Conditions: Sjogren-Larsson Syndrome
Keywords: ADX-102, Sjögren-Larsson Syndrome
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 11
Healthy volunteers: no

Brief summary:
A Phase 3 Randomized, Double-Blind, Vehicle-Controlled, Parallel Group Trial to Evaluate the Safety and Efficacy of ADX-102 1% Topical Dermal Cream in Subjects with Sjögren-Larsson Syndrome (SLS).

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: ADX-102 1% Topical Dermal Cream (reproxalap) intervention 2: Vehicle of ADX-102 Topical Dermal Cream
Intervention descriptions: intervention 1: ADX-102 1% Topical Dermal Cream administered approximately every 24 hours for 6 months. intervention 2: Vehicle of ADX-102 Topical Dermal Cream administered approximately every 24 hours for 6 months.

Protocol document:
Prot_002.pdf: 


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INVESTIGATOR STATEMENT 
 
Protocol Number:  ADX-102-SLS-006 
 
Protocol Title: A Phase 3 Randomized, Double-Blind, Vehicle-Controlled, Parallel Group Trial to 
Evaluate the Safety and Efficacy of ADX-102 1% Topical Dermal Cream in Subjects with 
Sjögren-Larsson Syndrome (SLS). 
 
I understand that all information concerning ADX-102 in connection with this study and not 
previously published is confidential. This confidential information includes the Investigator’s 
Brochure, Clinical Study Protocol, Case Report Form, clinical methodology, and basic scientific 
data. 
 
I will not initiate this study without approval from the Institutional Review Board (IRB)/Research 
Ethics Board (REB)/Independent Ethics Committee (IEC) and I understand that any changes in 
the protocol must be approved in writing by Aldeyra Therapeutics, Inc., and the Institutional 
Review Board/Ethics Committee before they can be implemented, except when necessary to 
eliminate immediate hazards to the subjects. 
 
I will use only the informed consent form approved by Aldeyra Therapeutics and by my 
IRB/REB/IEC and will fulfill all responsibilities for submitting pertinent information to the 
IRB/REB/IEC responsible for this study.  
 
By my signature below, I attest that I have read, understand, and agree to abide by all the 
conditions, instructions, and restrictions contained in Protocol Number ADX-102-SLS-006, and 
will conduct the trial in accordance with the International Council for Harmonisation (ICH) 
guidelines on Good Clinical Practice (GCP) and applicable regulatory requirements.   
 
 
 
 
Site Name 
 
 
 
 
 
Site Address  
 
 
 
 
 
 
Investigator’s Printed Name 
 
 
 
 
 
Investigator’s Signature  
 
Date 
 
 


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SYNOPSIS 
Name of Sponsor Company:  
Aldeyra Therapeutics, Inc. 
Drug Under Study:  
ADX-102  
Title of Protocol: A Phase 3 Randomized, Double-Blind, Vehicle-Controlled, Parallel Group Trial to 
Evaluate the Safety and Efficacy of ADX-102 1% Topical Dermal Cream in Subjects with 
Sjögren-Larsson Syndrome (SLS) 
Protocol Number: 
ADX-102-SLS-006 
Phase: 3  
Indication: Sjögren-Larsson Syndrome; 
Dermatological Signs and Symptoms 
Subject Population:  Subjects 3 years of age and older with genetically-confirmed diagnosis of SLS 
and active ichthyosis. 
Number of Subjects:  
Part 1: Approximately 9 subjects   
Part 2: Approximately 30 subjects, to be confirmed in Part 1 
Number of Centers:   
Approximately 8 centers globally 
Test Products / Doses / Mode of Administration: 
ADX-102 1% drug product is formulated as a topical dermal cream.   
 
   
ADX-102 or vehicle topical dermal cream will be applied once daily to the designated treatment area with 
each application administered approximately 24 hours apart. A standard amount of study drug for the 
percent body surface area (BSA) under treatment will be measured for application.  
Primary Objective:  To evaluate the efficacy of ADX-102 1% topical dermal cream for treatment of 
ichthyosis associated with SLS. 
Secondary Objectives:  To evaluate the safety and secondary efficacy endpoints of ADX-102 1% 
topical dermal cream in subjects with SLS. 
Study Endpoints 
Primary Endpoint: 
The primary efficacy endpoint is the Visual Index for Ichthyosis Severity (VIIS) scaling severity score as 
assessed by the Investigator in the target efficacy area.   
 
 
   
 
 
 
  
 
 
 
 
 
  
 
  
 
 


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Study Design:  
This is a two-part, randomized, double-blind, vehicle-controlled, parallel-group Phase 3 clinical trial with 
an initial assessment of increasing BSA treatment (Part 1).  After the completion of Part 1, a separate 
set of eligible subjects will be enrolled to assess all areas affected by ichthyosis (Part 2).   
Part 1 Design:  
Part 1 will evaluate the safety, tolerability, and efficacy of treatment to the affected area of ichthyosis 
 
 
Qualified subjects will be randomized in a 2:1 ratio to receive ADX-102 1% or vehicle. Subjects or 
caregivers will apply study drug (i.e., ADX-102 1% or vehicle) once daily to a treatment area identified 
by the Investigator from Week 1 through Week 12.  If the Investigator determines that there are no safety 
or tolerability issues at the end of Week 12, treatment will increase to all of the affected areas of ichthyosis 
on one-half of the body from Week 13 through Week 20.  If no safety or tolerability issues are identified 
at the end of Week 20 the treatment will increase to all affected areas of ichthyosis on the entire body 
from Week 21 through Week 24.  
Subjects completing 24 weeks of study drug treatment will then be monitored for an additional 4 weeks 
for safety.   
In total, subjects will be followed for up to 28 weeks and monitored for safety and efficacy at up to 
10 study visits: up to 6 site visits and 4 home visits.  Apart from the Day 1 and Day 2 visits, each study 
visit has a ± 5-day window, and home visits have a ± 3-day window. 
Study procedures are outlined in the Schedule of Assessments (Table 1 and Table 1-1). 
Subjects who are randomized in Part 1 will not be eligible to participate in Part 2. 
Part 2 Design:  
Part 2 will evaluate the safety, tolerability, and efficacy of treatment to the affected area of ichthyosis on 
the body (approximately 80-90% BSA in a typical SLS patient) over 24 weeks of exposure.   
Qualified subjects will be randomized in a 2:1 ratio to receive either ADX-102 1% or vehicle. The 
appropriate sample size for Part 2 will be confirmed in Part 1. Subjects will be followed for up to 28 weeks 
and monitored for safety and efficacy at up to 10 study visits: up to 7 clinic visits and 3 telephone calls 
with the site.  Apart from the Day 1 and Day 2 visits, each study visit has a ± 5-day window, and telephone 
calls have a ± 3-day window. 
Study procedures are outlined in the Schedule of Assessments (Table 2 and Table 2-1). 
Subjects who complete Part 1 or Part 2 of the study will be eligible to continue into a separate open-label 
extension study. 


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Criteria for Inclusion: 
Subjects meeting all the following criteria will be considered eligible for study entry: 
1. Subject is aged 3 years or older.   
2. Subject has a genetically-confirmed diagnosis of SLS. 
3. Subject has active ichthyosis that is Grade 2 or higher on the VIIS scaling severity score. 
4. Subject or subject’s caretaker is willing and able to provide written informed consent prior to 
the initiation of any study procedures.  Assent will be solicited from pediatric subjects capable 
of providing assent. 
5. Females of child-bearing potential: Negative pregnancy test at Screening and Baseline Visits. 
6. Subjects who are sexually active agree to use medically acceptable method (as defined by the 
Investigator) of birth control as follows: 
• 
For females: Compliant with a contraceptive regimen during the study if of child-bearing 
potential or documented to be surgically sterile or post-menopausal. 
• 
For males: Compliant with a contraceptive regimen during the study or documented to be 
surgically sterile. 
Criteria for Exclusion: 
Subjects meeting any of the following criteria will be excluded from the study:  
1. Subject has evidence of a serious active infection. 
2. Systemic or topical retinoids or other topical medications, not including emollients, within the 
past 30 days Baseline Visit 1.  
3. Subject has received an investigational systemic or topically administered drug within the past 
30 days prior to Baseline Visit 1. 
4. Subject is currently taking and was unwilling or unable to discontinue any medication excluded 
in Section 5.7.1. 
5. Subject is currently receiving immunosuppressive therapy, including intermittent or low-dose 
systemic corticosteroids. 
6. Subject has a known allergic reaction to any ingredients of study drug formulation. 
7. Subject has a history of any malignancy. 
8. Subject is known to be human immunodeficiency virus positive or had other known 
immunodeficiency. 
9. Subject has any clinically significant laboratory test abnormalities or a history of any other 
condition that, in the opinion of the Investigator, could compromise the subject’s ability to 
comply with the protocol or that could compromise the subject’s safety or the interpretation of 
the study results. 
10. Subject is currently participating in any other therapeutic clinical study. 
11. Subject is pregnant or lactating. 
Statistical Analysis:  
Part 1 and Part 2 will be analyzed in a similar fashion with the exception that the Part 1 analysis will 
include a sample size evaluation.  Part 1 analyses in some instances may be confined to the descriptive 
aspect of the evaluation (i.e., inferential p-values may be omitted) due to the small sample size of 6 
treated and 3 control patients. 
The primary efficacy endpoint (VIIS scaling severity as assessed by the Investigator in the target efficacy 
area) as well as all secondary efficacy variables that are captured on a continuous or semi-continuous 


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scale 
 
 
 will be expressed as baseline to ending change scores.  Two-sided 95% 
confidence intervals (CIs) will be computed and used descriptively for all variables but also to evaluate 
change relative to a standard for some variables (i.e., by determining whether the CI includes or excludes 
the standard).   
The two-sided 95% CI for VIIS scaling severity will be used to evaluate the primary endpoint as follows. 
An efficacy claim from Part 2 will be made if: 1) the lower confidence interval is above zero, 2) the mid-
point of the confidence interval is at least 0.5 units is size, and 3) at least 50% of subjects have favorable 
change scores of one or greater.  
Response over time will be converted to one or more Area Under the Curve parameters and evaluated 
using a generalized linear model. VIIS outcome scores and other continuous or semi-continuous 
outcome variables will be evaluated using a Mixed Model Repeated Measures (MMRM) analysis.  
Conversion of VIIS or other scales to indicate response (yes/no) will occur (e.g., 0.5 VIIS improvement, 
1 unit VIIS improvement) and be evaluated as secondary endpoints.  Logistic or Generalized Estimating 
Equation (GEE) modeling will be used to evaluate incidence of response overall and/or by time.  Time 
to Event analysis (e.g., Kaplan-Meier with log rank test, proportional hazards [PH] modeling) will be used 
to evaluate time to response.    
To increase statistical power, covariates may be incorporated into the computation of 95% confidence 
intervals (e.g., through the use of a mean centered covariate in a regression model to predict the mean 
pre-treatment to post-treatment difference) and/or into logistic, GEE, PH, MMRM and generalized linear 
models.    
All analyses will be specified a priori in an Statistical Analysis Plan (SAP) to be completed prior to 
database lock for Part 1.  The SAP will serve as the summative and definitive plan of analysis.  Analyses 
not described in the SAP will be labeled as post-hoc.  The SAP will outline all analyses that will be 
performed in Part 1 and in Part 2 of this study.   
Sample Size Rationale: 
Part 1 will assess the effect size on the VIIS scaling severity score, and will confirm the sample size 
needed for Part 2. Part 2 is expected to require approximately 30 subjects. 
Data Safety Monitoring Board: 
An independent data safety monitoring board (DSMB) will be established to review all available safety 
data after approximately 9 subjects have completed Week 24 in Part 1.  The assessment of safety will 
be determined from dermatological endpoints, vital sign measurements, physical examinations, 
hematology and chemistry laboratory testing, ECG readings, use of concomitant medications, and review 
of AEs.  Based on the safety data provided, the DSMB will provide recommendations about stopping or 
continuing the trial.  
The DSMB will be advisory to the Sponsor’s clinical trial leadership group Steering Committee which will 
be blinded during Part 1 until database lock. The Steering Committee will be responsible for promptly 
reviewing the DSMB recommendations, to decide whether to continue or terminate the trial, and to 
determine whether amendments to the protocol or changes in study conduct are required.  
Additional DSMB reviews will occur approximately every 6 months throughout the trial, or as deemed 
necessary by the DSMB or Sponsor to ensure subject safety and well-being. Study enrollment and 
dosing will continue while the DSMB evaluates data. A DSMB charter will be prepared. The charter will 
contain the required information for the formation, activities, and conduct of the DSMB. 


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Table 1. Part 1 Schedule of Events and Assessments  
ET = early termination; ECG = electrocardiogram; PD = pharmacodynamic; PK = pharmacokinetic; VIIS = Visual Index for Ichthyosis Severity 
1. 
Samples collected for urinalysis and clinical laboratory tests may be analyzed at a local lab.   
2. 
Subjects who terminate early from the study will undergo, if possible, all of the assessments and procedures scheduled for Visit 8 (Week 24). 
3. 
Urine pregnancy test for female subjects of child-bearing potential only.  Test can be analyzed at the study site. 
4. 
Complete physical exam, including height and weight collection, performed at Screening Visit only; symptom directed physical exams at all other timepoints. 
Evaluation 
Screening1  
Baseline 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
ET  
Visit 82 
Safety 
Follow-Up 
Visit 9 
Day -7 to -1 
Week 1 
Day 1 
Week 1 
 Day 2 
Week 4 
± 3 days 
Week 8 
± 3 days 
Week 12 
± 5 days 
Week 16 
± 3 days 
Week 20 
± 5 days 
Week 24 
± 5 days 
Week 28 
± 3 days 
Site Visit 
Site Visit 
Site Visit 
Home Visit 
Home Visit 
Site Visit 
Home Visit 
Site Visit 
Site Visit 
Home Visit 
Informed consent / assent 
X 
 
 
 
 
 
 
 
 
 
Eligibility review 
X 
X 
 
 
 
 
 
 
 
 
Demographics / medical history 
X 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis / pregnancy test3 
X 
X 
 
 
 
X 
 
X 
X 
 
12-Lead ECG (see Table 1-1) 
X 
X 
 
 
 
X 
 
X 
X 
 
Vital Signs (see Table 1-1) 
X 
X 
X 
 
 
X 
 
X 
X 
 
Physical exam4 
X 
X 
X 
 
 
X 
 
X 
X 
 
Dermatologic exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Digital photography5 
 
X 
 
X6 
X6 
X 
X6 
X 
X 
X6 
VIIS (Investigator-assessed) 
 
X 
X 
 
 
X 
 
X 
X 
 
Global impression of severity 
 
X 
 
 
 
X 
 
X 
X 
 
Patient/Observer-reported scales7 
 
X 
 
 
 
X 
 
X 
X 
 
PD sample collection8 
 
X 
X 
 
 
X 
 
X 
X 
 
Clinical laboratory testing9  
X 
X 
 
 
 
X 
 
X 
X 
 
PK sample collection10 (see Table 1-1) 
 
X 
X 
 
 
X 
 
X 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Administer study drug  
 
X11 
X 
X 
X 
X11 
X 
X11 
 
 
Dispense study drug & diary 
 
 
X 
 
 
X 
 
X 
 
 
Collect study drug & diary 
 
 
 
 
 
X 
 
X 
X 
 


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5. 
Subjects should refrain from bathing and applying study drug or as-needed topical symptom control therapy (emollients) to the treatment area within 12 hours of obtaining digital 
photographs.   
6. 
During at-home visits, photographs will only be taken if there are any safety concerns. 
7. 
Patient/Observer-reported scales to be administered: EQ-5D-5L, global impression of severity, global impression of bother, global impression of treatment, itching, scratching, burden 
of bathing/showering, and Children's Dermatology Life Quality Index (CDLQI) / Dermatology Life Quality Index (DLQI). 
8. 
PD assessments include skin cell samples and transepidermal water loss (TEWL) procedures. 
9. 
Clinical laboratory includes hematology and chemistry.  Refer to Sections 6.15.1.1 and 6.15.1.2 for more detail. 
10. PK collection include blood and urine samples. 
11. Study drug will be administered daily.  At study visits when PK samples are collected, study drug may be administered at the study clinic after pre-dose PK samples have been obtained.  
At Visit 1, Investigator should apply study drug to the initial treatment area (~20% BSA) during the visit.  At Visit 2, study drug may be applied to the initial treatment area during the visit 
(after pre-dose PK sample collection) by the Investigator or subject/caregiver.  At Visit 5, if the treatment area is expanded to up to 45% BSA, the Investigator should apply study drug 
to the treatment area.  At Visit 7, if the treatment area is expanded to up to 90% BSA, Investigator should apply study drug to the treatment area. 
 
Table 1-1. Part 1 Pharmacokinetic and Cardiac Monitoring 
Visit  
Visit 1 
Visit 2 
Visits 5, 7 and 8 
Time (hours) 
Pre-Dose 
1 
2 
4 
8 
24 
Pre-Dose 
1 
2 
4 
8 
Window 
- 
± 15 min 
± 15 min 
± 15 min 
± 15 min 
± 60 min 
- 
± 15 min 
± 15 min 
± 15 min 
± 15 min 
Adults (age ≥ 12 years old) 
12-Lead ECG  
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood PK Samples 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine PK Samples 
X 
 
 
 
X 
 
X 
 
 
 
X 
Children (age < 12 years old) 
12-Lead ECG 
X 
X 
 
X 
 
 
X 
X 
 
X 
 
Vital Signs 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
Blood PK Samples 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
Urine PK Samples 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 


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Table 2. Part 2 Schedule of Events and Assessments  
ECG = electrocardiogram; ET = early termination; PD = pharmacodynamic; PK = pharmacokinetic; VIIS = Visual Index for Ichthyosis Severity 
1. 
Samples collected for urinalysis and clinical laboratory tests may be analyzed at a local lab.   
Evaluation 
Screening1  
Baseline 
Visit 11 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
ET  
Visit 82 
Safety  
Follow-up 
Visit 9 
Day -7 to -1 
Week 1 
Day 1 
Week 1  
Day 2 
Week 4 
± 3 days 
Week 8 
± 5 days 
Week 12 
± 3 days 
Week 16 
± 5 days 
Week 20 
± 3 days 
Week 24 
± 5 days 
Week 28  
± 5 days 
Site Visit 
Site Visit 
Site Visit 
Telephone 
Site Visit 
Telephone 
Site Visit 
Telephone 
Site Visit 
Site Visit 
Informed consent / assent 
X 
 
 
 
 
 
 
 
 
 
Eligibility review 
X 
X 
 
 
 
 
 
 
 
 
Demographics / medical history 
X 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis / pregnancy test3 
X 
X 
 
 
X 
 
X 
 
X 
 
12-Lead ECG (see Table 1-1) 
X 
X 
 
 
X 
 
 
 
X 
 
Holter Monitoring 
 
X 
 
 
X 
 
 
 
X 
 
Vital Signs (see Table 1-1) 
X 
X 
X 
 
X 
 
X 
 
X 
 
Physical exam4 
X 
X 
X 
 
X 
 
X 
 
X 
 
Dermatologic exam 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Digital photography5 
 
X 
 
 
X 
 
X 
 
X 
X 
VIIS (Investigator-assessed) 
 
X6 
X 
 
X 
 
X 
 
X 
X 
Global impression of severity 
 
X 
 
 
X 
 
X 
 
X 
X 
Patient/Observer-reported scales7 
 
X 
 
 
X 
 
X 
 
X 
X 
PD sample collection8 
 
X 
X 
 
X 
 
X 
 
X 
 
Clinical laboratory testing9  
X 
X 
 
 
X 
 
X 
 
X 
 
PK sample collection10 (see Table 1-1) 
 
X 
X 
 
X 
 
X 
 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Administer study drug11  
 
X 
X 
X 
X 
X 
X 
X 
 
 
Dispense study drug & diary 
 
 
X 
 
X 
 
X 
 
 
 
Collect study drug & diary 
 
 
 
 
X 
 
X 
 
X 
 
Exit interview 
 
 
 
 
 
 
 
 
X12 
 


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2. 
Subjects who terminate early from the study will undergo, if possible, all of the assessments and procedures scheduled for Visit 8 (Week 24). 
3. 
Urine pregnancy test for female subjects of child-bearing potential only.  Tests can be analyzed at the study site. 
4. 
Complete physical exam, including height and weight collection, performed at Screening Visit only; symptom directed physical exams at all other timepoints. 
5. 
Subjects should refrain from bathing and applying study drug or as-needed topical symptom control therapy (emollients) to the treatment area within 12 hours of obtaining digital 
photographs.   
6. 
VIIS must be independently assessed by two different Investigators at Baseline Visit 1 only. 
7. 
Patient-/caregiver-reported scales to be administered: EQ-5D-5L, global impression of severity, global impression of bother, global impression of treatment, itching, scratching, burden 
of bathing/showering, and Children's Dermatology Life Quality Index (CDLQI) / Dermatology Life Quality Index (DLQI). 
8. 
PD assessments include skin cell samples and transepidermal water loss (TEWL) procedures. 
9. 
Clinical laboratory includes hematology and chemistry.  Refer to Sections 6.15.1.1 and 6.15.1.2 for more details. 
10. PK sample collection (blood and urine) from approximately 16 subjects.   
11. Study drug will be administered daily.  At study visits when PK samples are collected, study drug may be administered at the study site after pre-dose PK samples have been obtained.   
12. Exit interviews should be conducted within 30 days of Visit 8. 
 
 
Table 2-1. Part 2 Pharmacokinetic and Cardiac Monitoring 
Visit  
Visit 1 
Visit 2 
Visits 4 and 8  
Visit 6 
Time (hours) 
Pre-
Dose 
1 
2 
4 
8 
12 
24 
Pre-
Dose 
1 
2 
4 
8 
12 
Pre-
Dose 
Window 
- 
± 15 min 
± 15 min 
± 15 min 
± 15 min 
± 15 min 
± 60 min 
- 
± 15 min 
± 15 min 
± 15 min 
± 15 min 
± 15 min 
- 
Adults (age ≥12 years old) 
12-Lead ECG  
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood PK Samples 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine PK Samples 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Children (age < 12 years old) 
12-Lead ECG 
X 
X 
 
X 
 
 
 
X 
X 
 
X 
 
 
 
Vital Signs 
X 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
 
X 
Blood PK Samples 
X 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
 
X 
Urine PK Samples 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 


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TABLE OF CONTENTS 
INVESTIGATOR STATEMENT ................................................................................................... 2 
SYNOPSIS  ................................................................................................................................. 3 
TABLE OF CONTENTS ............................................................................................................ 11 
LIST OF TABLES ...................................................................................................................... 15 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...................................................... 16 
1 
INTRODUCTION .................................................................................................... 18 
1.1 
Sjögren-Larsson Syndrome .................................................................................... 18 
1.2 
Therapeutic Rationale for ADX-102 in Sjögren-Larsson Syndrome ........................ 18 
1.3 
Clinical Trials of ADX-102 ....................................................................................... 19 
1.3.1 
Sjögren-Larsson Syndrome .............................................................................. 19 
1.3.2 
Ocular Indications ............................................................................................. 20 
1.4 
Minimization of Risk ................................................................................................ 20 
1.5 
Potential Benefit ..................................................................................................... 20 
1.6 
Rationale for Dose Selection .................................................................................. 21 
2 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 21 
2.1 
Study Objectives..................................................................................................... 21 
2.1.1 
Primary Objective ............................................................................................. 21 
2.1.2 
Secondary Objective ......................................................................................... 21 
2.2 
Study Endpoints ..................................................................................................... 21 
2.2.1 
Primary Endpoint .............................................................................................. 21 
2.2.2 
Secondary Endpoints ........................................................................................ 21 
3 
INVESTIGATIONAL PLAN ..................................................................................... 22 
3.1 
Overall Study Design and Plan ............................................................................... 22 
3.2 
Assigning Subjects to Treatment Groups ................................................................ 23 
3.2.1 
Subject Numbering ........................................................................................... 23 
3.2.2 
Randomization .................................................................................................. 23 
3.3 
Blinding and Unblinding .......................................................................................... 23 
3.3.1 
Blinding ............................................................................................................. 23 
3.3.2 
Emergency Unblinding ...................................................................................... 23 
3.4 
Safety Oversight ..................................................................................................... 24 
3.4.1 
Data Safety Monitoring Board ........................................................................... 24 
3.5 
Study Duration for Individual Subjects .................................................................... 25 
4 
STUDY POPULATION SELECTION ...................................................................... 25 


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4.1 
Inclusion Criteria ..................................................................................................... 25 
4.2 
Exclusion Criteria .................................................................................................... 25 
4.3 
Subject Withdrawal and Replacement .................................................................... 26 
5 
STUDY TREATMENT............................................................................................. 26 
5.1 
Description of Study Treatment .............................................................................. 26 
5.2 
Packaging and Labeling ......................................................................................... 26 
5.3 
Study Drug Storage ................................................................................................ 26 
5.4 
Study Drug Accountability ....................................................................................... 27 
5.5 
Study Drug Retention ............................................................................................. 27 
5.6 
Treatment Administration ........................................................................................ 27 
5.7 
Concomitant Therapy and Procedures ................................................................... 28 
5.7.1 
Prohibited Concurrent Therapies and Procedures ............................................ 28 
5.7.2 
Allowed Concurrent Therapies and Treatment .................................................. 28 
5.8 
Restrictions ............................................................................................................. 29 
5.8.1 
Bathing ............................................................................................................. 29 
5.9 
Treatment Compliance ........................................................................................... 29 
6 
STUDY PROCEDURES ......................................................................................... 29 
6.1 
Informed Consent / Assent ..................................................................................... 29 
6.2 
Eligibility Review ..................................................................................................... 29 
6.3 
Demographics and Medical History ........................................................................ 29 
6.4 
Concomitant Medications ....................................................................................... 30 
6.5 
Adverse Events ...................................................................................................... 30 
6.6 
Electrocardiography / Holter Monitoring .................................................................. 30 
6.7 
Vital Signs .............................................................................................................. 30 
6.8 
Physical Examination ............................................................................................. 30 
6.9 
Visual Index for Ichthyosis Severity ........................................................................ 31 
6.10 
Clinician Global Impression of Severity ................................................................... 31 
6.11 
Patient-/Caregiver-Reported Scales ....................................................................... 31 
6.12 
Dermatologic Exam ................................................................................................ 31 
6.13 
Digital Photography ................................................................................................ 31 
6.14 
Pharmacodynamic Assessments ............................................................................ 32 
6.14.1 
Skin Cell Samples ....................................................................................... 32 
6.14.2 
Transepidermal Water Loss ........................................................................ 32 
6.15 
Clinical Laboratory Tests ........................................................................................ 32 


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Full details of equipment and procedures for laboratory testing will be listed in 
the Laboratory Manual. ............................................................................... 32 
6.15.1 
Laboratory Parameters ............................................................................... 32 
6.16 
Pharmacokinetic Assessments ............................................................................... 33 
6.17 
Randomization ....................................................................................................... 33 
6.18 
Study Drug Treatment ............................................................................................ 33 
6.18.1 
Study Drug Dispensation and Collection ..................................................... 33 
6.18.2 
Study Drug Diary ......................................................................................... 34 
6.19 
Home Visits ............................................................................................................ 34 
6.20 
Site Telephone Check-In ........................................................................................ 34 
6.21 
Exit Interview .......................................................................................................... 34 
7 
STUDY ACTIVITIES FOR PART 1 ......................................................................... 34 
7.1 
Screening Visit (Day -7 to -1) – Site Visit ................................................................ 34 
7.2 
Baseline Visit 1 (Week 1/Day 1) – Site Visit ............................................................ 35 
7.3 
Visit 2 (Week 1/Day 2) – Site Visit .......................................................................... 35 
7.4 
Visits 3 and 4 (Weeks 4 and 8 ± 3 days) – Home Visit (Section 6.19) ..................... 36 
7.5 
Visit 5 (Week 12 ± 5 days) – Site Visit .................................................................... 36 
7.6 
Visit 6 (Week 16 ± 3 days) – Home Visit (Section 6.19) .......................................... 37 
7.7 
Visit 7 (Week 20 ± 5 days) – Site Visit .................................................................... 37 
7.8 
Visit 8 (Week 24 ± 5 days) – Early Termination – Site Visit ..................................... 37 
7.9 
Visits 9 (Week 28 ± 3 days) – Safety Follow-up - Home Visit (Section 6.19) ........... 38 
8 
STUDY ACTIVITIES FOR PART 2 ......................................................................... 38 
8.1 
Screening Visit (Day -7 to -1) – Site Visit ................................................................ 38 
8.2 
Baseline Visit 1 (Week 1/Day 1) – Site Visit ............................................................ 39 
8.3 
Visit 2 (Week 1/Day 2) – Site Visit .......................................................................... 39 
8.4 
Visit 3 (Week 4 ± 3 days) – Telephone Check-In (Section 6.20) ............................. 39 
8.5 
Visit 4 (Week 8 ± 5 days) – Site Visit ...................................................................... 40 
8.6 
Visit 5 (Week 12 ± 3 days) – Telephone Check-In (Section 6.20) ........................... 40 
8.7 
Visit 6 (Week 16 ± 5 days) – Site Visit .................................................................... 40 
8.8 
Visit 7 (Week 20 ± 3 days) – Telephone Check-In (Section 6.20) ........................... 41 
8.9 
Visit 8 (Week 24 ± 5 days) – Early Termination – Site Visit ..................................... 41 
8.10 
Visit 9 (Week 28 ± 5 days) – Safety Follow-up – Site Visit ...................................... 41 
9 
ADVERSE EVENT REPORTING ........................................................................... 42 
9.1.1 
Adverse Event .................................................................................................. 42 
9.1.2 
Treatment Emergent Adverse Events ............................................................... 43 


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9.1.3 
Serious Adverse Events .................................................................................... 43 
9.1.4 
Unexpected Adverse Event............................................................................... 44 
9.1.5 
Reporting Serious Adverse Events ................................................................... 44 
9.1.6 
Follow-up of Adverse Events ............................................................................ 45 
9.1.7 
Reporting Serious Adverse Events to Regulatory Health Authorities/ 
Institutional Review Boards/Research Ethics Boards/Independent 
Ethics Committees ...................................................................................... 45 
9.1.8 
Reporting Pregnancies ..................................................................................... 45 
10 
STATISTICS ........................................................................................................... 46 
10.1 
Sample Size ........................................................................................................... 47 
10.2 
Analysis Populations .............................................................................................. 47 
10.3 
Accountability and Background Characteristics ...................................................... 47 
10.3.1 
Enrollment and Disposition.......................................................................... 47 
10.3.2 
Subject Characteristics ............................................................................... 47 
10.3.3 
Treatment Compliance ................................................................................ 48 
10.4 
Efficacy Analyses ................................................................................................... 48 
10.5 
Safety Analyses ...................................................................................................... 49 
10.5.1 
Adverse Events ........................................................................................... 49 
11 
QUALITY CONTROL AND QUALITY ASSURANCE .............................................. 49 
12 
STUDY ADMINISTRATION .................................................................................... 49 
12.1 
Institutional Review Board / Research Ethics Board / Independent Ethics 
Committee ........................................................................................................ 49 
12.2 
Ethical Conduct of the Study .................................................................................. 50 
12.3 
Subject Informed Consent / Assent......................................................................... 50 
12.4 
Confidentiality ......................................................................................................... 51 
12.5 
Protection of Subject Data ...................................................................................... 51 
12.6 
Study Monitoring..................................................................................................... 51 
12.7 
Case Report Forms and Source Documents .......................................................... 52 
12.8 
Access to Source Documents and Audits ............................................................... 52 
12.9 
Protocol Deviations and Violations ......................................................................... 52 
12.10 
Amendments to the Protocol .................................................................................. 53 
12.11 
Discontinuation of the Study ................................................................................... 53 
12.12 
Investigator Responsibilities ................................................................................... 53 
12.13 
Financial Disclosure ............................................................................................... 53 
12.14 
Registration of Clinical Studies and Disclosure of Results ...................................... 53 


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12.15 
Publication and Disclosure Policy ........................................................................... 54 
13 
RETENTION OF RECORDS .................................................................................. 54 
14 
REFERENCES ....................................................................................................... 54 
 
 
List of Tables 
Table 1. 
Part 1 Schedule of Events and Assessments ........................................................... 7 
Table 1-1 Part 1 Pharmacokinetic and Cardiac Monitoring 
Table 2. 
Part 2 Schedule of Events and Assessments ........................................................... 9 
Table 2-1 Part 2 Pharmacokinetic and Cardiac Monitoring 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
≥ 
Greater than or equal to 
< 
Less than 
% 
Percent 
mg/cm2 
Milligram per square centimeter  
μM 
Micromolar 
w/w 
Weight per weight 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT/SGPT 
Alanine aminotransferase 
AST/SGOT 
Aspartate aminotransferase 
BP 
 
Blood pressure 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CDLQI 
Children's Dermatology Life Quality Index 
CI 
Confidence interval 
CNS 
Central nervous system 
CO2 
Carbon dioxide 
CFR 
Code of Federal Regulations 
COA 
Clinical outcomes assessments 
CPK 
Creatinine phosphokinase 
CR 
Central Reader 
CRF 
Case report form 
CRO 
Contract Research Organization 
CS 
Clinically significant 
DLQI 
Dermatology Life Quality Index 
DNA 
Deoxyribonucleic acid 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
ET 
Early termination 
FALDH 
Fatty aldehyde dehydrogenase 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GEE 
Generalized Estimated Equation 
GLP 
Good Laboratory Practice 
HEENT 
Head, eyes, ears, nose, and throat 
HR 
Heart rate 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IP 
Intraperitoneal 


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IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISS 
Ichthyosis Severity Score 
IV 
Intravenous 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model repeated measures   
NCS 
Not clinically significant 
PI 
Principal Investigator 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PH 
Proportional hazards 
PO 
Oral 
RBC 
Red blood cell 
REB 
Research Ethics Board 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SLS 
Sjögren-Larsson Syndrome 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
TD 
Topical dermal 
TEAE 
Treatment-emergent adverse event 
TEWL 
Transepidermal Water Loss 
TO 
Topical ocular 
VIIS 
Visual Index for Ichthyosis Score 
WBC 
White blood cell 
 
 


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1 
INTRODUCTION 
1.1 Sjögren-Larsson Syndrome 
ADX-102 1% is being developed for the treatment of ichthyosis associated with Sjögren-Larsson 
Syndrome (SLS).  SLS (ICD Q87.1) is a rare, chronically-debilitating, autosomal-recessive 
disorder characterized by generalized ichthyosis, cognitive deficit in a majority of patients, and 
spastic diplegia or tetraplegia.  SLS is caused by mutations in the ALDH3A2 gene that encodes 
fatty aldehyde dehydrogenase (FALDH), an enzyme that catalyzes the oxidation of aliphatic 
aldehydes to fatty acids (3).  
In most patients, ichthyosis (dry, thickened, scaly, erythematous skin that is pruritic and, due to 
frequent excoriation, friable) is moderate or severe, particularly prominent in flexure areas, and 
involves much of the body surface except the face and glabrous skin (3).  The dermal symptoms 
are generally recalcitrant to therapy, and are associated with significant daily physical and 
emotional burden and social stigma for patients and caregivers.  The cutaneous symptoms are 
apparent at birth in almost all patients; they become more established by several months of age 
and remain throughout life (2).  Developmental delay, spasticity, and other neurological symptoms 
become apparent over the first 2 years of life.  The onset of neurologic symptoms usually prompts 
recognition of a diagnosis of SLS rather than another type of ichthyotic disorder (2). 
SLS ichthyosis pathophysiology is well understood; fatty aldehydes disrupt dermal function, 
particularly the epidermal fatty moisture barrier, resulting in pathologic water loss, cutaneous 
desiccation, and compensatory keratinocytic hypertrophy (1).  In epidermal cells, FALDH 
deficiency results in impaired oxidation of long-chain fatty aldehydes to fatty acids.  The 
consequent accumulation of aldehydes disrupts the normal function and secretion of lamellar 
bodies and leads to intercellular lipid deposits in the stratum corneum and a defective water barrier 
in the skin layer, resulting in the cutaneous symptoms of SLS (2). 
Ichthyosis related to SLS is a serious disease and there is no currently approved treatment that 
targets the underlying disease.  Bathing several hours per day and over-the-counter moisturizing 
creams are the main interventions used to attempt to treat the symptoms, but have only limited 
and variable results, lasting for no more than a few hours.  Keratolytic agents, salicylic acid, and 
urea are also considered for treatment.  Patients with severe ichthyosis who are unresponsive to 
topical agents typically receive treatment with systemic retinoids, which are associated with a 
variety of toxicities.  Patients are not usually maintained on retinoids due to concerns about 
toxicity, particularly in pediatric patients.  No clinical intervention has been well studied in SLS 
patients, and therapeutic efficacy is generally variable.  There is considerable social stigma in 
SLS since the skin appearance resembles disseminated cutaneous infectious disease and scales 
often emit a foul odor due to bacterial overgrowth and putrefaction. 
1.2 Therapeutic Rationale for ADX-102 in Sjögren-Larsson Syndrome 
 
 
 
  
 
 
 
   
 


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1.3 Clinical Trials of ADX-102 
1.3.1 Sjögren-Larsson Syndrome 
Study NS-003 was a randomized, double-blind, vehicle-controlled, parallel group Phase 2 clinical 
trial evaluating the activity of ADX-102 1% topical dermal cream at a dose of 8 mg/cm2 in subjects 
with ichthyosis associated with SLS.  
A total of 12 male and female subjects aged 6 years or older (range 8 to 25 years) with genetically 
confirmed SLS and active ichthyosis on the lower extremities that was determined to be of 
moderate severity or higher were enrolled and randomized 1:1 to ADX-102 1% or vehicle. 
Subjects received study drug (ADX-102 1% or vehicle) once daily for 8 weeks.   
The target area for treatment was an area on the lateral aspect of the lower leg, up to 
approximately 10 inches in height by 4 inches wide.  In the cases where the lower leg did not 
have an ideal target area for treatment, the Investigator chose an area on another portion of the 
body as the target area.  The lower leg was not utilized in only one subject whose right upper 
back was identified by the Investigator as the target treatment area. 
 
 
 
 
In this Phase 2 clinical trial, the reduction in the severity of the ichthyosis in ADX-102-treated 
subjects was statistically significant relative to baseline.  The most common reduction in the 
severity of the ichthyosis (assessed by the scaling ISS sub-score) in ADX-102-treated subjects 
over the duration of drug exposure (eight weeks) was one point from a median baseline severity 
of 3, representing an average change from moderate to mild disease.  In addition, the activity of 
drug was statistically superior to that of vehicle.  ADX-102-treated subjects showed greater mean 
and percentage decreases from baseline, and a higher proportion of ADX-102-treated subjects 
exhibited favorable individual responses than that of the vehicle-treated subjects for all the ISS 
sub-scores, except for excoriations. 
ADX-102 1% w/w topical dermal formulation was generally well-tolerated and there were no 
significant or serious adverse events (SAE), or treatment-emergent adverse events (TEAEs) that 
led to treatment discontinuation.  
 
 
 
  No 
pattern of changes was observed with ADX-102 for chemistry analytes, hematology parameters, 
or vital signs.   
Overall, the results of Study NS-003 demonstrated that the ADX-102 1% w/w topical dermal 
formulation was safe and well-tolerated, and improved SLS ichthyosis in a clinically and 
statistically significant manner superior to that of vehicle.   


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1.3.2 Ocular Indications 
As a topical ocular formulation, ADX-102 was safe and well-tolerated in a Phase 1 clinical trial 
and demonstrated efficacy and safety in Phase 2 clinical trials in allergic conjunctivitis and 
noninfectious anterior uveitis.   
Please refer to the Investigator’s Brochure for additional information. 
1.4 Minimization of Risk  
In the Phase 2 clinical trial in SLS patients (NS-003), 8 weeks of daily application of ADX-102 1% 
w/w topical dermal formulation over ~3% body surface area (BSA) has been shown to be safe 
and well-tolerated.  
ADX-102 has been well-tolerated in multiple nonclinical, single dose and repeat dose 
pharmacology and toxicology studies in mice, rats, rabbits, dogs, and non-human primates, via 
topical dermal (TD), topical ocular (TO), oral (PO), intraperitoneal (IP), subcutaneous (SC), and 
intravenous (IV) routes of administration. Of particular relevance to TD application, Good 
Laboratory Practice (GLP) studies testing up to ADX-102 5% topical dermal cream have shown 
that TD administration of ADX-102 to Göttingen minipigs for 21 days and nine weeks was 
well-tolerated, with no local or systemic adverse effects observed. In a standard battery of 
genotoxicity tests, ADX-102 was non-mutagenic and non-clastogenic. Furthermore, in vivo central 
nervous system (CNS), respiratory, and cardiovascular safety pharmacology studies showed no 
adverse effects with ADX-102. Please refer to the Investigator’s Brochure for additional 
information. 
The Phase 3 study design includes an assessment of increasing BSA treatment (Part 1) lasting 
24 weeks in approximately 9 eligible subjects receiving ADX-102 1% or vehicle topical dermal 
cream initially over approximately 20% BSA then increasing to up to 90% BSA.  The assessment 
in Part 1 will allow for real-time evaluation of the safety and effectiveness of ADX-102 1% relative 
to vehicle treatment dosed over longer durations and greater BSA than in the Phase 2 study. After 
completion of Part 1 of the Phase 3 study, a separate set of eligible subjects will be enrolled into 
Part 2 that allows for the assessment of the safety of vehicle relative to ADX-102 1% treatment 
on all areas of ichthyosis. 
In addition, an independent Data Safety Monitoring Board (DSMB) will be established to review 
all available safety data after approximately 9 subjects have completed study Week 24 in Part 1.  
Additional DSMB reviews will occur approximately every 6 months throughout the trial, or as 
deemed necessary by the DSMB or Sponsor to ensure subject safety and well-being. The 
assessment of safety will be determined from dermatological endpoints, vital sign measurements, 
physical examinations, hematology and chemistry laboratory testing, cardiac monitoring, use of 
concomitant medications, and review of adverse events (AEs).  Refer to Section 3.4.1. 
1.5 Potential Benefit 
As described above, SLS ichthyosis is generally recalcitrant to therapy. Phase 2 clinical trial 
results in SLS patients treated over ~3% BSA with ADX-102 1% for 8 weeks demonstrated that 
ADX-102 was effective in treating the ichthyosis associated with SLS.  
The Phase 3 study will assess he activity of ADX-102 1% after 24-weeks of dosing over all skin 
area affected by ichthyosis (approximately 80 – 90% BSA in a typical SLS patient).     


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1.6 Rationale for Dose Selection 
It has been shown that free aldehydes are cytotoxic. In one study, free all-trans-retinal resulted 
dose-dependent cell death of ARPE19 cells, with complete or nearly complete cell death observed 
at 10 µM (5).  A similar phenomenon was observed in HEK293 cells.  Since tissue necrosis is not 
evident in the skin of SLS patients, the theoretical maximum aldehyde concentration likely less 
than 10 µM. Because ADX-102 binds aldehydes with a 1:1 stoichiometry, maximal drug target 
levels in skin are 10 µM. GLP nonclinical studies in Göttingen minipigs have shown that once-daily 
application of 1% w/w ADX-102 topical dermal cream results in ADX-102 skin concentrations that 
meet or exceed this target.  The Phase 2 clinical trial results confirmed the activity of once-daily 
ADX-102 1% administration. 
2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 Study Objectives 
2.1.1 Primary Objective 
To evaluate the efficacy of ADX-102 1% topical dermal cream on ichthyosis associated with SLS. 
2.1.2 Secondary Objective 
To evaluate the safety and secondary efficacy endpoints of ADX-102 1% topical dermal cream in 
subjects with SLS. 
2.2 Study Endpoints 
2.2.1 Primary Endpoint 
The primary efficacy endpoint is the Visual Index for Ichthyosis Severity (VIIS) scaling severity 
score as assessed by the Investigator in the target efficacy area.   
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 


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3 
INVESTIGATIONAL PLAN 
3.1 Overall Study Design and Plan  
This is a two-part, randomized, double-blind, vehicle-controlled, parallel-group Phase 3 clinical 
trial with an initial assessment of increasing BSA treatment (Part 1).  After the completion of Part 1, 
a separate set of eligible subjects will be enrolled into Part 2.   
Part 1 Design: 
Part 1 will evaluate the safety, tolerability, and efficacy of treatment to the affected area of 
ichthyosis initially on approximately 20% BSA and then increasing up to 90% BSA over 24 weeks 
of exposure and will confirm an appropriate sample size for Part 2. 
Subjects will be consented and screened for eligibility.  Approximately 9 subjects will be 
randomized in a 2:1 ratio to receive ADX-102 1% or vehicle.   
Subjects or caregivers will apply study drug (i.e., ADX-102 1% or vehicle) to a treatment area 
identified by the Investigator.   
The initial treatment area will be defined as approximately 20% BSA with Grade 2 or higher on 
the VIIS scaling severity score, as assessed by the Investigator, and will include one of the body 
sites as defined in the VIIS tool (target efficacy area).1 From Week 1 through Week 12, subjects 
will receive treatment once daily in the initial treatment area only.   
If the Investigator determines that there are no safety or tolerability issues at the end of Week 12, 
the treatment area will increase to all of the affected areas of ichthyosis on one-half of the body 
(approximately 40-45% BSA in a typical SLS patient). From Week 13 through Week 20, subjects 
will receive treatment once daily on the expanded treatment area. 
If there are still no safety or tolerability issues at the end of Week 20, the treatment area will further 
increase to all affected areas of ichthyosis on the entire body (approximately, 80-90% BSA in a 
typical SLS patient). Subjects will receive treatment once daily treatment on all affected areas 
from Week 21 through Week 24.    
Subjects completing the 24 weeks of study drug treatment will then be monitored for an additional 
4 weeks for safety.   
Subjects who are randomized in Part 1 will not be eligible to participate in Part 2.   
                                               
 
1 Dorsal foot cannot be selected as the target efficacy area. 


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Part 2 Design: 
Part 2 will evaluate the safety, tolerability, and efficacy of treatment to the affected area of 
ichthyosis on the body (approximately 80-90% BSA in a typical SLS patient) over 24 weeks of 
exposure.   
Subjects will be consented and screened for eligibility.  Qualified subjects will be randomized in a 
2:1 ratio to either ADX-102 1% or vehicle. The appropriate sample size for Part 2 will be confirmed 
in Part 1.  Subjects or caregivers will apply study drug (i.e., ADX-102 1% or vehicle) once daily to 
all affected areas of ichthyosis on the body (approximately 80 – 90% of BSA in a typical SLS 
patient).  
The target efficacy area for all efficacy analyses at Week 24 will be one of the body sites as 
defined in the VIIS tool with Grade 2 or higher on the VIIS scaling severity as assessed by the 
Investigator.1 
3.2 Assigning Subjects to Treatment Groups 
3.2.1 Subject Numbering 
Each subject screened for the study will be assigned a unique subject number that will be used 
to identify the subject throughout their participation in the study. If a subject fails to be randomized, 
the reason should be documented in the source documents and case report form (CRF). The 
subject will be considered a screen failure. 
3.2.2 Randomization  
Subjects will be randomized 2:1 to receive ADX-102 1% or vehicle through interactive response 
technology (IRT) at Baseline Visit Day 1.   
3.3 Blinding and Unblinding 
3.3.1 Blinding 
Subjects will be randomized in a double-blind fashion. Investigators, qualified study personnel, 
subjects, and caregivers will be blinded to the study drug treatment administered.  The Sponsor 
will also be blinded to the study drug treatment administered until database lock (Part 1 and Part 
2). 
3.3.2 Emergency Unblinding  
Emergency unblinding should only be performed when necessary to treat the subject.  Most often, 
knowledge of the possible treatment assignments is sufficient to treat a study subject who 
presents with an emergency condition. 
Unblinding will result in the subject being discontinued from the study, irrespective of whether the 
Investigator the event is deemed related to study drug.  
                                               
 
1Dorsal foot cannot be selected as the target efficacy area. 


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There is no known antidote to ADX-102, so symptomatic and supportive management of any 
suspected and treatment-related adverse event, if necessary, is clinically indicated. 
The treatment code for a subject may only be broken by the Investigator or Sponsor for reasons 
of subject safety or in an emergency when knowledge of the study drug administered would be 
important for the treatment of the patient.  However, the Investigator should make every effort to 
contact the Medical Monitor to discuss the subject’s emergency and the need to unblind, prior to 
unblinding any subject.  
In situations in which the Investigator has tried but is unable to reach the Medical Monitor, the 
Investigator should use his/her best judgment, based on the nature and urgency of the clinical 
situation, and may proceed with unblinding without having successfully reached and discussed 
the situation with the Medical Monitor.  Once a subject's treatment assignment has been 
unblinded, the Medical Monitor should be notified within 24 hours of unblinding of the treatment, 
without revealing the study treatment.   
The blind may be broken in the case of a pregnancy should the subject desire this information.  
The date, time and reason for breaking the blind are to be recorded in the subject’s CRF and 
source documents. 
In the event of a drug-related, serious, unexpected AE, the Sponsor’s Pharmacovigilance 
Department or designee will be provided with the treatment assignment for the subject for 
regulatory reporting. 
3.4 Safety Oversight  
During the study, subject safety will be monitored on a continuous basis by the Medical Monitor 
until the last subject completes his or her last scheduled study assessment. 
3.4.1 Data Safety Monitoring Board  
An independent DSMB will be established to review all available safety data after approximately 
9 subjects have completed Week 24 in Part 1.  The assessment of safety will be determined from 
dermatological endpoints, vital sign measurements, physical examinations, hematology and 
chemistry laboratory testing, ECG readings, use of concomitant medications, and review of 
adverse events.  Based on the safety data provided, the DSMB will provide recommendations 
about stopping or continuing the trial.  
The DSMB will be advisory to the Sponsor’s clinical trial leadership group Steering Committee 
which will be blinded during Part 1 until database lock. The Steering Committee will be responsible 
for promptly reviewing the DSMB recommendations, to decide whether to continue or terminate 
the trial, and to determine whether amendments to the protocol or changes in study conduct are 
required.  
Additional DSMB reviews will occur approximately every 6 months throughout the trial, or as 
deemed necessary by the DSMB or Sponsor to ensure subject safety and well-being. Study 
enrollment and dosing will continue while the DSMB evaluates data.  A DSMB charter will be 
prepared.  The charter will contain the required information for the formation, activities, and 
conduct of the DSMB. 


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3.5 Study Duration for Individual Subjects 
Following the Screening Visit, eligible subjects will enter the study for up to 28 weeks in each 
Part 1 and Part 2.  This comprises of a 24-week study treatment phase followed by a 4-week 
follow-up period. 
4 
STUDY POPULATION SELECTION 
4.1 Inclusion Criteria 
1. Subject is aged 3 years or older.   
2. Subject has a genetically-confirmed diagnosis of SLS. 
3. Subject has active ichthyosis that is Grade 2 or higher on the VIIS scaling severity score. 
4. Subject or subject’s caretaker is willing and able to provide written informed consent prior 
to the initiation of any study procedures.  Assent will be solicited from pediatric subjects 
capable of providing assent. 
5. Females of child-bearing potential: Negative pregnancy test at Screening and Baseline 
Visits. 
6. Subjects who are sexually active agree to use medically acceptable method (as defined 
by the Investigator) of birth control as follows: 
• 
For females:  Compliant with a contraceptive regimen if of child-bearing potential 
during the study, or documented to be surgically sterile or post-menopausal. 
• 
For males:  Compliant with a contraceptive regimen during the study or documented 
to be surgically sterile. 
4.2 Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from the study:  
1. Subject has evidence of a serious active infection. 
2. Systemic or topical retinoids or other topical medications, not including emollients, within 
the past 30 days Baseline Visit 1. 
3. Subject has received an investigational systemic or topically administered drug within the 
past 30 days prior to Baseline Visit 1. 
4. Subject is currently taking and was unwilling or unable to discontinue any medication 
excluded in Section 5.7.1. 
5. Subject is currently receiving immunosuppressive therapy, including intermittent or 
low-dose systemic corticosteroids. 
6. Subject has a known allergic reaction to any ingredients of study drug formulation. 
7. Subject has a history of any malignancy. 
8. Subject is known to be human immunodeficiency virus positive or had other known 
immunodeficiency. 
9. Subject has clinically significant laboratory test abnormalities or a history of any other 
condition that, in the opinion of the Investigator, could compromise the subject’s ability to 
Subjects meeting all the following criteria will be considered eligible for study entry: 


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comply with the protocol or that could compromise the subject’s safety or the interpretation 
of the study results. 
10. Subject is currently participating in any other therapeutic clinical study. 
11. Subject is pregnant or lactating. 
4.3 Subject Withdrawal and Replacement 
Subjects and caregivers will be informed that they have the right to withdraw the subject from the 
study at any time for any reason, without prejudice to their medical care.  The Investigator also 
has the right to withdraw subjects from the study for any of the following reasons: 
• 
Progression of disease that, in the opinion of the Investigator, precludes further study 
drug treatment, 
• 
Development of an unacceptable AE or SAE, 
• 
Subject or Sponsor request, 
• 
Subject non-adherence to study drug dosing or protocol requirements, or 
• 
Pregnancy. 
The reason for study withdrawal is to be documented in the subject’s source documents and CRF. 
Withdrawn subjects may be replaced at the discretion of the Sponsor. 
Subjects who prematurely discontinue from the study should be seen as soon as possible for 
Week 24 assessments (Part 1:Table ; Part 2:Table 2). 
For subjects who are lost to follow-up (i.e., those subjects whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the Investigator should show 
due diligence by documenting in the source documents all steps taken to contact the subject 
(e.g., dates of telephone calls, registered letters, etc.). 
5 
STUDY TREATMENT 
5.1 Description of Study Treatment 
 
 
 
 
 
 
 
 
  
 
 
5.2 Packaging and Labeling 
  
Labels will be in the local language and comply with the legal requirements of each country.  
Clinical supplies are to be dispensed only in accordance with the protocol.  Study drug labels will 
not bear any statement that is false or misleading in any manner or represent that the study drug 
is safe or effective for the purposes for which it is being investigated.   
5.3 Study Drug Storage  
Study drugs must be received by a designated person at the study site, handled and stored safely 
and properly, and kept in a secured location.  
 
   


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5.4 Study Drug Accountability 
The Investigator or designee will maintain accurate records of receipt and condition of study drug, 
including dates of receipt. In addition, accurate records will be kept of the date dispensed, quantity 
dispensed, and the subject to whom study drug was dispensed. Any reasons for departure from 
the protocol-specified dispensing regimen must also be recorded. 
The Investigator or designee is responsible for monitoring the inventory of study drug and for the 
accountability of all used and unused study drug.  Drug accountability will be verified by the study 
monitor during site visits and at the completion of the trial.   
Refer to the Pharmacy Manual for additional details. 
5.5 Study Drug Retention  
Study drug must be retained until completion or termination of the study, and written authorization 
from the Sponsor has been received. All unused and used study drug should be destroyed at the 
site or returned to the distributor, as specified by Sponsor. It is the Investigator’s responsibility to 
ensure that the Sponsor has provided written authorization prior to return or destruction, and that 
appropriate records of the disposal are documented and maintained. No used or unused study 
drug may be disposed until fully accounted for by the study monitor. 
5.6 Treatment Administration 
The target efficacy and treatment areas will be identified by the Investigator as noted below.  The 
Investigator will apply the initial dose of study drug and at designated timepoints when study drug 
will be applied to expanded treatment areas.  These applications will be observed by the subject 
and caregiver at the study center.  Thereafter, subjects or caregivers will apply subsequent doses 
throughout the duration of the study.   
A 
standard 
amount 
of 
study 
drug 
for 
the 
percent  
BSA under treatment will be measured and applied to the treatment area once daily to achieve a 
dose of approximately 8 mg/cm2, with each application administered approximately 24 hours 
apart. Study drug should only be administered to the treatment area, as directed by the 
Investigator, during the study.   
Subjects or caregivers are required to wear protective gloves during application and thoroughly 
wash their hands after application to prevent study drug exposure.   
At scheduled study visits at the site, subjects may not bathe or apply study drug or as-needed 
topical symptom control therapy (emollients) to the treatment area within 12 hours of examination 
or photographic assessment.  Subjects should refrain from applying as-needed topical symptom 
control therapy and bathing within 4 hours of applying study drug to the treatment area.  The 
treated area should be covered by loose clothing to minimize light exposure.  
Target Efficacy Area used for the primary endpoint assessment in Part 1 and Part 2 will be based 
on one of the body sites as defined in the VIIS tool (upper back, upper arm or lower leg/shin)1 that 
has a VIIS scaling severity score of Grade 2 or higher as assessed by the Investigator. The body 
                                               
 
1 Dorsal foot cannot be selected as the target efficacy area. 


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site with the worse VIIS scaling severity score should be selected, if applicable.  The target 
efficacy area will be used for all efficacy analyses. 
Treatment Area will be determined by the Investigator as follows: 
In Part 1, the initial treatment area will be defined as approximately 20% BSA with Grade 2 or 
higher on the VIIS scaling severity score, on one-half of the body, left or right side, and will include 
the target efficacy area. From Week 1 through Week 12, study drug will be applied in the initial 
treatment area. 
If the Investigator determines that there are no safety or tolerability issues at the end of Week 12, 
the treatment area will increase to all of the affected areas of ichthyosis on one-half of the body 
(approximately 40-45% BSA in a typical SLS patient), left or right side.  From Week 13 through 
Week 20, the study drug will be applied to the extended treatment area affected by ichthyosis. 
If there are still no safety or tolerability issues at the end of Week 20, the treatment area will further 
increase to all affected areas of ichthyosis on the entire body (approximately 80-90% BSA in a 
typical SLS patient).  From Week 21 through Week 24, the study drug will be applied to the entire 
body affected by ichthyosis.   
For example, if the left lower leg is determined by the Investigator to be the target efficacy area, 
then the entire left leg would likely be defined as the initial treatment area.  At the end of Week 12, 
if there are no safety or tolerability issues, the treatment area would extend to the entire left side 
of the body.  At the end of Week 20, if there are no safety or tolerability issues, the treatment area 
would include the entire body. 
In Part 2, the treatment area will be defined as all affected areas of ichthyosis on the body 
(approximately 80 – 90% of BSA in a typical SLS patient).  Subjects will be treated for 24 weeks 
followed by a safety follow-up visit 4 weeks after the end of dosing.   
Refer to the Pharmacy Manual for detailed information regarding treatment administration. 
5.7 Concomitant Therapy and Procedures 
5.7.1 Prohibited Concurrent Therapies and Procedures 
The following therapies are prohibited during study participation: 
• 
Systemic or topical retinoids or other topical medications, not including emollients  
• 
Immunosuppressive therapy, including intermittent or low-dose systemic corticosteroids 
5.7.2 Allowed Concurrent Therapies and Treatment 
5.7.2.1 Standard of Care  
During the study, emollients used as standard of care may be applied to other areas of the body 
affected by ichthyosis not being treated with study drug.   
Subjects may apply as-needed topical symptom control therapy (emollients) to areas of the body 
being treated with study drug.  As-needed therapy should not be applied within 4 hours of applying 
study drug.  At scheduled study visits at the site, subjects may not apply as-needed topical 
symptom control therapy to the treatment area within 12 hours of examination or photographic 
assessment.   


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5.8 Restrictions 
5.8.1 Bathing  
Subjects should refrain from bathing 4 hours after applying study drug to the treatment area. 
On scheduled study visits at the site, subjects should refrain from bathing for at least 12 hours 
prior to obtaining digital photographs.   
5.9 Treatment Compliance 
To evaluate the safety, tolerability, PK, pharmacodynamic (PD), and exploratory activity of the 
study drug, it is critical that subjects and caregivers apply the study drug as directed.  Subjects 
and caregivers will be trained on proper study drug application by watching the Investigator apply 
the initial dose of study drug.  Subjects and caregivers will also be given detailed instructions on 
how to measure the amount of study drug to apply to the treatment area.   
A dosing diary will be used to record the amount, date and time of each study drug application 
and any missed doses of the study drug. The reason for the missed doses must be documented. 
The dosing diary and all used and unused study drug will be brought to the designated study visits 
to assess compliance with the protocol. Qualified study personnel will review the information with 
the subject and caregiver.  
6 
STUDY PROCEDURES 
Study assessments and evaluations should be performed by the Investigator and/or qualified 
study personnel according to Study Activities (Section 7).  Unless specified otherwise, procedures 
listed will be performed in both Part 1 and Part 2.  Refer to the Study Activities Schedule for Part 1 
(Table 1) and Part 2 (Table 2).   
6.1 Informed Consent / Assent 
Informed consent and assent forms must be approved for use by the reviewing Institutional 
Review Board (IRB)/Research Ethics Board (REB)/Independent Ethics Committee (IEC).  
Informed consent, and assent when applicable, must be obtained for all subjects participating in 
the study prior to performing any study procedures.  The informed consent process must be 
adequately documented in the source records. 
6.2 Eligibility Review 
The Investigator or qualified study personnel will confirm that all inclusion and exclusion criteria 
have been met. 
6.3 Demographics and Medical History 
Demographic information to be captured include subject initials (where locally permitted), date of 
birth (alternatively year of birth, if full date of birth is not allowed to be collected for legal reasons), 
age, sex, race and ethnicity will be obtained from the subject and recorded in the CRF. 
Medical history will be recorded in the CRF and will include information relating to any prior to 
existing medical conditions involving the following disease types or systems: infectious diseases, 
allergic, metabolic/endocrine/nutritional, hematopoietic, musculoskeletal, dermatologic, head, 


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eyes, 
ears, 
nose 
and 
throat 
(HEENT), 
breasts, 
respiratory, 
cardiovascular, 
gastrointestinal/hepatic, genitourinary/renal, neurological, and psychiatric/psychosocial.   
This will also include date and/or age of diagnosis of SLS, genotype, and all prior treatments for 
SLS. The presence or absence of SLS symptoms, including motor disability in the arms and/or 
legs, foot deformity, speech disorder, seizures, and photophobia, are to be documented. The 
location and nature of ichthyosis and presence and intensity of associated symptoms, including 
scaling, pruritus, and erythema, are to be documented. 
6.4 Concomitant Medications 
Concomitant medications used 30 days prior to consent/assent to treat any medical conditions 
will be recorded in the CRF.  Any changes in dosage or new medications added must be recorded 
in the subject’s CRF. The Sponsor and Investigator or qualified study personnel will review and 
evaluate concomitant medication usage on an ongoing basis. 
6.5 Adverse Events 
AEs will be collected from the time the subject signs the informed consent form through 30 days 
after the last dose of study drug.  AEs must be recorded in the subject’s CRF.  The Sponsor and 
Investigator or qualified study personnel will review and evaluate adverse events on an ongoing 
basis. See Section 9 for further detail on AE reporting. 
6.6 Electrocardiography / Holter Monitoring 
A standard 12-lead ECG (single recording) will be collected at the designated timepoints at 
specific scheduled visits.  Refer to Table 1-1 and 2-1 for details of these timepoints.  The date 
and time of each ECG and its results will be documented in the source documents and CRF.     
A Holter monitor will record ECG activity for 12 hours at specific scheduled visits in Part 2 only.  
The date and time and results of the monitoring will be documented in the source documents and 
CRF. 
Both ECGs and Holter data will be sent to a central reader for assessment. 
6.7 Vital Signs 
Vital sign assessments will be taken with the subject in the sitting or supine position after 
5 minutes at rest and will include body temperature, heart rate (HR), blood pressure (BP) and 
respiratory rate (RR).  
6.8 Physical Examination 
A complete physical examination including height, weight and BSA, will be conducted for all 
subjects during the Screening Visit in Part 1 and Part 2 only.  The complete physical examination 
should include the following systems: HEENT, respiratory, cardiovascular, gastrointestinal, 
hepatic, 
musculoskeletal, 
neurological, 
metabolic/endocrine/nutritional, 
hematopoietic, 
psychiatric/psychosocial, genitourinary/renal, allergies, breasts, infectious disease, and general 
appearance.  Dermatological examinations should be conducted as per Section 6.12. 
Symptom-directed physical examinations will be conducted for all other designated study visits. 


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6.9 Visual Index for Ichthyosis Severity  
The Investigator will utilize the VIIS tool to evaluate the scaling and erythema components of 
ichthyosis in each body site/region (upper back, upper arm, lower leg/shin, and dorsal foot) as 
define in the VIIS scale.   
At baseline, two Investigators should administer the VIIS in Part 2. 
6.10 Clinician Global Impression of Severity  
The Investigator will rate the severity of a subject’s ichthyosis on a 5-point scale. 
6.11 Patient-/Caregiver-Reported Scales  
At designated site visits, subjects 12 years of age and older with proper cognitive and expressive 
capacity will rate their experience on the scales listed.  In addition, for all subjects, the caretaker 
will rate on a similar scale their observation of the subject’s experience. 
• 
EQ-5D-5L (Patient/Proxy) 
• 
Patient-Reported Itching 
• 
Patient/Observer-Reported Scratching 
• 
Patient/Observer Global Impression of Severity  
• 
Patient/Observer Global Impression of Bother  
• 
Patient/Observer Global Impression of Treatment  
• 
Patient/Observer-Reported Burden of Bathing/Showering  
• 
Children's Dermatology Life Quality Index / Dermatology Life Quality Index  
6.12 Dermatologic Exam 
A complete dermatological exam will be performed during the designated study visits.   
The VIIS scaling severity scale will be utilized to document ichthyosis. 
6.13 Digital Photography 
Photography equipment and services will be provided by the photography vendor, Canfield 
Scientific (Parsippany, NJ) to document cutaneous disease using a series of half-body images 
(anterior and posterior, from neck down and from feet up) to document the extent of involvement 
as well as close-up views of select target area(s) at required visits.  Additional images may be 
taken if there are any safety concerns.  For standardization across investigative sites and visits, 
all study photographs will be captured using the equipment, supplies, and guidelines provided by 
Canfield.  Images will be uploaded to a secure website hosted by Canfield and monitored for 
technical quality.  Detailed instructions for all aspects of the photography procedures will be 
supplied separately in the Investigator user manuals to be provided by Canfield. 
Prior to obtaining digital photographs at the study site, subjects should refrain from bathing and 
applying study drug or as-needed topical symptom control therapy (emollients) to the treatment 
area within 12 hours of photographic assessment.   


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6.14 Pharmacodynamic Assessments 
6.14.1 Skin Cell Samples 
Skin cell samples for exploratory biomarker analyses will be collected from the target treatment 
area of using a non-invasive tape-stripping method.   
The sampling site must not be cleaned with water, detergents, or solvents prior to collection of 
skin samples.  Full details of equipment and procedures for skin cell sample collection will be 
listed in the Laboratory Manual.   
6.14.2 Transepidermal Water Loss  
TEWL will be measured during the study.  Full details of equipment and procedures for TEWL 
measurement will be listed in the Laboratory Manual. 
6.15 Clinical Laboratory Tests 
Full details of equipment and procedures for laboratory testing will be listed in the Laboratory 
Manual.   
 
The amount of blood drawn assessments from adult subjects for clinical laboratory testing and 
PK will not exceed 450 mL over any eight-week period. The amount of blood drawn in pediatric 
subjects will not exceed 8 mL/kg over any eight-week period. 
6.15.1 Laboratory Parameters 
Samples of blood and urine will be collected for clinical laboratory tests which includes general 
safety parameters (hematology, serum chemistry, and urinalysis) and pregnancy tests. 
Blood samples for laboratory assessments will be collected at the site by the Investigator, or 
qualified study personnel.   
Samples collected at the Screening Visit may be analyzed at a local lab.  All other samples will 
be shipped to a central laboratory.  Full details of equipment and procedures for laboratory testing 
will be listed in the Laboratory Manual.   
The Investigator must categorize all abnormal urine, hematology and chemistry laboratory values 
as either clinically significant (CS) or not clinically significant (NCS). Clinical significance is defined 
as any variation in laboratory parameters, which has medical consequences that result in an 
alteration in the subject’s medical care. In case of CS laboratory results, the Investigator will 
continue to monitor the subject with additional laboratory assessments until values have reached 
normal range and/or baseline levels. CS laboratory results should be reported as an adverse 
event in accordance with Section 9. 
Biological material will be stored and secured in a manner that ensures that unauthorized access 
is prohibited and the samples are not lost, allowed to deteriorate, or accidentally or illegally 
destroyed. 
6.15.1.1 Hematology 
Hematology profile includes hemoglobin, hematocrit, red blood cell (RBC) count, RBC 
morphology, white blood cell (WBC) count with differential, mean corpuscular volume (MCV), 


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mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and 
absolute platelet count. 
6.15.1.2 Chemistry 
Serum chemistry profile includes albumin, alkaline phosphatase (ALP), alanine aminotransferase 
(ALT; SGPT), aspartate aminotransferase (AST; SGOT), bilirubin (total and direct), blood urea 
nitrogen (BUN), calcium, carbon dioxide (CO2), chloride, creatinine, creatinine phosphokinase 
(CPK), glucose, phosphate, potassium, sodium, total protein, and uric acid. 
6.15.1.3 Urinalysis 
Urinalysis includes bilirubin, glucose, ketones, blood, nitrite, pH, protein, specific gravity, and 
microscopy (if indicated by macroscopic findings). 
6.15.1.4 Pregnancy Test 
For female subjects of child-bearing potential, a urine pregnancy test will be collected.  Results 
must be available and confirmed to be negative before the subject may be enrolled in the study. 
Study drug must be discontinued for any subject with a positive pregnancy test result.  
6.16 Pharmacokinetic Assessments 
Blood and urine samples will be collected to evaluate the levels of ADX-102 and its metabolites.  
In Part 1, samples will be obtained from all subjects.  In Part 2, samples will be obtained from 
approximately 16 subjects. 
Refer to Table 1-1 and Table 2-1 for details of PK collection timepoints.  Full details of equipment 
and procedures for laboratory testing will be listed in the Laboratory Manual.   
6.17 Randomization  
After eligibility is confirmed, subjects will be randomized as described in Section 3.2.2..   
6.18 Study Drug Treatment 
Refer to Section 5.6 for details on study drug treatment. 
6.18.1 Study Drug Dispensation and Collection 
Study drug will be dispensed to subjects or caregivers at designated study visits by the 
Investigator, study personnel, or appropriate designees.  In certain cases, subjects will require 
study drug to be shipped.  All used and unused study drug dispensed to subjects or caregivers 
will be collected at designated study visits to assess compliance with the protocol.  The 
requirements for maintaining study drug accountability are provided in Section 5.4.   
Refer to the Pharmacy Manual for additional details. 


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6.18.2 Study Drug Diary 
A dosing diary will be dispensed at the designated study visits to record the date and time of each 
study drug application and any missed doses of the study drug. The reason for the missed doses 
must be documented. Subjects and caregivers will be instructed to bring the completed diary to 
the designated study visits. Study personnel will review the information with the subject and 
caregiver. 
6.19 Home Visits 
Subjects will be visited by a home nurse on designated study visits.  The home nurse will conduct 
the following procedures/assessments: collection of concomitant medication(s), AE(s), and vital 
signs and conduct dermatological exams. Digital photographs will only be taken to document any 
safety-related concerns.  Refer to Section 6.13 for details on digital photography. 
6.20 Site Telephone Check-In  
The Investigator or qualified study personnel are to contact subjects at the designated study visit.  
The following will be conducted over the phone: collection of concomitant medication(s) and 
AE(s). 
6.21 Exit Interview  
Subject exit interviews will be conducted with study participants and/or their caregivers.  The 
actual interviews will be semi-structured in nature, conducted one-on-one, either face-to-face or 
over the telephone, and facilitated by an interviewer trained in qualitative research methods.  Each 
interview will be audio-recorded and transcribed for analysis.  The primary aim of these interviews 
is to enrich understanding of the patient’s disease experience, treatment journey, and treatment 
outcomes; support the development and interpretation of the trials clinical outcome assessments 
(COAs); and inform future trial design.   
7 
STUDY ACTIVITIES FOR PART 1  
Study activities for Part 1 are summarized in the Study Activities Schedule (Table 1).   
7.1 Screening Visit (Day -7 to -1) – Site Visit 
• 
Obtain written informed consent/assent (Section 6.1) 
• 
Review eligibility criteria (Section 6.2) 
• 
Collect demographic information and document medical history (Sections 6.3)  
• 
Record concomitant medications and AEs (Sections 6.4 and 6.5) 
• 
Collect urine sample for urinalysis1 and pregnancy test, if applicable (Sections 6.15.1.3 and 
6.15.1.4) 
                                               
 
1 Samples collected for urinalysis and clinical laboratory tests at the Screening Visit may be analyzed at a 
local lab. 


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• 
12-lead ECG (Section 6.6) 
• 
Collect vital signs (Section 6.7) 
• 
Complete physical examination, including height and weight collection (Section 6.8) 
• 
Complete dermatologic examination (Section 6.12) 
• 
Collect blood samples for hematology and chemistry4 (Sections 6.15.1.1 and 6.15.1.2) 
 
7.2 Baseline Visit 1 (Week 1/Day 1) – Site Visit 
• 
Review eligibility criteria (Section 6.2) 
• 
Record concomitant medications and adverse events (Sections 6.4 and 6.5) 
• 
Collect urine sample for urinalysis and pregnancy test, if applicable (Sections 6.15.1.3 and 
6.15.1.4) 
• 
12-lead ECG (Section 6.6) 
• 
Collect vital signs (Section 6.7) 
• 
Symptom-directed physical exam (Section 6.8)  
• 
Complete dermatologic examination (Section 6.12) 
• 
Take digital photography (Section 6.13) 
• 
Complete VIIS (Section 6.9) 
• 
Complete Global Impression of Severity (Section 6.10) 
• 
Collect Patient/Observer-reported scales (Section 6.11) 
• 
PD sample collection (Section 6.14) 
• 
Collect blood samples for hematology and chemistry (Sections 6.15.1.1 and 6.15.1.2) 
• 
PK sample collection (blood and urine) (Section 6.16) 
• 
Randomization to treatment (Section 6.17) 
• 
Apply study drug to target treatment area1  (Section 5.6) 
7.3 Visit 2 (Week 1/Day 2) – Site Visit 
• 
Record concomitant medications and adverse events (Sections 6.4 and 6.5) 
• 
Collect vital signs (Section 6.7) 
• 
Symptom-directed physical exam (Section 6.8) 
• 
Complete dermatologic examination (Section 6.12) 
• 
Complete VIIS (Section 6.9) 
                                               
 
1 Investigator should apply study drug to the initial treatment area (~20% BSA) during the visit. 


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• 
PD sample collection (Section 6.13) 
• 
PK sample collection (blood only) (Section 6.16) 
• 
Apply study drug to target treatment area1  (Section 5.6) 
• 
Dispense study drug supply and diary (Sections 6.18.1 and 6.18.2) 
7.4 Visits 3 and 4 (Weeks 4 and 8 ± 3 days) – Home Visit (Section 6.19) 
• 
Record concomitant medications and adverse events (Sections 6.4 and 6.5) 
• 
Complete dermatologic examination (Section 6.12) 
• 
Take digital photography (Section 6.13) 
7.5 Visit 5 (Week 12 ± 5 days) – Site Visit 
• 
Collect Patient/Observer-reported scales (Section 6.11) 
• 
Collect study drug supply and diary (Sections 6.18.1 and 6.18.2) 
• 
Record concomitant medications and adverse events (Sections 6.4 and 6.5) 
• 
Collect urine sample for urinalysis and pregnancy test, if applicable (Sections 6.15.1.3 and 
6.15.1.4) 
• 
12-lead ECG (Section 6.6) 
• 
Collect vital signs (Section 6.7) 
• 
Symptom-directed physical exam (Section 6.8) 
• 
Complete dermatologic examination (Section 6.12) 
• 
Take digital photography (Section 6.13) 
• 
Complete VIIS (Section 6.9) 
• 
Complete Global Impression of Severity (Section 6.10) 
• 
PD sample collection (Section 6.14) 
• 
Collect blood samples for hematology and chemistry (Sections 6.15.1.1 and 6.15.1.2) 
• 
PK sample collection (blood and urine) (Section 6.16) 
• 
Apply study drug to target treatment area2 (Section 5.6) 
• 
Dispense study drug supply and diary (Sections 6.18.1 and 6.18.2) 
                                               
 
1 Study drug may be applied to the initial treatment area (~20% BSA) by the Investigator during the visit 
(but after the collection of pre-dose PK samples) or may be applied by the subject/caregiver after the study 
visit. 
2 If treatment area will be expanded up to 45% BSA, Investigator should apply study drug to this expanded 
treatment area during the visit but after the collection of pre-dose PK samples. 


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7.6 Visit 6 (Week 16 ± 3 days) – Home Visit (Section 6.19) 
• 
Record concomitant medications and adverse events (Sections 6.4 and 6.5) 
• 
Complete dermatologic examination (Section 6.12) 
• 
Take digital photography (Section 6.13) 
7.7 Visit 7 (Week 20 ± 5 days) – Site Visit 
• 
Collect Patient/Observer-reported scales (Section 6.11) 
• 
Collect study drug supply and diary (Sections 6.18.1 and 6.18.2) 
• 
Record concomitant medications and adverse events (Sections 6.4 and 6.5) 
• 
Collect urine sample for urinalysis and pregnancy test, if applicable (Sections 6.15.1.3 and 
6.15.1.4) 
• 
12-lead ECG (Section 6.6) 
• 
Collect vital signs (Section 6.7) 
• 
Symptom-directed physical exam (Section 6.8) 
• 
Complete dermatologic examination (Section 6.12) 
• 
Take digital photography (Section 6.13) 
• 
Complete VIIS (Section 6.9) 
• 
Complete Global Impression of Severity (Section 6.10) 
• 
PD sample collection (Section 6.14) 
• 
Collect blood samples for hematology and chemistry (Sections 6.15.1.1 and 6.15.1.2) 
• 
PK sample collection (blood and urine) (Section 6.16) 
• 
Apply study drug to target treatment area1 (Section 5.6) 
• 
Dispense study drug supply and diary (Sections 6.18.1 and 6.18.2) 
7.8 Visit 8 (Week 24 ± 5 days) – Early Termination – Site Visit 
• 
Collect Patient/Observer-reported scales (Section 6.11) 
• 
Collect study drug supply and diary (Sections 6.18.1 and 6.18.2) 
• 
Record concomitant medications and adverse events (Sections 6.4 and 6.5) 
• 
Collect urine sample for urinalysis and pregnancy test, if applicable (Sections 6.15.1.3 and 
6.15.1.4) 
• 
12-lead ECG (Section 6.6) 
                                               
 
1 If treatment area will be expanded up to 90% BSA, Investigator should apply study drug to this expanded 
treatment area during the visit but after the collection of pre-dose PK samples. 


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• 
Collect vital signs (Section 6.7) 
• 
Symptom-directed physical exam (Section 6.8) 
• 
Complete dermatologic examination (Section 6.12) 
• 
Take digital photography (Section 6.13) 
• 
Complete VIIS (Section 6.9) 
• 
Complete Global Impression of Severity (Section 6.10) 
• 
PD sample collection (Section 6.14) 
• 
Collect blood samples for hematology and chemistry (Sections 6.15.1.1 and 6.15.1.2) 
• 
PK sample collection (blood and urine) (Section 6.16) 
7.9 Visits 9 (Week 28 ± 3 days) – Safety Follow-up - Home Visit (Section 6.19) 
• 
Record concomitant medications and adverse events (Sections 6.4 and 6.5) 
• 
Complete dermatologic examination (Section 6.12) 
• 
Take digital photography (Section 6.13) 
8 
STUDY ACTIVITIES FOR PART 2  
Study activities for Part 2 are summarized in the Study Activities Schedule (Table 2). 
8.1 Screening Visit (Day -7 to -1) – Site Visit 
• 
Obtain written informed consent/assent (Section 6.1) 
• 
Review eligibility criteria (Section 6.2) 
• 
Collect demographic information and document medical history (Sections 6.3)  
• 
Record concomitant medications and adverse events (Sections 6.4 and 6.5) 
• 
Collect urine sample for urinalysis1 and pregnancy test, if applicable (Sections 6.15.1.3 and 
6.15.1.4) 
• 
12-lead ECG (Section 6.6) 
• 
Collect vital signs (Section 6.7) 
• 
Complete physical examination, including height and weight collection (Section 6.8) 
• 
Complete dermatologic examination (Section 6.12) 
• 
Collect blood samples for hematology and chemistry9 (Sections 6.15.1.1 and 6.15.1.2) 
                                               
 
1 Samples collected for urinalysis and clinical laboratory tests at the Screening Visit may be analyzed at a 
local lab. 


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8.2 Baseline Visit 1 (Week 1/Day 1) – Site Visit 
• 
Collect Patient/Observer-reported scales (Section 6.11) 
• 
Review eligibility criteria (Section 6.2) 
• 
Record concomitant medications and adverse events (Sections 6.4 and 6.5) 
• 
Collect urine sample for urinalysis and pregnancy test, if applicable (Sections 6.15.1.3 and 
6.15.1.4) 
• 
12-lead ECG and Holter monitoring (Section 6.6) 
• 
Collect vital signs (Section 6.7) 
• 
Symptom-directed physical exam (Section 6.8) 
• 
Complete dermatologic examination (Section 6.12) 
• 
Take digital photography (Section 6.13) 
• 
Complete VIIS (Section 6.9) 
• 
Complete clinician-reported global impression of severity scale (Section 6.10) 
• 
PD sample collection (Section 6.14) 
• 
Collect blood samples for hematology and chemistry (Sections 6.15.1.1 and 6.15.1.2) 
• 
PK sample collection (blood and urine) (Section 6.16) 
• 
Randomize subject (Section 6.18) 
• 
Apply study drug to all areas of ichthyosis (Section 5.6) 
8.3 Visit 2 (Week 1/Day 2) – Site Visit 
• 
Record concomitant medications and adverse events (Sections 6.4 and 6.5) 
• 
Collect vital signs (Section 6.7) 
• 
Symptom-directed physical exam (Section 6.8) 
• 
Complete dermatologic examination (Section 6.12) 
• 
Complete VIIS (Section 6.9) 
• 
PD sample collection (Section 6.14) 
• 
PK sample collection1 (blood only) (Section 6.16) 
• 
Apply study drug to all areas of ichthyosis (Section 5.6) 
• 
Dispense study drug supply and diary (Sections 6.18.1 and 6.18.2) 
8.4 Visit 3 (Week 4 ± 3 days) – Telephone Check-In (Section 6.20) 
• 
Record concomitant medications and adverse events (Sections 6.4 and 6.5) 
                                               
 
1 Study drug may be administered at the study site after pre-dose PK samples have been collected. 


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8.5 Visit 4 (Week 8 ± 5 days) – Site Visit 
• 
Collect Patient/Observer-reported scales (Section 6.11) 
• 
Record concomitant medications and adverse events (Sections 6.4 and 6.5) 
• 
Collect urine sample for urinalysis and pregnancy test, if applicable (Sections 6.15.1.3 and 
6.15.1.4) 
• 
12-lead ECG and Holter monitoring (Section 6.6) 
• 
Collect vital signs (Section 6.7) 
• 
Symptom-directed physical exam (Section 6.8) 
• 
Complete dermatologic examination (Section 6.12) 
• 
Take digital photography (Section 6.13) 
• 
Complete VIIS (Section 6.9) 
• 
Complete clinician-reported global impression of severity scale (Section 6.10) 
• 
PD sample collection (Section 6.14) 
• 
Collect blood samples for hematology and chemistry (Sections 6.15.1.1 and 6.15.1.2) 
• 
PK sample collection1 (blood and urine) (Section 6.16) 
• 
Apply study drug to all areas of ichthyosis (Section 5.6) 
• 
Dispense and collect study drug supply and diary (Sections 6.18.1 and 6.18.2) 
8.6 Visit 5 (Week 12 ± 3 days) – Telephone Check-In (Section 6.20) 
• 
Record concomitant medications and adverse events (Sections 6.4 and 6.5) 
8.7 Visit 6 (Week 16 ± 5 days) – Site Visit 
• 
Collect Patient/Observer-reported scales (Section 6.11) 
• 
Record concomitant medications and adverse events (Sections 6.4 and 6.5) 
• 
Collect urine sample for urinalysis and pregnancy test, if applicable (Sections 6.15.1.3 and 
6.15.1.4) 
• 
Collect vital signs (Section 6.7) 
• 
Symptom-directed physical exam (Section 6.8) 
• 
Complete dermatologic examination (Section 6.12) 
• 
Take digital photography (Section 6.13) 
• 
Complete VIIS (Section 6.9) 
• 
Complete clinician-reported global impression of severity scale (Section 6.10) 
                                               
 
1 Study drug may be administered at the study site after pre-dose PK samples have been collected. 


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• 
PD sample collection (Section 6.14) 
• 
Collect blood samples for hematology and chemistry (Sections 6.15.1.1 and 6.15.1.2) 
• 
PK sample collection11 (blood only) (Section 6.16) 
• 
Apply study drug to all areas of ichthyosis (Section 5.6) 
• 
Dispense and collect study drug supply and diary (Sections 6.18.1 and 6.18.2) 
8.8 Visit 7 (Week 20 ± 3 days) – Telephone Check-In (Section 6.20) 
• 
Record concomitant medications and adverse events (Sections 6.4 and 6.5) 
8.9 Visit 8 (Week 24 ± 5 days) – Early Termination – Site Visit 
• 
Collect Patient/Observer-reported scales (Section 6.11) 
• 
Record concomitant medications and adverse events (Sections 6.4 and 6.5) 
• 
Collect urine sample for urinalysis and pregnancy test, if applicable (Sections 6.15.1.3 and 
6.15.1.4) 
• 
12-lead ECG and Holter monitoring (Section 6.6) 
• 
Collect vital signs (Section 6.7) 
• 
Symptom-directed physical exam (Section 6.8) 
• 
Complete dermatologic examination (Section 6.12) 
• 
Take digital photography (Section 6.13) 
• 
Complete VIIS (Section 6.9) 
• 
Complete clinician-reported global impression of severity scale (Section 6.10) 
• 
PD sample collection (Section 6.14) 
• 
Collect blood samples for hematology and chemistry (Sections 6.15.1.1 and 6.15.1.2) 
• 
PK sample collection (blood and urine) (Section 6.16) 
• 
Collect study drug supply and diary (Sections 6.18.1 and 6.18.2) 
• 
Conduct Subject Exit Interview1 (Section 6.21) 
8.10 Visit 9 (Week 28 ± 5 days) – Safety Follow-up – Site Visit 
• 
Collect Patient/Observer-reported scales (Section 6.11) 
• 
Record concomitant medications and adverse events (Sections 6.4 and 6.5) 
• 
Complete dermatologic examination (Section 6.12) 
• 
Take digital photography (Section 6.13) 
                                               
 
1 Subject Exit Interview should be conducted within 30 days of the scheduled visit. 


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• 
Complete VIIS (Section 6.9) 
• 
Complete Global Impression of Severity (Section 6.10) 
9 
ADVERSE EVENT REPORTING 
AEs will be collected from the time the subject signs the informed consent form through 30 days 
after the last study drug administration. 
9.1.1 Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a study drug and which does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of the study drug, 
whether or not it is considered related to the study drug.  
Abnormal laboratory and other abnormal investigational findings (i.e., physical exam) should not 
be reported as AEs unless they are associated with clinical signs and symptoms, lead to treatment 
discontinuation or are otherwise considered clinically relevant by the Investigator.  In cases of 
surgical or diagnostic procedures, the condition/illness leading to such a procedure is considered 
as the AE rather than the procedure itself.  In case of a fatality, the cause of death is considered 
as the AE, and the death is considered as its outcome. 
9.1.1.1 Events Not to Be Considered as Adverse Events 
Pre-existing medical conditions/signs/symptoms present before the Screening Visit that do not 
worsen in severity or frequency during the study are defined as baseline medical conditions, and 
are not to be considered AEs. 
Pregnancies are not considered AEs but must be reported, see Section 9.1.8. 
9.1.1.2 
Recording Adverse Events 
All AEs must be recorded in the site’s study records and the AE CRF.  Investigators should use 
correct medical terminology when recording events and avoid abbreviations.   
The Investigator should attempt to establish a diagnosis of the AE based on signs, symptoms 
and/or other clinical information.  The diagnosis, and not the individual signs/symptoms or 
laboratory abnormalities, should be documented in the subject’s source documents and the CRF 
unless the etiology of the event is unknown.   If signs/symptoms cannot be medically characterized 
as a single diagnosis or syndrome at the time of reporting, each individual event should be 
recorded as an AE.  If a diagnosis is subsequently established, it should be reported as follow-up 
information. 
An assessment should be made at each visit (or more frequently if necessary) of any changes in 
severity, the suspected relationship to study drug, the interventions required to treat it, and the 
outcome. 
9.1.1.3 
Assessment of Causality and Severity 
For each AE recorded, the Investigator will make an assessment of causality and severity as 
follows: 


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1. Relationship to Study Drug:  The Investigator must assess whether they consider an AE 
to be drug-related. In assessing this relationship, the Investigator must use information 
about the drug as outlined in the Investigator’s Brochure, the subject’s pre-existent 
medical conditions/concurrent medication, and chronology of the event relative to drug 
administration. The following definitions will be used: 
• 
Definitely or possibly related applies to those AEs that, after careful medical 
consideration at the time they are evaluated, are considered by the Investigator (or 
other qualified physician) to have at least a possible relationship to study drug. 
• 
Unlikely or not related applies to those AEs that, after careful medical consideration 
at the time they are evaluated, are considered by the Investigator (or other qualified 
physician) to have no relationship, or an unlikely possibility of a relationship, to study 
drug. 
2. Event Severity:  The Investigator will be asked to use their medical judgment to assess 
the severity of the AE. 
The following are guidelines to be used by the Investigator to judge the event severity of 
an AE: 
• 
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 perform usual activity 
• 
Life-Threatening 
3. Duration: Start and end dates and times, or if continuing. 
4. Frequency: whether the event is a single episode, recurrent or continuous. 
5. Action taken. 
6. Whether it constitutes a SAE, per definition below. 
7. Outcome: resolved, resolved with sequelae, continuing, death, or unknown (only for 
subjects that are lost to follow-up). 
9.1.2 Treatment-Emergent Adverse Events 
A TEAE will be an AE that occurred during the study after the first dose of study drug or that was 
present prior to dosing and exacerbates after the first dose of study drug.  
9.1.3 Serious Adverse Events 
An SAE is any AE that results in any of the following outcomes: 
• 
Death: This includes death unrelated to the study drug (e.g., car accident).  If some subject 
dies during the study and an autopsy is performed, autopsy results will become part of the 
subject’s study chart and a copy should be sent to the Sponsor. 
• 
Life-threatening experience: Life-threatening means that the patient was at immediate risk 
of death from the reaction as it occurred (i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form). 
• 
Required or prolonged inpatient hospitalization: Exceptions will be hospitalizations for a) 
elective or preplanned treatment for a pre-existing condition that is unrelated to the 


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indication under study and has not worsened since the start of study drug or b) treatment 
on an emergency outpatient basis for an event not fulfilling any of the definitions of a SAE 
and not resulting in hospital admission.  
• 
Persistent or significant disability/incapacity. 
• 
Congenital anomaly. 
• 
Important medical events that may not result in death, be immediately life threatening, or 
require hospitalization may be considered a SAE when, based upon medical judgment, 
they may jeopardize the patient and may require intervention to prevent one of the 
outcomes listed above. 
9.1.4 Unexpected Adverse Event  
An unexpected adverse event is defined as an AE, the nature or severity of which is not consistent 
with the information in the Investigator’s Brochure. 
9.1.5 Reporting Serious Adverse Events 
The Investigator is responsible for reporting all SAEs, regardless of causality, to the Sponsor 
designee within 24 hours of learning of the occurrence. SAEs should be sent to: 
 
 
(Local toll-free numbers will be provided on the SAE report form cover sheet.)   
The reporting timeframe starts when the subject signs the informed consent or assent form 
through 30 days after the last study drug administration. At a minimum, a description of the event 
and the Investigator’s judgment of causality must be provided at the time of the initial report. 
These preliminary reports will be followed by detailed descriptions that will include copies of 
hospital case reports, autopsy reports, and other documents when requested and applicable. 
A follow-up SAE Report must be submitted within 24 hours of the Investigator receiving the 
follow-up information (such as information regarding complications, progression or resolution).   
An SAE that is considered completely unrelated to a previously reported event should be reported 
separately as a new SAE. 
The procedures for reporting SAEs are as follows: 
• 
Complete the “Serious Adverse Event Report Form.”  The Investigator may contact 
Pharmacovigilance via the telephone hotline for assistance with SAE reporting. 
• 
Fax or email the SAE Form to the attention of Pharmacovigilance within 24 hours of 
the Investigator’s knowledge of the event.  
The original copy of the SAE Report Form and the fax confirmation sheet (or email) must be kept 
with the source documentation at the study site. 
Follow-up information should be communicated the same way, using a new SAE Report Form 
stating that it is a follow-up to the previously reported SAE and giving the date of the original 
report. The follow-up information should describe whether the event has resolved or continues, if 
and how it was treated, and whether the subject continued or withdrew from study participation.  
The Investigator and study personnel should institute any supplemental investigations of SAEs 
based on their clinical judgment of likely causative factors. This may include clinical laboratory 


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tests not specified in the protocol, histopathologic examinations, or consultations with specialists. 
The Sponsor or their designee may also request the Investigator to conduct supplemental 
assessments.  
If the SAE was not previously documented in the Investigator’s Brochure and is thought to be 
related to study drug, the Sponsor or their designee may urgently require further information from 
the Investigator for regulatory authority reporting. The Sponsor may need to issue an Investigator 
Notification to inform all Investigators involved in any study with the same drug that this SAE has 
been reported. 
The Investigator should notify Pharmacovigilance of any death or SAE occurring after a subject 
has withdrawn from the study when such a death occurs within 30 days of the last dose of study 
drug and may reasonably be related to the study drug. 
9.1.6 Follow-up of Adverse Events 
All AEs will be followed until stabilization/resolution or until clinical database lock.   
All SAEs will undergo active follow-up until resolved or the event becomes chronic or stable.  
Follow-up data for SAEs obtained after clinical database lock will be incorporated into the safety 
database.  
9.1.7 Reporting Serious Adverse Events to Regulatory Health Authorities/ Institutional 
Review Boards/Research Ethics Boards/Independent Ethics Committees 
The Investigator is responsible for following all local regulations for the reporting of safety 
information, including the reporting of SAEs to their local IRB/REB/IEC. 
The Investigator must promptly report to his or her local IRB/REB/IEC all unanticipated problems 
involving risks to subjects.  This includes death from any cause and all serious adverse events 
reasonably or possibly associated with the use of study drug.   
The Sponsor or their designee is responsible for appropriate reporting of relevant AEs, suspected 
unexpected serious adverse reactions (SUSARs) involving study drug, to all regulatory 
authorities.  
In addition, the Sponsor or designee will be responsible for the submission of safety letters 
(e.g., SUSARs) to the central IRB/REB/IEC and to participating Investigators of all SUSARs 
involving study drug according to applicable regulations.  
After termination of the clinical study (determined as last subject, last visit), any unexpected safety 
issue that changes the risk-benefit analysis and is likely to have an impact on the subjects who 
have participated in it, will be reported by the Sponsor as soon as possible to the competent 
authority(ies) concerned together with proposed actions. 
9.1.8 Reporting Pregnancies 
Pregnancies will be reported from the time the subject signs the informed consent form through 
final study visit or 30 days after the last study drug administration, whichever is later. 
To ensure subject safety, each pregnancy in a subject on study drug must be reported to 
Pharmacovigilance within 24 hours of learning of its occurrence.  Subjects who become pregnant 
will be withdrawn from the study.  The pregnancy should be followed up to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or absence 
of any birth defects, congenital abnormalities, or maternal and/or newborn complications.  


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Pregnancy should be recorded on a subject’s source documents and a Pregnancy Notification 
and Outcome Form and reported by the Investigator to Pharmacovigilance using the same 
procedure for reporting SAEs detailed in Section 9.1.5. A pregnancy, by itself, is not an SAE.   
Pregnancy follow-up should also be recorded and should include an assessment of the possible 
relationship to the study drug of any pregnancy outcome. Any pregnancy-related SAE 
(e.g., spontaneous abortion, birth defect) or any other SAE experienced during pregnancy must 
be recorded on a separate SAE Report Form and reported per SAE reporting procedures in 
Section 9.1.5. 
10 STATISTICS 
Part 1 and Part 2.  Safety data will be systematically reviewed throughout Part 1 and Part 2 of 
the study by the independent, unblinded DSMB. Statistical analyses for Part 1 and Part 2 will be 
described a priori in a Statistical Analysis Plan (SAP) generated prior to Part 1 database lock.  
Any post-hoc analyses in either of the Part 1 or Part 2 final reports will be clearly labeled as such.  
Because both Part 1 and Part 2 will evaluate active treatment and vehicle subjects randomly 
assigned under a 2:1 active to vehicle schedule, it is anticipated that the Part 1 and Part 2 final 
reports will present a common set of analyses except for an additional sample size calculation in 
Part 1.  Efficacy and Safety parameters will be statistically evaluated under separate final reports 
for Part 1 and for Part 2 of the study.   
Part 1. Statistical analyses for Part 1 will address both efficacy and safety.  Both safety and 
efficacy data obtained throughout the Part 1 period will be evaluated at the end of Part 1 by the 
sponsor and/or a contracted statistical organization, both of whom will have remained blinded 
until Part 1 data lock.  The limited sample size of Part 1 may confine certain analyses to the 
descriptive aspect of the evaluation due to a limited sample size (i.e., inferential p-values may be 
omitted). Unblinded Part 1 safety and efficacy results will be available to the Sponsor for 
administrative consideration and use upon completion of Part 1.  Efficacy data will be used to 
generate a sample size estimation for Part 2 as well as to perform between groups and within 
group descriptive and inferential statistical analyses.  Baseline to ending Part 1 change scores for 
the primary efficacy endpoint (VIIS scaling severity) will be used to calculate a Part 2 samples 
size under the assumption of a mean change score of .5 units, a standard deviation obtained 
during Part 1, an alpha of 0.05 and a power of 90%.  The sample size will be based on the initial 
target efficacy area that will have been selected at the beginning of Part 1 and independently 
evaluated over the 24-week course of the Part 1 study period.  Assuming the absence of a safety 
impairment, the existence of a mean active treatment change score near or greater than 0.5 units, 
and recruitment feasibility of the estimated sample size, the Sponsor will instigate Part 2 of the 
trial.      
Part 2.  Statistical analysis of all Part 2 data will be carried out at the end of Part 2 by the Sponsor 
and/or a contracted statistical organization, both of whom will have remained blinded until Part 2 
data lock.  Part 2 analyses will be independent of Part 1 analyses with respect to efficacy 
parameters and will be used exclusively to support the sponsor’s claim.  However, at the end of 
Part 2, all available safety data will be stratified by Part 1 and Part 2 and presented in the Part 2 
final report by stratum and overall. 
 


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10.1 Sample Size 
Part 1 of the study will assess the effect size on the VIIS scaling severity score with ADX-102 1% 
topical dermal cream, and will confirm the sample size needed for Part 2. Part 2 is expected to 
require approximately 30 subjects. 
The approximate number of 30 subjects for Part 2 was based on the NS-003 Phase 2 study which 
used the ISS endpoint. The mean ISS Scaling sub-score change from baseline was -0.7 with a 
standard deviation of 0.52.  Conservatively, the change was set to -0.5 and the standard deviation 
to 0.6.  A sample size of 20 achieves 94% power to detect a difference of 0.5 between the null 
hypothesis mean of 0.0 and the alternative hypothesis mean of -0.5 with an estimated standard 
deviation of 0.6 and with a significance level (alpha) of 0.05 using a two-sided one-sample t-test.  
If the above assumptions remain, except that the standard deviation is increased to 0.7, then a 
sample size of 20 achieves a power of 85%.  The sample size of 30 is therefore based on these 
estimates requiring 20 subjects to be treated with ADX-102 1%.  As subjects will be randomized 
in a 2:1 ratio, 10 subjects will be treated with vehicle.   
10.2 Analysis Populations 
The statistical analysis will be based on the analysis populations as defined below 
Safety Population 
All randomized subjects who use at least one dose of study 
drug, regardless of whether they undergo any study 
assessments. 
Intent-to-Treat (ITT) Population 
All randomized subjects who use at least one dose of study 
drug and have any post-dose assessments.  Subjects are 
evaluated according to the study drug to which they are 
randomized. 
Per-Protocol (PP) Population 
All ITT subjects will be considered PP if they dose with study 
drug and do not deviate from the protocol. 
The following is a list of protocol violations which would exclude subjects from the PP population:   
• 
Subject did not receive study drug as assigned. 
• 
Subject did not meet all inclusion/exclusion criteria. 
10.3 Accountability and Background Characteristics 
10.3.1 Enrollment and Disposition 
The number of subjects enrolled, by study population and Investigative site, will be presented by 
treatment group.  The primary reasons for discontinuation will be summarized by treatment and 
based on the safety population.  The number and percentage of subjects with protocol deviations 
or subjects requiring rescue therapy leading to exclusion from the PP population will be presented 
by reason for exclusion, stratified by treatment.  All deviations and rescued subjects will be listed. 
10.3.2 Subject Characteristics 
Subject characteristics will be obtained at the Screening prior to randomization and will be 
summarized by treatment group and overall.  Summaries will include descriptive statistics for 


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continuous measures (sample size, mean, standard deviation [SD], median, minimum, maximum) 
and for categorical measures (sample size, frequency and percentages).   
Subject characteristics will be summarized on all study populations. 
10.3.3 Treatment Compliance  
Treatment compliance will be assessed in terms of the actual dose.  Treatment compliance will 
be used to characterize the subjects and determine clinical evaluability for some analyses.  
Treatment compliance will be summarized within each treatment group by means of descriptive 
statistics (sample size, mean, SD, median, minimum and maximum). 
10.4 Efficacy Analyses 
A conclusion concerning efficacy will be based on evaluation of data in Part 2.  A primary efficacy 
analysis will be conducted as well as a number of secondary efficacy analyses. 
The primary efficacy endpoint (VIIS scaling severity as assessed by the Investigator in the target 
efficacy area) as well as all secondary efficacy variables that are captured on a continuous or 
semi-continuous scale (e.g., VIIS erythema score, central reader assessed VIIS scales, 
EQ-5D-5L, clinical global impression of severity, Patient/Observer impression scales, 
Patient-Reported Itching, CDLQI/DLQI, lipid biomarkers and TEWL) will be expressed as baseline 
to ending change scores.  Two-sided 95% confidence intervals (CIs) will be computed and used 
descriptively for all variables but also to evaluate change relative to a standard for some variables 
(i.e., by determining whether the CI includes or excludes the standard).   
The two-sided 95% CI for VIIS scaling severity will serve as the primary analysis and will be used 
to evaluate this primary endpoint as follows. An efficacy claim will be made if: 1) the lower 
confidence interval is above zero, 2) the mid-point of the confidence interval is at least 0.5 units 
is size, and 3) at least 50% of subjects have favorable change scores of one or greater.  
The primary and secondary scores measured on a continuous or semi-continuous scale also will 
be evaluated using Mixed Model Repeated Measures to assess the effects of treatment (active 
vs. vehicle), time (per collection schedule), and treatment x time.  In addition to descriptive 
statistics for the raw data used in each model, the LS means and standard errors will be reported 
for each main effect and interaction, as well as for treatment contrasts (i.e., active LS mean minus 
vehicle LS mean) at each data collection time point.  If informative, covariates may be added to 
one or more models.  Statistical significance unadjusted for multiplicity for main effects, 
interactions and contrasts will be reported.  However, neither the main effect of treatment nor the 
treatment contrasts at time points are expected to be statistically significant (p ≤ 0.05) due to 
power restrictions at the between group level imposed by recruiting realities. 
Response over time will be converted to one or more Area Under the Curve parameters and 
evaluated using a generalized linear model. VIIS outcome scores and other continuous or semi-
continuous outcome variables will be evaluated using a Mixed Model Repeated Measures 
(MMRM) analysis.  Conversion of VIIS or other scales to indicate response (yes/no) will occur 
(e.g., 0.5 VIIS improvement, 1 unit VIIS improvement) and will be evaluated as secondary 
endpoints.  Logistic or Generalized Estimating Equation (GEE) modeling will be used to evaluate 
incidence of response overall and/or by time.  Time to Event analysis (e.g., Kaplan-Meier with log 
rank test, proportional hazards [PH] modeling) will be used to evaluate time to response. 
To increase statistical power, covariates may be incorporated into the computation of 95% 
confidence intervals (e.g., through the use of a mean centered covariate in a regression model to 


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predict the mean pre-treatment to post-treatment difference) and/or incorporated into logistic, 
GEE, PH, MMRM and generalized linear models.  
Categorical variables other than responder status will be descriptively summarized in contingency 
tables.  Selective inferential analysis at each time point or across time points will be conducted 
using non-parametric or exact statistics with or without further stratification as described in the 
SAP.  
10.5 Safety Analyses 
10.5.1 Adverse Events  
The assessment of safety will be determined from dermatological endpoints, vital sign 
measurements, physical examinations, hematology and chemistry laboratory testing, ECG 
readings, use of concomitant medications, and review of adverse events.   
The SAP will contain mock tables for all safety relevant information which will be produced for 
each study part and over the entire study.   
Safety tables will contain by treatment and combined treatments information concerning AEs, 
TEAEs, SAEs, unexpected AEs and clinical safety laboratory values.  Treatment and vehicle 
group safety narratives will be written.  If required a safety narrative will be written for selected 
subjects.  AEs, TEAEs, unexpected AEs and SAEs will be coded according to the Medical 
dictionary for Regulatory Activities (MedDRA) preferred terms.  Tables variously organized by 
preferred terms, system organ class, treatment emergence, treatment relationship, severity and 
study termination will be presented for AEs, TEAEs, unexpected AEs and SAEs.   
Descriptive statistics will be presented by treatment and time for safety laboratory values or in 
change tables for categorized lab variables (e.g., normal vs. abnormal, present vs. absent). Other 
safety information (e.g., normality of dermatological endpoints, normality of vital signs, normality 
of physical examinations, normality of ECG outcomes, concomitant medication usage) will be 
summarized in tables and medically evaluated.  
If inferential analysis for any safety variable seems appropriate, the comparison will be made 
using an appropriate statistical test and designated as post-hoc.  
11 QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor and the Contract Research Organization (CRO) conducting trial management will 
implement a system of quality assurance that includes all elements described in this protocol. 
Within this system, standard operating procedures (SOPs) from the Sponsor and CRO will be 
implemented to ensure that the clinical trial is conducted in compliance with regulatory 
requirements and Good Clinical Practices (GCP). Quality control will be applied to each stage of 
data handling to ensure that data are accurate, reliable and processed correctly.  
12 STUDY ADMINISTRATION 
12.1 Institutional Review Board / Research Ethics Board / Independent Ethics 
Committee  
The protocol and all protocol amendments must be signed and dated by the Investigator and 
approved in writing by the applicable IRB/REB/IEC in accordance with GCP prior to 


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implementation.  In addition, the IRB/REB/IEC must approve the written informed consent and 
assent forms, any consent or assent form updates, subject recruitment procedures 
(e.g., advertisements), and any written information to be provided to subjects prior to 
implementation.  
The Investigator must provide an annual report to the IRB/REB/IEC on the progress of the study 
including number of subjects enrolled, discontinued, and SAEs, unless otherwise specified by the 
IRB/REB/IEC. It is required that a yearly review of the protocol by the IRB/REB/IEC be 
documented in a letter from the IRB/REB/IEC. The Investigator must provide notification to the 
IRB/REB/IEC of the completion, termination or discontinuation of the study. 
The Investigator must supply the Sponsor with copies of all written correspondence with the 
IRB/REB/IEC. 
The Investigator will make all attempts to ensure that the IRB is constituted and operates in 
accordance with regulatory requirements, ICH GCP and any local requirements. 
12.2 Ethical Conduct of the Study 
The clinical study will be carried out in keeping with national and local legal requirements, 
including in accordance with regulatory requirements outlined in Food and Drug Administration 
(FDA) Code of Federal Regulations (CFR) Title 21 [Part 50, Part 54, Part 56, Part 312 and Part 11] 
as well as the ICH GCP E6 Guidelines. This clinical study was designed and shall be implemented 
and reported in accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical 
Practice, with applicable local regulations [including European Directive 2001/20/EC, US CFR 
Title 21], and with the ethical principles laid down in the Declaration of Helsinki.  
12.3 Subject Informed Consent / Assent 
The Sponsor will provide sample Informed Consent and Assent Forms for use in this trial.  Any 
changes to the proposed consent and assent forms suggested by the Investigator must be agreed 
to by the Sponsor before submission to the IRB/REB/EC.  The Investigator or designee will 
provide the Sponsor with a copy of the IRB/REB/IEC-approved informed consent and assent 
forms prior to the start of the study.   
Before each subject is enrolled in the clinical study, written informed consent will be obtained 
according to the regulatory and legal requirements of the participating site. Subjects who are 
under the age of 18 (or lower if age of consent is less than 18 in a specific country) and whose 
legal guardian or caretaker has provided written informed consent will provide their assent to 
participate.  
The subjects should sign the current final IRB/REC/EC approved consent form.  The process of 
obtaining informed consent and assent should be documented in the subject source documents.  
Each Investigator must retain the original signed and dated informed consent and assent forms.  
A copy of the signed and dated informed consent and assent forms will be given to the subject.  
No subject can enter the study, or have study specific assessments performed before his/her 
informed consent has been obtained. 
The Informed Consent and Assent Forms should be revised whenever there are substantial 
changes to procedures or when new information becomes available that may affect the 
willingness of the patient to participate.  Revisions to the consent forms required during the study 
must be approved by the Sponsor, and a copy of the revised consent forms provided to the 
Sponsor. For any updated or revised forms, the subjects must be re-consented for continued 
participation in the study. 


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12.4 Confidentiality 
All study findings and documents will be regarded as confidential.  The Investigator and qualified 
study personnel must not disclose such information without prior written approval from the 
Sponsor. The Investigator agrees not to use or disclose protected health information other than 
as permitted or required by the subject authorization or as required by law. 
Subject confidentiality will be strictly maintained to the extent possible under the law.  Subject 
names must not be disclosed.  Subjects will be identified on the CRFs and other documents 
submitted to the Sponsor by their initials (if locally permissible) and/or assigned subject number; 
not by name.  Documents that identify the subject (e.g., the signed informed consent form) must 
be maintained in confidence by the Investigator. All study documents are provided by the Sponsor 
in confidence to the Investigator and his/her qualified study personnel.  None of this material may 
be disclosed to any party not directly involved in the study without Sponsor’s written permission. 
The Investigator must assure that subjects’ anonymity will be maintained.  The Investigator will 
maintain this for the longest period of time allowed by his/her own institution and, in any case, 
until further communication from the Sponsor. 
12.5 Protection of Subject Data 
The collection and processing of personal data from subjects enrolled in this study will be limited 
to those data that are necessary to investigate the safety, quality, and utility of the investigational 
study drug(s) used in this study and to support the development and interpretation of the trials 
clinical outcomes assessments. 
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of study subjects confidential. 
The informed consent obtained from the subject includes explicit consent for the collection and 
processing of personal data and for the Investigator to allow direct access to his or her original 
medical records for study-related monitoring, audit(s), IRB/REB/EC review, and regulatory 
inspection. This consent also addresses the transfer of the data to other entities and to other 
countries. 
12.6 Study Monitoring 
Prior to initiation of the study at a study site, the Study Monitor, who is an authorized individual 
designated by the Sponsor, will visit the study site to verify the qualifications of the Investigator 
and study team, inspect the adequacy of the facilities and inform the study team of their 
responsibilities and the procedures to ensure proper conduct of the study. During the conduct of 
the study the Study Monitor will visit the sites to verify adherence to the protocol, assess drug 
accountability, data integrity and subject safety. The monitors will conduct 100% source document 
verification of subject data by comparing the CRFs with the source documents to ensure accuracy 
and consistency.  
All aspects of the study will be carefully monitored with respect to GCP and SOPs for compliance 
with applicable government regulations. The Study Monitor will have access to all records 
necessary to ensure integrity of the data and safety of the subject, and will periodically review the 
progress of the study with the Investigator. 


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Frequent communication between the clinical site and the Sponsor is essential to ensure that the 
safety of the study is monitored adequately.  
12.7 Case Report Forms and Source Documents 
An electronic data capture (EDC) system will serve as the data management system for this study.  
The Investigator will be responsible for the accuracy of the data entered in the EDC system and 
ensure that the data collected are accurate and complete.  Data will be monitored within the EDC 
system by the study monitor who has only reading rights. Any changes required following 
monitoring will be made by the Investigator or qualified study personnel and will be documented 
with a full audit trail within the EDC system. The responsible study monitor will check data at the 
monitoring visits to the clinical study site.   
The Investigator or qualified study personnel will prepare and maintain adequate and accurate 
study documents (e.g., medical records, ECGs, AE and concomitant medication reporting, source 
data collection forms, etc.) designed to record all observations and other pertinent data for each 
subject. It is recommended that the author of an entry in the source documents be identifiable. 
Source data may be directly captured from devices, transferred from third parties (e.g., laboratory 
data), or entered manually into the EDC system in use at the clinical center. In such case, many 
of the source data will only be available electronically. The remainder of the data, captured initially 
on paper, may be entered retrospectively into the EDC system. 
For each subject, CRF and corresponding source records will be maintained at each clinical site.  
CRFs should be completed in a timely manner, and every effort should be made to have forms 
completed and current in anticipation of a visit by the Sponsor or designee.  Upon study 
completion, the monitor will arrange for a final review of the study files, after which the file should 
be secured by storage for the appropriate period as specified in Section 13.  
The Investigator will allow the Sponsor or designee(s), contract designees, authorized regulatory 
authority inspectors, and the IRB/REB/IEC to have direct access to all documents pertaining to 
the study.  
12.8 Access to Source Documents and Audits 
Regulatory agencies may request access to all study records, including source documents, for 
inspection and copying, in keeping with country regulations. The Investigator should immediately 
notify the Sponsor of any announced or unannounced regulatory agency inspections. An auditing 
inspection may also be conducted by the Sponsor representative or designee. Any aspect of the 
trial may be subject to audit by the Sponsor and/or inspection by regulatory authorities or the 
IRB/REB/IEC. Such audits/inspections may take place at the Sponsor’s site(s), the CRO, or at 
the clinical sites, including laboratories, pharmacies and any other facilities used for the study.  
The Investigator will permit the designated Sponsor representatives and regulatory bodies to have 
direct access to the source documents to verify data represented in the EDC system.   
12.9 Protocol Deviations and Violations 
Exceptions to the eligibility criteria will not be granted. It is expected that subjects will meet all 
eligibility criteria.  Departures from the protocol should be avoided, unless required for the safety 
of the subject.  Should other unexpected circumstances arise that will require deviation from 
protocol-specific procedures, the Investigator should contact the Sponsor to discuss the 
appropriate course of action.   


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The Investigator should document all protocol deviations/violations in the subject’s CRF and 
source documents or the Investigator Site File, if appropriate. Protocol deviations will be 
documented by the study monitor and will be included in the final clinical study report. Protocol 
deviations should be submitted to IRB/REB/IEC, in accordance with the site’s IRB/REB/IEC 
requirements. 
12.10 Amendments to the Protocol 
To alter the protocol, amendments must be written by the Sponsor and approvals must be 
received from all parties that approved the original protocol (IRB/REB/IEC, and if applicable, the 
local regulatory authorities) before implementation.  Notwithstanding the need for approval of 
formal protocol amendments, the Investigator is expected to take any immediate action required 
for the safety of any subject included in this study, even if this action represents a deviation from 
the protocol.   
The Sponsor may make administrative changes (i.e., changes that do not significantly affect 
subject safety, the study’s scope or scientific quality) without a formal protocol amendment. 
12.11 Discontinuation of the Study 
The Sponsor reserves the right to discontinue this study under the conditions specified in the 
clinical trial agreement. 
12.12 Investigator Responsibilities 
The Investigator(s) should be qualified by education, training, and experience to assume 
responsibility for the proper conduct of the study, should meet all the qualifications specified by 
the applicable regulatory requirement(s), and should provide evidence of such qualifications 
through up-to-date curriculum vitae and/or other relevant documentation requested by the 
Sponsor, the IEC/REB/IRB, and/or the regulatory authority(ies). 
The Investigator is responsible for ensuring that the clinical study is performed in accordance with 
the protocol, current ICH guidelines on GCP, and applicable regulatory and local requirements. 
GCP is an international ethical and scientific quality standard for designing, conducting, recording, 
and reporting studies that involve the participation of human subjects. Compliance with this 
standard provides public assurance that the rights, safety, and well-being of study subjects are 
protected, consistent with the principles that originated in the Declaration of Helsinki, and that the 
clinical study data are credible. 
12.13 Financial Disclosure 
The Investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the Investigator received from the Sponsor. The following 
information is collected: any significant payments from the Sponsor or subsidiaries such as a 
grant to fund ongoing research, compensation in the form of equipment, retainer for ongoing 
consultation or honoraria; any proprietary interest in investigational product; any significant equity 
interest in the Sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998). 
12.14 Registration of Clinical Studies and Disclosure of Results 
The Sponsor or designee will register and/or disclose the existence of and the results of clinical 
studies as required by law. 


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12.15 Publication and Disclosure Policy 
As is customary for multicenter trials, publication by individual study sites or Investigator/Institution 
will not be allowed without the explicit written permission of the Sponsor.  The Sponsor will 
determine authorship of the principal study manuscript(s) in conjunction with the Investigators, in 
abiding with current guidelines and requirements of medical journals. For such manuscript(s), 
masthead roles for Investigators will be determined based on subject enrollment and scientific 
contributions to the study.   
13 RETENTION OF RECORDS 
The Investigator agrees to adhere to the document retention procedures by signing the protocol.  
Essential documents, as listed below, must be retained by the Investigator for as long as required 
by national and international regulations.  The Sponsor will notify the Investigator(s)/institution(s) 
when the study-related records are no longer required.   
Essential documents include but are not limited to: 
• 
IRB/REB/IEC approvals for the study protocol and all amendments 
• 
All source documents and laboratory records 
• 
CRF copies  
• 
Subjects' informed consent / assent forms (with study number and title of trial) 
• 
FDA form 1572 
• 
Any other pertinent study document 
All source documents (e.g., informed consent forms, laboratory reports, progress notes, medical 
histories, physical and diagnostic findings, diagnosis and pharmacy records, study drug 
dispensing/disposition records) that support data in the CRFs of each study subject must be 
retained in the files of the responsible Investigator.   
According to ICH guidelines for GCP, essential documents should be retained for a minimum of 
2 years after the last approval of a marketing application in an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product. However, 
these documents should be retained for a longer period if required by relevant regulatory or legal 
authorities. 
If the responsible Investigator retires, relocates or for any other reason withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The Sponsor representative must be notified in writing of the name and 
address of the new custodian, prior to the transfer. 
No records should be disposed of without written approval of the Sponsor.   
14 REFERENCES 
1. Rizzo WB, S'Aulis D, Jennings MA, Crumrine DA, Williams ML, Elias PM. Ichthyosis in 
Sjögren-Larsson syndrome reflects defective barrier function due to abnormal lamellar body 
structure and secretion. Arch Dermatol Res. 2010 Aug;302(6):443-51. 
2. Rizzo WB. The role of fatty aldehyde dehydrogenase in epidermal structure and function.  
Dermatoendocrinol. 2011 Apr-Jun; 3(2): 91–99. 
3. Rizzo WB. Fatty aldehyde and fatty alcohol metabolism: review and importance for epidermal 
structure and function. Biochim. Biophys. Acta., 2014. 1841(3): 377 - 89. 


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Final Protocol V1.0 17OCT2017  
 
 
 
 
 
 
 
  
 
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4. Rizzo WB, Bailey Z, S’Aulis D., Ergasheva N. Aldehyde Trapping Agent NS2 Blocks 
Formation of Fatty Aldehyde Adducts with Phosphatidylethanolamine and Suggests Potential 
Therapeutic Approach for Sjogren-Larsson Syndrome. [Abstract] Mol Genet and Metab, 2015 
Mar; 114 (3): Page 362A.  
5. Maeda A, Maeda T, Golczak M, Chou S, Desai, A, Hoppel CL, Matsuyama S, Palczewski K. 
Involvement of all-trans-retinal in acute light-induced retinopathy of mice. J Biol. Chem. 2009 
May; 284 (22): 15173-15183. 

SAP_003.pdf: 
Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
This document is proprietary and confidential to Syneos Health 
03.007A.03     
  Syneos Health 
Page 1 of 78 
+Document 
Type: 
Template 
Document ID: 
03.007A.03 
Issue Date:            02 MAY 2016  
Effective Date:    30 MAY 2016  
 
Sponsor Name: 
Aldeyra Therapeutics 
Protocol Number and Title: 
 
ADX-102-SLS-006 
A Phase 3 Randomized, Double Blind, Vehicle 
Controlled, Parallel Group Trial to Evaluate 
the Safety and Efficacy of ADX-102 1% 
Topical Dermal Cream in Subjects with 
Sjögren-Larsson Syndrome (SLS). Part 1 Only. 
 
Protocol Version and Date: 
 
V5.0 28 SEP 2018 
 
Protocol Amendment 
numbers and dates 
 
V4.0 28 AUG 2018 
V3.0 29 JUN 2018 
V2.0 05 APR 2018 
V1.0 17 OCT 2017 
 
 
Syneos Health Project 
Code: 
1009367 
Author(s): 
 
SAP Version: 
1.0 
SAP Version Date:  
07MAR2019 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Aldeyra Therapeutics. 
Acceptance of this document constitutes agreement by the recipient that no information 
contained herein will be published or disclosed without prior written authorization from an 
official of Aldeyra Therapeutics.  However, this document may be disclosed to appropriate 
Institutional Review Board and Ethics Committees or duly authorized representatives of a 
national regulatory authority under the condition that they are requested to keep it confidential. 
In the event of an actual or suspected breach of this obligation, Syneos Health should be notified 
promptly. 
 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
This document is proprietary and confidential to Syneos Health 
03.007A.03     
  Syneos Health 
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Revision History 
 
Version # 
Date 
(dd-mmm-yyyy) 
Document Owner 
Revision Summary 
1.0 
07MAR2019 
 
Part 1 Only SAP Initial Release Version 
 
 




Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
This document is proprietary and confidential to Syneos Health 
03.007A.03     
  Syneos Health 
Page 4 of 78 
 
TABLE OF CONTENTS 
Contents 
CONTENTS .............................................................................................................. 4 
1. 
GLOSSARY OF ABBREVIATIONS ................................................................. 9 
2. 
PURPOSE ...................................................................................................... 11 
2.1. 
Responsibilities ................................................................................................................. 11 
2.2. 
Data Safety Monitoring Board .......................................................................................... 11 
3. 
STUDY OVERVIEW ....................................................................................... 12 
4. 
STUDY PROCEDURES AND FLOWCHART ................................................ 14 
5. 
STUDY OBJECTIVES ................................................................................... 17 
5.1. 
Primary Objective .............................................................................................................. 17 
5.2. 
Secondary Objective(s) ..................................................................................................... 17 
5.3. 
Determination of Sample Size .......................................................................................... 17 
5.4. 
Subject Numbering ............................................................................................................ 17 
5.5. 
Randomization and Blinding ............................................................................................ 17 
5.6. 
Emergency Unblinding ...................................................................................................... 18 
5.7. 
Administration of Study Medication ................................................................................ 18 
6. 
ENDPOINTS .................................................................................................. 20 
6.1. 
Primary Efficacy Endpoint ................................................................................................ 20 
6.2. 
Secondary Efficacy Endpoints ......................................................................................... 20 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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6.3. 
Pharmacokinetic Endpoints ............................................................................................. 20 
6.4. 
Clinical Outcomes Assessment Endpoints .................................................................... 21 
6.5. 
Safety Endpoints ................................................................................................................ 21 
6.6. 
Planned Analyses .............................................................................................................. 21 
7. 
ANALYSIS POPULATIONS .......................................................................... 22 
7.1. 
Enrolled Population ........................................................................................................... 22 
7.2. 
Safety Population ............................................................................................................... 22 
7.3. 
Modified Intent-to-Treat (M-ITT) Population .................................................................... 22 
7.4. 
Per Protocol Population .................................................................................................... 22 
7.5. 
Pharmacokinetic (PK) Population .................................................................................... 23 
7.6. 
Protocol Deviations ........................................................................................................... 23 
8. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ................................ 24 
8.1. 
General Methods ................................................................................................................ 24 
8.2. 
Contingencies Due To Limitations Inherent in SLS Research ...................................... 24 
8.3. 
Data Considerations .......................................................................................................... 25 
8.4. 
Key Definitions and Terminology ..................................................................................... 25 
8.5. 
Missing Data ....................................................................................................................... 27 
8.6. 
Visit Windows ..................................................................................................................... 28 
8.7. 
Pooling of Centers ............................................................................................................. 28 
9. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION................................................................................................. 29 
9.1. 
Subject Disposition and Withdrawals .............................................................................. 29 
9.2. 
Exposure and Treatment Compliance ............................................................................. 29 
9.2.1. 
Extent of exposure ...................................................................................................... 29 
9.2.2. 
Treatment Compliance ................................................................................................ 30 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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9.3. 
Demographic and Other Baseline Characteristics ......................................................... 30 
9.4. 
Medical History and Concomitant Diseases ................................................................... 31 
9.5. 
Other Baseline Characteristics ........................................................................................ 31 
9.6. 
Medication .......................................................................................................................... 31 
9.6.1. 
Prior Medication .......................................................................................................... 31 
9.6.2. 
Concomitant Medication .............................................................................................. 32 
10. EFFICACY ..................................................................................................... 33 
10.1. 
Primary Efficacy Endpoint and Analysis ......................................................................... 33 
10.2. 
Secondary Efficacy Endpoints and Analyses ................................................................. 35 
10.3. 
Subgroups Analysis .......................................................................................................... 39 
10.4. 
Exploratory Analyses ........................................................................................................ 40 
11. SAFETY OUTCOMES ................................................................................... 42 
11.1. 
Safety Narratives ................................................................................................................ 42 
11.2. 
Adverse Events / Adverse Drug Reactions ..................................................................... 42 
11.3. 
Clinical Laboratory Evaluations ....................................................................................... 45 
11.4. 
Vital Signs ........................................................................................................................... 46 
11.5. 
ECG ..................................................................................................................................... 47 
11.6. 
Physical Examination ........................................................................................................ 48 
11.7. 
Dermatology Examination ................................................................................................ 48 
12. INTERIM ANALYSES .................................................................................... 49 
13. CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ............................. 50 
14. PROGRAMMING CONSIDERATIONS .......................................................... 51 
14.1. 
General Considerations .................................................................................................... 51 
14.2. 
Table, Listing, and Figure Format .................................................................................... 51 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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14.2.1. 
General ........................................................................................................................ 51 
14.2.2. 
Headers ....................................................................................................................... 51 
14.2.3. 
Display Titles ............................................................................................................... 52 
14.2.4. 
Column Headers ......................................................................................................... 52 
14.2.5. 
Body of the Data Display ............................................................................................. 53 
14.2.6. 
Footnotes .................................................................................................................... 55 
15. QUALITY CONTROL ..................................................................................... 56 
16. INDEX OF TABLES ....................................................................................... 57 
17. INDEX OF FIGURES ..................................................................................... 58 
18. INDEX OF LISTINGS ..................................................................................... 59 
19. MOCK-UPS .................................................................................................... 60 
19.1. 
Table Mock-Ups ................................................................................................................. 60 
19.2. 
Figure Mock-Ups ................................................................................................................ 60 
19.3. 
Listing Mock-Ups ............................................................................................................... 60 
20. APPENDIX 1-OUTCOME SCALES ............................................................... 62 
20.1. 
VIIS Description ................................................................................................................. 62 
20.2. 
VIIS collection form ........................................................................................................... 63 
20.3. 
EQ-5D-5L ............................................................................................................................. 64 
20.3.1. 
EQ-5d-5l descriptive system scoring .......................................................................... 64 
20.3.2. 
EQ-5D-5L VAS scoring ............................................................................................... 65 
20.4. 
Clinician Global Impression of Severity (CGIS) .............................................................. 66 
20.5. 
Patient Reported Outcome Scales ................................................................................... 67 
20.5.1. 
Patient Global Impression of Severity (PGIS) ............................................................. 67 
20.5.2. 
Patient Global Impression of Bother (PGIB) ............................................................... 68 
20.5.3. 
Patient Global Impression of Treatment (PGIT) .......................................................... 69 
20.5.4. 
Patient-Reported Itching/ Scratching Questionnaire (PRIQ/PRSQ) ........................... 70 
20.5.5. 
Patient Reported Burden of Bathing / Showering Questionnaire (PRBBQ) ............... 71 
20.6. 
Observer Reported Outcome Scales ............................................................................... 72 
20.6.1. 
Observer Reported Scratching Questionnaire (ORSQ) .............................................. 72 
20.6.2. 
Observer-Reported Burden of Bathing/Showering Questionnaire (ORBBQ) ............. 73 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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20.6.3. 
Observer-Reported Scales: Observer Global Impression of Severity (OGIS) ............ 74 
20.6.4. 
Observer-Reported Scales: Observer Global Impression of Bother (OGIB) .............. 75 
20.6.5. 
Observer-Reported Scales: Observer Global Impression of Treatment (OGIT) ......... 76 
20.7. 
Dermatology Life Quality Index (DLQI) ............................................................................ 77 
20.8. 
Childrens Dermatology Life Quality Index (CDLQI) ....................................................... 78 
 
 
 
 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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1. 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
AE 
Adverse Event 
ADR 
Adverse Drug Reaction 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BMI 
Body Mass index 
BSA 
Body Surface Area 
CFB 
Change From Baseline 
CI 
Confidence Interval 
CDLQI 
Children’s Dermatology Life Quality Index 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
DBL 
Database Lock 
DLQI 
Dermatology Life Quality Index 
DRM 
Data Review Meeting 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GEE 
Generalized Estimating Equations 
GPP 
Good Pharmacoepidemiology Practice 
ICH 
International Conference on Harmonization 
LS 
Least Squares 
m-ITT 
Modified Intent-to-Treat 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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Abbreviation 
Description 
Min 
Minimum 
MMRM 
Mixed Effect Model Repeated Measures 
N/A 
Not Applicable 
NA 
Not Applicable 
OR 
Observational Research 
PASS 
Post Authorization Safety Study 
PAES 
Post Authorization Efficacy Study 
PD 
Pharmacodynamics 
PPP 
Per Protocol Population 
PK 
Pharmacokinetics 
PT 
Preferred Term 
QC 
Quality Control 
QTc 
Corrected QT Interval 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Population 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Standard Error 
SI 
Standard International System of Units 
SLS 
Sjögren-Larsson Syndrome 
SMP 
Safety Management Plan 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment Emergent Adverse Event 
TEWL 
Transepidermal Water Loss  
TLF 
Table, Listing and Figure 
VIIS 
Visual Index for Ichthyosis Severity  
WHO 
World Health Organization 
 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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2. 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses 
and reporting for Part 1 of protocol ADX-102-SLS-006., Final Version 5.0 28 September, 
2018. 
This SAP is being written with due consideration of the recommendations outlined in the 
most recent International Council on Harmonization (ICH) E9 Guideline entitled 
Guidance for Industry: Statistical Principles for Clinical Trials and the most recent ICH 
E3 Guideline, entitled Guidance for Industry: Structure and Content of Clinical Study 
Reports (CSR).  
This SAP is a summative and definitive plan. It describes the data that will be analyzed 
and the subject characteristics, efficacy, and safety assessments that will be evaluated.  
This SAP provides details of the specific statistical methods that will be used. The 
statistical analysis methods presented in this document will supersede the statistical 
analysis methods described in the clinical protocol. If additional analyses are required 
to supplement the planned analyses described in the SAP, they will be labeled as post-
hoc and will be identified in the CSR. 
2.1. 
RESPONSIBILITIES 
Syneos Health will perform the statistical analyses described herein and is responsible 
for the production and quality control (QC) of all tables, figures, and listings associated 
with these analyses. ECG, Pharmacokinetics (PK) and Pharmacodynamics (PD) analysis 
will be conducted independently and are outside the scope of this SAP and will be 
detailed in separate analysis plans. 
2.2. 
DATA SAFETY MONITORING BOARD 
An independent, unblinded DSMB has been established.  The DSMB will review safety 
data upon completion of Part 1 clinical trial. The assessment of safety will be 
determined from dermatological endpoints, vital sign measurements, physical 
examinations, hematology and chemistry laboratory testing, ECG readings, use of 
concomitant medications, and review of adverse events. The DSMB will review efficacy 
data to assess risk/benefit, but will not perform a formal interim analysis of efficacy or 
futility. Based on the safety data provided, the DSMB will provide recommendations 
about stopping or continuing the trial. Please defer to the DSMB Charter Version 1.0, 
dated May 3rd 2018 for further details. 
 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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3. 
STUDY OVERVIEW 
ADX-103-SLS-006 is a multicenter, randomized, double-blind, vehicle-controlled, 
parallel-group Phase 3 clinical trial to evaluate the safety and efficacy of ADX-102 1% 
topical dermal cream in subjects with Sjögren-Larsson Syndrome (SLS).  
This is a two-part clinical trial, with an initial assessment of increasing BSA treatment 
(Part 1). After the completion of Part 1, a separate set of eligible subjects will be 
enrolled into Part 2. 
Subjects 3 years of age or older with genetically-confirmed diagnosis of SLS and active 
ichthyosis are eligible for enrollment. For detailed inclusion and exclusion criteria, see 
Section 4.1 and 4.2 in the protocol, version 5.0. 
Part 1 Design: 
Part 1 will evaluate the safety, tolerability, and efficacy of treatment to the affected 
area of ichthyosis initially on approximately 20% BSA and then increasing up to 90% BSA 
over 24 weeks of exposure and will confirm an appropriate sample size for Part 2. 
Subjects will be consented and screened for eligibility. Approximately nine subjects will 
be randomized in a 2:1 ratio to receive ADX-102 1% or vehicle. 
Subjects or caregivers will apply study drug (i.e., ADX-102 1% or vehicle) to a treatment 
area identified by the Investigator. 
The initial treatment area will be defined as approximately 20% BSA with Grade 2 or 
higher on the Visual Index for Ichthyosis Severity (VIIS) scaling score, as assessed by the 
Investigator, and will include one of the body sites as defined in the VIIS tool (target 
efficacy area). From Week 1 through Week 12, subjects will receive treatment once 
daily in the initial treatment area only. 
If the Investigator determines that there are no safety or tolerability issues at the end 
of Week 12, the treatment area will increase to all of the affected areas of ichthyosis 
on one-half of the body (approximately 40-45% BSA in a typical SLS patient). From Week 
13 through Week 20, subjects will receive treatment once daily on the expanded 
treatment area. 
If there are still no safety or tolerability issues at the end of Week 20, the treatment 
area will further increase to all affected areas of ichthyosis on the entire body 
(approximately, 80-90% BSA in a typical SLS patient). Subjects will receive treatment 
once daily treatment on all affected areas from Week 21 through Week 24. 
Subjects completing the 24 weeks of study drug treatment will then be monitored for an 
additional four weeks for safety. 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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Part 2 Design: 
Part 2 will evaluate the safety, tolerability, and efficacy of treatment to the affected 
area of ichthyosis on the body (approximately 80-90% BSA in a typical SLS patient) over 
24 weeks of exposure.  


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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4. 
STUDY PROCEDURES AND FLOWCHART 
Table 4.1.1-Part 1 Schedule of Events 
Evaluation 
Screening1 
Baseline 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 
5 
Visit 6 
Visit 
7 
ET  
Visit 
82 
Safety 
Follow-
Up 
Visit 9 
Day -7 to 
-1 
Week 1 
Day 1 
Week 
1 
Day 2 
Week 4 
± 3 
days 
Week 8 
± 3 
days 
Week 
12 
± 5 
days 
Week 
16 
± 3 
days 
Week 
20 
± 5 
days 
Week 
24 
± 5 
days 
Week 
28 
± 3 days 
Site Visit 
Site Visit 
Site 
Visit 
Home 
Visit 
Home 
Visit 
Site 
Visit 
Home 
Visit 
Site 
Visit 
Site 
Visit 
Home 
Visit 
Informed consent / 
assent 
X 
 
 
 
 
 
 
 
 
 
Eligibility review 
X 
X 
 
 
 
 
 
 
 
 
Demographics / 
medical history 
X 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis/ urine 
pregnancy test3 
X 
X 
 
 
 
X 
 
X 
X 
 
12-Lead ECG  
X 
X 
 
 
 
X 
 
X 
X 
 
Vital Signs  
X 
X 
X 
 
 
X 
 
X 
X 
 
Physical exam4 
X 
X 
X 
 
 
X 
 
X 
X 
 
Dermatologic exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Digital photography5 
 
X 
 
X6 
X6 
X 
X6 
X 
X 
X6 
VIIS (Investigator-
assessed) 
 
X 
X 
 
 
X 
 
X 
X 
 
Global impression of 
severity 
 
X 
 
 
 
X 
 
X 
X 
 
Patient/Observer-
reported scales7 
 
X 
 
 
 
X 
 
X 
X 
 
PD sample collection8 
 
X 
 
 
 
X 
 
X 
X 
 
Clinical laboratory 
testing9  
X 
X 
 
X 
 
X 
 
X 
X 
 
PK sample 
collection10  
 
X 
X 
 
 
X 
 
X 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Administer study drug  
 
X11 
X 
X 
X 
X11 
X 
X11 
X 
 
Dispense study drug 
& diary 
 
 
X 
 
 
X 
 
X 
 
 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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ET = early termination; ECG = electrocardiogram; PD = pharmacodynamic; PK = pharmacokinetic; VIIS = Visual Index for Ichthyosis 
Severity 
1. 
Samples collected for urinalysis and clinical laboratory tests may be analyzed at a local lab.   
2. 
Subjects who terminate early from the study will not require post-dose assessments at Visit 8 (Week 24). 
3. 
Urine pregnancy test for female subjects of child-bearing potential only.  Test can be analyzed at the study site. 
4. 
Complete physical exam, including height and weight collection, performed at Screening Visit only; symptom-
directed physical exams at all other timepoints. 
5. 
Subjects should refrain from bathing and applying study drug or as-needed topical symptom control therapy 
(emollients) to the treatment area within 12 hours of obtaining digital photographs.   
6. 
During at-home visits, photographs will only be taken if there are any safety concerns. 
7. 
Patient/Observer-reported scales to be administered: EQ-5D-5L, global impression of severity, global impression of 
bother, global impression of treatment, itching, scratching, burden of bathing/showering, and Children's 
Dermatology Life Quality Index (CDLQI) / Dermatology Life Quality Index (DLQI). 
8. 
PD assessments include skin cell samples and transepidermal water loss (TEWL) procedures. 
9. 
Clinical laboratory includes hematology and chemistry.  Refer to Sections 6.15.1 and 6.15.2 in  the study protocol, 
for more detail. 
10. PK collection includes blood and urine samples. 
11. Study drug will be administered daily.  At study visits when PK samples are collected, study drug may be 
administered at the study clinic after pre-dose PK samples have been obtained.  At Visit 1, Investigator should apply 
study drug to the initial treatment area (~20% BSA) during the visit.  At Visit 2, study drug may be applied to the 
initial treatment area during the visit (after pre-dose PK sample collection) by the Investigator or subject/caregiver.  
At Visit 5, if the treatment area is expanded to up to 45% BSA, the Investigator should apply study drug to the 
treatment area.  At Visit 7, if the treatment area is expanded to up to 90% BSA, Investigator should apply study drug 
to the treatment area. 
 
Table 4.1.2-Part 1 Pharmacokinetic and Cardiac Monitoring 
 
 
 
Collect study drug & 
diary 
 
 
 
 
 
X 
 
X 
X 
 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
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Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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5. 
STUDY OBJECTIVES 
5.1. 
PRIMARY OBJECTIVE 
To evaluate the efficacy of ADX-102 1% topical dermal cream on ichthyosis associated 
with SLS. 
5.2. 
SECONDARY OBJECTIVE(S) 
To evaluate the safety and secondary efficacy endpoints of ADX-102 1% topical dermal 
cream in subjects with SLS. 
5.3. 
DETERMINATION OF SAMPLE SIZE 
Part 1 of the clinical trial will assess the effect size on the VIIS scaling score with ADX-
102 1% topical dermal cream, and will confirm the sample size needed for Part 2. 
Unblinded Part 1 safety and efficacy results will be available to the Sponsor for 
administrative consideration and use upon completion of Part 1. Efficacy data will be 
used to confirm the sample size estimation for Part 2 as well as to perform between 
groups and within group descriptive and inferential statistical analyses 
 
5.4. 
SUBJECT NUMBERING 
Each subject screened for the clinical trial will be assigned a unique subject number 
that will be used to identify the subject throughout their participation in the clinical 
trial. If a subject fails to be randomized, the reason should be documented in the 
source documents and case report form (CRF). The subject will be considered a screen 
failure. 
5.5. 
RANDOMIZATION AND BLINDING 
Subjects will be randomized 2:1 to receive ADX-102 1% or vehicle through interactive 
response technology (IRT) at Baseline Visit Day 1. 
Subjects will be randomized in a double-blind fashion. Investigators, qualified study 
personnel, subjects, and caregivers will be blinded to the study drug treatment 
administered. The Sponsor will also be blinded to the study drug treatment 
administered until database lock. 
In the event a replacement of a subject is required (see Section 4.3 in the protocol), 
the next available subject number will be assigned to either ADX-102 or vehicle based 
on the randomization scheme.  


Statistical Analysis Plan 
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Protocol # ADX-102-SLS-006 
Version 1.0 
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In the event that randomization assignment results in an active to vehicle ratio of less 
than 2:1 then the clinical trial may be extended until the ratio is achieved per sponsor 
discretion. 
5.6. 
EMERGENCY UNBLINDING 
Emergency unblinding should only be performed when necessary to treat the subject. 
Most often, knowledge of the possible treatment assignments is sufficient to treat a 
subject who presents with an emergency condition. 
Unblinding will result in the subject being discontinued from the clinical trial, 
irrespective of whether the Investigator the event is deemed related to study drug. 
The treatment code for a subject may only be broken by the Investigator or Sponsor for 
reasons of subject safety or in an emergency when knowledge of the study drug 
administered would be important for the treatment of the patient. However, the 
Investigator should make every effort to contact the Medical Monitor to discuss the 
emergency and the need to unblind, prior to unblinding any subject. Please refer to the 
Safety Management Plan (SMP), Version 1.0, dated April 12, 2018. 
The blind may be broken in the case of a pregnancy should the subject desire this 
information. 
The date, time and reason for breaking the blind are to be recorded in the subject’s 
CRF and source documents. 
In the event of a drug-related, serious, unexpected AE, the Sponsor’s Unblinded 
Pharmacovigilance Department or designee will be provided with the treatment 
assignment for the subject for regulatory reporting (detailed process outlined in ADX-
102-SLS-006 Safety Monitoring Plan). 
5.7. 
ADMINISTRATION OF STUDY MEDICATION 
A standard amount of study drug for the percent BSA under treatment will be measured 
and applied to the treatment area once daily to achieve a dose of approximately 8 
mg/cm2, with each application administered approximately 24 hours apart. Study drug 
should only be administered to the treatment area, as directed by the Investigator, 
during the clinical trial. 
The Target Efficacy Area used for the primary endpoint assessment in Part 1 will be 
based on one of the body sites as defined in the VIIS tool (upper back, upper arm or 
lower leg/shin) that has a VIIS scaling score of Grade 2 or higher as assessed by the 
Investigator. The body site with the worst VIIS scaling score should be selected, if 
applicable. The target efficacy area will be used for all efficacy analyses; for all other 
treated areas, data will be summarized.  


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
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The Treatment Area will be determined by the Investigator as follows: 
In Part 1, the initial treatment area will be defined as approximately 20% BSA with 
Grade 2 or higher on the VIIS scaling score, on one-half of the body, left or right side, 
and will include the target efficacy area. From Week 1 through Week 12, study drug will 
be applied in the initial treatment area. 
If the Investigator determines that there are no safety or tolerability issues at the end 
of Week 12, the treatment area will increase to all of the affected areas of ichthyosis 
on one-half of the body (approximately 40-45% BSA in a typical SLS patient), left or right 
side. From Week 13 through Week 20, the study drug will be applied to the extended 
treatment area affected by ichthyosis. 
If there are still no safety or tolerability issues at the end of Week 20, the treatment 
area will further increase to all affected areas of ichthyosis on the entire body 
(approximately 80-90% BSA in a typical SLS patient). From Week 21 through Week 24, 
the study drug will be applied to the entire body affected by ichthyosis. 
For example, if the left lower leg is determined by the Investigator to be the target 
efficacy area, then the entire left leg would likely be defined as the initial treatment 
area. At the end of Week 12, if there are no safety or tolerability issues, the treatment 
area would extend to the entire left side of the body. At the end of Week 20, if there 
are no safety or tolerability issues, the treatment area would include the entire body. 
 
 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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6. 
ENDPOINTS 
All endpoints will be based on an evaluation period spanning Day 1 through Week 24 in 
Part 1.  
6.1. 
PRIMARY EFFICACY ENDPOINT 
The primary efficacy endpoint is the Visual Index for Ichthyosis Severity (VIIS) scaling 
score as assessed by the Investigator in the target efficacy area. 
6.2. 
SECONDARY EFFICACY ENDPOINTS 
Secondary endpoints include: 
VIIS score 
• 
VIIS erythema score as assessed by the Investigator in the target efficacy area 
• 
VIIS scaling score as assessed by a central reader in the target efficacy area 
• 
VIIS erythema score as assessed by a central reader in the target efficacy area 
Clinical Outcome Assessments 
• 
EQ-5D-5L 
• 
Clinician global impression of severity 
• 
Patient/Observer global impression of severity 
• 
Patient/Observer global impression of bother 
• 
Patient/Observer global impression of treatment 
• 
Patient-reported itching 
• 
Patient/Observer-reported scratching 
• 
Patient/Observer Burden of bathing/showering 
• 
Children’s Dermatology Life of Quality Index (CDLQI) / Dermatology Life Quality 
Index (DLQI) 
Biomarker Parameters 
• 
Transepidermal Water Loss (TEWL) 
Exploratory Biomarker Parameters 
• 
Lipid biomarkers from skin cells 
All analyses involving lipid biomarkers will be considered exploratory and will be 
conducted post-hoc.  
6.3. 
PHARMACOKINETIC ENDPOINTS 
Full pharmacokinetic (PK) profile on Day 1 and at steady state following treatment up to 
90% BSA.  Planned analysis detailed in separate PK analysis plan. 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
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6.4. 
CLINICAL OUTCOMES ASSESSMENT ENDPOINTS 
Clinical Outcomes Assessments are collected at predefined study visits.  Data will be 
analyzed per a separate Clinical Outcomes Assessments Analysis plan. 
6.5. 
SAFETY ENDPOINTS  
The safety endpoints include dermatological endpoints, vital sign measurements, 
physical examinations, hematology and chemistry laboratory testing, ECG readings, use 
of concomitant medications, and adverse events.   
6.6. 
PLANNED ANALYSES 
The following analyses will be performed for the ADX-102-SLS-006 Phase 3 clinical trial 
Part 1: 
• Analyses for the Data Safety Monitoring Board (DSMB) 
• Analysis of unblinded data following completion of Part 1 
 
All safety and efficacy data collected from the approximately 9 subjects will be 
analyzed upon completion of Part 1.  
 


Statistical Analysis Plan 
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Protocol # ADX-102-SLS-006 
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7. 
ANALYSIS POPULATIONS 
7.1. 
ENROLLED POPULATION 
The enrolled population will include all patients who gave informed consent to 
participate in the clinical trial. 
7.2. 
SAFETY POPULATION  
The Safety Population (SAF) consists of all randomized subjects who use at least one 
dose of study drug, regardless of whether they undergo any clinical trial assessments. 
Patients will be included in the treatment group corresponding to the study treatment 
they actually received for the analysis of safety data. The SAF will be used for the 
analysis of safety data for this clinical trial. 
7.3. 
MODIFIED INTENT-TO-TREAT (M-ITT) POPULATION  
The modified-Intent-to-Treat (m-ITT) Population will include all randomized subjects 
from the SAF who received at least one dose of study drug and have at least one VIIS 
assessment post visit 2. Subjects will be analyzed according to randomized treatment.  
Unless otherwise specified, efficacy analysis will be performed on this population. 
7.4. 
PER PROTOCOL POPULATION  
The Per-Protocol Population (PPP) will include the patients from the m-ITT population 
who had no major protocol deviations that could impact the efficacy analysis. The list 
of protocol deviations that may exclude a patient from the PPP will be reviewed and 
approved by the sponsor prior to database lock. 
Patients could be excluded from the PPP if:  
• 
Subjects did not receive study drug as assigned 
• 
Subject did not meet all inclusion/exclusion criteria 
• 
The final determination on major protocol deviations and potential impact on 
efficacy parameters and thereby the composition of the PPP, will be made prior 
to the unblinding of the database and will be documented separately. 
Regardless of randomized treatment group, patients will be included in the analysis 
group based on the treatment actually received for the analysis of efficacy data using 
the PPP. 
Due to the small sample size in Part 1, efficacy analysis will not be conducted on PPP.  


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
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7.5. 
PHARMACOKINETIC (PK) POPULATION 
The PK Population will include all subjects who received at least one dose of study drug 
and have at least one measured post-dose PK concentration in plasma or urine. The PK 
Population will be used for the analysis of all PK data. 
7.6. 
PROTOCOL DEVIATIONS 
Possible protocol deviations will be identified and displayed in a data listing, sorted by 
subject and clinical trial site (where applicable). Protocol deviations will be evaluated 
at the data review meeting (DRM), prior to database lock (DBL), to determine protocol 
deviations considered to have significant impact on patient safety, efficacy or the 
validity of the data. Patients with protocol deviations may be excluded from the per 
protocol population if the deviation has an impact on the efficacy analysis. 
 
 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
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8. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
8.1. 
GENERAL METHODS 
All patients entered into the database will be included in patient data listings. Summary 
tables will be provided for all patients.  
Unless otherwise specified, all demographic, baseline and safety data will be presented 
by treatment arm and overall. Efficacy data will be presented by treatment arm.   
Quantitative (continuous) data - absolute values and changes from baseline, where 
appropriate - will be summarized with number of observations (n), mean, standard 
deviation (SD), median, minimum, and maximum and 1st and 3rd quartiles for efficacy 
tables only.  
Qualitative (categorical) data will be summarized using number of observations (n), and 
frequency and percentages of patients. Unless stated otherwise, the calculation of 
percentages will be based on the total number of patients with non-missing data in the 
set of interest.  
Comparisons will contrast outcomes between time points within both ADX-102 1% and 
Vehicle treatment groups as well as contrast outcomes between each of these 
treatment groups.  
• 
All primary and secondary efficacy analyses will be performed on the m-ITT 
population.  
• 
The safety analysis will be performed on the SAF population.  
Summary tables will include outcomes for a given treatment at a given time point, the 
between group differences in change from baseline at each time point, and the within 
group difference at each time point. 
8.2. 
CONTINGENCIES DUE TO LIMITATIONS INHERENT IN SLS RESEARCH   
There will be no adjustment for multiplicity in the analyses of primary and secondary 
endpoints.  The limitations of achieving statistical power due to the limited availability 
of subjects as well as the longevity and consistency of SLS symptoms make statistical 
significance difficult to achieve.   
In this Phase 3 clinical trial, efficacy decisions must rely upon a clearly observable trend 
in change in skin scaling, a socially stigmatic symptom of great discomfort that absent a 
novel treatment will require an inordinate amount of attentiveness on a daily basis for 
the life of the patient.  Thus, significance levels are provided in this clinical trial as an 
additional index of change rather than an inferential expectation.   


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If warranted by observed data characteristics relative to model assumptions, non-
parametric methods and small sample statistical methods may be substituted for one or 
more of the below anticipated model based analyses.  The rationale for any such change 
will be provided.  
Finally, if statistical power is materially increased through the addition of one or more 
continuous or stratification covariates to a statistical model described in this SAP, the 
model will include the covariate(s).  Analogously, if stratification adds power to a non-
parametric or small sample procedure, the analysis will include stratification. 
8.3. 
DATA CONSIDERATIONS  
Due to the limited sample size for Part 1 of the clinical trial, descriptive statistics are 
planned for the primary and secondary endpoints.  Inferential statistics will be used for 
the primary analysis.  
8.4. 
KEY DEFINITIONS AND TERMINOLOGY 
Reference start date and study day 
Study Day will be calculated from the reference start date and will be used to show 
start/stop day of assessments and events. 
Baseline Value 
For purposes of analysis, the baseline value is defined as the last non-missing value 
obtained prior to initiation of study drug.   
Change from Baseline. 
Change from baseline for a given endpoint is defined as the difference between a post-
treatment study day value and the baseline variable value and will be calculated 
directionally as post-study minus baseline. 
Note that for the VIIS, it is planned that a single investigator will complete this 
instrument prior to randomization on day 1 of Part 1.   
 
Day 1 (Baseline) 
Day 1 is the earliest day that the study drug is first initiated. 
Age 


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Age is calculated as the number of whole years from a subject’s date of birth to the 
date of informed consent. 
Study Visit. 
Study visit is the nominal visit as recorded on the eCRF. 
Total Days on Study 
Total days on study is defined as the number of days from Day 1 to the date of 
completion or early termination. 
Last Dose of study drug 
Last dose of study drug is defined as the number of days from day 1 to the date of last 
dose of study drug. 
Duration of SLS. 
The duration of SLS is defined as the number of whole years from the date of onset of 
SLS diagnosis to the date of informed consent. 
Adverse Event 
An adverse event is any untoward medical occurrence in a patient or clinical 
investigation patient, temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
Treatment Period 
The Treatment Period covers the duration that a patient is in the study from Baseline 
(Day 1) to Week 24. 
Safety Follow-up Period 
The Safety Follow-up Period continues for 28 days after the last dose of study treatment 
at Week 24 through Week 28.  
Definition of Study Completion 
A patient will be defined as “completed” if she or he completes the Week 24 study visit. 
End of Study Definition 


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End of study is defined as the date when the patient has completed one of the 
following:  completed the follow-up visit after the Week 24 visit, permanently 
discontinued from the study, or lost to follow-up.  
Day of Study Termination 
Day of study termination = Termination Date – Date of Baseline (Day 1) + 1.  
Percent Change from Baseline  
Percent CFB = 100 * (Post-baseline value – Value at baseline) / Value at baseline 
8.5. 
MISSING DATA 
All available safety, PK and efficacy data will be included in data listings and 
tabulations. No imputation of missing data is planned for primary and secondary 
endpoints. Abnormal values for assessments (outliers) will be confirmed during the DRM 
and the primary analysis may be performed with and without inclusion of outliers.  
IMPUTATION OF INCOMPLETE DATES. 
An incomplete date is any date for which either the day, month or year is unknown, but 
all three fields are not unknown. An incomplete date occurs when the exact date an 
event occurred or ended cannot be obtained from a subject. For many of the analyses, 
a complete date is necessary in order to determine if the event should be included in 
the analysis (i.e., if the event is treatment-emergent) or to establish the duration of an 
event. In such cases, incomplete dates will be imputed. 
For purposes of imputation, all events with an incomplete end date are assumed to have 
ended on or before the day the form was completed. In an effort to minimize bias, the 
project statistician will impute dates in a systematic, reasonable manner. A list of 
incomplete and imputed dates will be prepared by the project statistician or statistical 
programmer(s) and will be submitted for review by the clinical project manager and 
sponsor.  


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Incomplete/missing start and stop dates will be handled as follows:  
Table 8.4.1: Imputation of missing dates 
Missing 
Imputation 
Start day 
The start day will be imputed as the first day of the month with the 
following exception:  if the partial date is the same month and year 
as the date of first dose of double-blind medication, then the partial 
date will be imputed as the date of first dose of double-blind. 
End Day 
The end day will be imputed as the last day (28/29/30/31) of the 
month.  
End 
Day 
and 
Month 
The end date will be imputed as the 31st of December or last day of 
study follow up. 
For all other data, all available data will be included in the analyses and will be 
summarized as far as possible. Unless otherwise specified, there will be no substitution 
of missing data, i.e., missing data will not be replaced; missing data will be handled as 
‘missing’ in the statistical evaluation. 
8.6. 
VISIT WINDOWS 
The safety and efficacy data will be analyzed per study visit; the named visit as 
collected on the CRF will be displayed.  
During the course of the study, blood draws and certain laboratory measurements for 
some subjects were delayed. A subset of subjects also experienced a ‘treatment 
interruption’ during which treatment was interrupted due to laboratory findings. 
Further detail will be provided in the Clinical Study Report.  As a result, some study 
visits to occurred outside the pre-specified visit window.  In the case where a scheduled 
study visit was delayed, the labelled study visit from the raw database will be used. 
All unscheduled visit values will be excluded from summary tables but will be included 
on data listings. 
8.7. 
POOLING OF CENTERS 
No investigation of center effects is planned. Data from all centers will be pooled. 


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9. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
9.1. 
SUBJECT DISPOSITION AND WITHDRAWALS 
Subject disposition will be summarized by treatment group and overall in terms of the 
number and percentage of subjects who were randomized, completed the clinical trial 
and discontinued from the clinical trial.   
The number and percentage of subjects prematurely discontinued from the clinical trial 
and the reasons for discontinuation will be summarized by treatment group and overall. 
Subjects who are not discontinued from the clinical trial will be considered completers.  
The reasons for study discontinuation that will be summarized include: (AE, protocol 
violation, administrative reasons (e.g., inability to continue, lost to follow up), sponsor 
termination of study, subject choice, and other.   
The number and percentage of subjects with major protocol deviations will be 
summarized by treatment group for all randomized subjects. 
All data will be listed. 
9.2. 
EXPOSURE AND TREATMENT COMPLIANCE 
9.2.1. Extent of exposure 
The duration of exposure during the treatment period will be expressed as the time in 
days from the first treatment through to last treatment day (inclusive). This is given by 
the following formula: 
A subset of subjects had a treatment interruption. When study drug was reinstated 
many of these subjects still received the full course of study medication. To account for 
these cases, exposure to study drug will be calculated using the following formula: 
Duration (days) = (date last double blind dose – date first double blind dose + 1)-Total 
days ‘treatment interruption’. 
Duration of exposure, number of doses received and doses delayed, missed or not per 
protocol will be summarized for the SAF using summary statistics for continuous 
variables.  
Drug exposure in grams, defined as the number of tubes used at each visit converted 
into grams as 15*number of tubes and %BSA treated for the whole study part and each 
dosing period (20%, 40-45% and 80-90%) will also be summarized. 


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9.2.2. Treatment Compliance 
Study Treatment compliance (%) will be calculated as the actual number of doses 
divided by the prescribed number of doses, multiplied by 100 and summarized by 
treatment group. 
These numbers will be determined by the number tubes/day dispensed and returned 
unused by the patient. 
 
 
 
All data will be listed; subjects with a treatment interruption will be flagged in the 
listing. 
9.3. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
All demographic and baseline characteristic data will be summarized by treatment 
group using descriptive statistics for all patients for each of the following analysis sets:  
SAF, m-ITT and PPP. 
• 
Gender, Ethnicity and Race will be summarized by the number and percentage 
of patients in each category 
• 
Age (years), height (cm) and weight (kg) captured at Screening will be 
summarized as a continuous variable 
• 
Body Surface Area (m2) at captured at Screening 
• 
Estimated Glomerular Filtration Rate (eGFR, ml/min/BSA) 
• 
Systolic blood pressure (mm Hg) 
• 
Diastolic blood pressure (mm Hg) 
• 
Heart Rate (beats/minute) 
• 
Pulse (beats/min) 
• 
Respiratory Rate (breaths/min) 
Unless otherwise stated, percentages will be calculated out of the number of patients in 
the given Analysis Set 
All demographic data will be listed. 


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9.4. 
MEDICAL HISTORY AND CONCOMITANT DISEASES 
Descriptions of medical history and concomitant disease findings prior to the Screening 
Visit will be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 
20.0 or higher. Information related to the following disease types or systems: head, 
eyes, ears, nose and throat (HEENT), respiratory, neurological, cardiovascular, 
musculoskeletal, metabolic/endocrine/nutritional, hematopoietic, allergies, abdominal 
and general appearance.  
Medical history, as recorded at Screening, will be summarized for the Safety Population 
(SAF) by the number and percentage of patients within each system organ class (SOC) 
and preferred term (PT), by treatment. 
A disease or illness reported as medical history without a start date will be included in 
medical history without a date assigned.  
Medical history will be sorted by descending overall frequency, by SOC and PT in the 
summary table. Medical history data listings will be sorted by treatment, patient 
number, start date, SOC and PT. 
9.5. 
OTHER BASELINE CHARACTERISTICS 
The age of diagnosis of SLS, genotype, and all prior treatments for SLS at screening will 
be summarized by treatment group using summary statistics. The presence or absence 
of SLS symptoms, including motor disability in the arms and/or legs, foot deformity, 
speech disorder, seizures, and photophobia, will be summarized.  
9.6. 
MEDICATION 
Previous and concomitant medication will be coded using the World Health Organization 
Drug Dictionary (WHO-DD).  The number and percentage of patients taking prior 
medications and concomitant medications will be summarized overall by ATC 
(Anatomical Therapeutic Chemical) Levels 2 and 4, in separate tables, for all patients in 
the SAF population. 
Prior and concomitant medications will be presented in a data listing for all patients in 
the SAF population. 
9.6.1. Prior Medication 
Prior medications will be defined as medications documented on the Prior and 
Concomitant Medications eCRF as having started within 30 days prior to assent/ consent 
and stopped prior to baseline visit. 


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9.6.2. Concomitant Medication 
Concomitant medications will be defined as medications documented on the 
Concomitant Medications eCRF as having started within 30 days prior to assent/ consent 
and ongoing at the time of or after the first dose of double blind study medication or 
any new medications started after the first dose of double blind study medication. 


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10. 
EFFICACY 
Overview 
All efficacy variables are initially captured on a continuous or semi-continuous scale.  
Observed values at the time of collection and change from baseline value at each time 
point will be summarized descriptively. Mixed Model Repeated Measures (MMRM) 
analysis will be carried out on change from baseline scores for the primary and 
secondary efficacy variables for reproxalap-treated subjects (not vehicle-treated 
subjects). Hereinafter, in this Statistical Analysis Plan, drug-treated shall mean 
reproxalap-treated. Additional analyses in drug-treated subjects will be performed on 
certain efficacy variables. Further details of the tests to be performed on each endpoint 
are given in Table 10.2.1 below.  The specific additional analyses are described below.   
1) The VIIS outcomes will be converted to a binary response variable (yes/no) 
defined as a 1-unit and 2-unit improvement from baseline.  The probability of 
response in drug-treated subjects will be analyzed over time using generalized 
estimating equation (GEE) models.   
2)  Change from baseline over time will be converted into an Area Under the 
Curve (AUC) value using the trapezoidal rule.  AUC for drug-treated subjects will 
be inferentially compared to zero (0 = no change from baseline) using a linear 
model.   
3)  Time to first response (1-unit improvement and 2-unit improvement) for the 
VIIS outcomes (scaling and erythema) will be evaluated using a Kaplan Meier 
survival curve for drug-treated subjects.  
Tables will be generated for each endpoint presenting appropriate descriptive and 
inferential statistics to convey the results of the analyses.  Tables will be augmented by 
figures for selected analyses.    
10.1. 
PRIMARY EFFICACY ENDPOINT AND ANALYSIS 
The primary endpoint for the clinical trial is change from baseline in the VIIS scaling 
score in drug-treated subjects, as assessed by the investigator, in the target efficacy 
area. The VIIS provides five-point Likert scales (range 0-4) for erythema and scaling that 
increases in severity with increasing score values.   
The target efficacy area for all efficacy analyses will be one of the body sites as defined 
in the VIIS tool (with the exception of Dorsal foot) with Grade 2 or higher on baseline 
VIIS scaling score as assessed by the Investigator.  
The within-group change from baseline will be the primary focus of interest in the 
primary analysis.   


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Primary Analysis 
A Mixed Model Repeated Measures (MMRM) model will be used to perform the primary 
analysis of the VIIS scaling score in drug-treated subjects (not vehicle-treated subjects).  
Change from baseline VIIS scaling score will serve as the dependent variable.  The 
model will include the baseline value (Visit 1) as a covariate (if useful) and visit 
(treated as a factor; the visit term will cover Visit 1, 5, 7, and 8). An unstructured 
covariance structure will be assumed and a Type III model will be evaluated. If the 
unstructured covariance structure matrix results in a lack of convergence, then Toeplitz 
(TOEP), first-order autoregressive (AR1), compound symmetric (CS) covariance structure 
will be used in that order. If the MMRM model cannot hit convergence with any 
correlation structure, then a within-subject t-test (baseline-adjusted, if useful) will be 
used to compare baseline to Visit 8. It should be noted that improvement will be 
signified by the existence of a negative change score.  
The primary efficacy endpoint will be summarized descriptively by visit and across all 
visits. The table will contain descriptive statistics on observed values and change from 
baseline at each time point. 
The primary analysis using the MMRM model will be summarized in a consolidated table 
containing the following: 
• 
Descriptive statistics for change scores at baseline and each post-treatment 
time point. 
• 
The LS mean change scores with accompanying standard errors and 95% 
confidence intervals for each visit. 
• 
Within-group contrasts for each given visit. 
• 
Significance levels for the visit effects. 
Along with the table detailing the results of the MMRM model, a consolidated table 
presenting the essential information for the primary analysis will be constructed. The 
primary endpoint will be deemed to have been met if the Visit 8 (week 24) term is 
significant, and the term coefficient is negative. 
Secondary and Sensitivity Analyses Related to the Primary Outcome Variable 
The following analyses will be performed to provide additional insight into VIIS scaling.   
Responder Analysis 
For drug-treated subjects, responder status will be assigned to a subject if at a given 
post treatment time point an improved change from baseline of at least 1 VIIS scaling 


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unit occurs. A Generalized Estimating Equation (GEE) model will be used to evaluate the 
predicted log odds, odds and probability of response. The model will include the effect 
of visit (treated as a factor). An unstructured covariance structure will be assumed and 
a Type III model will be evaluated. If the unstructured covariance structure matrix 
results in a lack of convergence, then first-order autoregressive (AR1) and compound 
symmetric (CS) covariance structure will be used in that order.  
Results will be captured in a consolidated table that contains the following information:  
• 
Number and percent of observed responders and non-responders at all post-
treatment time points;  
• 
Significance levels for the visit effects;  
• 
The model predicted log odds, odds and probability of response with standard 
errors and 95% confidence intervals for each visit;  
• 
Within-group contrasts expressed as an odds ratio, accompanied by a 95% 
confidence interval.  
AUC Analysis 
For drug-treated subjects, AUC for change from baseline over all post-treatment time 
points will be calculated for each subject using the trapezoidal rule. A linear model 
comparing AUC to zero (no change from baseline) will be performed. 
Survival Analysis    
For drug-treated subjects, time to first response (i.e., a one-unit VIIS scaling 
improvement) will be captured in a Kaplan Meier plot.  A hazard rate estimate will be 
generated. 
Analysis for Patients Experiencing one or more Treatment interruptions 
The impact of Treatment interruptions on the primary outcome will be evaluated 
through sensitivity analysis. Patients with a treatment interruption of more than 1 week 
will be flagged. The same MMRM model of the primary analysis will be conducted on the 
ITT population with the treatment interruption as a categorical variable and the 
treatment interruption by treatment interaction as an additional independent variable. 
The analysis outcome will be summarized in the similar way as the primary analysis. 
Estimates of the treatment interruption effect variable will also be tabulated.  
10.2. 
SECONDARY EFFICACY ENDPOINTS AND ANALYSES 
Change from baseline will be calculated for all secondary efficacy variables, namely:  


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VIIS Scores: 
• 
VIIS erythema score 
• 
Central reader assessed VIIS scaling and erythema scores 
Clinical Outcomes Assessments 
• 
The EQ 5D 5L patient/caregiver overall assessment score 
• 
The clinical global impression of severity scale, the patient/observer global 
impression scales 
• 
The patient-/observer-reported scratching scales,  
• 
The patient-/observer-reported burden of bathing/showering, the patient 
reported itching scale,  
• 
The CDLQI/DLQI scales, 
• 
Lipid biomarker measurements and TEWL (exploratory biomarkers).   
It will be noted that in addition to an overall Visual Analog Scale (0 to 100) assessment 
that measures self-reported health, the EQ-5D-5L also evaluates, by category (no 
problem, slight problems, moderate problems, severe problems and extreme problems), 
the status of a subject in five domains (Mobility, Self-Care, Usual Activities, 
Pain/Discomfort and Anxiety/Depression).  Guidance documentation for the use of the 
EQ-5D-5L specifically warns against the conceptualization of these categories as a 
mathematically meaningful 5-point scale, thus only the VAS scale (not individual domain 
categorical results) will be statistically evaluated.   
The secondary efficacy variables are given in section 6, with further detail of each score 
given in Table 10.2.1 below.  The schedule of assessments is given in Section 4 and each 
individual score is shown in Appendix 1-Outcome Scales.  
Table 10.2.1:  Description of secondary efficacy variables 


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EQ-5D-5L 
 
 
 
 
 
Clinical Global 
Impression of 
Severity 
 
 
  
Patient/Observer 
Global Impression of 
 


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Bother 
Patient/Observer 
Global Impression of 
Treatment 
 
 
Patient/Observer 
Global Impression of 
Severity 
 
 
Patient/Observer 
Reported Scratching  
 
Patient-Reported 
Itching 
 
Patient/Observer 
Burden of 
Bathing/Showering 
 
 
 
 
Children’s 
Dermatology Life of 
Quality Index 
(CDLQI) or 
Dermatology Life 
Quality Index (DLQI) 
 
 
Lipid Biomarkers 
Lipid biomarkers will be analyzed from skin cells samples taken from the 
target efficacy area  
TEWL 
Evaporation rate value in g/h/m2 
 
Secondary Analysis 
The secondary efficacy variables will be analyzed using one or more of the following 
analyses applied to the primary endpoint:  
1. A MMRM generalized linear model applied to secondary efficacy variable change 
scores derived from observed values;  


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2. A GEE model applied to secondary efficacy variable scales after dichotomization 
to reflect response (yes/no);  
3. A linear model applied to secondary efficacy variable observed values after 
transformation to an AUC measurement;  
4. A log rank analysis and a proportional hazards model applied to time to first 
response.   
These analyses will be carried out in an analogous fashion as for the primary efficacy 
variable (see above for a description of each analysis applied to the primary efficacy 
variable).   
As with the primary efficacy variable (VIIS scaling), the within-group change from 
baseline will be the primary focus of interest in the MMRM analysis.  Because SLS patient 
symptoms do not spontaneously improve over time, the within-group comparison 
provides a clinically meaningful evaluation.   The planned analyses for selected 
secondary efficacy endpoint are outlined in Table 10.2.2.  
 
 Table 10.2.2:  Analyses of the Secondary Efficacy Variables 
Secondary Efficacy Variable 
Analyses 
 
MMRM 
RESPONDER 
ANALYSIS 
(Estimating 
Equation) 
AUC 
(Linear 
Model) 
Survival 
VIIS Erythema (Investigator 
Assessment) 
 
 
 
 
VIIS Scaling (Photographic 
Assessment by Central Reader) 
 
 
 
 
VIIS Erythema (Photographic 
Assessment by Central Reader) 
 
 
 
 
1The 100 mm VAS will be analyzed using MMRM.  Categorical outcomes will be displayed in a 
contingency table (Treatment x Category) containing frequency and percent occurrence of categorical 
outcomes. 
2The total score (i.e., sum of 0 – 3 rating on 10 individual questions) will be analyzed using MMRM for 
change scores and a linear model for AUC.  Responses to individual questions will be provided in a 
listing. 
10.3. 
SUBGROUPS ANALYSIS 
Subgroup analysis on age group 


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To account for treatment differences between age ranges of subjects, analyses of 
efficacy and laboratory summary tables will be displayed by adult only (≥ 18 years), 
pediatric only (<18 years) and combined adult and pediatric.  
• 
Pending the final number of pediatric patients enrolled and distribution of age; 
additional analysis may be performed for patients ≤ 10 years of age and >10 to < 
18 years of age 
10.4. 
EXPLORATORY ANALYSES  
Efficacy Endpoint 
Additional exploratory analysis maybe conducted on primary efficacy endpoint by 
sponsor. Exploratory analysis will be conducted for both targeted efficacy area and for 
combined regions as appropriate, such as but not limit to: 
1) Repeat primary analysis MMRM model on drug-treatment patients to evaluate 
change from baseline for combined visits (Visit 5, Visit 7 and Visit 8)  
2) Repeat primary analysis MMRM model on all treated patients (including both 
drug-treatment and vehicle-treated patients) to evaluate change from baseline 
for combined visits (Visit 5, Visit 7 and Visit 8) and each individual visit 
3)  all patients (including both drug-treatment and vehicle treated patients) 
4) Responder analysis for patient with at least 2 units VIIS scaling improvement 
from baseline at any post treatment time point   
5) Survival analysis for the time to first response defined as 2 units VIIS scaling 
improvement from baseline  
6) AUC analysis for change from baseline of all VIIS regions combined  
7) Analyze change from baseline of VIIS total score at week 24 analysis using MMRM 
model 
8) Contralateral analysis of between group contrast comparing VIIS scaling score 
change from baseline between treated area vs. untreated area  
9) To further evaluate the impact of ‘treatment interruption’ on treatment effect, 
the same analysis approach used for primary analysis on primary endpoint may 
be repeated on following subgroups:  
a. patient with ‘treatment interruption’ for at least 1 week  


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b. patient without ‘treatment interruption’ or with ‘treatment interruption’ 
for less than 1 week 
 
Biomarker Endpoint 
Selected skin lipid bio markers, captured as the post-treatment value at Week 24 or at 
an early termination visit as the post-treatment minus baseline value (change score), 
may be correlated with various outcome symptom scales or functions of outcome 
symptom scales.  Such skin lipid biomarkers are listed in Table 10.3.1.  
Exploratory analyses will be performed on lipid biomarkers from skin cell analysis and 
TEWL using the following methodologies: 
Analysis between biomarkers and outcome scales (investigator and central reader VIIS 
scaling and erythema) for time matched assessments will be performed using 
appropriate correlation procedures. 
Table 10.3.1: Lipid Values Selected for correlational analysis (captured as post 
treatment values or change score values) 
 


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11. 
SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the SAF population.   
The safety outcomes include dermatological endpoints, vital sign measurements, 
physical examinations, hematology and chemistry laboratory testing, ECG readings, use 
of concomitant medications, and incidence, severity and duration of adverse events and 
TEAEs.  
Safety tables will be presented by treatment and overall.   
Tables variously organized by preferred terms, system organ class, treatment 
emergence, treatment relationship, severity and study termination will be presented 
for AEs, TEAEs, unexpected AEs and SAEs.   
Descriptive statistics will be presented by treatment and time for safety laboratory 
values or in change tables for categorized lab variables (e.g., normal vs. abnormal, 
present vs. absent).  Other safety information (e.g., normality of dermatological 
endpoints, normality of vital signs, normality of physical examinations, normality of ECG 
outcomes, concomitant medication usage) will be summarized in tables and medically 
evaluated.  
 
No inferential statistical testing is planned on the safety data, all data will be 
summarized and listed only. If any post-hoc inferential testing of any variable seems 
appropriate, the comparison will be made using an appropriate statistical test. 
11.1. 
SAFETY NARRATIVES 
Treatment and vehicle group safety narratives will be written.  If required a 
safety narrative will be written for selected subjects.   
11.2. 
ADVERSE EVENTS / ADVERSE DRUG REACTIONS 
Adverse events (AEs) will be coded using a Medical Dictionary for regulatory Activities 
(MedDRA) version 20.0 or later preferred term (PT) and system organ classification 
(SOC). 
Patients with multiple events within the same System Organ Class and/or same 
Preferred Term are only counted once within the respective frequencies. 
All reported AEs (whether treatment emergent or not) will be included in by-patient AE 
listings. Sorting will be by patient, date of event, SOC, PT and then verbatim 
description. 


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An AE will be considered treatment emergent (TEAE) if it begins or worsens in severity 
after the first dose of the double-blind Study Treatment through 28 days after the last 
dose of Study Treatment, or the date of initiation of another investigational agent or 
surgical intervention or rollover to the extension study, whichever occurs first. Partial 
AE start dates will be imputed as detailed in Section 8.5. 
ALL AEs and TEAEs. 
Incidence of AE and TEAEs will be presented by SOC and PT. The AE and TEAEs listings 
will include treatment group, the duration of the event, it severity and whether it was 
considered to be related to treatment. The listings will also include the number of days 
between first dose and event. 
SOC and PT will be presented, where the severity per patient will be counted at each 
level of summarization. In addition, a summary of all TEAEs by relationship to Study 
Treatment (related, not related), SOC and PT will be presented, where the strongest 
relationship to Study Treatment per patient will be counted at each level of 
summarization.   
SEVERITY. 
Severity is classified as mild, moderate, severe or life-threatening.  
Missing severity for TEAEs will be counted as ‘Severe’.  
RELATIONSHIP TO STUY MEDICATION. 
Relationship, as indicated by the investigator, will be defined as definitely, possibly, 
unlikely or not related. 
Adverse events with a missing relationship to study medication will be noted as 
“related” to study medication. If a patient reports the same AE more than once within 
the same SOC/PT, the AE with the strongest relationship to study medication will be 
used in the relationship summaries. 
TEAEs LEADING TO STUDY DRUG DISCONTINUATION. 
TEAEs leading to permanent discontinuation of study medication are those events that 
are marked as ‘discontinued from study’ under action taken with study medication in 
the adverse events page of the CRF.  
For TEAEs leading to permanent discontinuation, a summary table with incidence rates 
(frequencies and percentages) by SOC and PT will be prepared. 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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03.007A.03     
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SERIOUS ADVERSE EVENTS. 
Serious adverse events (SAEs) are those events recorded as a “serious Adverse Event 
(Y)” on the adverse events page of the CRF. A summary of serious TEAEs and Serious 
treatment related TEAEs by SOC and PT will be prepared.  
ADVERSE EVENTS LEADING TO DEATH. 
Adverse events leading to death are those events with ‘Death’ recorded under Outcome 
in the adverse events page of the CRF. A summary of TEAEs and SAEs leading to death 
by SOC and PT will be prepared. A listing of AEs leading to death will be included with 
the TEAEs flagged. 
SUMMARY TABLES AND LISTINGS. 
Summary tables will be based on treatment emergent adverse events (TEAEs). The 
incidence of TEAEs will be presented using counts and percentages of patients with 
TEAEs and tabulated by SOC and PT. SOC will be sorted in descending frequency and PT 
within SOC will be sorted by descending frequency based on the incidence across 
patients overall. If a patient has multiple occurrences (start and stop) of an event 
associated with a specific SOC or PT within a SOC, a patient will only be counted once 
in the incidence count for the SOC or PT within SOC respectively. 
An overall summary table of AEs by treatment group will be presented detailing the 
number and percentage of patients, and number of events for the following categories: 
• 
At least one AE 
• 
At least one TEAE; 
• 
Serious TEAEs; 
• 
Treatment Related TEAEs; 
• 
Treatment Related Serious TEAEs; 
• 
TEAEs leading to Discontinuation from Study Treatment; 
• 
TEAEs resulting in death; 
The incidence of all TEAEs by SOC and PT will be presented for the following: 
• 
All TEAEs; 
• 
Serious TEAEs; 
• 
Treatment Related TEAEs; 
• 
Treatment Related Serious TEAEs; 
• 
TEAEs leading to Discontinuation from Study Treatment; 
• 
TEAEs resulting in death; 
Treatment listings will include the treatment group, start and stop dates/times of the 
AE, and days on study relative to the day of first dose of Study Treatment.   


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
This document is proprietary and confidential to Syneos Health 
03.007A.03     
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Page 45 of 78 
The following additional listings will be provided: 
• 
Listing of deaths 
• 
Listing of Serious TEAEs 
• 
Listing of non-treatment-emergent SAEs 
• 
Listing of TEAEs leading to withdrawal or temporary withdrawal of Study 
Treatment 
• 
Listing of all AEs with a flag for TEAEs and onset (Prior = prior to first dose of 
double-blind medication, or Treatment = on or after first dose of double-blind 
medication.)  
11.3. 
CLINICAL LABORATORY EVALUATIONS 
Laboratory tests will be performed at Screening and periodically throughout the clinical 
trial as described in the schedule of events, Section 4. Only data collected by the 
central laboratory will be included in the analyses with the exception of the screening 
safety data. Standard international units will be used for all summaries. Laboratory 
tests within each category and scheduled visit are given in Table 9.4.1.  Data for all 
visits, scheduled or unscheduled, will be listed. 
At least one laboratory measurement obtained subsequent to at least one dose of Study 
Treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline or screening measurement is also required. 
Table 11.3.2: 
Laboratory Tests and Scheduled Study Visits 
Laboratory Category 
Laboratory Tests Included 
Hematology 
hemoglobin, hematocrit, red blood cell (RBC) count, RBC 
morphology, white blood cell (WBC) count with differential, mean 
corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), 
mean corpuscular hemoglobin concentration (MCHC), and absolute 
platelet count. 
Chemistry 
albumin, alkaline phosphatase (ALP), alanine aminotransferase 
(ALT; SGPT), aspartate aminotransferase (AST; SGOT), bilirubin 
(total and direct), blood urea nitrogen (BUN), calcium, carbon 
dioxide (CO2), chloride, creatinine, creatinine phosphokinase 
(CPK), glucose, phosphate, potassium, sodium, total protein, and 
uric acid. 
Urinalysis 
bilirubin, glucose, ketones, blood, nitrite, pH, protein, specific 
gravity, and microscopy (if indicated by macroscopic findings). 
Other 
Urine Pregnancy Test for Female Subjects 
Estimated Glomerular Filtration 
Rate (eGFR) 
Adult population (≥ 18 years of age): eGFR will be calculated by the 
MDRD equation at baseline: 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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eGFR (mL/min/1.73 m2) = 175 × (Scr)-1.154 × (Age)-0.203 × 
(0.742 if female) × (1.212 if African American) (Levey 2009) 
Pediatric population (3 – < 18 years of age): eGFR will be 
calculated by the Schwartz equation at baseline: 
eGFR (mL/min/1.73 m²) = (0.41 × Height in cm) / Creatinine in 
mg/dL (Schwartz 2009) 
 
• 
Actual (observed) values and changes from baseline in hematology and clinical 
chemistry laboratory parameters will be summarized by treatment group at each 
scheduled visit  
• 
The number and percentage of subjects with laboratory measurements outside 
of the normal range will also be summarized by treatment group and visit.  
• 
Shift from Baseline at each post-Baseline visit will be provided by treatment 
group in a 3-by-3 contingency table.  Denominators for percentages will be the 
number of subjects with non-missing data at the specific assessment and 
baseline. 
• 
Box and Whiskers Plots by visit will be produced for all quantitative hematology 
and clinical chemistry parameters. 
• 
Actual (observed) values in urinalysis and other laboratory parameters will be 
summarized by treatment group.  
• 
The number and percentage of subjects with laboratory measurements outside 
of the normal range will also be summarized by treatment group and visit. 
• 
Incidence of patients that have Potentially Clinically Significant (PCS) values at 
any post-baseline visit. 
All data will be listed. 
11.4. 
VITAL SIGNS  
The following vital sign data will be collected at all study visits: 
• 
Sitting Systolic Blood Pressure (SBP) (mmHg) 
• 
Sitting Diastolic Blood Pressure (DBP) (mmHg) 
• 
Heart Rate (beats/min) 
• 
Respiratory Rate (breaths/min) 
• 
Body Temperature (degree Celsius or Fahrenheit) 
• 
Body Weight (kg) 
• 
Height (cm) 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
This document is proprietary and confidential to Syneos Health 
03.007A.03     
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At least one vital sign measurement obtained subsequent to at least one dose of Study 
Treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a Baseline or screening measurement is also required. 
For all parameters, actual (observed) values will be presented and summarized for all 
scheduled study visits by treatment and overall. 
Vital signs data will be fully described using descriptive statistics. Actual values and 
change from baseline will be summarized. 
Vital signs data will be summarized by parameter, visit and time point, treatment group 
and overall for all subjects in the SAF. 
All vital signs data shall be listed chronologically by treatment group for subjects in the 
SAF. 
11.5. 
ECG  
Electrocardiograms (ECGs) will be read centrally and the following ECG parameters will 
be reported: 
• 
Overall assessment of ECG (by central reader) will be tabulated: 
o Normal 
o Abnormal, Not Clinically Significant 
o Abnormal, Clinically Significant. 
o The results will be included in a per patient listing. 
ECG data, along with the date and time of assessment, will be listed for all subjects in 
the SAF population. Any clinically significant ECG/ Holter results may be recorded as an 
AE. 
ECG data will be classified as “Normal”, “Abnormal, Not Clinically Significant” or 
“Abnormal, Clinically Significant”. 
ECG data will be summarized by visit, and by treatment group and overall for all 
subjects in the SAF population. Summary tables will show the number and percentage of 
subjects with normal, abnormal non-clinically significant (NCS) or abnormal clinically 
significant (CS) findings at each visit. 
Shift tables for ECG result to each study visit on treatment will be provided. Subjects 
with both a non-missing baseline and at least one non-missing post-baseline finding will 
be included in the shift table.  
ECG data will also be listed chronologically for all subjects in the SAF. 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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11.6. 
PHYSICAL EXAMINATION 
A physical examination will be performed according to the Schedule of Assessments 
described in Section 4. Body systems findings will be classified as “Normal” or 
“Abnormal” and abnormalities are described. Any physical examination findings are 
reported as medical history or adverse events.  
Physical examination findings will be fully summarized using the frequency and 
percentage of subjects under each classification for each body system with an 
indication as to whether the finding is clinically significant. Summary tables will be 
sorted by parameter, visit/time point and treatment group, and overall, for all subjects 
in the SS. 
Results from physical examinations will be listed chronologically for all subjects in the 
SAF population. 
11.7. 
DERMATOLOGY EXAMINATION 
A full dermatological examination will be performed according to the Schedule of 
Assessments described in Section 3.8 and will comprise of the dermatological 
examination of the following body systems: Scalp and Hair, Face, Neck, Chest and 
Abdomen, Back, Arms, Hands and Fingernails, Legs, Feet and Toenails and Other. Any 
clinically significant dermatological examination results may be recorded as an AE. 
Body systems will be classified as “Normal” or “Abnormal” and abnormalities are 
described. 
Dermatological examination findings will be fully summarized using the frequency and 
percentage of subjects under each classification for each body system. Summary tables 
will be sorted by parameter, visit/time point and treatment group, and overall, for all 
subjects in the SS. 
 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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12. 
INTERIM ANALYSES 
No interim analyses are planned for this clinical trial.  The analysis at the end of Part 1 
is a per-protocol planned analysis and will be fully unblinded. 
 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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13. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
Analysis visit windows will not be applied given that the analysis visits are not going to 
be within the 3-5 days as stated in the protocol, instead the visits will be displayed as 
collected on the CRF. 
 
 
 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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14. 
PROGRAMMING CONSIDERATIONS 
14.1. 
GENERAL CONSIDERATIONS 
• 
A separate SAS program will be created for each output. 
• 
Each output will be stored in a separate file. 
• 
Output files will be delivered in Word format and pdf format. 
• 
Numbering of TFLs will follow ICH E3 guidance (or other logical order for studies 
performed according to GPP) 
 
14.2. 
TABLE, LISTING, AND FIGURE FORMAT 
14.2.1. General 
• 
All TLFs will be produced in landscape format, unless otherwise specified. 
• 
All TLFs will be produced using the Courier New font, size eight which is the 
smallest acceptable point size for the Regulatory Authorities. 
• 
The data displays for all TLFs will have a minimum 1-inch margin on all four sides. 
• 
Headers and footers for figures will be in Courier New font, size eight which is the 
smallest acceptable point size for the Regulatory Authorities. 
• 
Legends will be used for all figures with more than one variable, group, or item 
displayed. 
• 
TLFs will be in black and white (no color), unless otherwise specified 
• 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted 
and subscripted text, will not be used in the TLFs, unless otherwise specified. On 
some occasions, superscripts 1, 2, or 3 may be used (see below). 
• 
Only standard keyboard characters will be used in the TLFs. Special characters, such 
as non-printable control characters, printer-specific, or font-specific characters, will 
not be used. Hexadecimal-derived characters will be used, where possible, if they 
are appropriate to help display math symbols (e.g., μ). Certain subscripts and 
superscripts (e.g., cm2, Cmax) will be employed on a case-by-case basis. 
• 
Mixed case will be used for all titles, footnotes, column headers, and programmer-
supplied formats, as appropriate. 
14.2.2. Headers 
• 
All output should have the following header at the top left of each page: 
Aldeyra Protocol ADX-102-SLS-006 (Syneos Health study number 1009367)      
          
Draft/Final Run <date> 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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• 
All output should have Page n of N at the top or bottom right corner of each page. 
TLFs should be internally paginated in relation to the total length (i.e., the page 
number should appear sequentially as page n of N, where N is the total number of 
pages in the table). 
• 
The date output was generated should appear along with the program name as a 
footer on each page. 
14.2.3. Display Titles 
• 
Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). 
ICH E3 numbering is strongly recommended but sponsor preferences should be 
obtained prior to final determination (see also template 03.007C “Table of Contents 
for Tables Listings and Figures in Statistical Analysis Plan”). A decimal system (x.y 
and x.y.z) should be used to identify TLFs with related contents. The title is 
centered. The analysis set should be identified on the line immediately following 
the title. The title and table designation are single spaced. A solid line spanning the 
margins will separate the display titles from the 
• 
 Column headers. There will be 1 blank line between the last title and the solid line. 
 
 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
ITT Analysis Set 
 
14.2.4. Column Headers 
• 
Column headings should be displayed immediately below the solid line described 
above in initial upper-case characters.  
• 
In the case of efficacy tables, the variable (or characteristic) column will be on the 
far left followed by the treatment group columns and total column (if applicable). 
P-values may be presented under the total column or in separate p-value column (if 
applicable). Within-treatment comparisons may have p-values presented in a row 
beneath the summary statistics for that treatment. 
• 
For numeric variables, include “unit” in column or row heading when appropriate. 
• 
Analysis set sizes will be presented for each treatment group in the column heading 
as (N=xx) (or in the row headings if applicable). This is distinct from the ‘n’ used for 
the descriptive statistics representing the number of subjects in the analysis set. 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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03.007A.03     
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• 
The order of treatments in the tables and listings will be Placebo first in the case of 
placebo controlled studies and Active comparators first in the case of active 
comparator trials, followed by a total column (if applicable). 
14.2.5. Body of the Data Display 
14.2.5.1. General Conventions 
Data in columns of a table or listing should be formatted as follows: 
• 
alphanumeric values are left-justified; 
• 
whole numbers (e.g., counts) are right-justified; and 
• 
numbers containing fractional portions are decimal aligned. 
14.2.5.2. Table Conventions 
• 
Units will be included where available 
• 
If the categories of a parameter are ordered, then all categories between the 
maximum and minimum category should be presented in the table, even if n=0 for 
all treatment groups in a given category that is between the minimum and maximum 
level for that parameter. For example, the frequency distribution for symptom 
severity would appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
Where percentages are presented in these tables, zero percentages will not be 
presented and so any counts of 0 will be presented as 0 and not as 0 (0%). 
• 
If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation, 
etc.), then only those categories for which there is at least one subject represented 
in one or more groups should be included. 
• 
An Unknown or Missing category should be added to any parameter for which 
information is not available for one or more subjects.  
• 
Unless otherwise specified, the estimated mean and median for a set of values 
should be printed out to one more significant digit than the original values, and 
standard deviations should be printed out to 2 more significant digits than the 
original values. The minimum and maximum should report the same significant digits 
as the original values. For example, for systolic blood pressure: 
N 
  XX 
Mean 
XXX.X 
Std Dev 
     X.XX 
Median 
XXX.X 
Minimum 
XXX 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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Maximum 
XXX 
• 
P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 
three decimal places. Any p-value less than 0.001 will be presented as <0.001. If the 
p-value should be less than 0.0001 then present as <0.0001. If the p-value is 
returned as >0.999 then present as >0.999 
• 
Percentage values should be printed to one decimal place, in parentheses with no 
spaces, one space after the count (e.g., 7 (12.8%), 13 (5.4%)). Pre-determine how to 
display values that round down to 0.0.  A common convention is to display as '<0.1', 
or as appropriate with additional decimal places. Unless otherwise noted, for all 
percentages, the number of subjects in the analysis set for the treatment group who 
have an observation will be the denominator. Percentages after zero counts should 
not be displayed and percentages equating to 100% should be presented as 100%, 
without any decimal places.  
• 
Tabular display of data for medical history, prior / concomitant medications, and all 
tabular displays of adverse event data should be presented by the body system, 
treatment class, or SOC with the highest occurrence in the active treatment group 
in decreasing order, assuming all terms are coded. Within the body system, drug 
class and SOC, medical history (by preferred term), drugs (by ATC1 code), and 
adverse events (by preferred term) should be displayed in decreasing order. If 
incidence for more than one term is identical, they should then be sorted 
alphabetically. Missing descriptive statistics or p-values that cannot be estimated 
should be reported as “-”. 
• 
The percentage of subjects is normally calculated as a proportion of the number of 
subjects assessed in the relevant treatment group (or overall) for the analysis set 
presented. However, careful consideration is required in many instances due to the 
complicated nature of selecting the denominator, usually the appropriate number of 
subjects exposed. Describe details of this in footnotes or programming notes. 
• 
For categorical summaries (number and percentage of subjects) where a subject can 
be included in more than one category, describe in a footnote or programming note 
if the subject should be included in the summary statistics for all relevant categories 
or just one category and the criteria for selecting the criteria. 
• 
Where a category with a subheading (such as system organ class) has to be split over 
more than one page, output the subheading followed by “(cont)” at the top of each 
subsequent page.  The overall summary statistics for the subheading should only be 
output on the first relevant page. 
14.2.5.3. Listing Conventions 
• 
Listings will be sorted for presentation in order of treatment groups as above, 
subject number, visit/collection day, and visit/collection time. 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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• 
Missing data should be represented on subject listings as either a hyphen (“-”) with 
a corresponding footnote (“- = unknown or not evaluated”), or as “N/A”, with the 
footnote “N/A = not applicable”, whichever is appropriate. 
• 
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing 
portions of dates should be represented on subject listings as dashes (--JUL2000). 
Dates that are missing because they are not applicable for the subject are output as 
“N/A”, unless otherwise specified. 
• 
All observed time values must be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (e.g., 11:26:45, or 11:26). Time will only be reported if it was 
measured as part of the clinical trial. 
• 
Units will be included where available 
14.2.5.4. Figure Conventions 
• 
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis 
and endpoint (e.g., treatment mean change from Baseline) values will be displayed 
on the Y-axis. 
14.2.6. Footnotes 
• 
A solid line spanning the margins will separate the body of the data display from the 
footnotes.  
• 
All footnotes will be left justified with single-line spacing immediately below the 
solid line underneath the data display. 
• 
Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, 
etc. if a reference footnote. Each new footnote should start on a new line where 
possible. 
• 
Subject specific footnotes should be avoided, where possible. 
• 
Footnotes will be used sparingly and must add value to the table, figure, or data 
listing. If more than six lines of footnotes are planned, then a cover page may be 
used to display footnotes, and only those essential to comprehension of the data will 
be repeated on each page.  
• 
The last line of the footnote section will be a standard source line that indicates the 
name of the program used to produce the data display, date the program was run, 
and the listing source (i.e., ‘Program : myprogram.sas    Listing source: 16.x.y.z’). 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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15. 
QUALITY CONTROL 
SAS programs are developed to produce output such as analysis data sets, summary 
tables, data listings, figures or statistical analyses. Syneos Health SOP 03.010 and 
03.013 provide an overview of the development of such SAS programs. 
Syneos Health SOP 03.009 describes the quality control procedures that are performed 
for all SAS programs and output. Quality control is defined here as the operational 
techniques and activities undertaken to verify that the SAS programs produce the 
output by checking for their logic, efficiency and commenting and by review of the 
produced output.   


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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16. 
INDEX OF TABLES 
See Excel spreadsheet 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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17. 
INDEX OF FIGURES 
See Excel spreadsheet 
 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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18. 
INDEX OF LISTINGS 
See Excel spreadsheet 
 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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19. 
MOCK-UPS 
19.1. 
TABLE MOCK-UPS 
Table templates should be included for all unique tables. Include footnotes and any 
programming notes, if appropriate.  
19.2. 
FIGURE MOCK-UPS 
Figure templates should be included here, if required. A detailed description of the 
figure may be used in lieu of a figure template.  For example: 
Figures 14.4.1.4:  Mean Plasma Concentration Over Time by Treatment Group (PK 
Analysis Set) 
PROGRAMMING NOTES: 
• 
This figure is a line plot and corresponds to Data Listing XXXXX Drug Concentration Data. 
• 
Axes: Vertical axis:  Mean plasma drug concentration (units), with range dependent on the 
observed values. Include vertical axes on both the left and right sides of the figure. 
Horizontal axis: Nominal time Post-Dose (hours), with range from 0 hour (pre-dose) to X 
hours post-dose. 
• 
Solid lines should connect the data points for the means. One line per treatment group will 
be plotted.  
• 
Solid circles will be used for mean values in treatment group X; triangles will be used for 
mean values in treatment group Y.  Include a legend that indicates the treatment group a 
circle represents and the treatment group a triangle represents. 
• 
Error bars should be used at each visit that represents inter-quartile ranges 
• 
Include the number of subjects with data at each time point below the horizontal axis. 
• 
Include footnote “Values below limit of quantification were imputed to xxxxx.” 
• 
The Syneos Health stamp (program name, date, etc.) should appear at the bottom of the 
figure. 
 
19.3. 
LISTING MOCK-UPS 
Include the analysis set in the title, if appropriate.  All listings should be sorted by 
centre, and either randomized treatment (usually baseline/efficacy) or actual 
treatment (usually safety/PK/PD). Add in programming notes for additional direction 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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on sort order as well as any other programming issues, as applicable.  


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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20. 
APPENDIX 1-OUTCOME SCALES 
20.1. 
VIIS DESCRIPTION 
 
 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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20.2. 
VIIS COLLECTION FORM 
 
 
 


Statistical Analysis Plan 
Aldeyra Therapeutics  
Protocol # ADX-102-SLS-006 
Version 1.0 
Syneos Health #1009367 
 
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20.3. 
EQ-5D-5L  
20.3.1. EQ-5d-5l descriptive system scoring 
 


Statistical Analysis Plan 
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20.3.2. EQ-5D-5L VAS scoring 


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20.4. 
CLINICIAN GLOBAL IMPRESSION OF SEVERITY (CGIS) 
 
 
 


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20.5. 
PATIENT REPORTED OUTCOME SCALES 
20.5.1. Patient Global Impression of Severity (PGIS) 
 
 


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20.5.2. Patient Global Impression of Bother (PGIB) 
 
 
 


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20.5.3. Patient Global Impression of Treatment (PGIT) 
 
 
 
 


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20.5.4. Patient-Reported Itching/ Scratching Questionnaire (PRIQ/PRSQ) 
 
 
 


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20.5.5. Patient Reported Burden of Bathing / Showering Questionnaire 
(PRBBQ) 
 
 
 
 
 


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20.6. 
OBSERVER REPORTED OUTCOME SCALES 
20.6.1. Observer Reported Scratching Questionnaire (ORSQ) 
 
 


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20.6.2. Observer-Reported Burden of Bathing/Showering Questionnaire 
(ORBBQ) 
 
 
 


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20.6.3. Observer-Reported Scales: Observer Global Impression of Severity 
(OGIS) 
 
 
 


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20.6.4. Observer-Reported Scales: Observer Global Impression of Bother 
(OGIB) 
 
 
 


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20.6.5. Observer-Reported Scales: Observer Global Impression of Treatment 
(OGIT) 
 
 
 


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20.7. 
DERMATOLOGY LIFE QUALITY INDEX (DLQI) 
 


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20.8. 
CHILDRENS DERMATOLOGY LIFE QUALITY INDEX (CDLQI)