., Ross, M.I., and Armer, J.M. (2010). 
Lymphedema beyond breast cancer: a systematic review and meta-analysis of cancer-related 
secondary lymphedema. Cancer 116, 5138–5149. 
King, T.E.J., Bradford, W.Z., Castro-Bernardini, S., Fagan, E.A., Glaspole, I., Glassberg, M.K., 
Gorina, E., Hopkins, P.M., Kardatzke, D., Lancaster, L., et al. (2014). A Phase 3 trial of 
pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 370, 2083–2092. 
Noble, P.W., Albera, C., Bradford, W.Z., Costabel, U., Glassberg, M.K., Kardatzke, D., King, 
T.E.J., Lancaster, L., Sahn, S.A., Szwarcberg, J., et al. (2011). Pirfenidone in patients with 
idiopathic pulmonary fibrosis (CAPACITY): two randomized trials. Lancet 377, 1760–1769. 
Rafii, R., Juarez, M.M., Albertson, T.E., and Chan, A.L. (2013). A review of current and novel 
therapies for idiopathic pulmonary fibrosis. J Thorac Dis 5, 48–73. 
Rockson, S.G., Keeley, V., Kilbreath, S., Szuba, A., and Towers, A. (2019). Cancer-associated 
secondary lymphoedema. Nat Rev Dis Primers 5, 22. 
Taniguchi, H., Ebina, M., Kondoh, Y., Ogura, T., Azuma, A., Suga, M., Taguchi, Y., Takahashi, 
H., Nakata, K., Sato, A., et al. (2010). Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 
35, 821–829. 
 
 
 


 
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APPENDIX 1: Blood Volumes 
Table 11: 
Estimated Blood Volumes  
Test 
Per Test Volume 
Total Number of 
Samples 
Total Volume 
CYP1A2, CYP2C9, 
CYP2C19, and 
CYP2D6 genotyping 
4 mL 
1 
4 mL 
Pregnancy test and/or 
FSH (as applicable) 
4 mL 
1 
4 mL 
Hematology 
3 mL 
6 
18 mL 
Blood chemistry 
5 mL 
10 
50 mL 
Coagulation 
4 mL 
6 
24 mL 
PK  
4 mL 
8 
32 mL 
Fibrotic and 
inflammatory 
biomarkers  
4 mL 
5 
20 mL 
Overall Blood Volume Collected Per Patient 
152 mL 
Abbreviations: FSH = Follicle-stimulating hormone; PK = Pharmacokinetics. 
 
 


 
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APPENDIX 2: LYMPH-Q—Upper Extremity Module  
 
LYMPH-Q UPPER EXTREMITY: SYMPTOMS 
 
How does your arm feel (symptoms)? 
NOTE: If your breast cancer surgery affected both of your arms, answer each question 
thinking about the arm that bothers you the most. 
Please answer thinking of the PAST WEEK. Please rate the severity of each of these 
symptoms: 
 
Severe 
Moderate 
Mild 
None 
1. Pain when your arm is touched? 
1 
2 
3 
4 
2. Pain when your arm is at rest? 
1 
2 
3 
4 
3. Arm feeling hotter or colder than normal? 
1 
2 
3 
4 
4. Arm feeling stiff? 
1 
2 
3 
4 
5. Arm symptoms disturbing your sleep (eg, pain, swelling)? 
1 
2 
3 
4 
6. Aching feeling in your arm? 
7. Arm feeling numb? 
1 
2 
3 
4 
8. Pressure in your arm? 
1 
2 
3 
4 
9. Pain when you move your arm? 
1 
2 
3 
4 
10.Clumsiness (eg, dropping or spilling things)? 
1 
2 
3 
4 
11.Tingling in your arm (ie, pins and needles feeling)? 
1 
2 
3 
4 
12.Arm feeling tired? 
1 
2 
3 
4 
13.Arm feeling weak (ie, lack of strength)? 
1 
2 
3 
4 


 
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14.Arm feeling heavy? 
1 
2 
3 
4 
15.Arm swelling? 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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LYMPH-Q UPPER EXTREMITY: FUNCTION 
 
How difficult is it for you to use your arm with lymphedema? 
 
 
 
Extremely 
difficult 
Moderately 
difficult 
A little 
difficult 
Not at all 
difficult 
1. Putting on or taking off clothes? 
1 
2 
3 
4 
2. Washing your hair? 
1 
2 
3 
4 
3. Buttoning a shirt or coat? 
1 
2 
3 
4 
4. Holding a phone to your ear? 
1 
2 
3 
4 
5. Reaching across yourself (eg, to put on a 
car seatbelt)? 
1 
2 
3 
4 
6. Gripping a handle (eg, tennis racket, 
broom)? 
1 
2 
3 
4 
7. Holding a book to read? 
1 
2 
3 
4 
8. Using your hand and fingers (eg, type, 
write)? 
1 
2 
3 
4 
9. Reaching for an object overhead? 
1 
2 
3 
4 
10. Holding a bag of groceries? 
1 
2 
3 
4 
11. Doing household chores that use your arm 
(eg, vacuum, make bed)? 
1 
2 
3 
4 
12. Doing physical activities that involve 
moving your arm (eg, throw a ball, tennis, 
gardening)? 
1 
2 
3 
4 


 
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LYMPH-Q UPPER EXTREMITY: PSYCHOLOGICAL 
 
Does lymphedema in your arm(s) affect how you feel? 
Please answer thinking of the PAST WEEK. With your arm lymphedema in mind, how 
often have you felt: 
 
 
Always 
Often 
Sometimes 
Never 
1. Desperate? 
1 
2 
3 
4 
2. Hopeless? 
1 
2 
3 
4 
3. Angry? 
1 
2 
3 
4 
4. Depressed? 
1 
2 
3 
4 
5. Stressed? 
1 
2 
3 
4 
6. Afraid? 
1 
2 
3 
4 
7. Anxious? 
1 
2 
3 
4 
8. Fed-up? 
1 
2 
3 
4 
9. Unattractive? 
1 
2 
3 
4 
10. Worried? 
1 
2 
3 
4 
11. Irritated? 
1 
2 
3 
4 
12. Frustrated? 
1 
2 
3 
4 


 
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APPENDIX 3: Lymphedema Quality of Life Tool, Arm (Sample) 
 
 
 
 


 
 
 
APPENDIX 4: Infection/Cellulitis Form (Sample) 


 
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