Clinical trial NCT05380635
Conditions: Cutaneous T-Cell Lymphoma/Mycosis Fungoides
Keywords: CTCL MF Hypericin HyBryte
Sponsor: Soligenix
Start date: 2022-05-09; Completion date: 2022-08-16
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To assess the blood levels of hypericin and any electrocardiogram (ECG) changes during 8 weeks of HyBryte (topical hypericin ointment) photodynamic therapy.

Detailed description:

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 5 J/cm\^2. Drug application/light session will be done twice a week (at least 2 calendar days apart) for 8 weeks.
Interventions: intervention 1: Hypericin
Intervention descriptions: intervention 1: HyBryte is synthetic hypericin formulated as a 0.25% hypericin ointment.

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol
Phase 2a Study of Systemic PK and Serial ECG Determinations Following HyBryte 
Treatment 
Confidential
HyBryte™ (0.25% hypericin ointment)
Page 1 of 67
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CLINICAL RESEARCH PROTOCOL
DRUG:
HyBryte™ (0.25% hypericin ointment)
STUDY NUMBER(S):
HPN-CTCL-02
PROTOCOL(S) TITLE:
Phase 2a Study of Systemic PK and Serial ECG 
Determinations Following 8 Weeks of HyBryte 
Treatment 
IND NUMBER:
SPONSOR:
Soligenix, Inc.
ORIGINAL PROTOCOL 
DATE:
20 January 2022
VERSION NUMBER:
Amendment 1
VERSION DATE:
22 April 2022
NCT05380635


Clinical Study Protocol
Phase 2a Study of Systemic PK and Serial ECG Determinations Following HyBryte 
Treatment 
Confidential
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Clinical Study Protocol
Phase 2a Study of Systemic PK and Serial ECG Determinations Following HyBryte 
Treatment 
Confidential
HyBryte™ (0.25% hypericin ointment)
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HPN-CTCL-02
PHASE 2A STUDY OF SYSTEMIC PK AND SERIAL ECG 
DETERMINATIONS FOLLOWING 8 WEEKS OF HYBRYTE 
TREATMENT 
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
Phase 2a Study of Systemic PK and Serial ECG Determinations Following HyBryte 
Treatment 
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STUDY SYNOPSIS 
Name of Sponsor/Company:
Soligenix, Inc.
Name of Finished Product
HyBryte™
Name of Active Ingredient
Hypericin (0.25% ointment)
(For National Authority Use 
only)
Title of Study: Phase 2a Study of Systemic PK and Serial ECG Determinations Following 8 Weeks of 
HyBryte Treatment
Investigators: Brian Poligone, MD; potentially one additional TBD Investigator
Study Centre(s): Rochester Skin Lymphoma Center; 1 other site TBD
Publication (reference): N/A
Study Period (years): 
0.4 year
Date of First Enrollment: 02 May 2022
Date of Last Completed: 
31 October 2022
Phase of Development:  Phase 2a
Objectives: The primary objectives of this study are to assess:
•
the systemic blood levels of hypericin during 8 weeks of standard HyBryte photodynamic 
therapy; and
•
any ECG changes during 8 weeks of standard HyBryte photodynamic therapy.
Methodology: This will be an open label trial. Subjects with CTCL (stage IB or IIA) with lesions of 
≥10% of body surface area will be enrolled and receive topical HyBryte applied to all accessible lesions 
twice per week followed by visible light treatment 18-24 hours later starting at 5 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). At baseline and at the end of weeks 4, 6, 8, and 10, serum 
for Hypericin levels will be obtained and 12-lead ECG’s will be performed at baseline (prior to drug 
application), at Week 4, Session 2 (immediately before and 2 hours after completion of the light 
session), at Week 6, Session 2 (immediately before the light session), Week 8, Session 2 Light Session 
visit (immediately before and 2 hours after completion of the light session), and Week 10/End of Study 
visit. Routine safety laboratories (hematology, clinical chemistries) will be analyzed at baseline, at the 
Week 8 Session 2 Light Session visit, and 2 weeks after completion of therapy (Week 10/End of Study). 
AE’s will be recorded throughout the study. 
Number of patients (planned): Approximately 6 subjects will be recruited


Clinical Study Protocol
Phase 2a Study of Systemic PK and Serial ECG Determinations Following HyBryte 
Treatment 
Confidential
HyBryte™ (0.25% hypericin ointment)
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Name of Sponsor/Company:
Soligenix, Inc.
Name of Finished Product
HyBryte™
Name of Active Ingredient
Hypericin (0.25% ointment)
(For National Authority Use 
only)
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.
Active treatment-accessible CTCL lesions covering ≥ 10% of their body surface area
3.
Subjects must have a clinical diagnosis of cutaneous T-cell lymphoma (CTCL, mycosis 
fungoides), Stage 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 allergy or hypersensitivity to any of the components of HyBryte
2.
Pregnancy or mothers who are breast-feeding
3.
Males and females not willing to use effective contraception
4.
Subjects with history of sun hypersensitivity or photosensitive dermatoses (e.g., porphyria, 
systemic lupus erythematosus (SLE), Sjogren’s syndrome, etc.)
5.
Subjects whose condition is spontaneously improving
6.
Subjects receiving topical steroids or other topical treatments (e.g., nitrogen mustard) on index 
lesions for CTCL within 2 weeks of enrollment
7.
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
8.
Subjects who have received electron beam irradiation within 3 months of enrollment
9.
Subjects with a history of significant systemic immunosuppression
10. Subjects taking other investigational drugs or drugs of abuse within 30 days of enrollment


Clinical Study Protocol
Phase 2a Study of Systemic PK and Serial ECG Determinations Following HyBryte 
Treatment 
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HyBryte™ (0.25% hypericin ointment)
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Name of Sponsor/Company:
Soligenix, Inc.
Name of Finished Product
HyBryte™
Name of Active Ingredient
Hypericin (0.25% ointment)
(For National Authority Use 
only)
11. Subject has any condition that, in the judgment of the PI, is likely to interfere with participation 
in the study
12. 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 
Test product, dose and mode of administration: HyBryte (0.25% hypericin ointment) applied in a 
thin film on all lesions avoiding treatment of healthy skin (weight of drug actually used will be 
measured by weighing the drug jar at the time of each light treatment by study personnel and estimating 
the amount applied by changes in jar weight) and covered with opaque covering.  The light panel for use 
in this study is the Daavlin 7 Series Phototherapy Device using visible light lamps (510K clearance 
K212510). The drug will be activated 18-24 hours after application starting at 5 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.
Duration of treatment: Subjects will apply HyBryte to all accessible lesions followed 18-24 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 8 weeks of treatment (16 
actual treatments). Subjects will have serum hypericin levels obtained at baseline (prior to drug 
application) and at weeks 4 (immediately before and 2 hours after light session), 6 (immediately before 
light session), and 8 (immediately before drug application, immediately before and 2 hours after light 
session). Subjects will have ECGs obtained at baseline (prior to drug application) and at weeks 4 
(immediately before and 2 hours after light session), 6 (immediately before light session), and 8 
(immediately before and 2 hours after light session). Subjects will return as outpatients 2 weeks after the 
final drug application (Week 10/End of Study) for safety laboratory assessments, PK samples, ECG, 
lesion evaluations and collection of adverse events.
Reference therapy, dose and mode of administration: Not applicable as there is no reference therapy 
in this uncontrolled study.
Criteria for evaluation:
Primary Objectives:
This is an exploratory study to assess the systemic exposure to hypericin following topical application of 
HyBryte. Given the relatively small sample size, no formal efficacy assessments will be performed.
Safety:
The safety variables evaluated are: Serial ECG’s, clinical hematology assessments, clinical chemistry 
assessments, vital signs, and the collection of adverse/serious adverse events. 


Clinical Study Protocol
Phase 2a Study of Systemic PK and Serial ECG Determinations Following HyBryte 
Treatment 
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TABLE OF CONTENTS
CLINICAL RESEARCH PROTOCOL ..............................................................................................................1
CONFIDENTIALITY AND INVESTIGATOR STATEMENT ...............................................................................3
STUDY SYNOPSIS.....................................................................................................................................4
TABLE OF CONTENTS...............................................................................................................................7
TABLE OF TABLES ..................................................................................................................................10
TABLE OF FIGURES ................................................................................................................................10
LIST OF ABBREVIATIONS........................................................................................................................11
INTRODUCTION AND RATIONALE..........................................................................................................13
1.1
BACKGROUND INTRODUCTION................................................................................................................13
1.1.1
Natural History and Treatment of Cutaneous T-cell Lymphoma...........................................13
1.1.2
Hypericin................................................................................................................................14
1.2
PHARMACOKINETICS.............................................................................................................................15
1.3
SYSTEMIC HYPERICIN PHARMACOKINETICS................................................................................................17
1.4
CLINICAL ADVERSE EVENT PROFILE..........................................................................................................17
1.4.1
Dosing Regimen.....................................................................................................................19
2
STUDY OBJECTIVES.......................................................................................................................20
2.1
PRIMARY............................................................................................................................................20
2.2
SECONDARY........................................................................................................................................20
3
STUDY ENDPOINTS.......................................................................................................................20
3.1
PRIMARY............................................................................................................................................20
3.2
SECONDARY........................................................................................................................................21
4
STUDY PLAN.................................................................................................................................21
4.1
STUDY DESIGN ....................................................................................................................................21
4.2
SCHEDULE OF ASSESSMENTS ..................................................................................................................22
5
POPULATION................................................................................................................................24
5.1
NUMBER OF SUBJECTS..........................................................................................................................24
5.2
SELECTION OF SUBJECTS........................................................................................................................24
5.2.1
Inclusion Criteria....................................................................................................................24
5.2.2
Exclusion Criteria ...................................................................................................................24
5.3
STUDY PROCEDURES BY TIME POINT........................................................................................................25
5.3.1
Screening Visit .......................................................................................................................25
5.3.2
Baseline .................................................................................................................................25
5.3.3
Week 1, Session 1; Week 1, Session 2; Week 2 Session 1; Week 2, Session 2; Week 3, Session 
1; Week 3, Session 2; Week 4, Session 1..............................................................................................26
5.3.4
Week 4, Session 2 ..................................................................................................................27
5.3.5
Week 5, Session 1; Week 5, Session 2; Week 6, Session 1 .....................................................28
5.3.6
Week 6, Session 2 ..................................................................................................................29
5.3.7
Week 7, Session 1; Week 7, Session 2; Week 8, Session 1 .....................................................29
5.3.8
Week 8, Session 2 Drug Application Visit ..............................................................................30
5.3.9
Week 8, Session 2 Light Session Visit.....................................................................................30


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Treatment 
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5.3.10
Week 10, Follow-up visit/End of Study .............................................................................31
5.4
PREMATURE DISCONTINUATION .............................................................................................................32
6
DESCRIPTION OF STUDY PROCEDURES .........................................................................................32
6.1
LIGHT SESSION ....................................................................................................................................32
6.2
ELECTROCARDIOGRAM (ECG) ................................................................................................................33
6.3
HYPERICIN BLOOD LEVELS......................................................................................................................34
6.4
CLINICAL LABORATORY TESTS.................................................................................................................34
6.4.1
Hematology Tests..................................................................................................................34
6.4.2
Clinical Chemistry Laboratory Tests.......................................................................................35
6.5
VITAL SIGNS........................................................................................................................................36
6.6
QUALITY OF LIFE ASSESSMENTS ..............................................................................................................36
6.7
VAS ITCH ASSESSMENT.........................................................................................................................36
6.8
COMPOSITE ASSESSMENT OF INDEX LESIONS SEVERITY (CAILS) SCORE ..........................................................36
6.9
THE PHYSICIAN GLOBAL ASSESSMENT (PGA) ............................................................................................38
6.10
MODIFIED SEVERITY WEIGHTED ASSESSMENT TOOL (MSWAT)...............................................................39
6.11
ERYTHEMA SCORING........................................................................................................................40
7
STUDY DRUG MANAGEMENT.......................................................................................................41
7.1
DESCRIPTION ......................................................................................................................................41
7.1.1
Study Drug Packaging and Labeling......................................................................................41
7.3
ADMINISTRATION.................................................................................................................................41
7.4
STUDY DRUG ACCOUNTABILITY...............................................................................................................41
7.5
STUDY DRUG HANDLING AND DISPOSAL...................................................................................................42
7.6
PROHIBITED CONCOMITANT MEDICATION ................................................................................................42
7.7
COMPLIANCE ......................................................................................................................................43
8
ADVERSE EVENTS .........................................................................................................................44
8.1
DEFINITIONS .......................................................................................................................................44
8.1.1
Adverse Event (AE).................................................................................................................44
8.1.2
Treatment-Emergent AE........................................................................................................44
8.1.3
Potentially Serious AE............................................................................................................44
8.2
RELATIONSHIP TO STUDY DRUG..............................................................................................................44
8.3
SEVERITY OF ADVERSE EVENT.................................................................................................................45
8.4
RECORDING ADVERSE EVENTS ................................................................................................................45
9
SERIOUS ADVERSE EVENT.............................................................................................................46
9.1
DEFINITION OF SERIOUS ADVERSE EVENT..................................................................................................46
9.2
REPORTING SERIOUS ADVERSE EVENTS ....................................................................................................47
10
STATISTICS ...................................................................................................................................49
10.1
GENERAL PROCEDURES ....................................................................................................................49
10.2
ANALYSIS OF SAFETY........................................................................................................................49
10.3
INTERIM ANALYSIS...........................................................................................................................49
11
ETHICS AND RESPONSIBILITIES .....................................................................................................50
11.1
INSTITUTIONAL REVIEW BOARD .........................................................................................................50
11.2
ETHICAL CONDUCT OF THE STUDY ......................................................................................................50


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11.3
WRITTEN INFORMED CONSENT..........................................................................................................50
11.4
SUBJECT DATA PROTECTION..............................................................................................................50
11.5
FINANCIAL DISCLOSURE....................................................................................................................50
12
RECORDS MANAGEMENT.............................................................................................................52
12.1
SOURCE DOCUMENTATION ...............................................................................................................52
13
AUDITING AND MONITORING ......................................................................................................53
13.1
STUDY MONITORING .......................................................................................................................53
13.1.1
Pre-study Evaluation.........................................................................................................53
13.1.2
Site Initiation Visit.............................................................................................................53
13.1.3
Monitoring Visits ..............................................................................................................53
13.1.4
Close-out Visit...................................................................................................................54
13.2
AUDITS AND INSPECTIONS.................................................................................................................54
14
AMENDMENTS.............................................................................................................................55
15
STUDY REPORT.............................................................................................................................56
16
STUDY DISCONTINUATION ...........................................................................................................57
17
CONFIDENTIALITY ........................................................................................................................58
18
REFERENCES.................................................................................................................................59
19
APPENDICES.................................................................................................................................64
19.1
APPENDIX I – NAMES OF STUDY PERSONNEL .....................................................................................64
19.2
APPENDIX II – BODY LESION DIAGRAM.............................................................................................65
19.3
APPENDIX III – SKINDEX-29 ASSESSMENT.........................................................................................66


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Treatment 
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TABLE OF TABLES
TABLE 1:
PK OF SYSTEMICALLY ADMINISTERED SYNTHETIC HYPERICIN....................................................................17
TABLE 2: ADVERSE EVENTS BY SYSTEM ORGAN CLASS AND PREFERRED TERM REPORTED IN ≥3% OF PATIENTS IN ANY 
TREATMENT GROUP..................................................................................................................................17
TABLE 3: SCHEDULE OF ASSESSMENTS....................................................................................................................22
TABLE 4: DURATION OF LIGHT EXPOSURE REQUIRED FOR GIVEN LIGHT DOSES...............................................................33
TABLE 5: ERYTHEMA SUBSCORE OF THE MODIFIED CAILS SCORE.................................................................................37
TABLE 6: SCALING SUBSCORE OF THE MODIFIED CAILS SCORE....................................................................................37
TABLE 7: PLAQUE ELEVATION SUBSCORE OF THE MODIFIED CAILS SCORE.....................................................................37
TABLE 8: SURFACE AREA SUBSCORE OF THE MODIFIED CAILS SCORE ...........................................................................38
TABLE 9: PHYSICIAN’S GLOBAL ASSESSMENT ...........................................................................................................39
TABLE 10: MODIFIED SEVERITY WEIGHTED ASSESSMENT TOOL (MSWAT) ...................................................................39
TABLE 11: SKIN PHOTOTOXICITY GRADING..............................................................................................................40
 TABLE OF FIGURES
FIGURE 1: HYPERICIN BLOOD LEVELS IN MINIPIGS ....................................................................................................16
 


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Treatment 
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LIST OF ABBREVIATIONS
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
BCNU
Carmustine
bid
Twice Daily
BP
Blood Pressure
BSA
Body Surface Area
BUN
Blood Urea Nitrogen
CONMED
Concomitant Medication
CRF
Case Report Form
CTCL
Cutaneous T-cell Lymphoma
ECG
Electrocardiogram
GCP
Good Clinical Practice
HCG
Human Chorionic Gonadotropin
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
IB
Investigator’s Brochure
ICD
Immunogenic Cell Death
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IRB
Institutional Review Board


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Kg
Kilogram
L
Liters
LN
Lymph Node
MF
Mycosis Fungoides
Mg
Milligram
Min
Minute
mmHg
Millimeters Mercury
mSWAT
Modified Severity Weighted Assessment Tool
NB-UVB
Narrow Band UVB 
PI
Principal Investigator
PK
Pharmacokinetic
Po
Per Os (By Mouth), Orally
PUVA
Psoralen Ultraviolet A Radiation Therapy
ROS
Reactive Oxygen Species
SAE
Serious Adverse Event
SLE
Systemic Lupus Erythematosus
SOP
Standard Operating Procedure
SS
Sézary Syndrome
ULN
Upper Limit of Normal
UV
Ultraviolet
UVA
Ultraviolet A
UVB
Ultraviolet B
WHO
World Health Organization


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INTRODUCTION AND RATIONALE
1.1
Background Introduction
This section contains a brief description of the rationale and available information 
concerning the chemistry, non-clinical pharmacology and toxicology, pharmacokinetics 
(PK), and previous clinical experience with HyBryte. Please refer to the Investigator's 
Brochure (IB) for additional details and information.
1.1.1
Natural History and Treatment of Cutaneous T-cell Lymphoma
Cutaneous T-cell lymphoma (CTCL), of which the most common early stages are also 
known as mycosis fungoides (MF), is the most common type of T-cell lymphoma. CTCL 
affects approximately 25,000 to 50,000 individuals in the US (1). MF most commonly 
presents with skin involvement only, manifested as scaly, erythematous patches. As MF 
progresses, patients develop thicker skin lesions (plaques), skin tumors, lymph node (LN) 
involvement, blood involvement (Sézary syndrome), and visceral organ involvement. A 
few patients will present with more advanced stages of CTCL requiring systemic therapy 
from the time of diagnosis (2). Advanced disease with diffuse LN and visceral organ 
involvement is usually associated with a poorer response rate to standard therapies and 
the patient’s survival can often be measured in months (3). A sub-group of CTCL 
patients present with extensive skin involvement (generalized erythroderma) and 
circulating malignant cerebriform T-cells that is commonly designated Sézary syndrome 
(SS) (4, 5).
MF has substantial morbidity and potential mortality. Mortality is related to stage of 
disease (6). Median survival for stage T1 (cutaneous patches or plaques <10% body 
surface area (BSA)) or T2 (patches or plaques >10% BSA) exceeds 12 years; T1 or T2 
patients with lymph node or blood involvement and T3 (one or more cutaneous tumors) 
or T4 patients (erythroderma) have a 5-year median survival; those with visceral 
involvement or LN effacement by tumor have only a 2.5-year median survival. 
The diagnosis of CTCL is confirmed by skin biopsy, which characteristically 
demonstrates the pathognomonic epidermal infiltration (Pautrier’s micro-abscesses) of 
hyperchromatic T-cells that are immunohistochemically positive for the CD4 marker 
identifying the “helper” T-cell subset and often fail to express CD7 (7, 8). Blood 
involvement can be investigated through flow cytometry, Sézary count and/or gene 
rearrangement studies to determine the presence of a circulating clone (6, 9). More 
advanced skin disease produces vertical growth resulting in tumors or ulcers and is 
frequently associated with regional LN involvement that can be detected via physical 
examination and radiological imaging. 
Treatment of MF involves skin directed therapies, biologic response modifying therapies 
(aimed at promoting a host response to tumor), radiation therapy (directed at individual 
tumors or total body electron beam irradiation), and in some instances multi-agent 
chemotherapeutic modalities. Most patients have received short courses of topical 


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corticosteroids prior to the diagnosis of MF (10). The malignancy-specific topical 
treatments include mechlorethamine (11-13) (nitrogen mustard or Mustargen®) 
administered in a tap water solution or as an ointment, and carmustine (BCNU) (14). 
Both treatments have significant response rates in early stage MF disease, but have 
virtually no effect on extra cutaneous disease or the circulating malignant T-cells in SS 
patients (13). Response to skin directed therapies is often slow with peak response seen 
only after 6-18 months of therapy.
1.1.2
Hypericin
Hypericin is a natural compound found in the stems and petals of plants of the genus 
Hypericum (15-17). HyBryte™ is chemically synthesized hypericin formulated for 
topical application and not extracted from plants. 
Hypericin is an effective virucidal agent that directly inactivates a broad range of viruses, 
including retroviruses (18-23), both as a stand-alone drug (24, 25) and after 
photoactivation (22, 26-29). Based on these promising in vitro virucidal effects, the 
compound was clinically evaluated for its utility in the management of human 
immunodeficiency virus (HIV) (30) and hepatitis C infections (31). However, no 
convincing evidence of clinical effectiveness as an antiviral was observed in these studies 
up to toxicity-limited doses, which were exclusively phototoxicity related. 
In addition to its antiviral activity, hypericin has been shown in animal models to 
accumulate selectively in cancer cells up to a ratio of 12:1 cancer to healthy cells (32, 
33). Again, hypericin appears to have tumoricidal effects both as a stand-alone drug (34-
37) and after activation with visible light (15, 38-45). A clinical trial of parenteral 
synthetic hypericin for the treatment of brain gliomas found the drug to be safe and 10 of 
the 41 treated patients were considered treatment responders (46). 
Although the information from these parenteral clinical trials is not directly applicable to 
the evaluation of the topical formulation of synthetic hypericin (HyBryte), the systemic 
doses of the drug were safe and at blood levels many magnitudes higher than expected 
following topical administration. 
The dose-limiting toxicity in the systemic hypericin clinical trials was phototoxicity. The 
existence of this photoactivity, however, forms a basis for considering hypericin as an 
agent in topical phototherapy. In vitro studies with T-cells showed that hypericin could 
inhibit induced proliferation and near complete apoptosis in malignant CTCL T-cells 
with substantially less effects on normal T-cells similarly treated (47) and induced the 
inhibition of cell proliferation in adult T-cell leukemia cell lines with minimal effect on 
peripheral blood CD4+ T lymphocytes (48).
In general, it appears that the primary mechanism of the light-activated hypericin is 
through a Type II photoreaction. Hypericin localizes in the perinuclear region within the 
endoplasmic reticulum and Golgi apparatus (50, 51). When activated with visible light in 


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the 500-650 nm range (exact activation wavelengths dependent on the solute used), the 
molecule is converted into a high energy state that transfers the energy to free oxygen 
creating high energy, singlet oxygen, 1O2. This, in turn, leads to a sequence of 
photochemical and photobiological processes generating highly reactive oxygen species 
(ROS), which activate the caspase signaling cascade leading to apoptosis via the 
mitochondrial pathway. Hypericin additionally interacts with a variety of cytosolic 
proteins and lipoproteins. ROS generation also leads to cell necrosis, a cell death pathway 
that may augment its anti-tumor effects through a process of immunogenic cell death 
(ICD) that activates the immune system against the tumor (52).
A Phase 2 clinical trial demonstrated a statistically significant reduction in both CTCL 
and psoriatic lesions after 6 weeks of treatment with HyBryte and treatment was well 
tolerated (49). 
A Phase 3 trial with a short, 6-week course of HyBryte therapy demonstrated a 
statistically significant improvement of lesion response as compared to the blinded 
placebo rate as well as further improvement afforded by an additional 6-week cycle of 
open label drug use. At the end of the initial treatment period, there was a statistically 
significant improvement in the response rate among the HyBryte group compared to the 
placebo group (p=0.0416) and this rate dramatically improved with more prolonged 
treatment with increased response rates of 40% with 12 weeks of therapy (p<0.0001) and 
49% with 18 weeks of therapy (p<0.0001). This benefit was similar in patch lesions as 
well as with the thicker, more difficult to treat plaque lesions. Treatment response was 
durable and more durable with extended treatment. HyBryte treatment was well tolerated, 
with a low rate of adverse events (AE). The most prevalent AEs were related to skin 
reactions and application site pain and irritation. The rate of skin/application site 
reactions was significantly lower than has been reported for other skin-directed therapies.
1.2
Pharmacokinetics 
Hypericin was initially developed for the systemic treatment of enveloped viral infections 
including HIV and hepatitis C virus (HCV) and gliomas. Following dosing with either 
intravenous (iv) or oral (po) routes, the only consistently reported AEs 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 
5-6 weeks of continuous therapy on multiple lesions). Specific serum 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 levels were <5 ng/mL (lower limit of detection of the bioanalytical method). 
This study is designed to expand the information about the systemic absorption of 
hypericin after topical application. Since the systemic levels of hypericin following 
topical administration were expected to be orders of magnitude lower than that following 
iv or po administration in which there was no evidence of electrocardiogram (ECG) 




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CTCL would provide more information about the PK of the topical drug over time (using 
the more sensitive assay) and allow contemporaneous assessment of ECG readings.
1.3
Systemic Hypericin Pharmacokinetics
The PK and safety margin afforded by topical application of HyBryte is best understood 
in the context of PK results obtained in studies of well tolerated systemic hypericin (po or 
iv administration) as shown in Table 1. With blood levels uniformly determined to be <5 
ng/ml after continuous hypericin use in the Phase 3 study, comparison to the well-
tolerated po and iv dosing suggest a safety margin 6-1280 fold. 
Table 1:
PK of Systemically Administered Synthetic Hypericin
Patients
Route
Dose
mg/kg
Cmax
ng/mL
t½ α
hrs
t½ β
hrs
AUC
ng-hr/mL
Healthy 
po- fasting
1.25
1,180
3.23
39.7
42,950
2.00
2,120
5.96
68.8
63,310
po- feeding
1.25
1,010
5.64
42.4
36,350
2.00
1,420
8.48
83.7
63,990
iv
0.25
4,200
2.50
24.2
41,900
0.375
6,400
3.3
40.2
66,600
HIV1
po
0.05
31.3
20.2
NR
522
0.10
72.9
21.0
NR
1,455
HCV2
po
0.05
30.6
36.1
NR
930
0.10
64.9
33.8
NR
3,100
1 HIV = human immunodeficiency virus patients
2 HCV = hepatitis C virus patients
1.4
Clinical Adverse Event Profile
The reported MedRA coded AE in ≥3% of patients in any treatment group from the 
Phase 3 Clinical Trial are shown in Table 2.
Table 2: Adverse Events by System Organ Class and Preferred Term Reported in ≥3% of Patients in 
Any Treatment Group 
System Organ Class
Cycle 1
Cycle 2
Cycle 3
Preferred Term
HyBryte
(N=116)
n (%)
Placebo
(N=50)
n (%)
HyBryte
(N=155)
n (%)
HyBryte
(N=110)
n (%)
HyBryte 
Overall
(N=161)
n (%)
Overall
(N=166)
n (%)
#Patients ≥1 TEAE
56 (48.3)
27 
(54.0)
66 (42.6)
49 (44.5)
108 
(67.1)
116 
(69.9)


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System Organ Class
Cycle 1
Cycle 2
Cycle 3
Preferred Term
HyBryte
(N=116)
n (%)
Placebo
(N=50)
n (%)
HyBryte
(N=155)
n (%)
HyBryte
(N=110)
n (%)
HyBryte 
Overall
(N=161)
n (%)
Overall
(N=166)
n (%)
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)
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 paresthesia
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)
Gastrointestinal disorders
11 (9.5)
6 (12.0)
7 (4.5)
7 (6.4)
20 (12.4)
24 (14.5)
Nausea
3 (2.6)
1 (2.0)
2 (1.3)
2 (1.8)
7 (4.3)
8 (4.8)
Diarrhea
4 (3.4)
0
3 (1.9)
0
6 (3.7)
6 (3.6)
Nervous system disorders
9 (7.8)
4 (8.0)
6 (3.9)
5 (4.5)
18 (11.2)
22 (13.3)
Headache
5 (4.3)
3 (6.0)
5 (3.2)
2 (1.8)
10 (6.2)
13 (7.8)
Dizziness
3 (2.6)
1 (2.0)
1 (0.6)
2 (1.8)
6 (3.7)
7 (4.2)
Respiratory, thoracic and 
mediastinal disorders
9 (7.8)
1 (2.0)
5 (3.2)
5 (4.5)
17 (10.6)
17 (10.2)


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System Organ Class
Cycle 1
Cycle 2
Cycle 3
Preferred Term
HyBryte
(N=116)
n (%)
Placebo
(N=50)
n (%)
HyBryte
(N=155)
n (%)
HyBryte
(N=110)
n (%)
HyBryte 
Overall
(N=161)
n (%)
Overall
(N=166)
n (%)
Injury, poisoning and 
procedural complications
6 (5.2)
2 (4.0)
4 (2.6)
5 (4.5)
14 (8.7)
16 (9.6)
Musculoskeletal and connective 
tissue disorders
3 (2.6)
3 (6.0)
6 (3.9)
4 (3.6)
11 (6.8)
14 (8.4)
Neoplasms benign, malignant 
and unspecified (incl.  cysts and 
polyps)
0
1 (2.0)
3 (1.9)
2 (1.8)
5 (3.1)
6 (3.6)
Eye disorders
3 (2.6)
0
2 (1.3)
0
5 (3.1)
5 (3.0)
Vascular disorders
2 (1.7)
1 (2.0)
1 (0.6)
1 (0.9)
4 (2.5)
5 (3.0)
# = 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. At each summary level (SOC, PT), a patient was 
counted only once or each AE he/she experienced within that level. All AEs were coded using the Medical 
Dictionary for Regulatory Activities (MedDRA), Version 20.
1.4.1
Dosing Regimen
HyBryte ointment will be applied to all accessible CTCL lesions by the patients 
following training by the site staff. Care will be taken to minimize application to other 
skin areas, and cover the treated area with opaque bandaging/clothing. The lesions will 
then be exposed to visible light using the Daavlin Series 7 Phototherapy Device with 
visible light lamps (FDA 510K approval K212510) 18-24 hours later starting at 5 J/cm2 
and titrated up until the treated lesions exhibit a mild erythema following the light 
session. Drug application/light session will be done twice a week (at least 2 calendar days 
apart) for 8 weeks. The light treatment will be performed at least 2 calendar days apart 
each week.  Light treatment is not permitted on consecutive days. 


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2
 STUDY OBJECTIVES
2.1
Primary
Assess any ECG changes during standard HyBryte photodynamic therapy.
Assess the systemic blood levels of hypericin during standard HyBryte photodynamic 
therapy.
2.2
Secondary
Assess the safety of HyBryte photodynamic therapy. 
3
STUDY ENDPOINTS 
This is an exploratory study to confirm the low-level systemic exposure to hypericin and 
the associated potential for any ECG changes. Given the small size of the study and its 
open label design, no formal efficacy assessments will be performed. 
3.1
Primary
The primary endpoints for the study are:
Serial assessments of ECG (including QT interval and QT interval corrected for heart rate 
using both the Bazett's and Fridericia formulas) will be obtained at the same timepoints 
as serum hypericin samples as follows:
a.
Baseline prior to drug application
b. Week 4, Session 2 obtained immediately before and 2 hours after the light session
c.
Week 6, Session 2 obtained immediately before the light session 
d. Week 8, Session 2 Light Session visit obtained immediately before and 2 hours 
after the light session 
e.
Week 10 follow-up visit
Serial measurements of serum hypericin levels obtained at:
f.
Baseline prior to drug application
g. Week 4, Session 2 obtained immediately before and 2 hours after the light session
h. Week 6, Session 2 obtained immediately before the light session 


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i.
Week 8, Session 2 Drug Application visit immediately prior to the drug 
application
j.
Week 8, Session 2 Light Session visit obtained immediately before and 2 hours 
after the light session 
k. Week 10/End of Study during the follow-up visit 
These levels will be correlated with amount of drug applied by the patient estimated 
by weighing the drug jars at each light session.
3.2
Secondary
Routine safety laboratory investigations and vitals will be obtained at baseline prior to 
drug application, at Week 8, Session 2 Light Session visit prior to light therapy and 2 
weeks after the completion of therapy (Week 10 follow-up visit/End of Study). 
4
STUDY PLAN
4.1
Study Design
This study is an observational, Phase 2a trial. Patients will receive treatments twice a 
week consisting of drug application followed 18-24 hours later with a light session (using 
Daavlin Series 7 Phototherapy Device with visible light lamps) for 8 weeks (up to 16 
total treatments). The light treatment will be performed at least 2 calendar days apart each 
week. Light treatment is not permitted on consecutive days. Blood samples for evaluation 
of serum hypericin concentration will be obtained at baseline, Week 4, Week 6, Week 8, 
and 2 weeks after the last light session (Week 10/End of Study), and ECGs will be 
obtained at baseline, Week 4, Week 6, Week 8, and the Week 10 follow-up visit. Safety 
laboratory tests and vital signs will be obtained at baseline, at the end of treatment (Week 
8), and at the end of the 2-week follow-up period (Week 10/End of Study).


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4.2
Schedule of Assessments
Subjects will be screened within 28 days of enrollment. Detailed timing of the assessments is shown in Table 3.
Table 3: Schedule of Assessments
Time point
Blood 
Hypericin 
Concentration
ECG1
Light 
Session2
CAILS 
Evaluations
mSWAT
PGA
VASitch
Skindex-29 
QoL
Safety 
Assessments3
AE 
Collection
Screening4
Baseline5
X6
X6
X6
X6
X6
X6
X6
Week 1, Session 1
X
X
X
Week 1, Session 2
X
X
X
Week 2, Session 1
X
X
X
Week 2, Session 2
X
X
X
Week 3, Session 1
X
X
X
Week 3, Session 2
X
X
X
Week 4, Session 1
X
X
X
Week 4, Session 2
X7X8
X7X8
X
X
X
Week 5, Session 1
X
X
X
Week 5, Session 2
X
X
X
Week 6, Session 1
X
X
X
Week 6, Session 2
X7
X7
X
X
X
Week 7, Session 1
X
X
X
Week 7, Session 2
X
X
X


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Time point
Blood 
Hypericin 
Concentration
ECG1
Light 
Session2
CAILS 
Evaluations
mSWAT
PGA
VASitch
Skindex-29 
QoL
Safety 
Assessments3
AE 
Collection
Week 8, Session 1
X
X
X
Week 8, Session 2 
Drug Application
X6
X
Week 8, Session 2 
Light Session
X7X8
X7X8
X
X
X
X7
X
Week 10/End of 
Study
X
X
X
X
X
X
X
X
1 ECG will include a standard 12-lead reading with QT interval measurements. Correction for heart rate will be performed electronically using both the Bazett's and 
Fridericia formulas
2 Light Session: Includes application of drug 18-24 hours earlier by the patient and the Erythema Scoring performed 5-10 minutes before and after light therapy 
3 Safety Assessments: consists of vital signs, and hematology and clinical chemistry blood tests
4 The following assessments will be performed at the Screening visit: Obtain Informed Consent Form (ICF) signature, Assessment of entry criteria, Complete Medical 
History, Vital Signs, Serum HCG pregnancy test (women of childbearing age only)
5 Baseline: Includes interval medical history from screening, Complete Physical Examination, review of the results of the serum pregnancy test for eligible female 
subjects, and charting of index lesions onto the Body Lesion Diagram.
6 Obtained prior to drug application
7 Prior to light session
8 2 hours after completion of the light session


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5
POPULATION
5.1
Number of Subjects
Approximately 6 subjects will be enrolled.
5.2
Selection of Subjects
5.2.1
Inclusion Criteria
In order to be enrolled into the trial, subjects must meet all of the criteria below:
1. ≥18 years of age
2. Active treatment-accessible CTCL lesions covering ≥ 10% of their body surface area
3. Subjects must have a clinical diagnosis of cutaneous T-cell lymphoma (CTCL, 
mycosis fungoides), Stage 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
5.2.2
Exclusion Criteria
In order to be enrolled into the trial, subjects cannot have any of the following criteria:
1. History of allergy or hypersensitivity to any of the components of HyBryte
2. Pregnancy or mothers who are breast-feeding
3. Males and females not willing to use effective contraception
4. Subjects with history of sun hypersensitivity or photosensitive dermatoses (e.g., 
porphyria, systemic lupus erythematosus (SLE), Sjogren’s syndrome, etc.)
5. Subjects whose condition is spontaneously improving
6. Subjects receiving topical steroids or other topical treatments (e.g., nitrogen mustard) 
on index lesions for CTCL within 2 weeks of enrollment


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7. 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
8. Subjects who have received electron beam irradiation within 3 months of enrollment
9. Subjects with a history of significant systemic immunosuppression
10. Subjects taking other investigational drugs or drugs of abuse within 30 days of 
enrollment
11. Subject has any condition that, in the judgment of the principal investigator (PI), is 
likely to interfere with participation in the study
12. 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 
5.3
Study Procedures by Time Point
5.3.1
Screening Visit
The screening visit must be done within 28 days prior to the start of the Baseline visit. 
Prior to starting the study medication, the results of all tests must be reviewed to assure 
that the patient meets all entry criteria. Procedures to be done at this visit are:
Obtain Informed Consent Form (ICF) signature
Assessment of entry criteria
Complete Medical History
Vital Signs
Serum HCG pregnancy test (women of childbearing age only)
5.3.2
Baseline 
After enrollment but prior to application of HyBryte the following assessments will be 
performed:
Interval medical history from screening obtained
Complete Physical Examination
Vitals taken (heart rate, respiratory rate, and sitting blood pressure)


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Hematology panel drawn 
Clinical chemistry panel drawn
Pregnancy test results reviewed 
Three 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” form (Appendix II) locating 
and numbering each of the index lesion
Each of the index lesions will have a CAILS score assessed and recorded
The mSWAT score will be assessed and recorded
5 mL of blood obtained and processed for serum hypericin levels
12-lead ECG obtained including QT interval measurements
The patient will complete the Skindex-29 (Appendix III) and VASitch forms and the data 
transcribed into the eCRF
A jar of ointment will be issued and the weight of the jar prior to dispensation will be 
recorded
Only after all of the above have been completed, patients will be instructed on proper 
drug application and demonstrate proficiency in drug application and all accessible 
lesions will be treated with study drug
The weight of the jar after drug application will be recorded
5.3.3
Week 1, Session 1; Week 1, Session 2; Week 2 Session 1; Week 2, 
Session 2; Week 3, Session 1; Week 3, Session 2; Week 4, 
Session 1
18-24 hours after drug application, the patient will return to clinic for their light session 
using the Daavlin 7 Series Phototherapy Device with visible light lamps. At that visit the 
following will be performed:
The patient will complete an VASitch form and the data transcribed into the eCRF. 
Adequate application of the drug will be verified by a pink staining on visual inspection 
of lesions.
Each patient will bring in their jar of study drug to the clinic. The jar will be weighed by 
clinic staff in order to estimate the amount of drug applied.


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5-10 minutes before the light session, lesions will be graded using the Erythema Grading 
Score.
During the first session, 5 J/cm2 of light will be administered. Subsequent light sessions 
will deliver light doses based on the Erythema Grading Score after the previous light 
treatment. If the Erythema score was <1, the next light dose should be increased as 
deemed appropriate by the PI. If the Erythema score is 1, the subsequent dose should be 
held at the same dose. If the score is >1, the next dose should be lowered.
The patient will undergo the light treatment (may require repositioning to assure that all 
lesions are being treated).
5-10 minutes after completion of the light session, lesions will be graded using the 
Erythema Grading Score. If the score is <1, the light dose should be increased in the next 
light session. If the Erythema score is 1, the subsequent dose should be held at the same 
dose. If the score is >1, the next dose may be lowered by at least 1 J/cm2.
Patients will be asked about any AEs experienced since the last light session and these 
will be recorded in the eCRF. Information on all unresolved, previously reported AEs 
will be obtained.
5.3.4
Week 4, Session 2
18-24 hours prior to the scheduled light session, the patient will be instructed to apply 
study drug to all accessible lesions. At that visit the following will be performed:
The patients will complete an VASitch form and the data transcribed into the eCRF. 
Prior to the light session, 5 mL of blood obtained and processed for serum hypericin 
levels.
Prior to the light session, a 12-lead ECG obtained including QT interval measurements.
Adequate application of the drug will be verified by a pink staining on visual inspection 
of lesions.
Each patient will bring in their jar of study drug to the clinic. The jar will be weighed by 
clinic staff in order to estimate the amount of drug applied.
5-10 minutes before the light session, lesions will be graded using the Erythema Grading 
Score.
Patients will undergo the light treatment (may require repositioning to assure that all 
lesions are being treated).


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5-10 minutes after completion of the light session, lesions will be graded using the 
Erythema Grading Score. If the score is <1, the next light dose should be increased. If the 
Erythema score is 1, the subsequent dose should be held at the same dose. If the score is 
>1, the next dose should be lowered by at least 1 J/cm2.
2 hours after completion of the light session, 5 mL of blood obtained for serum hypericin 
levels.
2 hours after completion of the light session, 12-lead ECG obtained including QT 
interval measurements.
Patients will be asked about any AEs experienced since the last light session and these 
will be recorded in the eCRF. Information on all unresolved, previously reported AEs 
will be obtained.
5.3.5
Week 5, Session 1; Week 5, Session 2; Week 6, Session 1
18-24 hours prior to the scheduled light session, the patient will be instructed to apply 
study drug to all accessible lesions. At that visit the following will be performed:
The patients will complete an VASitch form and the data transcribed into the eCRF. 
Adequate application of the drug will be verified by a pink staining on visual inspection 
of lesions.
Each patient will bring in their jar of study drug to the clinic. The jar will be weighed by 
clinic staff in order to estimate the amount of drug applied.
5-10 minutes before the light session, lesions will be graded using the Erythema Grading 
Score.
The light duration for the session to deliver the target dose of light determined by the 
Erythema Score of the previous treatment response of light will be calculated.
Patients will undergo the light treatment (may require repositioning to assure that all 
lesions are being treated).
5-10 minutes after completion of the light session, lesions will be graded using the 
Erythema Grading Score. If the score is <1, the next light dose should be increased. If the 
Erythema score is 1, the subsequent dose should be held at the same dose. If the score is 
>1, the next dose should be lowered by at least 1 J/cm2.
Patients will be asked about any AEs experienced since the last light session and these 
will be recorded in the eCRF. Information on all unresolved, previously reported AEs 
will be obtained. 


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5.3.6
Week 6, Session 2
18-24 hours prior to the scheduled light session, the patient will be instructed to apply 
study drug to all accessible lesions. At that visit the following will be performed:
The patients will complete an VASitch form and the data transcribed into the eCRF. 
Prior to the light session, 5 mL of blood obtained and processed for serum hypericin 
levels.
Prior to the light session, a 12-lead ECG obtained including QT interval measurements.
Adequate application of the drug will be verified by a pink staining on visual inspection 
of lesions.
Each patient will bring in their jar of study drug to the clinic. The jar will be weighed by 
clinic staff in order to estimate the amount of drug applied.
5-10 minutes before the light session, lesions will be graded using the Erythema Grading 
Score.
The light duration for the session to deliver the target dose of light determined by the 
Erythema Score of the previous treatment response of light will be calculated. 
Patients will undergo the light treatment (may require repositioning to assure that all 
lesions are being treated).
5-10 minutes after completion of the light session, lesions will be graded using the 
Erythema Grading Score. If the score is <1, the next light dose should be increased. If the 
Erythema score is 1, the subsequent dose should be held at the same dose. If the score is 
>1, the next dose should be lowered by at least 1 J/cm2.
Patients will be asked about any AEs experienced since the last light session and these 
will be recorded in the eCRF. Information on all unresolved, previously reported AEs 
will be obtained. 
5.3.7
Week 7, Session 1; Week 7, Session 2; Week 8, Session 1
18-24 hours prior to the scheduled light session, the patient will be instructed to apply 
study drug to all accessible lesions. At that visit the following will be performed:
The patients will complete an VASitch form and the data transcribed into the eCRF. 
Adequate application of the drug will be verified by a pink staining on visual inspection 
of lesions.


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Each patient will bring in their jar of study drug to the clinic. The jar will be weighed by 
clinic staff in order to estimate the amount of drug applied.
5-10 minutes before the light session, lesions will be graded using the Erythema Grading 
Score.
Patients will undergo the light treatment (may require repositioning to assure that all 
lesions are being treated).
5-10 minutes after completion of the light session, lesions will be graded using the 
Erythema Grading Score. If the score is <1, the next light dose should be increased. If the 
Erythema score is 1, the subsequent dose should be held at the same dose. If the score is 
>1, the next dose should be lowered by at least 1 J/cm2.
Patients will be asked about any AEs experienced since the last light session and these 
will be recorded in the eCRF. Information on all unresolved, previously reported AEs 
will be obtained. 
5.3.8
Week 8, Session 2 Drug Application Visit
Patients will be asked to attend the clinic for the last drug application. At that visit, the 
following will be performed:
5 mL of blood obtained and processed for serum hypericin levels.
The drug will be applied by the patient under supervision of the site personnel.
The weight of the drug container will be weighed prior and after application of the drug.
Patients will be asked about any AEs experienced since the last light session and these 
will be recorded in the eCRF. Information on all unresolved, previously reported AEs 
will be obtained. 
5.3.9
Week 8, Session 2 Light Session Visit
18-24 hours after application of study drug, patients will return to the clinic for their final 
light session. At that visit, the following will be performed:
The patients will complete an VASitch and Skindex-29 (Appendix III) forms and the data 
transcribed into the eCRF. 
Adequate application of the drug will be verified by a pink staining on visual inspection 
of lesions.
Prior to the light session, 5 mL of blood obtained and processed for serum hypericin 
levels.


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Prior to the light session, a 12-lead ECG obtained including QT interval measurements.
Prior to the light session, vitals will be taken (heart rate, respiratory rate, and sitting 
blood pressure).
Prior to the light session, a hematology panel will be drawn. 
Prior to the light session, a clinical chemistry panel will be drawn.
5-10 minutes before the light session, lesions will be graded using the Erythema Grading 
Score.
The light duration for the session to deliver the target dose of light determined by the 
Erythema Score of the previous treatment response of light will be calculated. 
Patients will undergo the light treatment (may require repositioning to assure that all 
lesions are being treated).
5-10 minutes after completion of the light session, lesions will be graded using the 
Erythema Grading Score.
2 hours after completion of the light session, 5 mL of blood obtained and processed for 
serum hypericin levels.
2 hours after completion of the light session, a 12-lead ECG obtained including QT 
interval measurements.
Patients will be asked about any AEs experienced since the last light session and these 
will be recorded in the eCRF. Information on all unresolved, previously reported AEs 
will be obtained. 
5.3.10
Week 10, Follow-up visit/End of Study
During the last visit of the study, expected to occur 2 weeks following the final light 
treatment, the following assessments will be performed:
The patient will complete the VASitch form and the data transcribed into the eCRF.
Vitals taken (heart rate, respiratory rate, and sitting blood pressure).
Hematology panel drawn. 
Clinical chemistry panel drawn.
5 mL of blood obtained and processed for serum hypericin levels.


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CAILS scores for the 3 index lesions will be measured and recorded.
The mSWAT and PGA scores will be assessed and recorded.
A 12-lead ECG obtained including QT interval measurements.
Patients will be asked about any AEs experienced since the last light session and these 
will be recorded in the eCRF. Information on all unresolved, previously reported AEs 
will be obtained.
5.4
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.
Patients withdrawn from the study may be replaced up to a total of 8 subjects provided 
that both the PI and the Soligenix Medical Monitor agree that the reasons for withdrawal 
do not suggest a change in the risk assessment of the HyBryte therapy.
6
DESCRIPTION OF STUDY PROCEDURES
Subjects will have the following procedures performed.
6.1
Light Session
The amount of visible light to be delivered will start at 5 J/cm2 and be titrated up until 
either the patient experiences a mild (Erythema Grade 1) response to the light treatment 
5-10 minutes post-treatment or a dose of 25 J/cm2 is reached, whichever occurs first. The 


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duration of light treatment is dictated by the light treatment table listed below (Table 4). 
Depending on the distribution of the patient’s lesions, more than one position for light 
treatments may be necessary. 
Table 4: Duration of Light Exposure Required for Given Light Doses
Light Dose (J/cm2)
Duration (Min: Sec)
5
10:49
6
12:59
7
15:09
8
17:19
9
19:29
10
21:39
11
23:49
12
25:58
13
28:08
14
30:18
15
32:28
16
34:38
17
36:48
18
38:58
19
41:08
20
43:17
21
45:27
22
47:37
23
49:47
24
51:57
25
54:07
6.2
Electrocardiogram (ECG)
12-lead ECGs, including QT interval measurement, will be done at baseline (prior to drug 
application), Week 4, Session 2 (immediately prior to and 2 hours after the light session), 
Week 6, Session 2 (immediately prior to the light session), Week 8, Session 2 Light 
Session Visit (immediately prior to and 2 hours after the light session), and at the Week 
10 Follow-up visit. ECG will be interpreted by site personnel trained in the evaluation of 
ECGs for any interval changes.




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Hemoglobin
Mean corpuscular volume (MCV)
Mean corpuscular hemoglobin (MCH)
Mean corpuscular hemoglobin concentration (MCHC)
Platelet count
White blood cell count (WBC)
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
6.4.2
Clinical Chemistry Laboratory Tests
The clinical chemistry panel will be performed on blood obtained at baseline, Week 8, 
Session 2 Light Session visit prior to the light session and during the Week 10/End of 
Study follow-up visit.  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)


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Alkaline phosphatase
6.5
Vital Signs
Vital signs will be obtained by site personnel at baseline, Week 8, Session 2 Light 
Session visit prior to the light session and during the Week 10/End of Study follow-up 
visit. Vital signs obtained will consist of:
•
Resting Blood Pressure
•
Heart Rate
•
Respiratory Rate
6.6
Quality of Life Assessments
The Skindex-29, a self-administered survey instrument to measure the effects of skin 
disease on patients’ quality of life will be administered at baseline and at Week 8 Session 
2 Light Session visit (Appendix III). Patients will complete the form on their own and site 
personnel will review and assure that the form is complete.
6.7
VAS Itch Assessment
The Visual Analog Score for Itch (VASitch) is a patient reported outcome measurement of 
the degree of itchiness that the patient has experienced over the preceding 24 hours and 
will be administered at baseline, each light treatment, and the Week 10/End of Study 
visit. Patients will be instructed to place a vertical mark on a 10 cm line with a 0 (none) at 
the right side and a 10 (the worst itch you can imagine) at the left indicating the amount 
of itch that they have experienced over the preceding day. The score will be recorded as 
the distance in centimeters (to 1 decimal place) between the 0 mark and the vertical line 
that the patient drew. 
6.8
Composite Assessment of Index Lesions Severity (CAILS) Score
The CAILS score will be assessed for the prospectively identified representative lesions 
at baseline and at the Week 10/End of Study visit. CAILS score will be calculated by 
assessing the erythema (Table 5), scaling (Table 6), plaque elevation (Table 7) and 
involved surface area (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 CAILS score will be calculated by adding the scores of all evaluated lesions 
together.


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Table 5: Erythema Subscore of the modified CAILS Score
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: Scaling Subscore of the modified CAILS Score
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
Table 7: Plaque Elevation Subscore of the modified CAILS Score
Score
Description
0
0 mm: No evidence of plaque above normal skin level
1
Mild elevation
2
Moderate elevation
3
Marked elevation


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Table 8: Surface Area Subscore of the modified CAILS Score
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
Score
Area
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
6.9
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 9. 
This assessment is designed to consider all cutaneous lesions, including both index and 
non-index lesions. PGA score will be assessed at Week 10/End of Study.


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Table 9: 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%
6.10
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 BSA. The 
types of lesions are weighted by the lesion characteristic (patch, plaque, or tumor) as 
shown in Table 10. The mSWAT score will be assessed at baseline and at Week 10/End 
of Study.
Table 10: 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%


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Body Region
% BSA1 in Body
Assessment of Involvement in Patient’s Skin
Region
Patch2
Plaque3
Tumor4
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.
6.11
Erythema Scoring
Approximately 5-10 minutes before and after the completion of light therapy, treated 
lesions will be graded for erythema with the worst, best, and “average” scores recorded. 
The reaction will be graded using the definitions in Table 11.
Table 11: Skin Phototoxicity Grading
Toxicity Grade: 
Erythema and/or Edema
Severity
Grade 0
No apparent reaction
Grade I
Mild
Grade II
Moderate
Grade III
Severe with edema
Grade IV
Life-threatening with vesiculation




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immediately after the study is completed. Any lost, spilled or missing drug must be 
documented.
Patients will be instructed to store the drug in their refrigerator.
7.5
Study Drug Handling and Disposal
Disposable gloves should be used when applying the drug to skin lesions and after 
applying the ointment, hands and any areas receiving other unintended ointment should 
be washed with soap and water. 
7.6
Prohibited Concomitant Medication
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. 
The following drugs are not allowed within 2 weeks of enrollment or during the study: 
Topical steroids (including 1% hydrocortisone cream or ointment) 
Other topicals (nitrogen mustard, carmustine/BCNU, retinoids, imiquimod)
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
Other systemic therapies for CTCL
The following drugs are not allowed within 30 days of enrollment or during the study:
Investigational drugs
Drugs of abuse
The following drugs are not allowed within 3 months of enrollment or during the study:
Radiation therapy (localized or total skin)


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Patients taking medication to cause photosensitization must be discontinued for at least 2 
weeks prior to initiating HyBryte or have been on a stable dose of such drugs without any 
evidence of photosensitivity for a period of no less than 4 weeks. A list of the most 
common photosensitizing agents are as follows: 
•
Antibiotics: tetracyclines (doxycycline, tetracycline), fluoroquinolones 
(ciprofloxacin, ofloxacin levofloxacin), sulfonamides
•
Nonsteroidal anti-inflammatories: ibuprofen and ketoprofen
•
Diuretics: furosemide and hydrochlorothiazide 
•
Retinoids: isotretinoin and acitretin 
•
Hypoglycemics: sulfonylureas (glipizide, glyburide)
•
PDT pro-photosensitizers: 5-aminolevulininc acid, methyl-5-aminolevulininc 
acid, verteporfin, Photofrin
•
Neuroleptic drugs: phenothiazines (chlorpromazine, fluphenazine, perazine, 
perphenazine, thioridazine), thioxanthenes (chlorprothixene, thiothixene)
•
Sunscreens: para-aminobenzoic acid (PABA), cinnamates, benzophenones, 
salicylates
•
Fragrances: musk ambrette, 6-methylcoumarin
•
Others: 5-FU, amiodarone
7.7
Compliance
Containers will be weighed before each light session. Any study drug discarded (eg, 
wiped off healthy skin, dropped or otherwise discarded) will be recorded. 


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8
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.
8.1
Definitions
8.1.1
Adverse Event (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.
8.1.2
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).
8.1.3
Potentially Serious AE
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.
8.2
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 


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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.
8.3
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.
8.4
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. 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.


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9
SERIOUS ADVERSE EVENT
9.1
Definition of Serious Adverse Event
An 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 HyBryte
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:
a.
Intensive treatment in an emergency room or at home for allergic bronchospasm
b. Blood dyscrasias or convulsions that do not result in inpatient hospitalization
c.
Development of drug dependency or drug abuse
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; i.e., 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 
an 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 
treatment that would not have been appropriate in the physician's office or outpatient 


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setting. When in doubt as to whether 'hospitalization' occurred or was necessary, the AE 
should be considered serious.
Disability/incapacitating: An AE is incapacitating or disabling if the experience results in 
a substantial and/or permanent disruption of the subject's ability to carry out normal life 
functions.
9.2
Reporting Serious Adverse Events
When the investigator, or trained designee, becomes aware that a serious or potentially 
serious AE (as defined above) has occurred, the site monitor or Medical Monitor must be 
notified immediately (and no later than 24 hours after notification) by telephone, 
regardless of the relationship (or lack thereof) of the AE to study therapy.
All reports of serious or potentially serious AEs must be followed within 24 hours (or 
sooner at the request of the Soligenix Medical Monitor) by the completion of a serious 
AE form signed by the investigator. This should be faxed to the site monitor and/or 
Medical Monitor.
In accordance with Soligenix SOPs and Health Authority regulations, investigators may 
be notified from time to time of the occurrence of serious, unexpected AEs. If such AEs 
are associated with the use of the study drug (i.e., there is a reasonable possibility that the 
AE may have been caused by the drug) and are thus deemed significant new AEs or risks 
with respect to the drug, the investigator must promptly inform the relevant Institutional 
Review Board (IRB), in accordance with the ICH Guidance on Good Clinical Practices 
(E6, April 1996).




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10 STATISTICS
10.1
General Procedures
This is an observational study. No analyses for efficacy will be performed.
10.2
Analysis of Safety
Listings of findings per patient will be provided. Average and median results for 
laboratory findings, vital signs, ECG findings and PK outcomes will be provided. Any 
significant outliers (>2x the standard deviation) will be highlighted. Listings of AEs 
within 48 hours of ointment application will be tabulated. Any serious or related AEs 
determined within 14 days of last drug application will be tabulated, in addition to any 
medications received during the 10-week period. 
10.3
Interim Analysis
No interim analysis is planned. 


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11 ETHICS AND RESPONSIBILITIES
11.1
Institutional Review Board
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 enrolment 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.
11.2
Ethical Conduct of the Study
The study will be performed in accordance with the ethical principles in the Declaration 
of Helsinki, Good Clinical Practices and applicable regulatory requirements. 
11.3
Written Informed Consent
The Investigator will ensure that the subject or a legally authorized representative of the 
subject are 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.
11.4
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 (e.g., MCC) may require direct access to parts of the trial site 
records relevant to the study, including subjects’ medical history for data verification 
purposes.
11.5
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 
could affect reliability of data submitted to the FDA in support of marketing approval, are 
identified and disclosed by the Sponsor.


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Clinical investigators shall be asked to disclose proprietary (e.g., patent, licensing 
agreement) and financial (e.g., 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 
question 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, e.g., 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.


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12 RECORDS MANAGEMENT
12.1
Source Documentation
Copies of CRFs should be retained by sites along with all original source documents 
(e.g., 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.


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13 AUDITING AND MONITORING
13.1
Study Monitoring
It is the responsibility of the PI and site personnel to assure that the data recorded in the 
CRFs 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 Good Clinical Practices (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.
13.1.1
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.
13.1.2
Site Initiation Visit
Once all required trial 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 
the IRB, and to keep Soligenix informed of such approval and subsequent 
actions concerning the study.
13.1.3
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 


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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.
13.1.4
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.
13.2
Audits and Inspections
Health Authorities (e.g., 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).


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14 AMENDMENTS
Protocol modifications, except those intended to reduce immediate risk to study subjects, 
may be made only by Soligenix, Inc. 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, Inc., will submit protocol 
amendments to the appropriate regulatory authorities for approval.
If in the judgment of the IRB/IEC, the investigator, and/or Soligenix, Inc., 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.


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15 STUDY REPORT 
Soligenix, Inc., is responsible for providing the appropriate regulatory authorities with 
clinical study reports according to the applicable regulatory requirements.


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16 STUDY DISCONTINUATION 
Both Soligenix, Inc., and the Principal Investigator reserve the right to terminate the 
study at the investigator’s site at any time. Should this be necessary, Soligenix, Inc. 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, Inc. and the Principal 
Investigator will assure that adequate consideration is given to the protection of the 
subjects’ interests.


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17 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, Inc. However, authorized regulatory officials, IRB/IEC 
personnel, Soligenix, Inc. 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.


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51.
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19.2
APPENDIX II – Body Lesion Diagram
BODY LESION DIAGRAM: SOLIGENIX / HyBryte
Please identify the index lesions location using supplied white reference labels with the 
appropriate numbering (Ex. 1, 2 or 3) written on them.


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19.3
APPENDIX III – Skindex-29 Assessment


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SAP_001.pdf: 
HyBryte™ (0.25% hypericin) ointment
HPN-CTCL-02
Phase 2a Study of Systemic PK and Serial ECG Determinations 
Following 8 Weeks of HyBryte Treatment
STATISTICAL ANALYSIS PLAN
Version:  
1.0
Release Date:
29 July 2022
Confidentiality Statement
The information in this document contains trade secrets and commercial information that 
are privileged or confidential and may not be disclosed unless such disclosure is required 
by federal or state law or regulations. In any event, persons to whom the information is 
disclosed must be informed that the information is privileged or confidential and may not 
be further disclosed by them. These restrictions on disclosure will apply equally to all 
future information supplied to you which is indicated as privileged or confidential.
NCT05380635


HPN-CTCL-02
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Signature Significance
The following significance is lent to the signatures on the Approvals page of this 
document.
Signature
Significance
Author
By signing, the author is attesting that the content of the document 
is complete and accurate.
Reviewer
By signing, the reviewer is attesting that the document’s approach 
and contents are compliant with the study protocol, all appropriate, 
regulatory requirements, and other significant guidelines. This 
individual(s) has reviewed the document for accuracy and 
completeness.


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Table of Contents
LIST OF ABBREVIATIONS..........................................................................................................................7
INTRODUCTION.......................................................................................................................................8
2.
STUDY OBJECTIVES.........................................................................................................................9
2.1.
PRIMARY OBJECTIVES.........................................................................................................................9
2.2.
SECONDARY OBJECTIVES.....................................................................................................................9
3.
STUDY DESIGN .............................................................................................................................10
4.
STUDY ENDPOINTS AND DEFINITION............................................................................................11
4.1.
PRIMARY ENDPOINTS.......................................................................................................................11
4.2.
SECONDARY ENDPOINTS...................................................................................................................11
4.3.
PATIENT TREATMENT RESPONSE PARAMETERS......................................................................................12
4.4.
STUDY ENDPOINT DEFINITION ...........................................................................................................12
4.4.1
Electrocardiograms (ECGs) ....................................................................................................12
4.4.2
Hypericin blood levels............................................................................................................12
4.4.3
Clinical Laboratory Tests........................................................................................................13
4.4.4
Vital Signs..............................................................................................................................14
4.4.5
Quality of Life Questionnaire.................................................................................................14
4.4.6
VASitch ....................................................................................................................................15
4.4.7
Composite Assessment of Lesions Severity (CAILS) Score......................................................16
4.4.8
The Physician Global Assessment (PGA)................................................................................17
4.4.9
Modified Severity Weighted Assessment Tool (mSWAT).......................................................18
4.4.10
Skin Reaction Safety Grading............................................................................................19
5.
STATISTICAL CONSIDERATIONS ....................................................................................................20
5.1.
SAMPLE SIZE CALCULATION...............................................................................................................20
5.2.
ANALYSIS POPULATIONS...................................................................................................................20
5.3.
METHODOLOGY AND CONVENTIONS...................................................................................................20
5.4.
ADDITIONAL DATA HANDLING RULES AND PRESENTATION SPECIFICATIONS.................................................20
5.5.
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS.......................................................................21
5.6.
MEDICAL HISTORY...........................................................................................................................21
5.7.
PRIOR AND CONCOMITANT MEDICATIONS ...........................................................................................22
5.8.
INTERIM ANALYSIS...........................................................................................................................22
6.
OUTCOMES..................................................................................................................................23
6.1.
ELECTROCARDIOGRAMS....................................................................................................................23
6.1.1
Analysis of Central Tendency.................................................................................................23
6.1.2
Categorical Analysis ..............................................................................................................23
6.2.
HYPERICIN BLOOD CONCENTRATIONS ..................................................................................................23
6.3.
EFFECTIVENESS OUTCOMES...............................................................................................................23
7.
SAFETY ANALYSES ........................................................................................................................25
7.1.
ADVERSE EVENTS............................................................................................................................25
7.2.
CLINICAL LABORATORY PARAMETERS ..................................................................................................26


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7.3.
VITAL SIGNS...................................................................................................................................26
7.4.
EXTENT OF EXPOSURE ......................................................................................................................27
8.
APPENDIX 1:  DATA HANDLING CONVENTIONS ............................................................................28
8.1.
MISSING SEVERITY ASSESSMENT FOR ADVERSE EVENTS ..........................................................................28
8.2.
MISSING RELATIONSHIP TO STUDY DRUG FOR ADVERSE EVENTS...............................................................28
8.3.
MISSING DATE INFORMATION FOR ADVERSE EVENTS .............................................................................28
8.4.
MISSING DATE INFORMATION FOR PRIOR OR CONCOMITANT MEDICATIONS...............................................29
8.5.
CLINICAL LABORATORY PARAMETERS ..................................................................................................30
9.
APPENDIX 2: SCHEDULE OF PROCEDURES.....................................................................................33


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List of Tables
Table 1: Skin Phototoxicity Grading..............................................................................................................10
Table 2: VASitch Grading................................................................................................................................16
Table 3: Composite Assessment of Index Lesion Severity ............................................................................16
Table 4: Physician Global Assessment...........................................................................................................17
Table 5: Modified Severity Weighted Assessment Tool (mSWAT)..............................................................18
Table 6: Phototoxicity/Erythema Score..........................................................................................................19
Table 7. Vital Signs Clinically Significant Values.........................................................................................27
Table 8: Example for Coding of Special Character Values  for Clinical Laboratory Parameters..................30
Table 9: Ranges of Potentially Clinically Significant Lab Values.................................................................31
Table 10: Schedule of Assessments................................................................................................................33


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LIST OF ABBREVIATIONS
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
ATC
Anatomical Therapeutic Chemical
BSA 
Body Surface Area 
CAILS 
Composite Assessment of Index Lesion Severity 
CTCL 
Cutaneous T-cell Lymphoma 
ECG
Electrocardiogram
eCRF 
Electronic Case Report Form 
EORTC
European Organisation for Research and Treatment of Cancer
ISCL
International Society for Cutaneous Lymphomas
ITT 
Intent-to-Treat population 
MedDRA
Medical Dictionary of Regulatory Activities
mSWAT 
Modified Severity-Weighted Assessment Tool 
PGA 
Physician Global Assessment 
PK
Pharmacokinetic
PP 
Per-Protocol Population 
SAE 
Serious Adverse Event 
SAP
Statistical Analysis Plan
SOC
System Organ Class
USCLC
United States Cutaneous Lymphoma Consortium
WHO 
World Health Organization Drug Dictionary


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INTRODUCTION
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of the 
statistical analyses of safety, pharmacokinetics (PK), and lesion response as outlined and/or specified 
in Amendment 1 of the final study protocol dated 22 April 2022.
Any deviations from this SAP will be described and justified in the Clinical Study Report (CSR). The 
preparation of this SAP has been based on International Conference on Harmonisation (ICH) E3 and 
E9 guidelines [1, 2]. If the protocol is subsequently amended, this SAP will be amended as well, if 
warranted. Should the SAP and the protocol be inconsistent with respect to the planned analyses, the 
language of the SAP prevails.
All data analyses and generation of TFLs will be performed using SAS® version 9.4 or higher. The 
SAP will be finalized and signed off prior to locking the database and subsequent unblinding of 
treatment arm assignments.


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2.
STUDY OBJECTIVES
2.1.
Primary Objectives
•
Assess any electrocardiogram (ECG) changes during standard HyBryte photodynamic 
therapy. 
•
Assess the systemic blood levels of hypericin during standard HyBryte photodynamic 
therapy.
2.2.
Secondary Objectives
•
Assess the safety of HyBryte photodynamic therapy 
•
Describe treatment outcome measures including: 
o
Skindex-29 quality of life questionnaire
o
Visual Assessment Scale of itch (VASitch)
o
Composite Assessment of Index Lesion Severity (CAILS) score of the 3 
prospectively chosen index lesions
o
Physician Global Assessment (PGA)
o
modified Severity Weighted Assessment Tool (mSWAT)


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3.
STUDY DESIGN
This study is an interventional, uncontrolled, Phase 2a trial. Patients will receive treatments twice 
a week consisting of drug application followed 18 to 24 hours later with a light session (using 
Daavlin Series 7 Phototherapy Device with visible light lamps) for 8 weeks (up to 16 total 
treatments). The light treatment will be performed at least 2 calendar days apart each week. Light 
treatment is not permitted on consecutive days. 
Blood samples for evaluation of serum hypericin concentration and ECGs will be obtained at 
Baseline, Week 4, Week 6, Week 8, and at End of Study. Safety laboratory tests and vital signs 
will be obtained at Baseline, at the end of treatment (Week 8), and at End of Study. 
The light dose will be started at 5 J/cm2 and may be increased each visit until symptoms or signs 
of mild phototoxicity (see Table 1 for grading scheme) appear in the treated areas or until a 
maximum light dose of 25 J/cm2 is reached, whichever occurs first. 
Table 1: Skin Phototoxicity Grading
Toxicity Grade: Erythema 
and/or edema
Severity
Grade 0
No apparent reaction
Grade I
Mild
Grade II
Moderate
Grade III
Severe with edema
Grade IV
Life-threatening with vesiculation


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4.
STUDY ENDPOINTS AND DEFINITION
This is an exploratory study to confirm the low-level systemic exposure to hypericin and the 
associated potential for any ECG changes as well as obtaining additional information on patient 
benefit including, but not limited to, lesion response to HyBryte photodynamic therapy utilizing 
the Daavlin 7 Series phototherapy device.
4.1.
Primary Endpoints
Serial assessments of ECG (including QT interval and QT interval corrected for heart rate using 
both the Bazett's and Fridericia’s formulas) will be obtained at the same timepoints as serum 
hypericin samples as follows:
•
Baseline prior to drug application 
•
Week 4, Session 2 obtained immediately before and 2 hours after the light session 
•
Week 6, Session 2 obtained immediately before the light session 
•
Week 8, Session 2 Light Session visit obtained immediately before and 2 hours after the 
light session 
•
End of Study during the follow-up visit 
Serial measurements of serum hypericin levels obtained at the following timepoints will be 
correlated with the cumulative amount of drug applied by the patient estimated by weighing the 
drug jars at each light session: 
•
Baseline prior to drug application 
•
Week 4, Session 2 obtained immediately before and 2 hours after the light session 
•
Week 6, Session 2 obtained immediately before the light session 
•
Week 8, Session 2 Drug Application visit immediately prior to the drug application 
•
Week 8, Session 2 Light Session visit obtained immediately before and 2 hours after the 
light session 
•
End of Study during the follow-up visit 
4.2.
Secondary Endpoints
Routine safety laboratory investigations and vitals will be obtained at Baseline prior to drug 
application, at Week 8, Session 2 Light Session visit prior to light therapy and 2 weeks after the 
completion of therapy (End of Study visit).


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4.3.
Patient Treatment Response Parameters
Given the small sample size in this open-label study, patient treatment response will be 
summarized as changes in in disease status from Baseline to the end of treatment:
•
Skindex-29 quality of life questionnaire
•
Visual Assessment Scale of itch (VASitch)
•
CAILS score of the 3 prospectively chosen index lesions
•
Physician Global Assessment (PGA)
•
modified Severity Weighted Assessment Tool (mSWAT)
In addition, the light dose schedules optimized for each patient will be characterized. 
4.4.
Study Endpoint Definition
4.4.1
Electrocardiograms (ECGs)
12-lead ECGs, including QT interval measurement, will be done at Baseline (prior to drug 
application), Week 4, Session 2 (immediately prior to and 2 hours after the light session), Week 
6, Session 2 (immediately prior to the light session), Week 8, Session 2 Light Session Visit 
(immediately prior to and 2 hours after the light session), and at the End of Study visit. ECGs 
will be interpreted by site personnel trained in the evaluation of ECGs for any interval changes.
QT intervals will be measured on each ECG. Heart rate corrected QT intervals will be calculated  
using the following 2 standard correction equations:
Bazett’s Formula:
QTcB = QTm / square root of RR
Where QTcB represents the Bazett’s corrected QT interval, QTm is the measured QT interval, and 
RR is the time interval between 2 consecutive QRS complexes in seconds.
Fridericia’s Formula:
QTcFri = QTm / cube root of RR
Where QTcFri represents the Fridericia’s corrected QT interval, QTm is the measured QT interval, 
and RR is the time interval between 2 consecutive QRS complexes in seconds.
4.4.2
Hypericin blood levels
Blood samples for pharmacokinetic analysis will be collected at the following timepoints: 
•
Baseline, prior to drug application 


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•
Week 4 Session 2, prior to light session 
•
Week 4 Session 2, 2 hours after completion of the light session 
•
Week 6 Session 2, prior to the light session 
•
Week 8 Session 2 Drug Application visit, prior to drug application 
•
Week 8 Session 2 Light Session visit, prior to light session
•
Week 8 Session 2 Light Session visit, 2 hours after completion of the light session 
•
End of Study follow-up visit 
Blood samples will be collected with K2EDTA tubes and mixed (inverting top to bottom) at least 
5 times after collection. Tubes will be placed on wet ice pending transfer to labeled 2 mL amber 
vials or tubes and then frozen (temperature ≤-60°C). The times that samples are collected and 
frozen must be noted. Blood will be processed and shipped to the central laboratory, Syneos 
Health.
4.4.3
Clinical Laboratory Tests
4.4.3.1.
Hematology Tests
The hematology panel will be performed on blood obtained at Baseline, Week 8 Session 2 Light 
Session visit prior to the light session, and End of Study. 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) 
•
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


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4.4.3.2.
Clinical Chemistry Tests
The clinical chemistry panel will be performed on blood obtained at Baseline, Week 8 Session 2 
Light Session visit prior to the light session and during the End of Study follow-up visit. 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
4.4.4
Vital Signs
Vital signs will be obtained by site personnel at Baseline, Week 8 Session 2 Light Session visit 
prior to the light session and during the End of Study follow-up visit. Vital signs obtained will 
consist of: 
•
Resting Blood Pressure 
•
Heart Rate 
•
Respiratory Rate 
4.4.5
Quality of Life Questionnaire
The Skindex-29, a self-administered survey instrument to measure the effects of skin disease on 
patients’ quality of life will be administered at Baseline and at Week 8 Session 2 Light Session 
visit. Patients will complete the form on their own and site personnel will review and assure that 
the form is complete.
Each questionnaire item is answered in a 5-point Likert-type scale and these answers will be 
transformed into a linear scale of 100 (0 = no effect; 100 = effect experienced all the time) using 
the following item scores:
Never = 
0


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Rarely = 
25
Sometimes = 50
Often = 
75
All the time = 100
The following criteria will be used for interpretation:
•
If responses to more than 25% of items are missing overall, the questionnaire will be 
considered “missing”.
•
If any domain scale has more than 25% of the responses missing, the score for that 
domain will be considered “missing”.
•
Domain scale scores are the average of non-missing items in a given domain scale.
•
An item with multiple answers is considered “missing”.
Individual questions will be grouped into 3 domains as follows:
Domain
Number of Items
Cluster Items
Emotions 
10
3, 6, 9, 12, 13; 15; 21, 23, 26, 28
Symptoms
7
1, 7, 10, 16, 19, 24, 27
Functioning
12
2, 4, 5, 8, 11, 14, 17, 20, 22, 25, 29, 30
For all domains, a higher score is associated with higher impact of disease.
4.4.6
VASitch
The Visual Analog Score for Itch (VASitch) is a patient reported outcome measurement of the 
degree of itchiness that the patient experienced over the preceding 24 hours and is administered 
at Baseline, each light treatment and the End of Study visit. Patients will be instructed to place a 
vertical mark on a 10 cm line with a 0 (none) at the right side and a 10 (the worst itch you can 
imagine) at the left indicating the amount of itch that they have experienced over the preceding 
day. The score is recorded as the distance in centimeters (to 1 decimal place) between the 0 mark 
and the vertical line the patient drew.
Patient responses will be categorized as shown in Table 2, with scores rounded to the nearest 
whole number.


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Table 2: VASitch Grading
VASitch Score
Category of Itch
0
no pruritus
<3
mild pruritus
3 to <7
moderate pruritus
≥7 to <9
severe pruritus
≥9
very severe pruritus
4.4.7
Composite Assessment of Lesions Severity (CAILS) Score
The CAILS score will be assessed for the 3 prospectively identified representative lesions at 
Baseline and at the End of Study visit. CAILS score will be calculated by assessing the index 
lesions for erythema, scaling, plaque elevation and involved surface area using the grading scale 
shown in Table 3 for each of the index lesions. Each of the assessments and the total score for 
each evaluated lesion will be recorded in the eCRF. The total CAILS score will be calculated by 
adding the scores of all evaluated lesions together.
Table 3: 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
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
PLAQUE ELEVATION


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Table 3: Composite Assessment of Index Lesion Severity
Score
Description
0
0 mm: No evidence of plaque above normal skin level
1
Mild elevation
2
Moderate elevation
3
Marked elevation
SURFACE AREA
Longest diameter and the longest diameter perpendicular to this diameter of each 
index lesion will be measured to the nearest millimeter. The lesion area will be the 
product of these two diameters.
Score
Area
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
4.4.8
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 4. This 
assessment is designed to consider all cutaneous lesions, including both index and non-index 
lesions. PGA score will be assessed at End of Study.
Table 4: Physician 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


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Grade
Description
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%
4.4.9
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, or tumor) as shown in 
Table 5. The mSWAT score will be assessed at Baseline and at End of Study.
Table 5: Modified Severity Weighted Assessment Tool (mSWAT)
Body Region
% BSA a  in Body
Assessment of Involvement in Patient’s Skin
Region
Patch b
Plaque c
Tumor d
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


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Body Region
% BSA a  in Body
Assessment of Involvement in Patient’s Skin
Region
Patch b
Plaque c
Tumor d
Subtotal lesion BSA x weighting factor
a BSA=body surface area
b Any size lesion without induration or significant elevation above the surrounding uninvolved skin; poikiloderma may be present
c Any size lesion that is elevated or indurated; crusting, ulceration, or poikiloderma may be present.
d Any solid or nodular lesion>1 cm in diameter with evidence of deep infiltration in the skin and/or vertical growth.
4.4.10
Skin Reaction Safety Grading
Approximately 5 to 10 minutes before and after the completion of light therapy, treated lesions 
will be graded for erythema with the worst, best, and “average” scores recorded. The reaction 
will be graded using the definitions in Table 6.
Table 6: Phototoxicity/Erythema Score
Toxicity Grade: 
Erythema and/or edema
Severity
Grade 0
No apparent reaction
Grade I
Mild
Grade II
Moderate
Grade III
Severe with edema
Grade IV
Life-threatening with vesiculation


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5.
STATISTICAL CONSIDERATIONS
This is an open-label, uncontrolled interventional trial. Data will be summarized as counts for 
categorical variables and the number, mean, standard deviation, median and ranges will be 
presented for continuous variables. 
5.1.
Sample Size Calculation
The sample size used for this trial is arbitrary and not based on power calculations.
5.2.
Analysis Populations
The analysis population is the Intent-to-Treat (ITT) population defined as all patients enrolled. 
All patients enrolled will be reported for all periods in which they have data available.
5.3.
Methodology and Conventions
All safety endpoints will be analyzed using all enrolled patients. 
Lab results obtained from the local laboratories, will be used for all safety analyses. All analyses 
will be performed using SAS® Version 9.4 or higher. 
5.4.
Additional Data Handling Rules and Presentation Specifications
The following general guidelines will apply to all statistical analyses and data presentations:
Baseline is defined as the last available value obtained prior to the first dose of study drug, unless 
otherwise specified in this SAP.
By default, US conventional units will be used for laboratory value presentations. A set of lab 
summary tables in International Standard Units (SIU) will also be provided based on tables, 
listings and figures.
Age is calculated as of date that the informed consent form was signed - age = floor ((date of 
Informed Consent – birth date+1)/365.25)
All percentages will be rounded to one decimal place and lined up by the decimal place. The 
percentage will be suppressed when the count is zero.
Any p-values will be rounded to three decimal places and will be presented as ‘<0.001’ if they 
are less than 0.001 after rounding.
For continuous variables that are recorded as “< X” or “> X”, the value of “X” will be used in 
the calculation of summary statistics. The original values will be used for the listings.
Decimal points will be presented as follows: N will be presented without decimal, minimum and 
maximum in same precision as in the database, mean and median in one more decimal than 
minimum and maximum, and SD in one more decimal than mean and median.


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5.5.
Demographics and Other Baseline Characteristics
Demographic data will be summarized descriptively and include:
•
Age
•
Sex
•
Race
•
Ethnic group
Listings of demographic data characteristics will be provided for each patient and summarized 
across the study population.
Baseline disease characteristics will be summarized descriptively and will include:
•
CTCL Stage (IB, IIA)
•
Number of previous CTCL treatments
•
Time since original diagnosis to randomization
•
Extent of disease (percent body area with lesions)
•
Cumulative CAILS score for the 3 index lesions at Baseline
•
Baseline VASitch score
•
Baseline mSWAT
•
Baseline Skindex-29 QoL score
5.6.
Medical History
Medical history and current conditions will be presented and will be coded using the MedDRA 
(Medical Dictionary of Regulatory Activities, Version 10.1) system organ class (SOC) and 
preferred term.
The summary tables will include counts of patients in each term. If a patient experiences more 
than one medical history or current condition event that is coded to the same preferred term, the 
patient will be counted only once for that preferred term. Similarly, if a patient has more than 
one medical history or current condition within a SOC, the patient will be counted only once in 
that SOC.
Listings of medical history and current conditions will be provided.


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5.7.
Prior and Concomitant Medications
The World Health Organization Drug Dictionary (WHO Drug) will be used to classify prior and 
concomitant medications by therapeutic class and generic name based on ATC code level 3. 
Prior medication is defined as any medication taken prior to the first dose of the study 
medication. Concomitant medication is defined as any medication taken between the day of first 
dose of the study medication and the day of last study medication date + 14 days. 
5.8.
Interim Analysis
No Interim Analysis is planned.


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6.
OUTCOMES
6.1.
Electrocardiograms
Changes in ECGs will be assessed by both continuous (analysis of central tendency) and 
categorical (shift tables) analyses. 
6.1.1
Analysis of Central Tendency
The mean and median response at Baseline and at each subsequent timepoint for each parameter 
will be assessed. Changes in response will be tracked and compared. The clinical meaningfulness 
of any alterations will be assessed. 
Individual changes in each parameter will also be plotted and compared for evidence of trends.
6.1.2
Categorical Analysis
Shift analysis will be conducted, evaluating the number of patients that meet the following 
criteria:
•
Measured QT interval >500 ms
•
QTc interval increased from baseline > 60 ms
The number of patients meeting these criteria at each timepoint will be tabulated. 
6.2.
Hypericin blood concentrations
Hypericin blood calculations will be summarized as the mean, standard deviation and range of 
blood concentrations for each timepoint. A regression between cumulative drug application and 
measured blood concentration per visit (average result where samples were collected before and 
after light collection) will be conducted excluding the End of Study sample, if at least 50% of 
samples had detectable levels of circulating hypericin. 
Changes in blood concentration over time will be described for each individual subject to assess 
the potential for accumulation. 
6.3.
Effectiveness Outcomes
Descriptive analyses will include: 
•
Percent of cumulative CAILS score for index lesion as a proportion of the baseline 
CAILS score ([cumulative score at End of Study] / [cumulative score at Baseline] * 100). 
The average, standard deviation and range of the %response at Week 10 will be 
summarized. 
•
Mean, standard deviation and range of the PGA score at End of Study. 


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•
Mean, standard deviation and range of the mSWAT score at Baseline and End of Study.
•
Mean, standard deviation and range of the change in the mSWAT score (calculated as the 
mSWAT score at End of Study – mSWAT score at Baseline).
•
Mean, standard deviation and range of the Skindex 29 score and its 3 domains (emotions, 
symptoms, functioning) at Baseline and Week 8. 
•
Mean, standard deviation and range of the change in Skindex 29 score and its 3 domains.
•
Mean, standard deviation and range of the VASitch score at baseline, each light treatment 
and the end of study visit. 
•
Shift analysis of VASitch categories (none/mild/moderate/severe) over all study 
timepoints. 
•
Mean, standard deviation and range for the treatment visit at which the maximum light 
dose was obtained. 
•
Mean, standard deviation and range for the maximum light dose that was used.
•
Listing of changes of drug used (change in drug jar weight)


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7.
SAFETY ANALYSES
The safety analysis will be performed in all patients enrolled. Safety parameters include adverse 
events, laboratory parameters, vital signs, ECG parameters, and physical examinations. 
7.1.
Adverse Events
Summary tables will be provided for all treatment-emergent adverse events (TEAEs). Treatment-
emergent AEs are defined as events whose onsets occur, or severity worsens on or after the date 
of first dose of study drug. All TEAEs will be included in summaries.
An overview table will contain the number and percentage of patients with any TEAEs, with 
study drug related TEAEs, serious adverse events (SAEs), with AEs causing death, with related 
AEs causing death, with related SAEs, with AEs causing study drug discontinuation, and with 
AEs causing discontinuation from the study.
The TEAE summary tables will include counts of patients. Therefore, if a patient experiences 
more than one episode of a particular TEAE, the patient will be counted only once for that event. 
If a patient has more than one AE that is coded to the same preferred term, the patient will be 
counted only once for that preferred term. Similarly, if a patient has more than one TEAE within 
a SOC, the patient will be counted only once in that SOC.
All AEs are to be reported from the time of first administration of study drug until study 
completion or discontinuation. The severity of all AEs is recorded as mild, moderate, or severe. 
If severity is missing for TEAE, it will be set to severe. If severity is missing for AE at pre-
treatment, the severity will be set to mild: if severity change is not reported during the study, 
then severity of mild is retained for analysis. A treatment-related AE is defined as an AE with 
relationship to study drug recorded as related or missing in the CRF. All AEs will be coded using 
the MedDRA (Version 10.1).
The maximum severity of AE is defined as the AE with the worst severity experienced overall 
during the study, within a SOC, or within a preferred term. 
The following TEAE summaries will be presented:
•
Frequency of TEAEs by preferred term, sorted by decreasing overall total
•
Frequency of TEAEs related to study drug, by SOC and preferred term
•
Frequency of TEAEs related to study drug by preferred term, sorted by decreasing 
overall total
•
Frequency of TEAEs by maximum severity, SOC, and preferred term
•
Frequency of AEs causing discontinuation from the study drug and study by SOC and 
preferred term
•
Frequency of SAEs by SOC and preferred term
•
Frequency of TEAEs with seriousness of fatal by SOC and preferred term.


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Listings will be presented to show SAEs, AEs that resulted in early discontinuation from the 
study or study drug, and AEs with seriousness of fatal. A listing of all reported AEs will also be 
presented. For each adverse event the following will be specified: the treatment group, MedDRA 
system organ class, preferred term and adverse event description from the CRF, onset and 
resolution dates and their respective study days, duration, time of onset, severity, seriousness, AE 
or current condition number associated with the AE, and relationships to study procedure, the 
study drug and concomitant medication. The listing will display the outcomes as reported by the 
investigator.
7.2.
Clinical Laboratory Parameters
Descriptive statistics for laboratory values (in US conventional and SI units) and changes from 
baseline at each assessment time point will be presented for the following laboratory parameters 
collected in the study including but are not limited to the following:
•
Hematology: hemoglobin, hematocrit, RBC count, MCV, MCH, MCHC, WBC count, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, and platelet counts
•
Chemistry: alkaline phosphatase, ALT, AST, bicarbonate, total bilirubin, BUN, chloride, 
creatinine, potassium, total protein, and sodium.
Laboratory tests values are clinically significant (CS) if they meet either the low or high CS 
defined by the normal ranges at the site’s local laboratory. The number and percentage of 
subjects with post-Baseline CS values will be tabulated by treatment group. The percentages are 
to be calculated relative to the number of subjects with available non-CS baseline values and at 
least one post-Baseline assessment. The numerator is the total number of subjects with at least 
one post-Baseline CS value. In addition, shift tables will be presented by treatment group and 
time point. The following three data listings will be presented by subject:
•
A listing of lab values for all lab tests at all collected time points.
•
A listing of subjects with post-Baseline CS values will be provided including the 
Baseline and post-Baseline values.
•
A listing of all AEs for subjects with CS laboratory values will also be provided.
7.3.
Vital Signs
Vital signs (systolic and diastolic blood pressures, heart rate, and respiratory rate) will be measured 
at Baseline, Week 8, Session 2 Light Session visit prior to the light session and during the End of 
Study follow-up visit.
For vital signs summaries, the Baseline values will be defined as the assessment obtained at 
Baseline assessment.
Vital signs data and change from Baseline will be summarized using descriptive statistics.


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Criteria for clinically significant values have been defined as shown in Table 7. For each vital 
sign variable, clinically significant value at Baseline and minimum and maximum clinically 
significant values during Treatment Cycles will be identified. Shift in number of patients with 
clinically significant values at baseline to the number of patients with minimum and maximum 
clinically significant values on-therapy will be displayed. 
Table 7: Vital Signs Clinically Significant Values
Vital Sign Variable
Absolute Value
Systolic Blood Pressure
>180 mmHg and increase of >20 mmHg from baseline
<90 mmHg and decrease of >20 mmHg from baseline
Diastolic Blood Pressure
>105 mmHg and increase of  >15 mmHg from baseline
<50 mmHg and decrease of >15 mmHg from baseline
Pulse
>120 bpm and increase of  >15 bpm from baseline
<50 bpm and decrease of >15 bpm from baseline
Listings of all vital sign values will be presented.
7.4.
Extent of Exposure
The number of exposures of drug applications and phototherapy for the study population will be 
summarized by frequency table. Descriptive statistics will be provided.


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8.
APPENDIX 1:  DATA HANDLING CONVENTIONS
8.1.
Missing Severity Assessment for Adverse Events
If severity is missing for an AE started prior to the first study medication, then a severity of 
“Mild” will be assigned. If the severity is missing for an AE started on or after the first study 
medication dosing, then a severity of “Severe” will be assigned. The imputed values for severity 
assessment will be used for incidence summary, while the actual missing values will be 
presented in data listings. 
8.2.
Missing Relationship to Study Drug for Adverse Events
If the relationship to the study medication is missing for an AE started after baseline, a causality 
of “Related” will be assigned. The imputed values for relationship to study medication will be 
used for incidence summary, while the actual values will be presented in data listings. 
8.3.
Missing Date Information for Adverse Events
The following imputation rules only apply to the case where the date is incomplete (i.e., partial 
missing) for adverse events. Missing day and month
•
If the year is same as the year of first day on study medication, then the day and month of 
the start date of study medication will be assigned to the missing fields.
•
If the year is prior to the year of first day on study medication, then December 31 will be 
assigned to the missing fields.
•
If the year is after the year of first day on study medication, then January 1 will be 
assigned to the missing fields.
Missing month only
•
Treat day as also missing and replace both month and day according to the above 
procedure.
Missing day only 
•
If the month and year are same as the year and month of first day on study medication, 
then the start date of study medication will be assigned to the missing day.
•
If the month and year are before the year and month of first day on study medication, 
then the last day of the month will be assigned to the missing day.
•
If the month and year are after the year and month of first day on study medication, then 
the first day of the month will be assigned to the missing day.
If the stop date is complete and the imputed start date as above is after the stop date, the start 
date will be imputed by the stop date. 


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8.4.
Missing Date Information for Prior or Concomitant Medications
For prior or concomitant medications, including rescue medications, incomplete (i.e., partial 
missing) start date and/or stop date will be imputed. When the start date and the stop date are 
both incomplete for a patient, impute the start date first.
•
Incomplete Start Date
The following rules will be applied to impute the missing numerical fields. If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date.
Missing day and month
•
If the year of the incomplete start date is the same as the year of the first dose date of 
study medication, then the day and month of the first dose date will be assigned to the 
missing fields. 
•
If the year of the incomplete start date is prior to the year of the first dose date of study 
medication, then December 31 will be assigned to the missing fields. 
•
If the year of the incomplete start date is after the year of the first dose date of study 
medication, then January 1 will be assigned to the missing fields.
Missing month only
•
Treat day as also missing and replace both month and day according to the above 
procedure.
Missing day only 
•
If the month and year of the incomplete start date are the same as the month and year of 
the first dose date of study medication, then the day of the first dose date will be assigned 
to the missing day. 
•
If either the year is before the year of the first dose date of study medication or if both 
years are the same but the month is before the month of the first dose date of study 
medication, then the last day of the month will be assigned to the missing day.
•
If either the year is after the year of the first dose date of study medication or if both 
years are the same but the month is after the month of the first dose date of study 
medication, then the first day of the month will be assigned to the missing day.
•
Incomplete Stop Date  
The following rules will be applied to impute the missing numerical fields. If the last dose date 
of study medication is missing, replace it with the last visit date. If the imputed stop date is 
before the start date (imputed or non-imputed start date), then the imputed stop date will be equal 
to the start date.


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Missing day and month
If the year of the incomplete stop date is the same as the year of the last dose date of study 
medication, then the day and month of the last dose date will be assigned to the missing fields. 
•
If the year of the incomplete stop date is prior to the year of the last dose date of study 
medication, then December 31 will be assigned to the missing fields. 
•
If the year of the incomplete stop date is after the year of the last dose date of study 
medication, then January 1 will be assigned to the missing fields.
Missing month only
•
Treat day as also missing and replace both month and day according to the above 
procedure.
Missing day only 
•
If the month and year of the incomplete stop date are the same as the month and year of 
the last dose date of study medication, then the day of the last dose date will be assigned 
to the missing day. 
•
If either the year is before the year of the last dose date of study medication or if both 
years are the same but the month is before the month of the last dose date of study 
medication, then the last day of the month will be assigned to the missing day.
•
If either the year is after the year of the last dose date of study medication or if both years 
are the same but the month is after the month of the last dose date of study medication, 
then the first day of the month will be assigned to the missing day.
8.5.
Clinical Laboratory Parameters
If the reported value of a clinical laboratory parameter cannot be used in a statistical summary 
table due to, for example, that a character string is reported for a parameter of the numerical type, 
coded value needs to be appropriately determined and used in the statistical analyses (Table 8). 
However, the actual values as reported in the database will be presented in data listings. 
Categorization of laboratory results into low/normal/high group will be done using the 
laboratory’s scaled lower and upper limits of normal value as present in Table 8 and Table 9.   
Table 8: Example for Coding of Special Character Values for Clinical Laboratory 
Parameters
Lab Test
Reported Lab Results (in SI units)
Coded Value for Analysis
Chemistry: ALT
<5
0


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Lab Test
Reported Lab Results (in SI units)
Coded Value for Analysis
Chemistry: AST
<5
0
Chemistry: Bilirubin, Total
<2
0
Table 9: Ranges of Potentially Clinically Significant Lab Values
Parameter
SI Unit
Lower Limit
Higher Limit
CHEMISTRY
Alanine 
Aminotransferase  
(ALT)
U/L
3 * ULN
Alkaline Phosphatase
U/L
3 * ULN
Aspartate 
Aminotransferase (AST)
U/L
3 * ULN
Bicarbonate
mmol/L
3 * ULN
Creatinine
mg/dL
>1.5 * Day 1
Potassium
mmol/L
<0.75*LLN
>1.2 * UNL
Sodium
mmol/L
<0.9*LLN
>1.1 * UNL
Chloride
mmol/L
Total Bilirubin
mg/dL
>1.5 * UNL
Total Protein
g/dL
<0.9*LLN
>1.1 * UNL
Urea (BUN)
mg/dL
>1.5 * Day 1
HEMATOLOGY
Red blood cell count (RBC)
106/µL
Hematocrit
%
Hemoglobin
g/dL
Mean corpuscular volume 
(MCV)
fL
Mean corpuscular 
hemoglobin (MCH)
pg
Mean corpuscular 
hemoglobin concentration 
(MCHC)
g/dL
Neutrophil Percentage
%


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Parameter
SI Unit
Lower Limit
Higher Limit
Neutrophil Count
103/µL
1
Lymphocyte Percentage
%
Lymphocyte Count
103/µL
Monocyte Percentage
%
Monocyte Count
103/µL
Eosinophil Percentage
%
Eosinophil Count
103/µL
Basophil Percentage
%
Basophil Count
103/µL
Platelet Count
103/µL
100
700
White Blood Cell Count
103/µL
2.5
15
LLN:  Lower limit of normal, value provided by the laboratory
ULN: Upper limit of normal, value provided by the laboratory


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9.
APPENDIX 2: SCHEDULE OF PROCEDURES
Subjects will be screened within 28 days of enrollment. Detailed timing of the assessments is shown in Table 9. 
Table 10: Schedule of Assessments
Time point
Blood 
Hypericin 
Concentration
ECG1
Light 
Session2
CAILS 
Evaluations
mSWAT
PGA
VASitch
Skindex-29 
QoL
Safety 
Assessments3
AE 
Collection
Screening4
Baseline5
X6
X6
X6
X6
X6
X6
X6
Week 1, Session 1
X
X
X
Week 1, Session 2
X
X
X
Week 2, Session 1
X
X
X
Week 2, Session 2
X
X
X
Week 3, Session 1
X
X
X
Week 3, Session 2
X
X
X
Week 4, Session 1
X
X
X
Week 4, Session 2
X7X8
X7X8
X
X
X
Week 5, Session 1
X
X
X
Week 5, Session 2
X
X
X
Week 6, Session 1
X
X
X
Week 6, Session 2
X7
X7
X
X
X


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Time point
Blood 
Hypericin 
Concentration
ECG1
Light 
Session2
CAILS 
Evaluations
mSWAT
PGA
VASitch
Skindex-29 
QoL
Safety 
Assessments3
AE 
Collection
Week 7, Session 1
X
X
X
Week 7, Session 2
X
X
X
Week 8, Session 1
X
X
X
Week 8, Session 2 
Drug Application
X6
X
Week 8, Session 2 
Light Session
X7X8
X7X8
X
X
X
X7
X
Week 10/End of 
Study
X
X
X
X
X
X
X
X
1 ECG will include a standard 12-lead reading with QT interval measurements. Correction for heart rate will be performed electronically using both the Bazett's and Fridericia formulas.
2 Light Session:  Includes application of drug 18-24 hours earlier by the patient and the Erythema Scoring performed 5-10 minutes before and after light therapy 
3 Safety Assessments: consists of vital signs, and hematology and clinical chemistry blood tests
4 The following assessments will be performed at the Screening visit:  Obtain Informed Consent Form (ICF) signature, Assessment of entry criteria, Complete Medical History, Complete 
Vital Signs, Serum HCG pregnancy test (women of childbearing age only)
5 Baseline: Includes interval medical history from screening, Complete Physical Examination, review of the results of the serum pregnancy test for eligible female subjects, and charting of 
index lesions onto the Body Lesion Diagram.
6 Obtained prior to drug application
7 Prior to light session
8 2 hours after completion of the light session