Clinical trial NCT06149247
Conditions: Cutaneous T-Cell Lymphoma/Mycosis Fungoides
Keywords: CTCL MF Hypericin HyBryte
Sponsor: Soligenix
Start date: 2023-12-05; Completion date: 2024-06-27
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this clinical study is to compare the safety and effectiveness of Valchlor versus HyBryte following 12 weeks of treatment.

Detailed description:
Participants will be randomized to receive HyBryte or Valchlor in a 1:1 randomization. Participants will be treated for 12 weeks and follow-up visits will be conducted 1, 2, and 4 weeks after completion of the treatment phase of the trial.

Prior to randomization, each participant will have at least 3 and up to 5 lesions identified (index lesions) that will be evaluated during the treatment phase and during the follow-up visits.

Arms: arm 1: HyBryte (0.25 % hypericin) ointment will be applied to CTCL lesions and treated with visible light 18-24 hours later starting at 6 J/cm\^2. Drug application/light session will be done twice a week (at least 2 calendar days apart) for 12 weeks. arm 2: Valchlor (0.016% mechlorethamine) gel will be applied to CTCL lesions once daily for 12 weeks.
Interventions: intervention 1: Hypericin intervention 2: Mechlorethamine Topical Gel
Intervention descriptions: intervention 1: HyBryte is synthetic hypericin formulated as a 0.25% hypericin ointment. intervention 2: Valchlor is an FDA-approved drug for the treatment of CTCL.

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 1 of 78
Original: 02 August 2023 
Amendment 1: 18 September 2023 
Amendment 2: 05 March 2024 
 
CLINICAL RESEARCH PROTOCOL 
DRUG: 
HyBryte™ (0.25% hypericin ointment) 
STUDY NUMBER(S): 
HPN-CTCL-04 
PROTOCOL(S) TITLE: 
Pilot Study of HyBryte™ (synthetic hypericin) 
versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
IND NUMBER: 
 
SPONSOR: 
Soligenix, Inc. 
ORIGINAL PROTOCOL 
DATE: 
02 August 2023 
VERSION NUMBER: 
Amendment 2 
VERSION DATE: 
05 March 2024 
NCT06149247




Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 3 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
HPN-CTCL-04 
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) 
in the Treatment of CTCL   
 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT 
The information contained in this protocol and all other information relevant to 
HyBryte™ are the confidential and proprietary information of Soligenix, Inc., and except 
as may be required by federal, state or local laws or regulation, may not be disclosed to 
others without prior written permission of Soligenix. 
I have read the protocol, including all appendices, and I agree that it contains all of the 
necessary information for me and my staff to conduct this study as described. I will 
conduct this study as outlined herein, in accordance with the regulations stated in the 
Federal Code of Regulations for Good Clinical Practices and International Conference on 
Harmonization guidelines, and will make a reasonable effort to complete the study within 
the time designated. 
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by Soligenix, Inc. or specified 
designees. I will discuss the material with them to ensure that they are fully informed 
about HyBryte and the study. 
 
 
 
 
 
 
 
 
 
 
Principal Investigator Name (printed) 
 
Signature 
 
___________ ___________ 
Date 
 
Site Number 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 4 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
STUDY SYNOPSIS 
Name of Sponsor/Company: 
Soligenix, Inc. 
 
(For National Authority Use 
only) 
Name of Finished Product 
HyBryte™ 
Name of Active Ingredient 
Hypericin (0.25% ointment) 
Title of Study: Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in 
the Treatment of CTCL     
Investigators: Brian Poligone, MD 
Study Centre(s): Rochester Skin Lymphoma Center 
Publication (reference): N/A 
Study Period (years): 0.5 year 
Date of First Enrollment: January 2024 
Planned Date of Last Completed: May 2024 
Phase of Development:  Phase 2 
Objectives: The objectives of this study are to: 
• 
Obtain experience with tactical issues of conducting an open-label study of HyBryte versus 
Valchlor 
• 
Obtain preliminary comparative assessment of safety and efficacy of Valchlor versus HyBryte 
following 12 weeks of treatment 
• 
Obtain data on the impact of timing on the ease of measuring mCAILS (modified Composite 
Assessment of Index Lesion Severity) during treatment of CTCL patients receiving HyBryte 
therapy 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 5 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
Name of Sponsor/Company: 
Soligenix, Inc. 
 
(For National Authority Use 
only) 
Name of Finished Product 
HyBryte™ 
Name of Active Ingredient 
Hypericin (0.25% ointment) 
Methodology: This will be an open-label trial enrolling patients with CTCL (stage IA, IB, or IIA) 
randomized to receive topical HyBryte or topical Valchlor for 12 weeks.  
Patients randomized to HyBryte will apply the drug to all accessible lesions twice per week followed by 
visible light treatment 21 (±3) hours later starting at 6 J/cm2 and titrated up at each visit until there is 
evidence of mild erythema of the treated lesions following the light session (Grade 1 erythema on the 
Erythema Score) and dropping the light dose if there is Grade 2 erythema. Should the patient have 
Grade ≥3, treatment will be suspended for 1 week and treatment may be restarted at a 1 J/cm2 lower than 
the last well-tolerated light dose. 
Patients randomized to Valchlor will receive commercially available drug applied as per the package 
insert.  
Three to 5 prospectively identified index lesions will be evaluated for mCAILS assessment and the 
lesions chosen will be representative of the patient’s overall disease and, if the patient has both patch 
and plaque lesions, the index lesions should include each type in the approximate same percentage as 
their total lesions.   
Patients will be treated for a total of 12 weeks, with follow-up visits at Week 13, Week 14, and Week 
16/End of Study. Every three weeks, patients will come to the clinic for an assessment visit (ie, at Week 
3, Week 6, Week 9, and Week 12). At these evaluation visits, a cumulative mCAILS, modified Severity-
Weighted Assessment Tool (mSWAT), Physician Global Assessment (PGA), Skin Adverse Event 
Questionnaire (SAEQ) will be completed, and Scoring Dermatitis (SCORD) collected. 
For HyBryte patients, these assessments will be done immediately prior to light treatment at the second 
light treatment visit of the evaluation week (ie, Weeks 3, 6, 9, 12).  
Follow-up assessments will be conducted at Week 13 (1-week post-treatment), Week 14 (2 weeks post-
treatment), and Week 16/End of Study (4 weeks post-treatment) and will also include mCAILS, 
mSWAT, PGA, SAEQ, and SCORD assessments. 
Physical examinations and safety labs (hematology and chemistry) will be analyzed at Baseline, at the 
Week 12 assessment visit, and 4 weeks after completion of therapy (Week 16/End of Study). AE’s will 
be recorded throughout the study. Vital signs will be collected at Baseline and Weeks 3, 6, 9, 12, 13, 14 
and 16. 
Number of patients (planned): Approximately 10 subjects will be randomized 1:1 (HyBryte: Valchlor) 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 6 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
Name of Sponsor/Company: 
Soligenix, Inc. 
 
(For National Authority Use 
only) 
Name of Finished Product 
HyBryte™ 
Name of Active Ingredient 
Hypericin (0.25% ointment) 
Diagnosis and main criteria for inclusion:  
Inclusion Criteria: 
In order to be enrolled into the trial, subjects must meet all of the criteria below: 
1. ≥18 years of age 
2. Minimum of 3 active treatment-accessible CTCL lesions 
3. Subjects must have a clinical diagnosis of cutaneous T-cell lymphoma (CTCL, mycosis 
fungoides), Stage IA, IB, or Stage IIA 
4. Subjects willing to follow the clinical protocol and voluntarily give their written informed 
consent 
5. Female subjects not pregnant nor nursing and willing to undergo a pregnancy test within 30 
days prior to treatment initiation 
Exclusion Criteria: 
In order to be enrolled into the trial, subjects cannot have any of the following criteria: 
1. History of severe allergic reaction to any of the components of HyBryte or mechlorethamine 
(Valchlor) 
2. Pregnancy or mothers who are breast-feeding 
3. All women of childbearing potential (WOCBP) and males with female partners who are 
WOCBP not willing to use effective contraception (see section 5.3, Exclusion Criteria; 
Exclusion Criterion #3 for more details) 
4. Subjects with history of sun hypersensitivity or photosensitive dermatoses (eg, porphyria, 
systemic lupus erythematosus (SLE), Sjogren’s syndrome, etc.) 
5. Subjects whose condition is spontaneously improving 
6. Subjects receiving Valchlor in the preceding 2 months 
7. Subjects receiving topical steroids or other topical treatments (eg, Targretin gel) on treatment 
accessible lesions for CTCL within 2 weeks of enrollment 
8. Subjects receiving systemic steroids, psoralen ultraviolet A (UVA) radiation therapy (PUVA), 
narrow band ultraviolet B (UVB) light therapy (NB-UVB) or carmustine (BCNU) or other 
systemic therapies for CTCL within 3 weeks of enrollment 
9. Subjects who have received electron beam irradiation within 3 months of enrollment 
10. Subjects with a history of significant systemic immunosuppression 
11. Subjects taking other investigational drugs or drugs of abuse within 30 days of enrollment 
12. Subject has any condition that, in the judgment of the PI, is likely to interfere with participation 
in the study 
13. Subjects receiving drugs known to cause photosensitization within 2 weeks of starting HyBryte 
therapy unless they have not had evidence of photosensitization after receiving a stable dose of 
the medication for a minimum of 4 weeks  


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 7 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
Name of Sponsor/Company: 
Soligenix, Inc. 
 
(For National Authority Use 
only) 
Name of Finished Product 
HyBryte™ 
Name of Active Ingredient 
Hypericin (0.25% ointment) 
Test product, dose and mode of administration: HyBryte (0.25% hypericin) will be applied in a thin 
film on all lesions avoiding treatment of healthy skin. The drug will be activated 21 ± 3 hours after 
application starting at 6 J/cm2 of visible light metered by duration of exposure and titrated up at each 
visit until a mild erythema (Grade I Erythema Score) in the treated lesions is seen following the light 
session and dropping the light dose if there is Grade 2 erythema. Should the patient have Grade ≥3, 
treatment will be suspended for 1 week and treatment may be restarted at a 1 J/cm2 lower than the last 
well-tolerated light dose. 
Valchlor will be administered in accordance with the FDA-approved package insert. 
Duration of treatment: Subjects will be randomized to 12 weeks of treatment with either HyBryte or 
Valchlor in a 1:1 ratio.  Subjects randomized to HyBryte will apply HyBryte to all accessible lesions 
followed 21 (±3) hours later by visible light treatment twice per week using the Daavlin 7 Series 
Phototherapy Device. Treatments will continue twice per week (at least 2 calendar days apart) for a total 
of 12 weeks of treatment (24 actual treatments). Patients randomized to Valchlor will receive treatment 
for 12 weeks with Valchlor following the directions in the FDA-approved package insert.  
Patients will come to the clinic for an assessment visit at Baseline, Week 3, Week 6, Week 9, and Week 
12. Patients will have mCAILS scores collected on their 3 to 5 index lesions, an mSWAT score, PGA, 
SAEQ, and a SCORD score collected. 
For patients randomized to HyBryte, the assessments will be conducted immediately prior to light 
treatment at the second light treatment visit of the evaluation week (ie, Weeks 3, 6, 9, 12) immediately 
prior to the corresponding light treatment. 
Patients will return to the clinic for follow-up visits and have assessments (SCORD, mCAILS, mSWAT, 
PGA, SAEQ, and SCORD) at Week 13, Week 14, and Week 16/End of Study. 
Safety laboratory assessments and physical exams will be done at Baseline, the Week 12 assessment 
visit, and the Week 16/End of Study visit. Vital signs will be collected at Baseline and Weeks 3, 6, 9, 
12, 13, 14 and 16. Adverse events will be collected throughout the study. 
Reference therapy, dose and mode of administration: Valchlor treatment in accordance with 
prescribing information in package insert. 
Criteria for evaluation: 
Efficacy: 
This is a pilot study to obtain preliminary comparative assessments of safety and efficacy and determine 
the practical issues likely to arise in a larger clinical study comparing HyBryte to Valchlor. No formal 
efficacy statistics will be performed. Results will be presented as tables and listings. 
Safety: 
The safety variables evaluated are: SAEQ, SCORD score, clinical hematology assessments, clinical 
chemistry assessments, physical examinations, vital signs, and the collection of adverse/serious adverse 
events.  
 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 8 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
 
STUDY SCHEMATIC 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 9 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
TABLE OF CONTENTS 
CLINICAL RESEARCH PROTOCOL ..........................................................................1 
CLINICAL PROTOCOL APPROVAL FORM .............................................................2 
STUDY SYNOPSIS ...........................................................................................................4 
STUDY SCHEMATIC ......................................................................................................8 
TABLE OF CONTENTS ..................................................................................................9 
TABLE OF TABLES .......................................................................................................12 
LIST OF ABBREVIATIONS .........................................................................................13 
1 
INTRODUCTION AND RATIONALE .................................................................16 
1.1 
Background ..........................................................................................................16 
1.2 
Study Rationale ....................................................................................................16 
1.2.1 
Pharmacokinetics ...........................................................................................16 
1.2.2 
Preclinical Pharmacology ..............................................................................17 
1.2.3 
Potential for Drug-Drug Interactions ..........................................................19 
1.2.4 
Clinical Adverse Event Profile ......................................................................19 
1.2.5 
Potential Risk to Fetal Development ............................................................20 
2 
STUDY OBJECTIVES ............................................................................................22 
3 
STUDY ENDPOINTS ..............................................................................................23 
4 
STUDY PLAN ...........................................................................................................24 
4.1 
Study Design .........................................................................................................24 
4.2 
Schedule of Assessments ......................................................................................25 
5 
POPULATION ..........................................................................................................28 
5.1 
Number of Subjects..............................................................................................28 
5.2 
Inclusion Criteria .................................................................................................28 
5.3 
Exclusion Criteria ................................................................................................28 
6 
STUDY CONDUCT..................................................................................................31 
6.1 
General Instructions ............................................................................................31 
6.2 
Study Procedures by Time Point ........................................................................31 
6.2.1 
Screening .........................................................................................................31 
6.2.2 
Baseline ...........................................................................................................31 
6.2.3 
HyBryte Patients ............................................................................................32 
6.2.4 
Valchlor Patients ............................................................................................37 
6.3 
Premature Discontinuation .................................................................................39 
7 
DESCRIPTION OF STUDY PROCEDURES .......................................................40 
7.1 
Efficacy Assessments ...........................................................................................40 
7.1.1 
Modified Composite Assessment of Index Lesion Severity 
(mCAILS) .......................................................................................................40 
7.1.2 
Modified Severity-Weighted Assessment Tool (mSWAT) .........................41 
7.1.3 
The Physician Global Assessment (PGA) ....................................................42 
7.2 
Safety Assessments ...............................................................................................43 
7.2.1 
Dermatologic Assessment Grading ..............................................................43 
7.2.2 
SCORD Scoring .............................................................................................43 
7.2.3 
Patient Reported SAEQ Score ......................................................................44 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 10 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
7.3 
Clinical Laboratory Tests....................................................................................44 
7.3.1 
Hematology .....................................................................................................44 
7.3.2 
Clinical Chemistry Laboratory Tests...........................................................45 
7.4 
Vital Signs .............................................................................................................45 
8 
STUDY DRUG MANAGEMENT ...........................................................................46 
8.1 
HyBryte .................................................................................................................46 
8.1.1 
Formulation ....................................................................................................46 
8.1.2 
Storage ............................................................................................................46 
8.1.3 
Packaging and Shipment ...............................................................................46 
8.1.4 
Dose and Administration ...............................................................................46 
8.2 
Valchlor .................................................................................................................46 
8.2.1 
Formulation ....................................................................................................47 
8.2.2 
Storage ............................................................................................................47 
8.2.3 
Packaging and Shipment ...............................................................................47 
8.2.4 
Dose and Administration ...............................................................................47 
8.3 
Accountability ......................................................................................................48 
8.4 
Prohibited Concomitant Therapy ......................................................................48 
8.5 
Compliance ...........................................................................................................50 
9 
ADVERSE EVENTS ................................................................................................51 
9.1 
Definitions .............................................................................................................51 
9.1.1 
Adverse Experience (AE) ..............................................................................51 
9.1.2 
Treatment-Emergent AE...............................................................................51 
9.1.3 
Potentially Serious Adverse Experience ......................................................51 
9.2 
Relationship to Study Drug .................................................................................51 
9.3 
Severity of Adverse Event ...................................................................................52 
9.4 
Recording Adverse Events ..................................................................................52 
10 SERIOUS ADVERSE EVENT ................................................................................53 
10.1 
Definition of Serious Adverse Event ..................................................................53 
10.2 
Definition of Terms ..............................................................................................53 
10.3 
Reporting Serious Adverse Events .....................................................................54 
10.4 
Overdose ...............................................................................................................55 
11 STATISTICS .............................................................................................................56 
11.1 
General Procedures .............................................................................................56 
12 ETHICS AND RESPONSIBILITIES .....................................................................57 
12.1 
Good Clinical Practice .........................................................................................57 
12.2 
Institutional Review Board/Independent Ethics Committee ...........................57 
12.3 
Informed Consent ................................................................................................57 
12.4 
Subject data protection........................................................................................57 
12.5 
Financial Disclosure .............................................................................................57 
13 RECORDS MANAGEMENT..................................................................................59 
13.1 
Source Documentation.........................................................................................59 
13.2 
Study Files and Record Retention ......................................................................59 
14 AUDITING AND MONITORING ..........................................................................60 
14.1 
Study Monitoring .................................................................................................60 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 11 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
14.1.1 
Pre-study Evaluation .....................................................................................60 
14.1.2 
Site Initiation Visit .........................................................................................60 
14.1.3 
Monitoring Visits ...........................................................................................61 
14.1.4 
Close-out Visit ................................................................................................61 
14.2 
Audits and Inspections ........................................................................................61 
15 AMENDMENTS .......................................................................................................62 
16 STUDY REPORT AND PUBLICATIONS ............................................................63 
17 STUDY DISCONTINUATION ...............................................................................64 
18 CONFIDENTIALITY ..............................................................................................65 
19 REFERENCES .........................................................................................................66 
20 APPENDICES ...........................................................................................................68 
20.1 
APPENDIX I – Names of Study Personnel........................................................68 
20.2 
APPENDIX II – SCORD Calculation Worksheet ............................................69 
20.3 
APPENDIX III – Body Lesion Diagram ............................................................70 
20.4 
Appendix IV - Skin Adverse Event Questionnaire ...........................................71 
20.5 
APPENDIX V – Declaration of Helsinki ...........................................................72 
 
 
 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 12 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
TABLE OF TABLES 
Table 1: 
TEAEs by System Organ Class and Preferred Term, Total Incidence 
≥3%: Safety Population ...........................................................................19 
Table 2: 
HyBryte Patients: Schedule of Assessments ..........................................25 
Table 3: 
Valchlor Patients: Schedule of Assessments ..........................................27 
Table 4:  
Dermatologic Assessment Grading ........................................................33 
Table 5: 
Composite Assessment of Index Lesion Severity – Erythema .............40 
Table 6: 
Composite Assessment of Index Lesion Severity – Scaling ..................40 
Table 7: 
Composite Assessment of Index Lesion Severity – Plaque Elevation .41 
Table 8: 
Composite Assessment of Index Lesion Severity – Surface Area ........41 
Table 9: 
Modified Severity-Weighted Assessment Tool (mSWAT) ...................42 
Table 10: 
Physician’s Global Assessment ...............................................................43 
 
 
 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 13 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATL 
Adult T-cell Leukemia 
BCNU 
Carmustine 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CRF 
Case Report Form 
CTCL 
Cutaneous T-cell Lymphoma 
ER 
Endoplasmic Reticulum 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HTLV-1 
Human T-cell Leukemic Virus Type I 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IUS 
Intrauterine Hormone-releasing System 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 14 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
Iv 
Intravenous 
mCAILS 
Modified Composite Assessment of Index Lesion Severity 
MF 
Mycosis Fungoides 
Min 
Minute 
mSWAT 
Modified Severity-Weighted Assessment Tool 
NB-UVB 
Narrow Band UVB  
NDA 
New Drug Application 
PDT 
Photodynamic Therapy 
PGA 
Physician Global Assessment 
PHA 
Phytohemagglutinin Antigen 
PI 
Principal Investigator 
Po 
Per Os (By Mouth), Orally 
PUVA 
Psoralen Ultraviolet A Radiation Therapy 
ROS 
Reactive Oxygen Species 
SAE 
Serious Adverse Event 
SAEQ 
Skin Adverse Event Questionnaire  
SCORD 
SCORing Dermatitis score 
SLE 
Systemic Lupus Erythematosus 
SOP 
Standard Operating Procedure 
TEAE 
Treatment Emergent Adverse Event 
ULN 
Upper Limit of Normal 
UV 
Ultraviolet 
UVA 
Ultraviolet A 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 15 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
UVB 
Ultraviolet B 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
WOCBP 
Women of Childbearing Potential 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 16 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
1 INTRODUCTION AND RATIONALE 
1.1 
Background 
HyBryte™ (0.25% hypericin) is a chemically synthesized hypericin formulated for 
topical use only for the treatment of early-stage Cutaneous T-cell Lymphoma (CTCL) 
and is intended to be administered only in conjunction with a schedule of controlled 
doses of visible light. Hypericin is a photodynamic radical generator that has been shown 
to have anti-cancer effects in the dark with substantially more effects after activation by 
light in the 500 to 650 nm wavelength range. More complete information on hypericin is 
available in the Investigator Brochure. 
1.2 
Study Rationale 
The Phase 3 trial, HPN-CTCL-01, demonstrated that HyBryte in combination with 
visible light activation given 2× per week for 6 weeks statistically significantly increased 
the number of patients with a ≥50% improvement in their treated lesions when compared 
to a concurrent placebo group (Kim 2022). Among those that continued HyBryte 
treatment for an additional 6 or 12 weeks, a significant and substantial improvement in 
their response rates was seen. Similar safety and efficacy findings were seen in 9 patients 
enrolled in HPN-CTCL-02 that treated patients for 8 weeks (NCT05380635). 
This study is a pilot study to obtain preliminary comparative assessments of the efficacy 
and safety of Valchlor compared to HyBryte as well explore the practical issues involved 
with an open-label HyBryte/ active control group design in early-stage CTCL. 
1.2.1 
Pharmacokinetics 
Hypericin was initially developed for the systemic treatment of enveloped viral infections 
including human immunodeficiency virus (HIV) (Gulick 1999), hepatitis C virus (HCV) 
(Jacobson 2001) and glioma (Couldwell 2011). Following dosing with either intravenous 
(iv) or oral (po) routes, the only consistently reported adverse events were caused by 
phototoxicity, the biologic effect that is being exploited and tightly regulated in the 
topical treatment of CTCL. Minimal blood levels of hypericin were expected to result 
from low dose topical application of the drug.  
During the Phase 3 trial, serum blood levels of systemic hypericin were assessed at the 
end of the third cycle of therapy (after 5 to 6 weeks of continuous therapy on multiple 
lesions). Blood samples were taken approximately 24 hours after the application of the 
drug, the time when the maximal skin effects were seen. Systemic hypericin was not 
detected in the blood, indicating circulating levels were <5 ng/mL (lower limit of 
detection of the bioanalytical method). 
A subsequent clinical study of 9 patients (HPN-CTCL-02) utilized a modified assay. 
Hypericin concentration in K2EDTA whole blood samples collected before and after light 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 17 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
activation at Weeks 4, 6 and 8 showed an average blood concentration of 0.13 ng/mL and 
achieved steady state by Week 4, as determined with a validated assay with a detection 
limit of 0.05 ng/mL. Patients within the study had a range of disease involvement (11 to 
65% BSA) and average dose application (maximum 1.7 to 10.3 g HyBryte per topical 
application). Maximum obtained circulating blood concentration was not well-correlated 
with either extent of disease or maximum average applied dose indicating that systemic 
concentration was likely driven by variability in skin permeability. There was no 
discernible role of gender or race on the measured systemic concentration. No patient had 
a blood level >0.5 ng/mL at any timepoint. Blood levels were below detection limit for 
7/9 patients by the end of study visit (2 weeks after cessation of dosing), with the 
remaining 2 patients recording blood concentrations of 0.06 and 0.10 ng/mL. 
In comparison, hypericin levels following oral or iv administration of the drug in viral 
and cancer trials were up to 10,000-fold higher and the major and dose limiting 
restriction was photosensitization - the biologic effect being exploited in this CTCL 
treatment. 
1.2.2 
Preclinical Pharmacology 
The pharmacology of hypericin has been extensively studied in the literature. Given its 
unique and highly conjugated structure, hypericin is both extremely chemically stable and 
easily photoactivated (with visible light in the yellow/red spectrum; 500 to 650 nm). 
While hypericin has been found to have some biological activities in the absence of light, 
it is between 10- and 100-fold more potent via photoactivated mechanisms, assuming the 
presence of oxygen. Photoactivation of hypericin contributes to the formation of singlet 
oxygen and reactive oxygen species (ROS), increasing oxidative stress on the cell 
(Dąbrowski 2017). Downstream of this oxidative stress, a number of intracellular 
pathways may be activated, depending on the specific characteristics of the cell. 
Generally speaking, the oxidative stress can drive apoptosis (at lower light/dose 
concentrations) and necrosis (at higher light/dose concentrations). Malignant cells are 
generally more sensitive to this oxidative stress condition. 
Hypericin is highly lipophilic, sparingly soluble in aqueous settings, and carries a single 
negative charge at the pHs relevant to the biological milieu. Because of these 
characteristics, hypericin is rapidly absorbed into the cellular membrane and then 
redistributed within the cell across all lipoprotein organelles including the Golgi 
apparatus, endoplasmic reticulum (ER), and lysosomes (de Andrade 2021).  
In the in vivo setting, hypericin has been found to be tumoritropic, favoring absorption 
into tumor cells over normal cells. In addition to its increased absorption into tumor cells 
and potentially other cells lacking E-cadherin, hypericin also has significant necrotic 
avidity. Indeed, hypericin has been explored as both a photodiagnostic agent (eg, for 
bladder cancer) and as a radiotherapy (via the use of radioiodinated hypericin). 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 18 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
The primary mode of biological activity relates to the photoactivation of hypericin, 
forming singlet and triplet hypericin and, upon interaction with oxygen and other 
intracellular species, generating ROS and driving apoptosis via the mitochondrial 
pathway. The degree of phototoxicity elicited by hypericin is related to its concentration, 
subcellular localization and light intensity (Jendzelovska 2016). The permeability, 
presence of oxygen and specific intramolecular pathways of the targeted cell will also 
impact outcomes. Generally, low doses of phototoxicity are associated with apoptosis 
while higher doses can also result in necrosis (de Andrade 2021). 
Observations in the laboratory of Dr. Alain Rook at the University of Pennsylvania have 
demonstrated a significant antiproliferative effect of synthetic hypericin on activated 
normal human lymphoid cells upon exposure of the synthetic hypericin-treated cells to 
visible light (Fox 1998). At concentrations of synthetic hypericin ranging between 0.1 
and 0.5 µM, a 20-minute exposure of normal lymphoid cells to fluorescent light resulted 
in complete inhibition of proliferative responses to the potent mitogens 
phytohemagglutinin antigen (PHA) and concanavalin A (Con A). Similarly, malignant T-
cells purified from the blood of patients with Sézary syndrome or the leukemic phase of 
CTCL displayed markedly inhibited growth rates in response to T-cell growth factors 
when treated with 0.3 µM of synthetic hypericin and 20-minute exposure to fluorescent 
light. While the precise mechanism of inhibition of proliferation is unclear, it appears that 
synthetic hypericin has the capacity to induce a high rate of apoptotic death in both 
normal and malignant lymphoid cells. The implications of these findings for the use of 
topical synthetic hypericin to treat CTCL, which is characterized by malignant 
lymphocytic infiltrates in the skin, are significant and serve as the mechanistic basis for 
the use of HyBryte in CTCL. 
Selective apoptosis has also been generated for T-cells infected with human T-cell 
leukemic virus type I (HTLV-1), known to be the primary etiologic agent for adult T-cell 
leukemia (ATL). In contrast, primary T-cells were shown to be resistant to apoptosis at 
similar concentrations and exposure to light between 520 and 750 nm at 11.28 J/cm2. Cell 
death was partially driven by caspase dependent apoptosis, as demonstrated by the 
increased concentration of cleaved caspase-3, 7 and 9. Similarly, hypericin photodynamic 
therapy (PDT) was also associated with inhibition of cell cycle progression (arresting 
ATL cells in G2/M phase) and with inhibition of viral genes (Xu 2019). 
Hypericin has been assessed for skin pre-malignancies and malignancies. Topical 
hypericin PDT for actinic keratosis was assessed in a model in which skin tumors were 
induced in mice by chronic UV irradiation, and antitumor activity of topical hypericin 
(0.1%) kept under occlusion for 24 hours prior to light exposure (587-589 nm, 40 J/cm2) 
was evaluated by measurement of lesion diameter (Boiy 2011). Hypericin fluorescence 
accumulated in the stratum corneum prior to irradiation, with greater accumulation in 
skin that was previously irradiated with UV light to encourage tumor formation and skin 
with overt lesions. Hypericin PDT groups demonstrated 44% total lesion clearance 3 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 19 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
weeks after a single treatment. In addition, hypericin PDT drove the replacement of 
atypical actinic keratosis cells with normal keratinocytes. 
1.2.3 
Potential for Drug-Drug Interactions 
No significant drug-drug interactions are expected due to increased expression or 
decreased activity of cytochrome P450 enzymes after topical application of HyBryte. 
There are reported interactions between hypericin and cytochrome P450 proteins at 
micromolar dose levels (Silva 2016). It is unlikely that significant cytochrome P450 
inhibition would occur with the proposed topical application given the very low systemic 
concentration of hypericin after topical applications. 
1.2.4 
Clinical Adverse Event Profile 
The best information on safety comes from the HPN-CTCL-01 Phase 3 study. Treatment 
Emergent Adverse Events (TEAEs) occurring in at least 3% of patients are shown in 
Table 1, below. In this trial, patients were randomized 2: 1 as HyBryte: placebo and their 
3 index lesions were treated 2×/week. In Cycle 1, patients received 6 weeks of treatment 
with either placebo or HyBryte and in Cycle 2, all patients received 6 weeks of treatment 
of their index lesions with HyBryte. An optional Cycle 3 was offered that treated all of 
the patient’s lesions for 6 weeks with HyBryte. 
Table 1: 
TEAEs by System Organ Class and Preferred Term, Total Incidence 
≥3%: Safety Population 
System Organ Class 
Cycle 1 
Cycle 2 
Cycle 3 
HyBryte  
Total  
(N=161) 
n (%) 
Total  
(N=166) 
n (%) 
Preferred Term 
HyBryte 
(N=116) 
n (%) 
Placebo 
(N=50) 
n (%) 
HyBryte 
(N=155) 
n (%) 
HyBryte 
(N=110) 
n (%) 
#Patients ≥1 TEAE 
56 (48.3) 
27 (54.0) 
66 (42.6) 
49 (44.5) 
108 
(67.1) 
116 
(69.9) 
Skin and 
subcutaneous tissue 
disorders 
19 (16.4) 
5 (10.0) 
21 (13.5) 
19 (17.3) 
48 (29.8) 
53 (31.9) 
Pruritus 
6 (5.2) 
2 (4.0) 
2 (1.3) 
5 (4.5) 
12 (7.5) 
14 (8.4) 
Erythema 
3 (2.6) 
0 
3 (1.9) 
1 (0.9) 
7 (4.3) 
7 (4.2) 
Infections and 
infestations 
20 (17.2) 
10 (20.0) 
19 (12.3) 
16 (14.5) 
43 (26.7) 
51 (30.7) 
Upper respiratory 
tract infection 
8 (6.9) 
4 (8.0) 
2 (1.3) 
2 (1.8) 
12 (7.5) 
16 (9.6) 
Viral upper 
respiratory tract 
infection 
4 (3.4) 
0 
4 (2.6) 
4 (3.6) 
11 (6.8) 
11 (6.6) 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 20 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
System Organ Class 
Cycle 1 
Cycle 2 
Cycle 3 
HyBryte  
Total  
(N=161) 
n (%) 
Total  
(N=166) 
n (%) 
Preferred Term 
HyBryte 
(N=116) 
n (%) 
Placebo 
(N=50) 
n (%) 
HyBryte 
(N=155) 
n (%) 
HyBryte 
(N=110) 
n (%) 
Sinusitis 
1 (0.9) 
0 
3 (1.9) 
3 (2.7) 
7 (4.3) 
7 (4.2) 
Urinary tract 
infection 
1 (0.9) 
2 (4.0) 
3 (1.9) 
0 
4 (2.5) 
6 (3.6) 
Influenza 
0 
2 (4.0) 
1 (0.6) 
2 (1.8) 
3 (1.9) 
5 (3.0) 
General disorders and 
administration-site 
conditions 
22 (19.0) 
5 (10.0) 
18 (11.6) 
12 (10.9) 
38 (23.6) 
42 (25.3) 
Application site 
pain 
8 (6.9) 
2 (4.0) 
5 (3.2) 
6 (5.5) 
16 (9.9) 
17 (10.2) 
Application site 
pruritus 
5 (4.3) 
1 (2.0) 
5 (3.2) 
0 
9 (5.6) 
9 (5.4) 
Fatigue 
3 (2.6) 
1 (2.0) 
3 (1.9) 
2 (1.8) 
8 (5.0) 
9 (5.4) 
Application site 
paraesthesia 
6 (5.2) 
0 
2 (1.3) 
2 (1.8) 
7 (4.3) 
7 (4.2) 
Pain 
3 (2.6) 
0 
2 (1.3) 
0 
5 (3.1) 
5 (3.0) 
 
n = Number; TEAE = treatment-emergent adverse event 
Note: TEAE was defined as an AE that was new or worsened in severity after the first dose of study drug  
and within 1 month following last evaluation visit. A patient was counted only once for each AE he/she 
experienced. All AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
Version 20. 
Note: The majority of the AEs shown were mild, required no intervention or treatment and did not interfere 
with continued use or light therapy and participation in the study. Study drop-out rate during the treatment 
cycles was 1.2% due to AEs. 
1.2.5 
Potential Risk to Fetal Development 
Although the available animal data suggest that the risk to pregnancy is low, available 
human data are insufficient to inform the drug-associated risk of major birth defects, 
miscarriage, or adverse maternal or fetal outcomes. Topically applied HyBryte is 
minimally systemically absorbed and maternal use is not expected to result in fetal 
exposure to the drug. Nonetheless, it is recommended pregnancy be avoided while taking 
HyBryte and treatments be discontinued immediately if the patient becomes pregnant. 
In a rat developmental toxicity study, hypericin was evaluated for maternal and 
embryo/fetal toxicity and teratogenic potential when orally administered to pregnant rats 
during the period of organogenesis. There was no evidence of an effect on in utero 
growth, survival, or development at any dose level. It is also not known whether HyBryte 
can cause fetal harm when administered to a pregnant woman or can affect reproductive 
capacity. 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 21 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
The developmental and health benefits of breastfeeding should be considered along with 
the mother’s clinical need for HyBryte and any potential adverse effects on the breastfed 
child from HyBryte or from the underlying maternal CTCL. It is recommended that 
breastfeeding be discontinued during HyBryte therapy. 
 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 22 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
2 STUDY OBJECTIVES 
Objectives: The objectives of this study are to: 
• Obtain experience with tactical issues of conducting an open-label study of 
HyBryte versus Valchlor 
• Obtain preliminary comparative assessment of safety and efficacy of Valchlor 
versus HyBryte following 12 weeks of treatment 
• Obtain data on the impact of timing on the ease of measuring mCAILS (modified 
Composite Assessment of Index Lesion Severity) during treatment of CTCL 
patients receiving HyBryte therapy 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 23 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
3 STUDY ENDPOINTS  
Efficacy: 
This is a pilot study to obtain preliminary comparative assessments of safety and efficacy 
and determine the practical issues likely to arise in a larger clinical study comparing 
HyBryte to Valchlor. No formal efficacy statistics will be performed. Results will be 
presented as tables and listings. Efficacy assessments are: 
• mCAILS score on 3 to 5 prospectively identified index lesions 
• Modified Severity-Weighted Assessment Tool (mSWAT) score 
• Physician Global Assessment (PGA) 
Safety: 
The safety variables evaluated are:  
• Skin Adverse Event Questionnaire (SAEQ) 
• SCORing Dermatitis (SCORD) score 
• Changes in clinical hematology results 
• Changes in clinical chemistry assessments 
• Changes in physical examinations 
• Changes in vital signs 
• Collection of adverse/serious adverse events 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 24 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
4 STUDY PLAN 
4.1 
Study Design 
This is a randomized, pilot study assessing outcomes of patients receiving HyBryte 
compared to Valchlor in patients with stage IA, IB, and IIA CTCL. Subjects will be 
randomized to 12 weeks of treatment with either HyBryte or Valchlor in a 1:1 ratio.  
Subjects randomized to HyBryte will apply HyBryte to all accessible lesions followed 21 
(±3) hours later by visible light treatment twice per week using the Daavlin 7 Series 
Phototherapy Device. Treatments will continue twice per week (at least 2 calendar days 
apart) for a total of 12 weeks of treatment (24 actual treatments). Patients randomized to 
Valchlor will receive treatment for 12 weeks with Valchlor following the directions in the 
FDA-approved package insert.  
Patients will come to the clinic for an assessment visit at Baseline, Week 3, Week 6, 
Week 9, and Week 12. Patients will have mCAILS scores collected on their 3 to 5 index 
lesions, an mSWAT score, PGA, SAEQ completed, and a SCORD score collected. 
For patients randomized to HyBryte, the assessments will be conducted immediately 
prior to light treatment at the second light treatment visit of the evaluation week (ie, 
Week 3, 6, 9, 12) immediately prior to the corresponding light treatment. 
Patients will return to the clinic for follow-up visits and have assessments (mCAILS, 
mSWAT, PGA, SAEQ, and SCORD) at Week 13, Week 14, and Week 16/End of Study. 
Safety laboratory assessments and physical exams will be done at Baseline, the Week 12 
assessment visit, and the Week 16/End of Study visit. Vital signs will be collected at 
Baseline and Weeks 3, 6, 9, 12, 13, 14 and 16. Adverse events will be collected 
throughout the study.


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 25 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
4.2 
Schedule of Assessments 
Patients randomized to receive HyBryte will have assessments and treatment as shown in Table 2. 
Table 2: 
HyBryte Patients: Schedule of Assessments 
Activity 
Screen 
Base- 
Week 
 
 
line 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
16 
Clinic visit 
X 
X 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
X 
X 
X 
Drug Treatmenta 
 
X 
X 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Entry criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum HCG 
(females only) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Identify index 
lesions 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interim medical 
history/AEs 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy 
assessmentsb 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
Safety 
assessmentsc 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
Vital signs 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
Physical Exam 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Labsd 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 26 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
a Patients will apply HyBryte and come in to clinic 21 ± 3 hours later for light treatments. applications will be done at home twice per week at least 2 calendar 
days apart except for the second treatment in Weeks 3, 6, 9, and 12 when application should occur following the assessment visit either in the clinic or at home. 
Patients will have erythema assessment and a dermatologic grading of treated areas before and 10-30 minutes after completion of the light treatment. 
b Efficacy assessments are: mCAILS, mSWAT, PGA 
c Safety Assessments are: SAEQ, SCORD, and collection of AEs 
d Labs are: Clinical hematology panel, Clinical Chemistry panel 
 
 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 27 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
Patients randomized to receive Valchlor will be treated as per the Package Insert and will apply a thin film of Valchlor on lesions 
daily. The Schedule of Assessments for this arm of the study is shown in Table 3. 
 Table 3: 
Valchlor Patients: Schedule of Assessments 
Activity 
Screen 
Base- 
Week 
 
 
line 
3 
6 
9 
12 
13 
14 
16 
Clinic visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
 
 
Entry criteria 
X 
X 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
Serum HCG (females only) 
X 
X 
 
 
 
X 
 
 
 
Identify index lesions 
 
X 
 
 
 
 
 
 
 
Interim medical history/AEs 
 
 
X 
X 
X 
X 
X 
X 
X 
Efficacy assessmentsa 
 
X 
X 
X 
X 
X 
X 
X 
X 
Safety assessmentsb 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
 
X 
 
 
 
X 
 
 
X 
Labsc 
 
X 
 
 
 
X 
 
 
X 
a Efficacy assessments are: mCAILS, mSWAT, PGA 
b Safety Assessments are: SAEQ, SCORD, and collection of AEs 
c Labs are: Clinical hematology panel, Clinical Chemistry panel 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 28 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
5 POPULATION 
5.1 
Number of Subjects 
Approximately 10 patients will be randomized 1:1 into the HyBryte: Valchlor arms.  
5.2 
Inclusion Criteria 
In order to be enrolled into the trial, subjects must meet all of the criteria below: 
1. ≥18 years of age 
2. Minimum of 3 active treatment-accessible CTCL lesions 
3. Subjects must have a clinical diagnosis of cutaneous T-cell lymphoma (CTCL, 
mycosis fungoides), Stage IA, IB, or Stage IIA 
4. Subjects willing to follow the clinical protocol and voluntarily give their written 
informed consent 
5. Female subjects not pregnant nor nursing and willing to undergo a pregnancy test 
within 30 days prior to treatment initiation 
 
5.3 
Exclusion Criteria 
In order to be enrolled into the trial, subjects cannot have any of the following criteria: 
1. History of severe allergic reaction to any of the components of HyBryte or 
mechlorethamine (Valchlor) 
2. Pregnancy or mothers who are breast-feeding 
3. All women of childbearing potential (WOCBP) and males with female partners who 
are WOCBP not willing to use effective contraception 
a. Women are considered to be WOCBP following menarche and until becoming 
post-menopausal unless permanently sterile (hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy). A postmenopausal state is defined as 
no menses for 12 months without an alternative medical cause. Effective 
contraception methods for WOCBP should be started prior to randomization and 
continued for a minimum of 35 days following completion of study drug 
administration. 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 29 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
b. Acceptable contraceptive methods for WOCBP are those that achieve a failure 
rate of less than 1% per year and include: 
i. Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
(1) Oral 
(2) Intravaginal 
(3) Transdermal  
ii. Progestogen-only hormonal contraception associated with inhibition of 
ovulation:  
(1) Oral  
(2) Injectable 
(3) Implantable 
iii. Intrauterine device (IUD)  
iv. Intrauterine hormone-releasing system (IUS)  
v. Bilateral tubal occlusion 
vi. Vasectomised partner 
vii. Sexual abstinence defined as refraining from heterosexual intercourse during 
the entire period of risk associated with the study treatments 
c. Male subjects should use condoms during treatment and for 98 days following the 
last study drug administration period. 
4. Subjects with history of sun hypersensitivity or photosensitive dermatoses (eg, 
porphyria, systemic lupus erythematosus (SLE), Sjogren’s syndrome, etc.) 
5. Subjects whose condition is spontaneously improving 
6. Subjects receiving Valchlor (or any topical compound containing Mechlorethamine) 
in the preceding 2 months 
7. Subjects receiving topical steroids or other topical treatments (eg, targretin gel) on 
treatment accessible lesions for CTCL within 2 weeks of enrollment 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 30 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
8. Subjects receiving systemic steroids, psoralen ultraviolet A (UVA) radiation therapy 
(PUVA), narrow band ultraviolet B (UVB) light therapy (NB-UVB) or carmustine 
(BCNU) or other systemic therapies for CTCL within 3 weeks of enrollment 
9. Subjects who have received electron beam irradiation within 3 months of enrollment 
10. Subjects with a history of significant systemic immunosuppression 
11. Subjects taking other investigational drugs or drugs of abuse within 30 days of 
enrollment 
12. Subject has any condition that, in the judgment of the PI, is likely to interfere with 
participation in the study 
13. Subjects receiving drugs known to cause photosensitization within 2 weeks of starting 
HyBryte therapy unless they have not had evidence of photosensitization after 
receiving a stable dose of the medication for a minimum of 4 weeks   
 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 31 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
6 STUDY CONDUCT 
6.1 
General Instructions 
This is a pilot, randomized, open-label, active comparator, US, single-center trial in 
which patients will be randomized to receive HyBryte or Valchlor in a 1:1 randomization. 
Patients will be treated for 12 weeks and follow-up visits will be conducted 1, 2, and 4 
weeks after completion of the treatment phase of the trial. 
Patients randomized to HyBryte will have HyBryte applied twice weekly and an opaque 
covering applied for 21 (±3) hours followed by the administration of visible light 
encompassing wavelengths of 500 to 650 nm. The light will be administered with a 
precisely calibrated device with a light dose starting at 6 J/cm2 twice weekly that is 
titrated up according to the physician’s discretion on subsequent sessions, limited by 
occurrence of Grade 2 erythema or greater but targeting a mild, Grade 1 reaction 
immediately following the light treatment. All of the patient’s lesions that are readily 
available for exposure to the visible light source will be treated. 
Patients randomized to Valchlor will apply a thin film of Valchlor gel once daily to 
affected areas of the skin and the dosing will follow the instructions for use in the 
package insert.  
Prior to randomization, each patient will have at least 3 and up to 5 index lesions 
identified. These lesions should be representative of the patient’s treated lesions and, if 
the patient has both plaque and patch lesions, include approximately the same distribution 
as the patient’s other lesions. 
6.2 
Study Procedures by Time Point 
6.2.1 
Screening 
Patients will be screened up to 30 days prior to randomization. At the screening visit the 
following will be done: 
• Signed, Informed Consent Form obtained 
• Inclusion/exclusion criteria reviewed 
• Complete medical history completed 
• Women of child-bearing potential will have a serum pregnancy test obtained 
6.2.2 
Baseline 
At the Baseline visit, the following will be done prior to randomization: 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 32 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
• Confirmation that the patient meets all inclusion/exclusion criteria 
• History of any medical changes obtained 
• Women of child-bearing potential will have a serum pregnancy test obtained unless 
the screening test was obtained 7 days or less 
• Physical exam 
• Vital signs obtained 
• Blood for the hematology panel obtained 
• Blood for the clinical chemistry panel obtained 
• Three to five lesions that are representative of the patient’s disease and are discrete 
with defined borders, will be chosen as the index lesions, and classified as patch or 
plaque lesions 
• Charting of all CTCL lesions on the “Body Lesion Diagram” (APPENDIX III – Body 
Lesion Diagram) locating and numbering each of the index lesions 
• Each index lesion will have an mCAILS score assessed and recorded 
• The mSWAT score will be assessed and recorded 
• The SAEQ score will be collected and recorded 
• The SCORD score will be collected and recorded 
Once all of these assessments are completed, the patient will be randomized into one of 
the two treatment arms, to receive HyBryte or Valchlor as the study drug. Patients who 
are randomized into the HyBryte treatment arm will follow the assessments outlined in 
Section 6.2.3. Patients who are randomized into the Valchlor treatment arm will follow 
the assessments outlined in Section 6.2.4. 
6.2.3 
HyBryte Patients 
Patients who are randomized into the HyBryte treatment arm will be given a jar of 
ointment at the Baseline visit. They will be instructed on proper drug application and 
demonstrate proficiency in drug application and all accessible lesions will be treated with 
study drug. 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 33 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
6.2.3.1 
Standard light treatment clinic visits 
Patients randomized to HyBryte will have HyBryte applied twice weekly and an opaque 
covering applied for 21 (±3) hours followed by the administration of visible light 
encompassing wavelengths of 500 to 650 nm. The light will be administered with a 
precisely calibrated device with a light dose starting at 6 J/cm2 twice weekly that is 
titrated up according to the physician’s discretion on subsequent sessions. Treatment will 
target a post-light treatment Erythema score of 1. The light dose will be reduced, 
maintained or treatment administrations may be suspended if a Grade 2 or greater 
erythema is present. Additional assessments of treated lesions and surrounding areas will 
include: 
o Erythema 
o Pain 
o Pruritus 
o Edema 
o Hyperpigmentation 
o Hypopigmentation 
o Rash 
o Vesiculation 
Each dermatological assessment will be graded according to Table 4. All of the patient’s 
lesions that are readily available for exposure to the visible light source will be treated. 
Table 4:  
Dermatologic Assessment Grading 
Toxicity Grade:  
Severity 
Grade 0 
No apparent reaction 
Grade I 
Mild 
Grade II 
Moderate 
Grade III 
Severe  
Grade IV 
Life-threatening  
At each visit, the following assessments will be conducted: 
• Interval medical history obtained 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 34 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
• Any AEs documented 
• Adequate application of the drug will be verified by a pink staining on visual 
inspection of lesions prior to administration of light 
• Delivery of light session, the time of treatment calculated by the target dose (starting 
at 6 J/cm² and titrated up at the Investigator’s discretion to a dose that generates an 
Erythema score >1 at the treated lesions or 25 J/cm2, whichever occurs first) 
• A dermatologic assessment of treated lesions will be performed immediately before 
and 10 to 30 minutes following completion of the light session.  
6.2.3.2 
Week 3 Session 6, Week 6 Session 12, and Week 9 Session 18 
6.2.3.2.1 
Light Treatment Day 
The patient will return to the clinic 21 (±3) hours after study drug is applied and the 
following assessments will be conducted prior to light treatment: 
• Each index lesion will have an mCAILS score assessed and recorded 
• The mSWAT score will be assessed and recorded 
• The PGA score will be assessed and recorded 
• The SAEQ score will be collected and recorded 
• The SCORD score will be collected and recorded 
Once the assessments are completed, the standard light treatment procedures will be 
conducted, as follows: 
• Interval medical history obtained 
• Any AEs documented 
• Adequate application of the drug will be verified by a pink staining on visual 
inspection of lesions 
• Delivery of light session, the time of treatment calculated by the target dose  
• A dermatologic assessment of treated lesions will be performed immediately before 
and 10 to 30 minutes following completion of the light session. This includes 
assessment of treated lesions and surrounding areas for: 
o Erythema 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 35 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
o Pain 
o Pruritus 
o Edema 
o Hyperpigmentation 
o Hypopigmentation 
o Rash 
o Vesiculation 
6.2.3.3 
Week 12 Session 24 
6.2.3.3.1 
Light Treatment Day 
The patient will return to the clinic 21 (±3) hours after study drug is applied and the 
following assessments and procedures will be conducted prior to light treatment: 
• Each index lesion will have an mCAILS score assessed and recorded 
• The mSWAT score will be assessed and recorded 
• The PGA score will be assessed and recorded 
• The SAEQ score will be collected and recorded 
• The SCORD score will be collected and recorded 
• Physical Exam 
• Vital Signs obtained 
• Blood for the hematology panel obtained 
• Blood for the clinical chemistry panel obtained 
Once the assessments are completed, the standard light treatment procedures will be 
conducted, as follows: 
• Interval medical history obtained 
• Any AEs documented 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 36 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
• Adequate application of the drug will be verified by a pink staining on visual 
inspection of lesions 
• Delivery of light session, the time of treatment calculated by the target dose  
• A dermatologic assessment of treated lesions will be performed immediately before 
and 10 to 30 minutes following completion of the light session. This includes 
assessment of treated lesions and surrounding areas for: 
o Erythema 
o Pain 
o Pruritus 
o Edema 
o Hyperpigmentation 
o Hypopigmentation 
o Rash 
o Vesiculation 
6.2.3.4 
Follow-Up Visits (Week 13, 14, and 16) 
Patients will return to the clinic during Weeks 13, 14, and 16 (End of Study) for follow-
up assessment. At each follow-up visit, the following will be conducted: 
• Interval medical history obtained 
• Any AEs documented 
• Each index lesion will have an mCAILS score assessed and recorded 
• The mSWAT score will be assessed and recorded 
• The PGA score will be assessed and recorded 
• The SAEQ score will be collected and recorded 
• The SCORD score will be collected and recorded 
• Vital signs obtained 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 37 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
In addition to the assessments above, the following will be done at the Week 16 Follow-
Up/End of Study visit: 
• Physical Exam 
• Vital Signs obtained 
• Blood for the hematology panel obtained 
• Blood for the clinical chemistry panel obtained 
6.2.4 
Valchlor Patients 
Patients who are randomized into the Valchlor treatment arm will be given a tube of gel 
at the Baseline visit. They will be instructed on proper drug application according to the 
instructions on the package insert. 
6.2.4.1 
Week 3, Week 6, and Week 9 
Patients will be instructed to come to the clinic during Weeks 3, 6, and 9.  
At the clinic, the following assessments will take place before Valchlor is applied: 
• Interval medical history obtained 
• Any AEs documented 
• Each index lesion will have an mCAILS score assessed and recorded 
• The mSWAT score will be assessed and recorded 
• The PGA score will be assessed and recorded 
• The SAEQ score will be collected and recorded 
• The SCORD score will be collected and recorded 
• Vital signs obtained 
Once these assessments have been completed, the patient will apply study drug at the 
clinic. 
6.2.4.2 
Week 12 
Patients will come in to the clinic at Week 12, and the following assessments and 
procedures will be completed before Valchlor is applied: 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 38 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
• Interval medical history obtained 
• Any AEs documented 
• Each index lesion will have an mCAILS score assessed and recorded 
• The mSWAT score will be assessed and recorded 
• The PGA score will be assessed and recorded 
• The SAEQ score will be collected and recorded 
• The SCORD score will be collected and recorded 
• Physical Exam 
• Vital Signs obtained 
• Blood for the hematology panel obtained 
• Blood for the clinical chemistry panel obtained 
Once these assessments and procedures have been completed, the patient will apply study 
drug at the clinic. 
6.2.4.3 
Follow-Up Visits (Week 13, 14, and 16) 
Patients will return to the clinic during Weeks 13, 14, and 16 (End of Study) for follow-
up assessment. At each follow-up visit, the following will be conducted: 
• Interval medical history obtained 
• Any AEs documented 
• Each index lesion will have an mCAILS score assessed and recorded 
• The mSWAT score will be assessed and recorded 
• The PGA score will be assessed and recorded 
• The SAEQ score will be collected and recorded 
• The SCORD score will be collected and recorded 
• Vital signs obtained 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 39 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
In addition to the assessments above, the following will be done at the Week 16 Follow-
Up/End of Study visit: 
• Physical Exam 
• Vital Signs obtained 
• Blood for the hematology panel obtained 
• Blood for the clinical chemistry panel obtained 
6.3 
Premature Discontinuation 
Patients have the right to withdraw from this trial at any time (as described in the 
informed consent document) without prejudice to further care. An investigator may 
withdraw a patient from the study at any time for any of the following reasons:  
• The patient withdraws his/her consent or refuses follow-up evaluations.  
• The patient is lost to follow-up and will not attend further study visits. 
• The investigator determines that further participation would be detrimental to the 
patient’s health or well-being. 
• The patient fails to comply with the study requirements so as to cause harm to self or 
seriously interfere with the validity of the study results. 
• The female patient becomes pregnant during the treatment period. In this case, 
treatment should be halted and the patient followed until the end of the pregnancy. If 
a child is born, the infant should be followed through at least 6 months of age. 
• At the discretion of the site investigator if he/she feels that it is in the best medical 
interest of the patient. 
Patients withdrawn from the study will have as many of the trial assessments completed 
as the patient permits including blood tests and lesion evaluations. 
 
 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 40 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
7 DESCRIPTION OF STUDY PROCEDURES 
7.1 
Efficacy Assessments 
7.1.1 
Modified Composite Assessment of Index Lesion Severity 
(mCAILS) 
mCAILS score will be calculated by assessing the erythema, scaling, plaque elevation 
and involved surface area using the grading scale shown in Table 5, Table 6, Table 7, and 
Table 8 for each of the index lesions. Each of the assessments and the total score for each 
evaluated lesion will be recorded in the Case Report Form (CRF). The total mCAILS 
score will be calculated by adding the scores of all evaluated lesions together. 
Table 5: 
Composite Assessment of Index Lesion Severity – Erythema 
Score 
Description 
0 
No evidence of erythema, possible brown hyperpigmentation 
1 
* 
2 
Mild: Light red lesion 
3 
* 
4 
Moderate: Red lesion 
5 
* 
6 
Severe: Very red lesion 
7 
* 
8 
Very severe: Extremely red lesion 
* Intermediate intervals 1, 3, 5, and 7 are to serve as mid-points between the defined grades 0, 2, 4, 6, and 8 
Table 6: 
Composite Assessment of Index Lesion Severity – Scaling 
Score 
Description 
0 
No evidence of scaling on lesion 
1 
* 
2 
Mild: Mainly fine scales: lesion partially covered 
3 
* 
4 
Moderate: Somewhat coarser scales: lesion partially covered 
5 
* 
6 
Severe: Coarse, thick scales; virtually all of the lesion covered; rough 
surface 
7 
* 
8 
Very severe:  Coarse, very thick scales; all of the lesion covered very 
rough surface 
* Intermediate intervals 1, 3, 5, and 7 are to serve as mid-points between the defined grades 0, 2, 4, 6, and 8 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 41 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
Table 7: 
Composite Assessment of Index Lesion Severity – Plaque Elevation 
Score 
Description 
0 
0 mm: No evidence of plaque above normal skin level 
1 
Mild elevation 
2 
Moderate elevation 
3 
Marked elevation 
 
Table 8: 
Composite Assessment of Index Lesion Severity – Surface Area 
Score 
Areaa 
0 
0 cm2 
1 
>0 and ≤4 cm2 
2 
>4 and ≤10 cm2 
3 
>10 and ≤16 cm2 
4 
>16 and ≤25 cm2 
5 
>25 and ≤35 cm2 
6 
>35 and ≤45 cm2 
7 
>45 and ≤55 cm2 
8 
>55 and ≤70 cm2 
9 
>70 and ≤90 cm2 
10 
>90 and ≤110 cm2 
11 
>110 and ≤130 cm2 
12 
>130 and ≤155 cm2 
13 
>155 and ≤180 cm2 
14 
>180 and ≤210 cm2 
15 
>210 and ≤240 cm2 
16 
>240 and ≤270 cm2 
17 
>270 and ≤300 cm2 
18 
>300 cm2 
a Longest diameter and the longest diameter perpendicular to this diameter of each index lesion will 
measured to the nearest millimeter. The lesion area will be the product of these two diameters 
7.1.2 
Modified Severity-Weighted Assessment Tool (mSWAT) 
The mSWAT is designed to quantify the disease burden associated with CTCL and is 
based on an estimate of the percent total area of skin involved based on the body surface 
area (BSA). The types of lesions are weighted by the lesion characteristic (patch, plaque, 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 42 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
or tumor) as shown in Table 9. It will be noted in the CRF if any lesions included in the 
mSWAT table will not be treated. 
Table 9: 
Modified Severity-Weighted Assessment Tool (mSWAT) 
Body Region 
% BSA1 in Body 
 
Assessment of Involvement in Patient’s Skin 
 
 
Region 
Patch2 
Plaque3 
Tumor4 
Head 
7% 
 
 
 
Neck 
2% 
 
 
 
Anterior trunk 
13% 
 
 
 
Arms 
8% 
 
 
 
Forearms 
6% 
 
 
 
Hands 
5% 
 
 
 
Posterior trunk 
13% 
 
 
 
Buttocks 
5% 
 
 
 
Thighs 
19% 
 
 
 
Legs 
14% 
 
 
 
Feet 
7% 
 
 
 
Groin 
1% 
 
 
 
Weighting Factor 
 
x1 
x2 
x4 
Subtotal lesion BSA x weighting factor 
 
 
 
 
1 BSA = body surface area 
2 Any size lesion without induration or significant elevation above the surrounding uninvolved skin; 
poikiloderma may be present. 
3 Any size lesion that is elevated or indurated; crusting, ulceration, or poikiloderma may be present. 
4 Any solid or nodular lesion >1 cm in diameter with evidence of deep infiltration in the skin and/or vertical 
growth. 
7.1.3 
The Physician Global Assessment (PGA) 
The PGA represents the investigator's assessment of the overall extent of improvement or 
worsening of the patient's cutaneous disease compared with Baseline as shown in Table 
10. This assessment is designed to consider all cutaneous lesions, including both index 
and non-index lesions. 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 43 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
Table 10: 
Physician’s Global Assessment 
Grade 
Description 
0  completely clear 
No evidence of disease; 100% improvement 
1  almost clear 
Very obvious improvement (≥90% to <100%);  
only traces of disease remain 
2  marked improvement 
Significant improvement (≥50 to <90% clear);  
some evidence of disease remains 
3  moderate improvement 
Intermediate between marked and mild (≥25% to <50%) 
4  slight improvement 
≥10% to <25%; significant evidence of disease remains 
5  no change 
Disease has not changed significantly from Baseline 
(10 to -25%) 
6  condition worse 
Disease is worse than Baseline by ≥25% 
7.2 
Safety Assessments 
7.2.1 
Dermatologic Assessment Grading 
For patients randomized to the HyBryte treatment arm, immediately prior to and 
approximately 10 to 30 minutes after the completion of light therapy, treated lesions and 
surrounding areas will be graded for erythema, pain, pruritus, edema, hyperpigmentation, 
hypopigmentation, rash, and vesiculation, with the average score recorded. The reaction 
will be graded using the definitions in Table 4. 
7.2.2 
SCORD Scoring 
The Scoring Atopic Dermatitis (SCORAD) tool is well established in Dermatology to 
provide a numeric assessment of the degree and severity of dermatitis in atopic 
dermatitis. Recently, this tool was modified to assess the severity of dermatitis in CTCL 
patients undergoing mechlorethamine treatment (Alexander-Savino 2022). This score is 
calculated as: 
• the percent of CTCL lesion showing dermatitis  
• the severity of the dermatitis on a 3-point scale (0-none, 1-mild, 2-moderate, 3-
severe) for redness, oozing/crusting, scratch marks, skin thickening, and dryness 
• the patient’s self-reported assessment of itch 
The scoring form for SCORD is attached in Appendix 20.2 APPENDIX II – SCORD 
Calculation Worksheet on page 69. 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 44 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
7.2.3 
Patient Reported SAEQ Score 
The Skin Adverse Event Questionnaire is a series of patient self-reported assessments of 
application site events over the last 24 hours recorded in a visual analog scale (VAS) 
format and reported as a score of 0 to 10 as shown in Appendix 20.4 Appendix IV - Skin 
Adverse Event Questionnaire. The number of application sites experiencing these 
symptoms will be noted. Symptoms specifically queried are: 
• Rash 
• Tenderness 
• Pain 
• Burning 
• Swelling 
• Redness 
• Blistering 
• Change in color 
7.3 
Clinical Laboratory Tests 
7.3.1 
Hematology 
The hematology panel will be performed at the Central Laboratory. The panel will consist 
of the following tests: 
• Red blood cell count (RBC) 
• Hematocrit 
• Hemoglobin 
• Mean corpuscular volume (MCV) 
• Mean corpuscular hemoglobin (MCH) 
• Mean corpuscular hemoglobin concentration (MCHC) 
• Platelet count 
• White blood cell count (WBC) 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 45 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
• Percent and absolute neutrophil count 
• Percent and absolute lymphocyte count 
• Percent and absolute monocyte count 
• Percent and absolute eosinophil count 
• Percent and absolute basophil count 
7.3.2 
Clinical Chemistry Laboratory Tests 
The clinical chemistry panel will be performed at the Central Laboratory. The panel will 
consist of the following tests: 
The panel will consist of the following tests: 
• Serum sodium 
• Serum potassium 
• Serum chloride 
• Serum bicarbonate (CO2) 
• Alanine aminotransferase (ALT) 
• Aspartate aminotransferase (AST) 
• Total bilirubin 
• Total protein 
• Serum creatinine 
• Blood urea nitrogen (BUN) 
• Alkaline phosphatase 
7.4 
Vital Signs 
Vital signs obtained will consist of: 
• Resting Blood Pressure 
• Heart Rate 
• Respiratory Rate 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 46 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
8 STUDY DRUG MANAGEMENT 
8.1 
HyBryte 
8.1.1 
Formulation  
HyBryte will be supplied in plastic screw-top jars containing 25 grams of 0.25% 
hypericin ointment (2.5 mg/gram). Jars are stored at room temperature.  
8.1.2 
Storage 
HyBryte can be kept at room temperature (23 to 27°C, 73 to 81°F). HyBryte should be 
mixed with an applicator (eg, tongue depressor) prior to application. 
8.1.3 
Packaging and Shipment 
HyBryte will be supplied in plastic screw-top jars containing 25 grams of 0.25% 
hypericin ointment (2.5 mg/gram). Jars will be labeled with the study number (HPN-
CTCL-04), a jar identification number, the designation “Topical HyBryte (0.25% 
hypericin)”, and the warning “Caution: New Drug-Limited by U.S. Federal Law to 
Investigational Use." 
8.1.4 
Dose and Administration 
Patients randomized to the HyBryte treatment arm will be instructed to mix and apply the 
study drug to cover the entire surface of each lesion in a thin layer. However, application 
to uninvolved skin should be as limited as possible. The amount of ointment used for 
each application will be dependent upon the amount of lesion surface area. The patient 
should wear disposable gloves and wash their hands after applying the study ointment. If 
someone else helps apply the study ointment, they should wear disposable gloves. If the 
medicine gets on the skin of other people, they will be instructed to wash with soap and 
water.  
8.2 
Valchlor 
Commercially available Valchlor will be used as the active comparator in this trial. 
Valchlor will not be provided by Soligenix and will be obtained by the site. All 
information below is extracted from the approved Valchlor package insert which should 
be followed for all storage, handling and administrations instructions.  If there are 
discrepancies between this protocol and the approved Valchlor package insert, the 
package insert should prevail and be followed by the site (this will not be considered a 
protocol deviation) 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 47 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
8.2.1 
Formulation  
The active ingredient in Valchlor is mechlorethamine. Each tube of Valchlor contains 60 
g of 0.016% w/w mechlorethamine clear gel (equivalent to 0.02% mechlorethamine 
HCl). 
8.2.2 
Storage 
Prior to dispensing, store in the freezer at ‐13°F to 5°F (‐25°C to ‐15°C). Advise patients 
that refrigerated storage is required once dispensed. 
8.2.3 
Packaging and Shipment 
Valchlor is supplied in 60 g tubes of 0.016% w/w mechlorethamine as a clear gel. 
8.2.4 
Dose and Administration 
Apply a thin film of Valchlor gel once daily to affected areas of the skin. 
Stop treatment with Valchlor for any grade of skin ulceration, blistering, or moderately‐
severe or severe dermatitis (ie, marked skin redness with edema). Upon improvement, 
treatment with Valchlor can be restarted at a reduced frequency of once every 3 days. If 
reintroduction of treatment is tolerated for at least one week, the frequency of application 
can be increased to every other day for at least one week and then to once daily 
application if tolerated. 
Valchlor is a cytotoxic drug. Follow applicable special handling and disposal procedures. 
Patients must wash hands thoroughly with soap and water after handling or applying 
Valchlor. Caregivers must wear disposable nitrile gloves when applying Valchlor to 
patients and wash hands thoroughly with soap and water after removal of gloves. If there 
is accidental skin exposure to Valchlor, caregivers must immediately wash exposed areas 
thoroughly with soap and water for at least 15 minutes and remove contaminated 
clothing. 
Patients or caregivers should follow these instructions when applying Valchlor: 
• Apply immediately or within 30 minutes after removal from the refrigerator. Return 
Valchlor to the refrigerator immediately after each use. 
• Apply to completely dry skin at least 4 hours before or 30 minutes after showering or 
washing. Allow treated areas to dry for 5 to 10 minutes after application before 
covering with clothing. 
• Emollients (moisturizers) may be applied to the treated areas 2 hours before or 2 
hours after application. 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 48 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
• Do not use occlusive dressings on areas of the skin where Valchlor was applied. 
• Avoid fire, flame, and smoking until Valchlor has dried. 
8.3 
Accountability 
The PI must ensure that all drug supplies are kept under lock and key with access limited 
to those authorized by the investigator. The PI must maintain accurate records of the 
receipt of all study medication shipped by the Sponsor, including date received, lot 
number, expiration/re-test date, amount received and disposition of all study medication. 
Current dispensing records will be maintained and include date and amount of medication 
dispensed, initials of subjects receiving the medication, and any amount of medication 
not used or returned (or lost) by the subject. All remaining medication not required by 
regulation to be held by the clinical facility, must be destroyed following all appropriate 
regulatory guidelines or returned to the Sponsor immediately after the study is completed. 
Any lost, spilled or missing drug must be documented. 
8.4 
Prohibited Concomitant Therapy 
Prior medications, going back 3 weeks from the screening date (systemic and topical), 
will be collected at the screening visit. Concomitant medications (systemic and topical) 
will be collected at each clinic visit. A detailed history of prior CTCL treatments will be 
collected.  
The following drugs are not allowed on treated lesions within 2 weeks of enrollment or 
during the study:  
• Topical steroids (including 1% hydrocortisone cream or ointment)  
The following drugs are not allowed within 3 weeks of enrollment or during the study: 
• Systemic steroids 
• Psoralen UVA radiation therapy (PUVA) 
• Narrow band-UVB 
• Carmustine (BCNU) 
• Other systemic therapies for CTCL 
The following drugs are not allowed within 30 days of enrollment or during the study: 
• 5-fluorouracil 
• Vinblastine 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 49 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
• Dacarbazine 
• ALA or 5-aminolevulinic acid  
• Methyl-5-aminolevulinic acid 
• Investigational drugs 
• Drugs of abuse 
• Agents known to cause photosensitization 
The following drugs can only be used if there have been no phototoxic reactions to the 
stable dose of the drug after a minimum of 14 days of treatment: 
o Quinolone antibiotic 
o Tetracycline 
o Sulfonamide  
o Diphenhydramine 
o Quinine  
o Chloroquine  
o Hydroxychloroquine  
o Amiodarone 
o Systemic nifedipine 
o Quinidine 
o Diltiazem 
o Furosemide  
o Thiazides 
o Sulfonylureas 
o Isotretinoin  
o Acitretin 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 50 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
o Phenothiazines 
o Tricyclic antidepressants 
The following drugs are not allowed within 2 months of enrollment. 
o Topical nitrogen mustard 
o Valchlor 
8.5 
Compliance 
Patients will be trained in the proper application of HyBryte and Valchlor. Application of 
HyBryte will be documented by site personnel by noting pink staining on lesions 
indicating application of the drug. Valchlor compliance will be determined by patient 
reports. 
 
 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 51 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
9 ADVERSE EVENTS 
Timely, accurate and complete reporting and analysis of safety information from trials is 
crucial for the protection of subjects, investigators and the Sponsor, and is mandated by 
regulatory agencies worldwide. Soligenix has established standard operating procedures 
(SOPs) in conformity with regulatory requirements to ensure appropriate reporting of 
safety information. All trials that are the responsibility of Soligenix must be conducted in 
accordance with the procedures as provided below. 
9.1 
Definitions 
9.1.1 
Adverse Experience (AE) 
Any noxious or unintended event that occurs in association with the use of an 
investigational agent in humans, whether considered related to the investigational agent 
or not. This definition encompasses symptoms or signs reported by the subject or 
detected by the Investigator or other competent observer, as well as medically important 
deviations from normality in the results of ancillary investigations. If present at time of 
first dose of study drug, such AEs must be recorded as part of the medical history. 
9.1.2 
Treatment-Emergent AE  
An AE that is new in onset or aggravated in severity or frequency following entry into the 
study. In addition, any pathological finding on physical examination or diagnostic 
procedure that is new in occurrence or exacerbated in comparison with the subject's status 
at study entry is considered a treatment-emergent AE if it requires any medical or 
surgical intervention whatsoever (including, but not limited to, additional diagnostic 
procedures or alteration of prescribed therapy). 
9.1.3 
Potentially Serious Adverse Experience  
Any AE that is sufficiently severe or alarming as to require any form of significant 
medical intervention. Note: Important medical events that may not result in death, be life 
threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and require medical or 
surgical intervention to prevent one of the outcomes listed in the SAE definition. 
9.2 
Relationship to Study Drug 
The relationship of an AE to the assigned study drug is assessed using the following 
definitions: 
Not Related: The drug experience is clearly related to other factors such as the 
patient’s/subject’s clinical state, therapeutic interventions or concomitant 
drugs. 
Possibly Related: The drug experience follows a reasonable sequence from the 
time of drug administration and/or follows a known response pattern to the 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 52 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
study drug, but could have been produced by other factors such as the 
patient’s/subject’s clinical state, therapeutic interventions or concomitant 
drugs. 
Related: The drug experience follows a reasonable temporal sequence from the 
time of drug administration and follows a known response pattern to the study 
drug, and cannot be reasonably explained by other factors such as the 
patient’s/subject’s clinical state, therapeutic interventions or concomitant 
drugs. 
9.3 
Severity of Adverse Event 
A clinical determination of the intensity of an AE should be done for all reported AEs. 
The severity assessment for AEs should be completed using the following definitions as 
guidelines: 
Mild: Awareness of sign or symptom, but easily tolerated. 
Moderate: Discomfort enough to cause interference with usual activity. 
Severe: Incapacitating with inability to work or do usual activity. 
Not applicable:  In some cases, an AE may be an “all or nothing” finding, which 
cannot be graded. 
9.4 
Recording Adverse Events 
All AEs, whether judged to be related or not to the study drug, should be recorded in both 
the medical record and the CRF. If photographic evidence is available and relevant, it 
may be recorded. The start and resolution dates, the judgment of the severity of the AE, 
the judgment of the relationship of the AE to the study drug, the action taken for 
subsequent dose of study drug, and the outcome should be noted.  


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 53 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
10 SERIOUS ADVERSE EVENT 
10.1 Definition of Serious Adverse Event 
A SAE is any event that meets any of the following criteria: 
• Death 
• Life-threatening 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect in the offspring of a subject who received study drug 
• Other: Important medical events that may not result in death, be life-threatening, or 
require hospitalization, may be considered an SAE when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such events are: 
o Intensive treatment in an emergency room or at home for allergic bronchospasm 
o Blood dyscrasias or convulsions that do not result in inpatient hospitalization 
o Development of drug dependency or drug abuse 
10.2 Definition of Terms 
Life threatening: An AE is life threatening if the subject was at immediate risk of death 
from the event as it occurred; ie, it does not include a reaction that if it had occurred in a 
more serious form might have caused death. For example, drug induced hepatitis that 
resolved without evidence of hepatic failure would not be considered life threatening 
even though drug induced hepatitis can be fatal. 
Hospitalization: AEs requiring hospitalization should be considered SAEs. 
Hospitalization for elective surgery or routine clinical procedures that are not the result of 
AE (eg, elective surgery for a pre-existing condition that has not worsened) need not be 
considered AEs or SAEs. If anything untoward is reported during the procedure, that 
occurrence must be reported as an AE, either 'serious' or 'non-serious' according to the 
usual criteria. 
In general, hospitalization signifies that the subject has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or 




Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 55 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
Christopher Pullion, DO 
Medical Director 
 
 
 
 
  
10.4 Overdose 
Any instance of overdose (suspected or confirmed and irrespective of whether or not it 
involved HyBryte or Valchlor) must be communicated to Soligenix, Inc within 24 hours 
and be fully documented as an SAE. Details of any signs or symptoms and their 
management should be recorded including details of any antidote(s) administered. 
 
 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 56 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
11 STATISTICS 
11.1 General Procedures 
This is a randomized, pilot study assessing outcomes of patients receiving HyBryte 
compared to Valchlor in patients with stage IA, IB, and IIA CTCL. Subjects will be 
randomized to 12 weeks of treatment with either HyBryte or Valchlor in a 1:1 ratio. 
Additionally, the practical issues likely to arise in a larger clinical study comparing 
HyBryte to Valchlor will be identified. No formal efficacy statistics will be performed. 
Results will be presented as tables that include group means, standard deviations, 
medians, maximum, and minimum values for continuous variables and counts and 
percentages for dichotomous variables as well as individual patient listings. 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 57 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
12 ETHICS AND RESPONSIBILITIES 
12.1 Good Clinical Practice 
The study will be performed in accordance with the ethical principles in the Declaration 
of Helsinki, Good Clinical Practices (GCPs) and applicable regulatory requirements.  
12.2 Institutional Review Board/Independent Ethics Committee 
The final study protocol, including the final version of the Subject Information and 
Consent Forms, must be approved in writing by an IRB that meets the minimum FDA 
standards before enrollment of any subject into the study. The PI or their designee is 
responsible for informing the IRB of any SAE and amendment(s) to the protocol as per 
regulatory requirements. 
12.3 Informed Consent 
The Investigator will ensure that the subject or a legally authorized representative of the 
subject is given full and adequate oral and written information about the nature, purpose, 
possible risk and benefit of the study. Subjects must also be notified that they are free to 
discontinue from the study at any time. The subject should be given the opportunity to 
ask questions and allowed time to consider the information provided. The subject’s 
signed and dated informed consent must be obtained before conducting any study 
specific procedure. The consent form that is used must meet the requirements as outlined 
in the ICH Guidance on GCPs (E6) and must be approved by both the reviewing IRB and 
by Soligenix. 
12.4 Subject data protection 
The Subject Information and Consent Form will explain that study data will be stored in a 
computer database, maintaining confidentiality. Subjects in this database will be 
identified by initials or enrollment code/subject number only. Authorized representatives 
of a regulatory authority (eg, FDA) may require direct access to parts of the trial site 
records relevant to the study, including subjects’ medical history for data verification 
purposes. 
12.5 Financial Disclosure 
The FDA has issued regulations (21 CFR Part 54) that require Sponsors (in this case 
Soligenix) to submit complete and accurate certification or disclosure statements to 
certify the absence of certain financial interests of clinical investigators and/or disclose 
those financial interests, as required, when clinical studies are submitted to the FDA in 
support of marketing approval of a new drug application (NDA). These regulations are 
intended to ensure that financial interests and arrangements of clinical investigators, that 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 58 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
could affect reliability of data submitted to the FDA in support of marketing approval, are 
identified and disclosed by the Sponsor. 
Clinical investigators shall be asked to disclose proprietary (eg, patent, licensing 
agreement) and financial (eg, stock options, royalty) interests as they pertain to Soligenix, 
prior to participating in the study. In addition, clinical investigators will be required to 
consult with Soligenix before acquiring any financial interest in the company and must 
disclose any change in their proprietary or financial interests if it occurs during the course 
of the study and for one year following study completion. Clinical Investigator is defined 
under Title 21 CFR Part 54 as an investigator or sub-investigator listed on the FDA Form 
1572 that is directly involved in the treatment or evaluation of research subjects. The 
requirement for proprietary and financial disclosure also includes any ownership by the 
spouse or any dependent child of the investigator. 
If the FDA determines that the financial interests of any clinical investigator raise serious 
questions about the integrity of the data, the FDA will take any action it deems necessary 
to ensure the reliability of the data, including: 
• Initiating agency audits of the data derived from the clinical investigator in question; 
• Requesting that the Sponsor submit further analyses of data, eg, to evaluate the effect 
of the clinical investigator’s data on overall study outcome; 
• Requesting that the applicant conduct additional independent studies to confirm the 
results of the questioned study; and/or 
• Refusing to treat the covered clinical study as providing data that can be the basis for 
an agency action. 
If the Sponsor does not include certification or disclosure, or both, if required, or does not 
certify that it was not possible to obtain the information, the FDA may refuse to file the 
NDA. 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 59 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
13 RECORDS MANAGEMENT 
13.1 Source Documentation 
Original source documents include all informed consent forms, laboratory reports, 
progress notes, medical histories, physical and diagnostic findings, diagnoses and dates of 
therapy prior to and during this study, drug dispensing/disposition records which are used 
to support the data recorded CRFs of each subject. When possible, all data should be 
documented in an original source document and copied into the CRF. 
13.2 Study Files and Record Retention 
Copies of CRFs should be retained by sites along with all original source documents (eg, 
informed consent forms, laboratory reports, progress notes, medical histories, physical 
and diagnostic findings, diagnoses and dates of therapy prior to and during this study, 
drug dispensing/disposition records) that support CRFs of each subject must be retained 
in the files of the responsible investigator or in hospital records for a minimum of two (2) 
years following notification by Soligenix that all investigations have been discontinued or 
that the last approval of a marketing application has been obtained. 
If the responsible investigator retires, relocates, or for other reason withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who 
will accept the responsibility. Soligenix must be notified in writing of the name and 
address of the new custodian. 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 60 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
14 AUDITING AND MONITORING 
14.1 Study Monitoring 
It is the responsibility of the PI and site personnel to assure that the data recorded in the 
CRF is accurate, complete and can be verified from the medical records.  
In accordance with the Guidelines for the Monitoring of Clinical Investigations presented 
in the ICH Guidance on GCPs (E6), Soligenix will select, either directly or through 
subcontract, qualified individuals to monitor the progress of the study and adherence to 
protocol by the individual clinical sites. 
It is the responsibility of the PI to assure that, at mutually agreed upon times, the clinical 
monitor has appropriate access to all medical records, study materials, study and 
regulatory binders, laboratory and radiographic results, study personnel, their time to 
allow adequate assessment as to the quality, completeness and adherence to all aspects of 
the protocol. 
14.1.1 
Pre-study Evaluation 
This initial encounter with the site will establish that the site has all of the necessary 
elements to successfully participate in the proposed protocol including adequately trained 
staff, adequate free time of the staff, adequate facilities for safe and proper trial conduct, 
evidence for potential enrollment of suitable patients, adequate research pharmacy 
support, the presence of an IRB meeting the local and FDA requirements, and a 
commitment for training of all involved staff on the protocol. 
14.1.2 
Site Initiation Visit 
Once all required trials documents have been processed, the Medical Monitor (or trained 
designee) will initiate the study after on-site training of the participating staff at the 
institution. Topics covered will include training on: 
• The investigational status of the study drug and the requirements for its 
accountability. 
• Background on the study drug. 
• Details of the protocol including patient selection, study drug administration, 
procedures to be performed, and visit schedules. 
• Critical nature of obtaining informed consent in accordance with the 
Declaration of Helsinki and ICH Guidance on GCPs (E6) before enrolling 
each subject in the study. 
• The obligation to ensure IRB review and approval for the study, including the 
protocol, amendments, ICF and any advertisements, is obtained prior to its 
initiation at his/her clinical site, to ensure continuing review of the study by 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 61 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
the IRB, and to keep Soligenix informed of such approval and subsequent 
actions concerning the study. 
14.1.3 
Monitoring Visits 
Soligenix or their trained designee will perform on-site monitoring visits as frequently as 
it deems necessary. At these visits, the site monitor will compare the data entered into the 
CRFs with the source documents and check for protocol compliance including a record of 
informed consent, enrollment criteria, all subject assessments, all AEs and all 
concomitant medications. In addition, study drug and supporting records will be 
reviewed. Additionally, they assure that all serious, life-threatening or fatal AEs are being 
reported immediately [and in no case later than twenty-four (24) hours after the event] to 
the Medical Monitor or designee at Soligenix. 
Findings from these reviews will be discussed with the investigator and staff. Completed 
pages of the CRFs will be evaluated at each visit. The dates of the monitoring visits will 
be recorded in a sign-in log that will be kept at the site. The study coordinator and 
investigator are expected to be available for questions, the source documentation readily 
available, and a suitable environment provided for review of study-related documents. 
14.1.4 
Close-out Visit 
The clinical research monitor(s) will perform an end of trial visit to ensure that: 
• All drug reconciliation forms are accurate and complete. 
• All unused study drug is returned to the appropriate location. 
• All data issues are resolved and CRFs are completed and verified. 
• The IRB has been notified that the study has been completed. 
• The investigator at each site is aware that the study has been completed and no 
further subjects are enrolled. 
14.2 Audits and Inspections 
Health Authorities (eg, FDA), in the person of a trained and properly authorized 
employee, may request access to all study records, including source documents, for 
inspection and copying. The investigator will immediately notify Soligenix of any 
upcoming inspections.  
Periodic auditing inspections may also be conducted by a representative of the Quality 
Assurance Department of Soligenix or its designee(s). 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 62 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
15 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study subjects, 
may be made only by Soligenix. A protocol change intended to eliminate an apparent 
immediate hazard to subjects may be implemented immediately, provided the IRB/IEC is 
notified within 5 days. 
Any permanent change to the protocol must be handled as a protocol amendment. The 
written amendment must be submitted to the IRB/IEC and the investigator must await 
approval before implementing the changes. Soligenix will submit protocol amendments 
to the appropriate regulatory authorities for approval. 
If in the judgment of the IRB/IEC, the investigator, and/or Soligenix, the amendment to 
the protocol substantially changes the study design and/or increases the potential risk to 
the subject and/or has an impact on the subject's involvement as a study participant, the 
currently approved written informed consent form will require similar modification. In 
such cases, informed consent will be renewed for subjects enrolled in the study before 
continued participation. 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 63 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
16 STUDY REPORT AND PUBLICATIONS 
Soligenix is responsible for preparing and providing the appropriate regulatory authorities 
with clinical study reports according to the applicable regulatory requirements. 
Soligenix’s publication policy is discussed in the investigator's Clinical Research 
Agreement. 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 64 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
17 STUDY DISCONTINUATION  
Both Soligenix and the Principal Investigator reserve the right to terminate the study at 
the investigator’s site at any time. Should this be necessary, Soligenix or a specified 
designee will inform the appropriate regulatory authorities of the termination of the study 
and the reasons for its termination, and the Principal Investigator will inform the IRB/IEC 
of the same. In terminating the study, Soligenix and the Principal Investigator will assure 
that adequate consideration is given to the protection of the subjects’ interests. 
 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 65 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
18 CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written 
consent is gained from Soligenix. However, authorized regulatory officials, IRB/IEC 
personnel, Soligenix and its authorized representatives are allowed full access to the 
records. 
Identification of subjects and CRFs shall be by initials, screening and treatment numbers 
only. If required, the subject's full name may be made known to an authorized regulatory 
agency or other authorized official. 
 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 66 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
19 REFERENCES 
Alexander-Savino, C. V., C. G. Chung, E. S. Gilmore, S. M. Carroll and B. Poligone 
(2022). "Randomized Mechlorethamine/Chlormethine Induced Dermatitis Assessment 
Study (MIDAS) Establishes Benefit of Topical Triamcinolone 0.1% Ointment 
Cotreatment in Mycosis Fungoides." Dermatol Ther (Heidelb) 12(3): 643-654. 
Boiy, A., R. Roelandts and P. A. de Witte (2011). "Photodynamic therapy using topically 
applied hypericin: comparative effect with methyl-aminolevulinic acid on UV induced 
skin tumours." J Photochem Photobiol B 102(2): 123-131. 
Couldwell, W. T., A. A. Surnock, A. J. Tobia, B. E. Cabana, C. B. Stillerman, P. A. 
Forsyth, A. J. Appley, A. M. Spence, D. R. Hinton and T. C. Chen (2011). "A phase 1/2 
study of orally administered synthetic hypericin for treatment of recurrent malignant 
gliomas." Cancer 117(21): 4905-4915. 
Dąbrowski, J. M. (2017). Reactive Oxygen Species in Photodynamic Therapy: 
Mechanisms of Their Generation and Potentiation. Inorganic Reaction Mechanisms: 343-
394. 
de Andrade, G. P., T. F. M. de Souza, G. Cerchiaro, M. Pinhal, A. O. Ribeiro and M. 
Girao (2021). "Hypericin in photobiological assays: An overview." Photodiagnosis 
Photodyn Ther 35: 102343. 
Fox, F. E., Z. Niu, A. Tobia and A. H. Rook (1998). "Photoactivated hypericin is an anti-
proliferative agent that induces a high rate of apoptotic death of normal, transformed, and 
malignant T lymphocytes: implications for the treatment of cutaneous 
lymphoproliferative and inflammatory disorders." J Invest Dermatol 111(2): 327-332. 
Gulick, R., V. McAuliffe, J. Holden-Witse, C. Crumpacker, L. Liebes, D. Stein, P. 
Meehan, SHussey, J. Forcht, F. Valentine and A. C. T. G. a. P. Team (1999). "Phase 1 
Studies of hypericin, the active compound in St. John's Wort, as an antiretroviral agent in 
HIV-infected adults." Ann Intern Med 130(6): 5. 
Jacobson, J. M., L. Feinman, L. Liebes, N. Ostrow, V. Koslowski, A. Tobia, B. E. 
Cabana, D. Lee, J. Spritzler and A. M. Prince (2001). "Pharmacokinetics, safety, and 
antiviral effects of hypericin, a derivative of St. John's wort plant, in patients with chronic 
hepatitis C virus infection." Antimicrob Agents Chemother 45(2): 517-524. 
Jendzelovska, Z., R. Jendzelovsky, B. Kucharova and P. Fedorocko (2016). "Hypericin in 
the Light and in the Dark: Two Sides of the Same Coin." Front Plant Sci 7: 560. 
Kim, E. J., A. R. Mangold, J. A. DeSimone, H. K. Wong, L. Seminario-Vidal, J. Guitart, 
J. Appel, L. Geskin, E. Lain, N. J. Korman, N. Zeitouni, N. Nikbakht, K. Dawes, O. 
Akilov, J. Carter, M. Shinohara, T. M. Kuzel, W. Piette, N. Bhatia, A. Musiek, D. 
Pariser, Y. H. Kim, D. Elston, E. Boh, M. Duvic, A. Huen, T. Pacheco, J. P. Zwerner, S. 
T. Lee, M. Girardi, C. Querfeld, K. Bohjanen, E. Olsen, G. S. Wood, A. Rumage, O. 
Donini, A. Haulenbeek, C. J. Schaber, R. Straube, C. Pullion, A. H. Rook and B. 
Poligone (2022). "Efficacy and Safety of Topical Hypericin Photodynamic Therapy for 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 67 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
Early-Stage Cutaneous T-Cell Lymphoma (Mycosis Fungoides): The FLASH Phase 3 
Randomized Clinical Trial." JAMA Dermatol 158(9): 1031-1039. 
Silva, S. M., A. Martinho, I. Moreno, S. Silvestre, L. B. Granadeiro, G. Alves, A. P. 
Duarte, F. Domingues and E. Gallardo (2016). "Effects of Hypericum perforatum extract 
and its main bioactive compounds on the cytotoxicity and expression of CYP1A2 and 
CYP2D6 in hepatic cells." Life Sci 144: 30-36. 
Xu, L., X. Zhang, W. Cheng, Y. Wang, K. Yi, Z. Wang, Y. Zhang, L. Shao and T. Zhao 
(2019). "Hypericin-photodynamic therapy inhibits the growth of adult T-cell leukemia 
cells through induction of apoptosis and suppression of viral transcription." Retrovirology 
16(1): 5. 
 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 68 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
20 APPENDICES 
20.1 APPENDIX I – Names of Study Personnel 
 
Sponsor: 
Soligenix, Inc. 
29 Emmons Drive 
Princeton, NJ 08540 
Medical Monitors: 
Richard Straube, MD 
29 Emmons Drive 
Princeton, NJ 08540 
 
Christopher Pullion, DO 
29 Emmons Drive 
Princeton, NJ 08540 
 
 
 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 69 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
20.2 APPENDIX II – SCORD Calculation Worksheet 
The following form will be used to calculate a severity of dermatitis score for treated 
lesions. 
SCORING DERMATITIS (SCORD) SCALE 
A. Percentage of lesions with dermatitis score (enter % of involved treated lesions) 
Score   _______ % 
 
Range 0 = no dermatitis in treated lesions to 100 = all treated lesions are entirely 
involved with dermatitis 
 
A score can range from  0 to 100 
 
B. Lesion severity score (circle average score of affected lesions for each finding) 
 
a. Redness 
0- None 
1- Mild 
2- Moderate 3- Severe 
 
 
b. Oozing/crusting 
0- None 
1- Mild 
2- Moderate 3- Severe 
 
 
c. Scratch marks 
0- None 
1- Mild 
2- Moderate 3- Severe 
 
 
d. Skin thickening 
0- None 
1- Mild 
2- Moderate 3- Severe 
 
 
e. Dryness 
0- None 
1- Mild 
2- Moderate 3- Severe 
 
 
B score is the sum of the 5 sub-scores and can range from 0 to 18 
 
C. Patient self-reported current itch measured on a 0 to 10 scale marking itch intensity on 
a visual analog scale. The scale will be 10 cm long and the score is the centimeter from 
0 to the patient’s slash. 
 
No itch                                                                                       Worst imaginable itch        
|___________________________________________________________________| 
0                                                                                                                       10 
 
                               C score is the number of centimeters from 0 and can range from 0 to 10 
 
Total SCORD score is calculated by adding the score for each of the subscores  
( A, B, and C) weighted as follows: 
 
Calculation of SCORD score = (A/5 +7B/2 +C) 
 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 70 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
20.3 APPENDIX III – Body Lesion Diagram 
BODY LESION DIAGRAM 
Please identify the index lesions’ location (Ex. 1, 2 or 3) in the diagram below. 
 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 71 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
20.4 Appendix IV - Skin Adverse Event Questionnaire 
Patient Number: ________           
 
      Date:__  __ / __  __ / 202 ___ 
 
Over the last 24 hours, please rate the degree of discomfort you have had at areas that 
have been treated with your drug. Place a vertical mark on each line corresponding the 
worst area that has been treated for each of the symptoms you have had. 
1. Rash: 
None |___________________________________________________| Worst imaginable 
2. Tenderness  
None |___________________________________________________| Worst imaginable 
3. Pain 
None |___________________________________________________| Worst imaginable 
4. Burning 
None |___________________________________________________| Worst imaginable 
5. Swelling 
None |___________________________________________________| Worst imaginable 
6. Redness 
None |___________________________________________________| Worst imaginable 
7. Blistering 
None |___________________________________________________| Worst imaginable 
8. Change in color 
None |___________________________________________________| Worst imaginable 
 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 72 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
20.5 APPENDIX V – Declaration of Helsinki 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
 
Ethical Principles 
for 
Medical Research Involving Human Subjects 
 
Adopted by the 18th WMA General Assembly 
Helsinki, Finland, June 1964 
and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of 
Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 73 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
PREAMBLE 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as 
a statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving 
human subjects to adopt these principles. 
GENERAL PRINCIPLES 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The 
health of my patient will be my first consideration,” and the International Code of 
Medical Ethics declares that, “A physician shall act in the patient’s best interest when 
providing medical care.” 
4. It is the duty of the physician to promote and safeguard the health, well-being and 
rights of patients, including those who are involved in medical research. The physician’s 
knowledge and conscience are dedicated to the fulfilment of this duty. 
5. Medical progress is based on research that ultimately must include studies involving 
human subjects. 
6. The primary purpose of medical research involving human subjects is to understand 
the causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best proven 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
7. Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
8. While the primary purpose of medical research is to generate new knowledge, this goal 
can never take precedence over the rights and interests of individual research subjects. 
9. It is the duty of physicians who are involved in medical research to protect the life, 
health, dignity, integrity, right to self-determination, privacy, and confidentiality of 
personal information of research subjects. The responsibility for the protection of 
research subjects must always rest with the physician or other health care professionals 
and never with the research subjects, even though they have given consent. 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 74 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
10. Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or regulatory 
requirement should reduce or eliminate any of the protections for research subjects set 
forth in this Declaration. 
11. Medical research should be conducted in a manner that minimises possible harm to 
the environment. 
12. Medical research involving human subjects must be conducted only by individuals 
with the appropriate ethics and scientific education, training and qualifications. Research 
on patients or healthy volunteers requires the supervision of a competent and 
appropriately qualified physician or other health care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14. Physicians who combine medical research with medical care should involve their 
patients in research only to the extent that this is justified by its potential preventive, 
diagnostic or therapeutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the health of the patients who 
serve as research subjects. 
15. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
RISKS, BURDENS AND BENEFITS 
16. In medical practice and in medical research, most interventions involve risks and 
burdens. 
Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the risks and burdens to the research subjects. 
17. All medical research involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and groups involved in the 
research in comparison with foreseeable benefits to them and to other individuals or 
groups affected by the condition under investigation. 
Measures to minimise the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher. 
18. Physicians may not be involved in a research study involving human subjects unless 
they are confident that the risks have been adequately assessed and can be satisfactorily 
managed. 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 75 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
When the risks are found to outweigh the potential benefits or when there is conclusive 
proof of definitive outcomes, physicians must assess whether to continue, modify or 
immediately stop the study. 
VULNERABLE GROUPS AND INDIVIDUALS 
19. Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive 
to the health needs or priorities of this group and the research cannot be carried out in a 
non-vulnerable group. In addition, this group should stand to benefit from the knowledge, 
practices or interventions that result from the research. 
SCIENTIFIC REQUIREMENTS AND RESEARCH PROTOCOLS 
21. Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, other 
relevant sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
22. The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, potential 
conflicts of interest, incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 
RESEARCH ETHICS COMMITTEES 
23. The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the researcher, 
the sponsor and any other undue influence and must be duly qualified. It must take into 
consideration the laws and regulations of the country or countries in which the research is 
to be performed as well as applicable international norms and standards but these must 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 76 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
not be allowed to reduce or eliminate any of the protections for research subjects set forth 
in this Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must 
provide monitoring information to the committee, especially information about any 
serious adverse events. No amendment to the protocol may be made without 
consideration and approval by the committee. After the end of the study, the researchers 
must submit a final report to the committee containing a summary of the study’s findings 
and conclusions. 
PRIVACY AND CONFIDENTIALITY 
24. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
INFORMED CONSENT 
25. Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members or 
community leaders, no individual capable of giving informed consent may be enrolled in 
a research study unless he or she freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, 
each potential subject must be adequately informed of the aims, methods, sources of 
funding, any possible conflicts of interest, institutional affiliations of the researcher, the 
anticipated benefits and potential risks of the study and the discomfort it may entail, post-
study provisions and any other relevant aspects of the study. The potential subject must 
be informed of the right to refuse to participate in the study or to withdraw consent to 
participate at any time without reprisal. Special attention should be given to the specific 
information needs of individual potential subjects as well as to the methods used to 
deliver the information. 
After ensuring that the potential subject has understood the information, the physician or 
another appropriately qualified individual must then seek the potential subject’s freely-
given informed consent, preferably in writing. If the consent cannot be expressed in 
writing, the non-written consent must be formally documented and witnessed. 
All medical research subjects should be given the option of being informed about the 
general outcome and results of the study. 
27. When seeking informed consent for participation in a research study the physician 
must be particularly cautious if the potential subject is in a dependent relationship with 
the physician or may consent under duress. In such situations the informed consent must 
be sought by an appropriately qualified individual who is completely independent of this 
relationship. 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 77 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
28. For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. These 
individuals must not be included in a research study that has no likelihood of benefit for 
them unless it is intended to promote the health of the group represented by the potential 
subject, the research cannot instead be performed with persons capable of providing 
informed consent, and the research entails only minimal risk and minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed 
consent is able to give assent to decisions about participation in research, the physician 
must seek that assent in addition to the consent of the legally authorised representative. 
The potential subject’s dissent should be respected. 
30. Research involving subjects who are physically or mentally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical or mental 
condition that prevents giving informed consent is a necessary characteristic of the 
research  group. In such circumstances the physician must seek informed consent from 
the legally authorised representative. If no such representative is available and if the 
research cannot be delayed, the study may proceed without informed consent provided 
that the specific reasons for involving subjects with a condition that renders them unable 
to give informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research must be 
obtained as soon as possible from the subject or a legally authorised representative. 
31. The physician must fully inform the patient which aspects of their care are related to 
the research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek 
informed consent for its collection, storage and/or reuse. There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such 
research. In such situations the research may be done only after consideration and 
approval of a research ethics committee. 
USE OF PLACEBO 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; 
or 
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention 
is necessary to determine the efficacy or safety of an intervention 


Clinical Study Protocol 
HPN-CTCL-04
Pilot Study of HyBryte™ (synthetic hypericin) versus Valchlor® (mechlorethamine) in the 
Treatment of CTCL   
Confidential
HyBryte™ (0.25% hypericin ointment) 
Page 78 of 78
 
 
Original: 02 August 2023 
Amendment 1: 18 September 2023 
 
Amendment 2: 05 March 2024 
 
and the patients who receive any intervention less effective than the best proven one, 
placebo, or no intervention will not be subject to additional risks of serious or irreversible 
harm as a result of not receiving the best proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
POST-TRIAL PROVISIONS 
34. In advance of a clinical trial, sponsors, researchers and host country governments 
should make provisions for post-trial access for all participants who still need an 
intervention identified as beneficial in the trial. This information must also be disclosed 
to participants during the informed consent process. 
RESEARCH REGISTRATION AND PUBLICATION AND 
DISSEMINATION OF RESULTS 
35. Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations 
with regard to the publication and dissemination of the results of research. Researchers 
have a duty to make publicly available the results of their research on human subjects and 
are accountable for the completeness and accuracy of their reports. All parties should 
adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as 
positive results must be published or otherwise made publicly available. Sources of 
funding, institutional affiliations and conflicts of interest must be declared in the 
publication. Reports of research not in accordance with the principles of this Declaration 
should not be accepted for publication. 
UNPROVEN INTERVENTIONS IN CLINICAL PRACTICE 
37. In the treatment of an individual patient, where proven interventions do not exist or 
other known interventions have been ineffective, the physician, after seeking expert 
advice, with informed consent from the patient or a legally authorised representative, may 
use an unproven intervention if in the physician’s judgement it offers hope of saving life, 
re-establishing health or alleviating suffering. This intervention should subsequently be 
made the object of research, designed to evaluate its safety and efficacy. In all cases, new 
information must be recorded and, where appropriate, made publicly available.